INTERNATIONAL PHARMACEUTICAL QUALITY IPQ Inside the Global Regulatory Dialogue IPQPUBS.COM VOL. 7, NO. 7

MONTHLY UPDATE - NOVEMBER / DECEMBER 2015

THE INTERNATIONAL EFFORT TO IMPROVE LIFECYCLE REGULATION

With the ICH Q12 effort operating as a catalyst, the dialogue has been intensifying on what is needed to make quality regulatory processes across the product lifecycle more cohesive, efficient, process im- provement and supply friendly, and internationally harmonized. This IPQ Monthly Update departs from the usual format to provide a series of stories exploring the various dimensions of the lifecycle manage- ment regulatory problem and the international effort to address it.

● ICH Q12 EWG Views Established Conditions as Pivotal in Evolving Product Lifecycle p. 3 Regulation Internationally; EMA Workshop Provides Input

● Broad Base of ICH Q12 EWG Supports Initiative’s Urgency and Viability, Its Members p. 23 Affirm at GPhA Conference

● Industry Experts Shed Hard Light on Negative Impacts of Current Complex Post-Approval p. 29 Change Regulatory Situation Globally, with ICH Q12 in View

● Global Change Protocols Proposed as Part of a More Standards-Based Approach to p. 40 Regulating Lifecycle Management Internationally

● More Structured, Interactive Process To Drive Convergence in Latin America Advocated by p. 51 Biotech Product Regulators and Industry at CMC Strategy Forum in Brasilia

● Industry is Urging Latin American Agencies to Cooperate in Filling Lifecycle Management p. 69 Regulatory Gaps for Biologics

UPDATES IN BRIEF p. 75 U.S CMC: ● CDER 2016 Priorities ● Emerging Technology ● HCT/P ● IND Communications ● Combining ANDAs ● Biosimi- lar Meetings ● Medical Gases ● OTC Sunscreens ● Fixed Combination Drugs ● Biosimilar Substitution U.S GMP: ● HCT/P Deviations ● Contaminated Chinese API ● Contaminated Chinese Drugs ● NIH Pharmacy ● Dietary Sup- plements ● Hikma Close Out Letter

EUROPE CMC: ● Co-processed Excipients ● Type IB Variations ● UK Human Factors Guide ● MHRA Baseline Submissions ● EMA Interactions ● EMA Labeling ● EMA Five-Year Plan ● MHRA Submissions ● EMA Variations EUROPE GMP: ● Catalent Plant in France ● French API Plant ● Italian Radipharm Plant ● AstraZeneca API Imports ● Wock- hardt GMP Certificate ● EDQM/EMVO Agreement

INTERNATIONAL CMC: ● ICH Reorg ● Restructured ICH ● China Drug Approval ● TGA Biosimilar Regulation ● TGA OTC Registration INTERNATIONAL GMP: ● WHO on Data Integrity ● PIC/S Update ● India Inspectors ● Vendors and Quality Agreements

FDA WARNING LETTERS AND RECALLS POSTED IN NOVEMBER AND DECEMBER p. 84 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

EDITOR’s NOTE: Welcome to IPQ’s “Monthly Update” on key CMC/GMP developments in the US, Europe, and internationally. The IPQ family of publications includes “The News in Depth” and”Updates in Brief” on our website as they occur, “Weekly News Alerts” sent via e-mail, and the “Monthly Update.” IPQ’s suite of offerings support our mission of helping readers under- stand, engage in and respond to the dialogue and developments around evolving and harmoniz- ing the regulation of drug and biologic quality and manufacturing.

Subscribers and license holders to IPQ have access to all of these sources of cutting-edge news and in-depth analysis as well as to the full IPQ archives. Visit IPQpubs.com for further informa- Bill Paulson, Editor-in-Chief tion.

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NOVEMBER / DECEMBER 2015 2 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 ICH Q12 EWG Views Established Conditions as Pivotal in Evolving Lifecycle Regulation Internationally; EMA Workshop Provides Input

The ICH Q12 Expert Working Group (EWG) is viewing what in the dossier is a regulatory commitment is a central “established conditions” as a linchpin concept in its effort to concern. Oates represents PhRMA on the EWG. define and drive a more improvement friendly, simplified, and harmonized regulatory approach to product lifecycle Accomplishing that in Q12, she said, would make it “clear to management internationally. firms as well as to regulators what will need to be submitted for a regulatory change.” However, the EWG members also recognize the challenges on the table in defining the concept in a way that achieves At issue is not only whether changes will need preclearance the desired objectives. to implement, but how to develop the transparency between manufacturers and regulators around the changes that are At issue are the interrelationships between established being made that will allow regulators to trust in the firm’s conditions (ECs) and the other lifecycle management change management capacities under the quality system, regulatory components across the development/ Oates explained. Greater transparency increases the leverage submission/control strategy/post-approval change/quality for reducing the preclearance burden. system/inspection continuum. Under EWG discussion, she said, is whether it is necessary, The draft guidance released by FDA in May for example, “to submit the changes as they are being made entitled “Established Conditions: Reportable CMC – maybe even those that historically would not have been Changes for Approved Drug and Biologic Products” submitted – so that the regulator has a full view of the is providing a useful foundation for the EWG current state of the manufacturing process.” discussions on the role that established conditions should play in evolving the lifecycle management In an update on Q12 progress provided at an regulatory paradigm. early fall PDA lifecycle management workshop, GlaxoSmithKline Global CMC Strategy VP and FDA’s goal in putting together the ECs guidance was not Q12 rapporteur Moheb Nasr explained the EWG’s to co-opt Q12, but, as the guidance explains, to clearly lay decision at its mid-June meeting in Fukuoka Japan out the relevant principles and expectations inherent in the to use the FDA draft guidance as a starting point to agency’s current regulatory approach and how they were work on the development of the ECs concept. arrived at. The EWG “did a good job determining how we could do that. In turn, the agency effort is providing an important reference They came up with working conditions, and the process is point for the Q12 EWG in understanding the problems that moving forward,” the Q12 rapporteur said. Prior to joining the current system presents and where viable opportunities GSK, Nasr was Director of the Office of New Drug Quality lie for creating a more user friendly and harmonized Assessment at CDER and participated in the development approach with a potentially global reach. and implementation of the ICH Q8-11 guideline series. Although generally synonymous with “regulatory Commenting on how the ECs issue became a priority for the commitments,” the term “established conditions” was chosen by FDA as more reflective of the terminology in EWG, Nasr explained that the default is that “everything in its regulations and less subject to varying interpretations. the file is a regulatory commitment, and obviously that is The ICH EWG has followed suit in using the “established not the starter to have a conversation” between industry and conditions” term to convey the “regulatory commitment” regulators. concept. “So we decided to have a serious discussion about what we EWG Members Stress Centrality of ECs mean by regulatory commitment or established condition and how can we make a distinction, if possible, between the In a review of the Q12 development process, the issues being information provided in the file to facilitate the review, to tackled, and the objectives at the ISPE Quality Manufacturing enhance the transparency, without really tying industry’s Conference in June, Pfizer Quality Operations, Environmental hands on how to manage manufacturing post-launch and Health and Safety VP Mary Oates stressed that determining so forth.”

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NOVEMBER / DECEMBER 2015 3 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 Nasr explained that he was in the process of pulling together in keeping with the normal ICH guideline industry-to- that section of the guideline based on the EWG discussions regulator hand-off process. and that it “looks really good. So ICH Q12 will deliver on clarifying what established conditions are and how that will The workshop included presentations, discussions, and be translated into practical implementation.” posters on issues related to the three lifecycle management topic areas around which the guideline will be structured: [Editor’s Note: Oates full remarks on Q12 at the June ISPE ● the regulatory dossier and established conditions for conference and Nasr’s update on the EWG progress at the manufacture and control ● the pharmaceutical quality fall PDA fall workshop are included at the end of the story.] system and its risk/change/knowledge management components, and ● the use of post-approval change At a session on Q12 at the Generic Pharmaceutical management plans and protocols. Informing the workshop Association (GPhA) Fall Technical Conference in November dialogue was the most recent Q12 rough draft, which was in Bethesda which he moderated, Perrigo Regulatory Affairs distributed to the attendees. Senior Director Keith Webber also highlighted the centrality of the ECs discussions in the EWG effort (see story on pp. Broad Focus, Examples, Training Advocated 23-28). Webber represents the International Generics and Biosimilars Association (IGBA) on the EWG. The final session provided the EWG members a chance to take stock on the input at the session and how their thinking The former FDA biotech and generics regulator provided about the guideline had been impacted. Highlighted at the examples involving an analytical method and a process session was the pivotal nature of established conditions and change of how clarity around established conditions would the “size of the prize” if this component can be appropriately be beneficial( see box on next page). handled in the guideline.

ECs In Focus at EMA Q12 Workshop The session began with Boam’s reflections on the workshop. FDA was pleased, she said, that there How established conditions should be defined in relationship with the other components of the lifecycle management appeared to be general agreement on the main regulatory process was a focal point in the discussions at concepts to be included in Q12, although for some a two-day workshop on ICH Q12 held at EMA’s London topics “there were more questions than answers.” headquarters in late October. Attendees advocated that the EWG should keep the The workshop brought EWG members together guideline broadly focused to encompass both brand and with members of EMA’s biologics working party generic products and to facilitate its adoption globally (BWP), quality working party (QWP), and good beyond the ICH regions, the CDER official pointed out. manufacturing and distribution practice (GMDP) She also underscored the comment made that quality risk inspector’s working group (GMDP/IWG), and management principles have relevance across the lifecycle other invited experts outside the group to assess the and that there are other “important aspects” of these progress to date on the guideline and brainstorm on principles than risk assessment “that need to be considered how to further advance the project in keeping with throughout Q12.” the tight timelines it is operating under (see story on The criticality of training for both assessors and inspectors pp. 23-28). when the guideline is finalized was another meeting “take Among the participants were the four FDA EWG members: away”— also that “examples might be an important way to ● Center for Drug Evaluation and Research (CDER) Office help provide some clarity, especially around, for example, of Pharmaceutical Quality (OPQ) Office of Policy for how one determined what the appropriate established Pharmaceutical Quality (OPPQ) Acting Director Ashley conditions are for a given product.” Boam ● OPQ Office of Process and Facilities (OPF) Acting Director Robert Iser ● OPQ OPF Division of Inspection Overall, the workshop “has provided us a lot of good infor- Assessment Acting Branch Chief Mahesh Ramanadham, mation that will help frame our discussion in Jacksonville and ● CBER Special Advisor to the Associate Director for [in early December] so that we can move the document Review Management Ingrid Markovic. forward,” the regulatory chair designate summarized. She added that FDA would be giving consideration, based on Boam will be taking over the helm of the ICH initiative from suggestions made to that effect, “whether a similar session industry rapporteur Nasr after a Step 2 version is in place, in the US might be useful.” WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 4 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

IGBA EWG Rep Keith Webber on ECs at GPhA Conference

The following is Webber’s comment at the November GPHA Conference regarding the ongoing EWG discussions on ECs. The Perrigo official represents IGBA on the EWG.

There are many modules, a lot of information, in your application. Only some of it really is binding in terms of impact on change. For instance, your P2 section is all about development of the product, but it does not really describe things that could change, per se, in your application. It is all about how you got to the status of your manufacturing process, the status of your product at the time of approval. That is an area where according to the guidance from the FDA that is not really part of the established conditions.

Things like your description of the product, what is it, how you are manufacturing the product, what facilities are being used, certain equipment in that facility, what your specifications are – those are the type of things that would fall under the established conditions category. They need to be communicated to the agencies.

If there is a change in an established condition post-approval, once you have an agreement with the agency on what your established conditions are, you need to provide a supplement or annual report to the agency to describe and justify the change in the established conditions. I will give you some examples, which will help you understand the value of established conditions.

One of the things that is being discussed are the changes that you might make in non-established conditions. Those things that are in your application but not listed as established conditions would be handled strictly under your product quality system and would not require a standard submission to the regulatory body. That is sort of a goal that we are working toward. But the definition between what is an established condition and what is not will take a lot of discussion to figure out, if we can get to that point.

Here are some of the benefits that might come from established conditions. Imagine you have an analytical method in your application, which I am sure you all do. Right now, we describe the analytical methods and the columns and the equipment that are going to be used. The whole methodology is described. And if you want to make a change to that methodology or equipment, you have to submit and get approval from the agency.

We can anticipate that there may be a way that you can use established conditions that will describe the performance characteristics of the analytical method, such as linearity, specificity, accuracy, etc. In a post approval world if you want to change that method without impacting the performance characteristics of the product – so volume, flow rate, the piece of equipment – you can do that without the need for prior approval or submission of a supplement to the agency, because you would not really be changing your established conditions.

Another would be a process change – for example, a manufacturing process where you defined your established conditions in terms of the performance characteristics of that process. Say it is a blending operation. If you have blend uniformity – a near IR system for monitoring the uniformity of the blend – then as long as you do not change those characteristics that you are measuring and you do not change the specifications or in-process controls for that process, you have the same ranges and everything, then you can change blenders. You could change to another blending process as long as you maintain those performance characteristics of the manufacturing process. That is another area we are hoping we can get to with Q12.

New Assembly Will Help Expand ICH Base ICH announced the organizational changes following the inaugural meetings of its new Assembly and Management At its meeting in Jacksonville, Florida, in December, the Committee in late October. In addition to changing “on” to restructured ICH “Assembly” met in person for the first time — bringing together regulators and industry members, “for” in its name, a new operating structure was established, including observers from WHO, regulatory agencies, and which includes the creation of an ICH association – a legal associations not previously a formal part of the ICH process. entity under Swiss law. The association establishes the new The Q12 EWG is reflective of the broader base that ICH is Assembly as the over-arching governing body that will building with its new structure (ibid.). facilitate broader regulatory agency membership.

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NOVEMBER / DECEMBER 2015 5 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 In addition to reviewing the revamped application process AstraZeneca Global Regulatory CMC Head Frank for new members and observers, the Assembly also Montgomery asked Iser if FDA views its guidance “as being encouraged members of the former Global Cooperation necessary going forward,” in view of Q12. Group (GCP) to take the opportunity to become formal observers before January 23, 2016, as allowed under the new “I would envision that we would put all of our efforts into membership process. Q12 and that our draft guidance would not be something that is finalized until after Q12 is out,” the CDER official The Southern African Development Community responded. He noted that FDA reopened the comment (SADC), the Gulf Cooperation Council (GCC), Brazil’s ANVISA, the Pan American Network for period on the draft with the idea that doing so could help Drug Regulatory Harmonization (PANDRH), and further inform the ICH process. the Asia-Pacific Economic Cooperation (APEC) were welcomed as the first observers under the new rules. Industry urges FDA to Align ECs Draft with Q12

In a press release after the December meeting, ICH provided FDA originally released the ECs draft at the beginning of updates on the progress of several safety and efficacy June for a 60-day comment period (links provided below). guidelines. It also noted that “work progressed” on the Q12 draft guideline. The next ICH meetings will be held June The Federal Register notice on the release explained that the 11-16 in Europe, and November 5-10 in Japan. guidance was developed to: ● address the “lack of clarity” with respect to what CMC information in a marketing Granularity on ECs at Issue for Q12 application constitutes an “established condition” or a Boam’s opening comments at the final session of the EMA “regulatory commitment,” which, if changed following workshop led into a discussion on the FDA established approval, requires reporting to FDA, and ● promote a better conditions draft and its relationship to the Q12 effort. understanding of CMC changes that can be made solely under the pharmaceutical quality system (PQS) without the The FDA guidance “is helpful in guiding this process need to report to FDA. Sections of the CTD that typically along,” EMA Head of Biologicals Peter Richardson contain information meeting the definition of an established said. However, “it is quite a high-level document.” condition are highlighted. He queried on the level of detail that would “be right to put into Q12 in terms of steering for the future.” In early October, the agency re-opened the comment process for an additional 90 days “to allow interested OGD’s Iser, who was actively involved in the ECs guidance persons additional time to submit comments without drafting process, fielded the question. FDA’s main emphasis significantly delaying agency decision-making on in developing the guidance was to bring CDER and CBER these important issues.” together in recognizing that “there are parts of an application that are established conditions,” and “importantly, that As of the end of December, comments from 24 companies there are things that are things that are not established and associations from the initial comment period were conditions.” posted to the docket, but none yet from the second comment The agency “did not go into a lot of detail because that detail period. would have taken a really long time” and the goal was to help inform the Q12 process, based on the indication in the The comments are generally supportive of the agency’s concept paper that the ECs or regulatory commitment issue efforts to define “established conditions” and clarify post- was going to be under discussion. “So we said ‘well, let’s approval reporting expectations with a goal of reducing the put ourselves out there’ and say, ‘here is something we are number of regulatory submissions and allowing firms to thinking in terms of established conditions,’ and let it inform manage more changes under their internal PQS. as it will.’” Also FDA “did not want to put something out there and then not have that be consistent with what the Several commenters pointed to the ICH Q12 effort expert working group was putting together.” and encouraged FDA to work cooperatively with the drafting team. Iser noted that the initial draft of the ICH guideline that was circulated for workshop discussion For example, PDA suggested that “a longer term goal purposes has more granularity – for example, in how should be a single guidance to avoid confusion among all development and knowledge gained on risks can stakeholders implementing these concepts.” Similarly, BIO feed in. FDA, he stressed, will want to make sure encouraged the agency to work with ICH, “specifically the that, if/when finalized, its guidance is consistent Q12 working group, on a global approach for these types of with the Q12 effort. changes.” WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 6 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 PhRMA “strongly” encouraged FDA to “continue its “improvement opportunities,” maintaining that the term alignment with this important international collaborative “can be subjectively viewed and may vary from person effort.” It also encouraged the agency to not finalize the to person in terms of interpretation and scientific and guidance until the ICH Q12 guideline has been signed off on operational rationale.” by the full ICH Steering Committee. At that point, PhRMA said it “would support FDA either harmonizing the draft GPhA also asserted that additional information being guidance, or withdrawing and replacing it with the final requested by the agency regarding ECs, and not previously ICH Steering Committee-approved ICH Q12 guideline.” part of an ANDA, be justified with respect to its relevance to “the overall safety and efficiency of the drug product.” It also Pfizer also voiced support, and commented that the draft questioned whether the information, which is “requested “seems to be reasonable and in line with proposals made but not required,” could lead to “an FDA citation that the by PhRMA to FDA and also with the current thinking in application is incomplete or fails to meet the substantially the ICH Q12 EWG. It is a step in the right direction toward complete threshold for acceptance.” improving post-approval change management and is generally consistent with industry’s current approach to FDA Puts Theory into Practice evaluating registrations with respect to post-approval changes.” After Boam’s opening remarks at the final EMA workshop session, the participants probed into other steps the agency Comments to FDA Reflect Q12 Challenges has been taking recently to realign its internal structure and policies in order to better integrate the review and inspection Along with the general support, some questions were posed functions and advance lifecycle quality regulation. and clarifications suggested in the comments that have relevance to the concerns before the EWG in developing and The substantive steps the agency has been taking to put implementing Q12. ideas into concrete form and practice did lend extra weight to the FDA comments at the meeting. For example, Pfizer requested clarification on whether or not the guidance supersedes previous guidance documents, Novartis Head of Quality Intelligence and External such as the 1995 SUPAC IR, the 1997 “Changes to an Relations Ursula Busse asked for comment on how Approved Application: Biological Products,” and the 2014 the newly formed OPQ was impacting assessor/ “CMC Post-approval Manufacturing Changes to Be inspector interactions. Documented in Annual Reports,” among others. Iser explained that the OPQ structure consolidates all of In its comments, ISPE noted that “in general, the document the quality assessment functions in one place, including the recognizes process validation not to be an established review functions for new drug, biotech and generic products condition. However, this is somewhat in conflict with and the facility and inspectional functions that used to be equipment settings and ranges that are considered part of the Office of Compliance. For new applications, established conditions (Ref. CTD Section 3.2.S.2.2). teams are formed that bring together the CMC reviews and Parameters, equipment settings, unless determined to field investigators, “so that we make better quality decisions be critical to quality attributes or well established, e.g., with all of this information and not have the separation that sterilization parameters, should generally not be considered we used to have.” (See IPQ October 25, 2014) established conditions.” This “structured iteration” and transparency, Iser’s OPQ ISPE also pointed out that a reference to maintenance for colleague Ramanadham added, results in “sharing risks chemometric and/or multivariate models “appears to be or concerns that we are seeing in the application as well as in direct conflict with ICH Q8R, Section 2.6, which clearly positive drivers, things that support quality – to really think states this should be maintained under the PQS.” about the holistic control strategy, the holistic assurance The Generic Pharmaceutical Association (GPhA) of product quality. And having these teams allows us to requested clarification of some terms and questioned communicate in many different ways and many different the rationale for providing additional information forms” and assure that “that knowledge is shared and is about “established conditions.” coordinated across the review cycle.”

GPhA asked that use of the term “sufficient detail” be Markovic pointed out that “CBER has always had a highly clarified by examples, due to “variances from reviewer to integrated review and inspection process. And that has reviewer” and inconsistency in how it might be interpreted. been traditional to CBER’s model, such that the reviewers Similarly it requested clarification on the definition of are actually trained to go on inspections and visa-versa, WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 7 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 information is shared ahead of time, and they are both Pointing to CBER’s “longstanding experience” with CPs,” interchangeably involved in inspection and in the review Marcovik stressed that “they are generally very highly process. So there has always been an integration. And it is desirable and appreciated by both the regulators and actually a highly valuable model that we plan to continue industry as well.” into the future.” “One thing that has actually worked very well in the past,” Noting that there had been a lot of discussion at the she emphasized, “is using the trans-BLA approach, which workshop around the amount of information in the means that one type of change can actually be applied PQS that needs to shared with assessors, UCB CMC across many products. And you can actually have up to 20 Regulatory Affairs Associate Director David Kirke products per trans-BLA. Those are submitted as sort of a asked Boam how “the quality metrics guidance can bundled single submission”(ibid.). fit into that.” She expressed her hope that this bundling “is something Quality metrics provide another piece of information we will continue in the future. And it will be interesting beyond an onsite inspection for assessing the effectiveness to see if we actually have an increase in the numbers of of a PQS, the CDER official responded. “And that it is one comparability protocols, especially for multiple related more piece of information that we have in addition to our types of changes.” onsite inspection or other records requests that would help us to assess the effectiveness of a particular site’s PQS.” Iser was asked to comment further on the agency’s plans for revising its CP guidance and how that FDA Espouses Comparability Protocols would interface with the Q12 effort.

The conversation turned to FDA’s experience with compar- The CDER official explained that it had been on the agency ability protocols (CPs) – a system, Sanofi Pasteur Associate agenda to release the revision in 2015, and if not, that the VP and Global Regulatory CMC Head Thierry Gastineau release would come in early 2016. He noted the drafting main-tained, that is “working very well” (see story on pp. group has “taken a lot of the discussions that we have had 40-50). within the Q12 working group and tried to put some of Iser commented that the agency is seeing more use of them those thoughts into the revised draft.” He stressed that “it in the biotech product text than for chemical products. As will be a draft, so comments are welcome.” came out in the discussions at the workshop, the protocols can be challenging to handle, he noted, when they are too Japanese Perspective Offered broad, without enough information, or not for the types of changes the agency had anticipated seeing in a protocol. The final session continued with some reflections by Pharmaceutical and Medical Device Agency (PMDA) The hope is that with the anticipated update of FDA’s CP Office of Standards and Guidelines Development Yoshihiro guidance and Q12, “we will have more opportunities for Matsuda, who represents the Japanese agency on the EWG these protocols to come in.” (see box below).

PMDA’s Yoshihiro Matsuda on the EMA Q12 Meeting Discussions

The following are the reflections on the EMA Q12 meeting discussions offered at its concluding session by PMDA EWG member Yoshihiro Matsuda.

First of all, I would like to thank our EU colleagues for inviting us to this wonderful workshop. This two-day discussion is informative, not only for our future discussion in EWG, but also the discussion in Japan. Unfortunately today our JPMA [Japan Pharmaceutical Manufacturers Association] colleague could not come. But I will bring this back to Japan and share with my JPMA colleagues.

So now I will briefly discuss what we are doing in Japan and some current thoughts on some topics. It might include my personal observations. We PMDA members communicate regularly with JPMA members. And in addition, we have additional opportunity to gather various opinions and ideas on Q12.

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NOVEMBER / DECEMBER 2015 8 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

We have a PMDA internal working group. This working group is composed of reviewers from different offices and inspectors. And we have a discussion group composed of people from industry, academia, and PMDA. To inform this kind of discussion group is a general approach to address ICH topics in Japan. We also communicate with MHLW [Ministry of Health, Labor and Welfare], as this topic may affect our current regulation and the MHLW is responsible for the adoption of ICH guidelines.

So now if we look at the Q12 concept paper, three issues have been identified: ● the regulatory dossier ● the PQS aspect, and ● post-approval change management plans and protocols. I would like to make a short comment on each topic.

What we discussed in Japan so far is mainly the regulatory dossier and post-approval change management plans and protocols.

On the PQS, of course we agree that Q12 should supplement the PQS aspect in terms of post-approval changes. But our concern is that it seems to start to mention the inspection itself. To my understanding, inspections…and the relationship between reviewers and inspectors may differ among regions. So we are a little worried about how we can make a harmonized document with a limited timeline.

With respect to the regulatory dossier, we always keep the application form in our minds. So what I said in the drafting team discussion in the EWG is the more I think about Q12, the stronger I believe the current Japanese system – the application form together with the QOS [quality overall summary] – is the ideal goal for Q12. [However,] through this discussion I would like to think more about the relation between the application form and established conditions, especially including the lifecycle strategy.

So, post-approval change management protocols: As I said yesterday, we are trying to adopt the concept. Our discussion is ongoing, and there is not much I can say here today. But we have identified some concerns with adopting the PACMP system. We notice from the beginning though, one thing is post-approval reporting categories. Japanese categories are risk-based. But the thing is, we only have two categories: partial change application and minor change notification. Due to this, we cannot adopt the exact same system as the EU or US. eW will not change our current reporting categories [based] on Q12 activity.

So why did we decide to consider adopting the [PACMP] concept? This is because this regulatory tool might be beneficial also in Japan for predictability and transparency in terms of the requirements for change…. But I have to say expanded protocols are more challenging for us.

As my conclusion, I would like to propose to discuss more about established conditions, because…I have been thinking that most topics eventually link to establish conditions.”

Genentech Policy and International Operations the lifecycle strategy. He suggested that the benefits of the Global Head Wassim Nashabeh, who represents lifecycle strategy had been touched on at the meeting and BIO on the EWG, asked Matsuda to comment further the topic needed further clarification. on the impact that Q12 might have on the elements in Japan’s application form related to established Of interest to the EWG regulators in considering the conditions. issue for Q12, EMA’s Richardson commented, is how challenging Japan has found the process of detailing The PMDA official pointed out that Japan’s application ECs and the reporting categories for each of them. form includes the reporting categories, while the established conditions definition before the Q12 EWG does not. He Europe, he pointed out, works “in a certain way, and I think reiterated a concern he had voiced during his presentation earlier in the day that adding the reporting category we do our assessment out of Module 3. We put a lot of information in the Q12 context would pose challenges and effort into that. So it is maybe just a rebalancing of energy, “the less new ideas the better from a regulatory perspective.” perhaps, in a new paradigm. But I am wondering whether anybody feels that there is an additional regulatory burden Along with established conditions, Matsuda said, the to do all of that extra definition of established conditions current Q12 draft proposes another new concept – that of and reporting categories?” WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 9 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 Pfizer CMC Advisor Ron Ogilvie commented Q12 – particularly how we are looking at non-established that he shares in Matsuda’s “positive view on the conditions and how we manage that.” Japanese JPAL system currently, and that it is a very useful foundation for some of these change As he had expressed at other junctures of the meeting, he management pieces.” underscored his belief that “the more we can empower the quality system when it is capable of being empowered, the Ogilvie along with Sanofi Pasteur’s Gastineau were invited better.” to attend the EMA meeting due to their participation on Ogilvie noted that he had come to the meeting “very the European Federation of Pharmaceutical Industries optimistic about post-approval change management Associations (EFPIA) European Biopharmaceutical protocols, and particularly the ability to extend those in Enterprises (EBE) group supporting the Q12 development different dimensions.” While he hopes to still have that process. Ogilvie’s Pfizer colleague Graham Cook is topic optimism when he sees the final version of Q12, he did lead for EFPIA on the EWG and Roche EU CMC Regulatory hear some challenges expressed at the meeting around “this Policy Lead Markus Goese is EFPIA deputy topic lead on broadening and extending.” the EWG. The central issue, he reiterated, is “how much we have to Ogilvie pointed out the target set values approach as among communicate back to the regulator rather than manage the “very interesting things” that Japan is incorporating. it in our systems. Whether we can get everything done immediately or we are on a journey, I do not know.” He suggested to Matsuda that in addition to the two categories for change management that he had mentioned Pharmacopeial Standards as a Lifecycle Enabler – minor change notification and partial change application – “you also have a third category where you allow the In his reflections, Dutch Medicines Evaluation Board pharmaceutical responsibility quality person to rule in an (DMEB) biologics assessor Martijn Van der Plas highlighted empowered way. I would just like to support the Japanese the meeting discussion the day before on the relationship perspective.” between established conditions and the control strategy as “very fruitful.” From “Tell and Do” to “Do and Tell” “In my mind,” he commented, “established conditions In offering his assessment of the workshop discussions, should be defined in the guideline in a sufficiently detailed Ogilvie pointed out that a central concern before the EWG way that they can be moved forward in an assessment. is what is entailed in “trying to move from a ‘tell and do’ Otherwise, we will have the guideline, which defines what world to a ‘do and tell’ world.” established conditions are on a high level, but then we will have years of discussion on the implementation of this “It is really interesting when you start to think about principle.” what that means,” the Pfizer official commented. The question that needs to be unraveled is “How Van der Plas went on to explore the “role of the much ‘tell’ does one need to ‘do’?” pharmacopeia” in product lifecycle management as being a potentially significant “enabler” of the Q12 The discussion on established conditions led to Ogilvie goals and needing to be “taken into account” (see box viewing the issue as “a very important thing to get right in below).

DMEB’s Van der Plas on the Pharmacopeial Role in Lifecycle Management

At the EMA meeting final session, DMEB biologics assessor Martijn Van der Plas offered the following comment on the connection of the Q12 effort to the pharmacopeia.

It is important that it is at least brought to the table, and that the expert working group thinks about this – the role of the pharmacopeia. Whatever your opinion about the pharmacopeia is, it is out there. You have to live with it. It has to be taken into account.

It has an influence on the lifecycle management of specific products.The pharmacopeia itself is already a prime example of an issue where all kinds of tests, limits, and requirements are moved outside the CTD into the pharmacopeia, and therefore also into the PQS.

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NOVEMBER / DECEMBER 2015 10 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

This is not a problem. From a lifecycle perspective, I think it is an opportunity. Some people seem to think that pharmacopeias are a disabler, but I think they could be viewed as an enabler if you do it correctly. And this is especially true for legacy and generic products.

As a biological assessor, I tend to focus on new biological products and their associated, complicated, very product- specific assays. But a specific product is also controlled by a number of general assays.And many products are not new – they are generics or follow-ons of existing products. In those cases, both the general tests and specific monographs are there or may be developed, and can be used as part of the lifecycle management.

The last part is more scientific. It is related to a number of slides that we saw this morning regarding the way the pharmacopeia is very strong on testing requirements, descriptions, associated limits, and system suitability tests. In this way the pharmacopeia offers a kind of model or template for the kind of level of information that assessors would normally expect in a specific CTD for a number of tests.

I do not know if this expectation can be directly translated into this guideline, but at least this expectation should be kept in mind when developing specific guidance in relation to tests and lifecycle management tests.

Session moderator and Q12 rapporteur Nasr asked Where Should Responsibilities Lie? Van der Plas to “elaborate further how we in ICH Q12 can benefit from the opportunities that some of Following the Dutch assessor’s comments, ANSM (France) us see, but maybe the majority do not.” Deputy Director of Inspections Jacques Morenas offered his thoughts on the EMA meeting discussions, focusing on “The most obvious one,” the Dutch official responded, “is the current review/inspection relationships in Europe and that the pharmacopeia contains a description of all kinds of the US and the issues that arise around responsibilities and general tests. Some of these are maybe, especially for this resources in altering it. Morenas serves on the EMA GMDP group, quite trivial – like a test for extractable volume. But Inspectors Working Group and has been playing a leadership because it describes these tests, in a specific CTD you do role in the Pharmaceutical Inspection Cooperation Scheme not have to say how the test is performed or validated. You (PIC/S). can just name the test and refer to the pharmacopeia. Then suddenly the whole associated lifecycle management of this He highlighted the EU difference from the US in requiring test is covered. This is a very simple example. But this is the a GMP certificate to perform manufacturing separate from line of thinking that you could take up.” an application approval. In turn, EU mutual recognition of inspection reports with its MRA partners is based on the Nasr thanked Van der Plas for his enunciation of the idea that exchange of the certificates, which are also used by other pharmacopeia standards can be relied on to minimize the countries in their GMP assessment process. regulatory process. “I hear clearly that you are suggesting that in the future – and we can guide that through Q12 – that Morenas pointed to the problem of inspection instead of providing a lot of analytical details, a reference resource limitations in adding a product-specific can be made to the pharmacopeial standards.” change management quality review to the normal global GMP inspection covering the various finished Van der Plas’ comments related to the pharmacopeia product manufacturing going on at the site, which is echo a dominant theme that emerged from the needed to issue the certificate. dialogue at the PDA forum on lifecycle management held a month earlier on the need to move quality He commented further on the concern that shifting regulation in the direction of universally agreed to responsibility for change management oversight from and auditable standards and away from a system assessors to inspectors would not be a net relief in regulatory based on one-off negotiations between companies burden, at least on the agencies. and reviewers at individual agencies (ibid.). What Q12 needs to explore, Morenas maintained, is how Globally standardized change management protocols that to increase regulator confidence in companies taking would build off the positive experience in the US with use responsibility for implementing changes, which if not going of “expanded” change protocols and clarify the expectations well can then have inspection and enforcement follow up. At internationally for implementing various types of issue is how to do so without overloading the regulator with manufacturing changes was among the proposals emerging data and putting the responsibility on the regulator if/when into relief at the forum. WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 11 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 problems ensue. “Finding a system to clearly define who is The flow of how it works seems relatively straight forward, responsible is important,” he stressed. Richardson suggested. “Essentially we are trying to get to the point where we potentially classify each regulatory Moderator Nasr suggested that, in his view, ICH Q12 change against each established condition at the time of the effort is envisioning making industry responsible marketing authorization review.” However, “it seems to me and not moving the responsibility from assessors to to be a fair challenge in terms of getting agreement across a inspectors. globe on whose classification system is the best.” “What we are envisioning,” the Q12 rapporteur said, “is He made an analogy with pharmacopeial harmonization, in that through a good change management system under the which “you have your monograph and I have mine.” Even quality system as is, with some good practices, industry in Europe, getting agreement on a classification guideline will remain responsible for assessing and implementing “is quite a job,” he pointed out, involving negotiations with manufacturing changes.” Industry will be expected to “implement the changes correctly and have the information the European Commission to “maintain its satisfaction.” on, and results, of these changes available on site that will be The EMA official suggested that it would be easier presented during an inspection if and when asked.” to move forward “if we had a softer approach to the Vast Pool of Misspent Resources at Play classification of change in the guideline in some way, but agreed on the general principles of what Participants at the PDA workshop held a month earlier established conditions are.” offered a different take on the resource issue, questioning the assumption reflected in some of the comments at the If the EWG at this point “wanted to go further and try to EMA workshop including those of Morenas, that resources negotiate specific changes associated with very detailed are fixed in a zero-sum game(see story on pp. 40-50). established conditions, I think that would be hard. It may be better to try and take that out of the process as a separate A central theme in the workshop presentations and step in some way, and keep it as sort of a parallel benefit to discussions was the vast resource drain and lost be delivered some time later.” opportunity cost that the current PAC regulatory situation globally is creating on both industry and Size of the Prize for ECs Stressed regulators, and the stakes in finding an international approach with enough power to address it (see story Richardson’s EMA colleague on the EWG, Principle Scientific on pp. 29-39). Administrator David Cockburn, described the discussions At issue at the workshop was how medicines could be over the previous two days as “very encouraging” – filling regulated across their lifecycles in a way that would liberate in some of the thinking on “how we are going to achieve technology and quality science to improve processes and some of the aspirations behind Q10, in particular,” and products, lower costs, and better assure patient availability. derive benefit from adopting enhanced development.

Pointing to “the amount of money in play here that is not “The whole discussion around established conditions and being used efficiently,” one participant noted that “if we non-established conditions, and perhaps having a process take a fraction of that and create a more efficient system, that will enable us to downgrade some of the variation everybody wins.” categories, I think, lends itself as a suite of tools that could actually help to differentiate some flexibility for companies Some of the current resources, for example, he suggested, that have generated far more information to support process could be redeployed to create the standards needed and potentially to fund a trans-agency government body like understanding.” WHO to oversee/audit industry’s change management Noting that he is “very hopeful that there is a way forward” programs – possibly resourced on a user-fee basis. and that “the size of the prize is clearly pretty enormous if Judging from the successful deployment of user fees in the we get this right,” Cockburn maintained “that it is certainly generics context in the US, the return on investment from worth still having some strong and invigorating discussions a streamlined regulatory process could be substantial, he pointed out. to see what we can achieve.”

Walk Before You Run The utility of the lifecycle strategy needs to be “reinforced,” Roche Pharma Technical Regulatory In his meeting reflections, EMA’s Richardson turned Policy expert Kowid Ho added – particularly attention back onto established conditions, which “seem to regarding non-established conditions and proving be the primary feature of what we are trying to get” common reviewers with more confidence on how they would agreement around. be managed. WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 12 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 Another participant at the workshop suggested that the Rapporteur Nasr took the opportunity to provide the EWG should give consideration to “how useful these EWG’s current thinking on how it would address the kinds of tools could be for enterprises that market orphan definitional concerns. medicinal products. Sometimes smaller enterprises have more difficulties with a very complex pharmaceutical The guideline will have definitions for new terminology like system, even though they have the same responsibility to established conditions, Nasr explained. The EWG is also manage their system as big pharma.” “considering providing a chapter in the guideline about frequent manufacturing changes and how the concepts EWG Urged to Make Q12 Widely Applicable in totality will be used to facilitate the implementation of manufacturing changes for analytical methods and so The dialogue at the concluding session of the EMA meeting forth.” ended with a focus on the need for making Q12 as relevant as possible in helping addressing the more difficult challenges On the other hand, trying to develop very detailed definitions industry faces with lifecycle management outside of the and descriptions has a downside as well, he explained. For ICH regions. example, as people pointed out at the meeting, agreement on classification of changes would entail “many more years Novartis’ Busse urged the EWG to keep in mind and many more man-hours.” the desire industry has to see the guideline widely The EWG will try to make the guideline as clear and adopted, suggesting that the recent reorganization of useful as possible. However, Nasr encouraged the meeting ICH may help. participants and their colleagues, once the draft is shared, Luxembourg Official National Laboratories Head Jean- to “provide your input” so that when it reaches Step 2 “we Louis Robert pointed out that there are political hurdles at have a very good document that we can implement without play in this regard that the EWG can’t address. Robert is the need for an implementation working group.” head of the EMA Quality Working Party and co-chaired the Legacy Products Will Also Benefit workshop. The last question at the session addressed the current EWG While recognizing the limitations in what developing an thinking around currently marketed/legacy products. ICH guideline can accomplish, Nasr urged “using this as an opportunity to engage colleagues from outside the ICH Dutch regulator Van der Plas reiterated a comment region, and make them part of the development of the he had made earlier at the meeting that Q12 “does discussion to encourage future implementation.” not have to resolve everything, but at least the things that are in the guidance should be clear. Once this Busse brought up the example of ICH’s 1996 guideline E6 happens, the scientific principles will probably be on good clinical practices, which has been widely adopted, used also with respect to existing products.” even outside of the ICH regions, and “is like the gold standard for GCPs.” She suggested that the EWG consider The concept of established conditions, for example, will “why this guideline was so adopted, and what makes it so not be one that “can be used immediately” in all contexts. successful.” Sanofi Pasteur’s Gastineau stressed that one However, if defined with sufficient clarity, the concept will way to influence other countries is to make sure that Q12 can “seep into regulatory practice.” “illustrate that it actually works.” Vander der Plas pointed out that this process has unfolded What’s in a Name? with a number of concepts in ICH Q8, noting that terminology such as CPPs and proven acceptable ranges Gastineau then switched the conversation to the many are now being used for products that are outside the formal definitional/interpretation challenges that were pointed scope of the guideline even if they don’t “fully comply with to during the meeting in addressing Q12, such as around each and every principle that is set out in the Q8 guideline.” established conditions. If the scientific principles in Q12 are clear enough, he The ECs definition in the current early draft “is still a very emphasized, “then we can also use this for legacy products” high level definition, and we need to get into much more to the benefit of “both industry and regulators.” detail and be very concrete in what we mean” to avoid being stuck with diverging opinions. Downloads from Story One approach, the Sanofi Pasteur official suggested, might be to have a “prototype of an ideal dossier” so that “we ● Established Conditions Draft guidance could concretely see what it really means for everyone.” ● Federal Register notice

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NOVEMBER / DECEMBER 2015 13 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

PhRMA REPS MARY OATES AND MOHEB NASR (RAPPORTEUR) ON ICH Q12

At the ISPE Quality Manufacturing Conference in early June, Pfizer Quality Global Operations, Environmental Health and Safety VP Mary Oates, who represents PhRMA on the ICH Q12 EWG, reviewed the development of the guideline, the issues it is tackling, and the objectives is it working to achieve. GlaxoSmithkline Global CMC Strategy VP Moheb Nasr, who is serving as the industry rapporteur for Q12, followed with an update at a PDA workshop, held in the early fall, on how the initiative had advanced in the intervening four months. [The first part of Nasr’s remarks at the workshop, in which he covered similar ground to Oates, is not included]. Prior to joining GSK, Nasr was Director of the Office of New Drug Quality Assessment at CDER and participated in the development and implementation of the ICH Q8-11 guideline series. Both Oates and Nasr clarified that, although their remarks were informed by their participation on the EWG, they were speaking for themselves and not for the EWG, PhRMA or their companies.

PFIZER’S OATES ON Q12 DEVELOPMENT AND ISSUES TO BE RESOLVED

I am delighted to give you a very brief overview of ICH Q12. I will talk for a few minutes both about the vision of Q12 as well as its current status.

I think that everyone who has any familiarity with Q12 is probably pretty enthusiastic about it, because we believe it has the potential to be quite impactful. It is taking on a very challenging topic. I will talk a little bit about those challenges as I go through the presentation. If we can address the challenges of change management, it will have a significant impact on all of us – and by all of us I mean regulators, every element of the pharmaceutical industry, as well as patients.

The exact title of ICH Q12 is ‘Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management.’ Put a little bit more simply, what that means is: How can we optimize the change management process throughout the pharmaceutical product lifecycle?

The vision is that Q12 will enable reliable supply of quality products to patients. How will it do that? It will do that by streamlining the change management process throughout the pharmaceutical lifecycle.

So when we think about ideally how that would work – and this is not a new concept, it is one that has been talked about for years – ideally, a firm would be able, within the confines of their own quality system, to make manufacturing changes. That is really what we are talking about here today – manufacturing changes – to make manufacturing changes without prior regulatory approval.

If we can accomplish that, and ensure that those changes are robust and that they meet all the requirements, and that patients will actually benefit from those changes, that would be a significant accomplishment.

The Problem

So why did ICH agree that Q12 is an important document? Well, first let’s talk about what the challenges are. These are incorporated in the problem statement identified for Q12.

One of the problems for change management – perhaps the most significant – is a lack of a globally harmonized approach on these technical and regulatory considerations.

So for a company like Pfizer – we have approximately 20,000 SKUs that we sell in more than 140 markets around the world – you can imagine that if we want to make a change to any of those manufacturing processes or products, it is quite an

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NOVEMBER / DECEMBER 2015 14 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 undertaking. I think five to eight years, as [moderator Steve Mahoney] said, is probably about right for a significant change. That has impact on patients, has impact on regulators, and it has impact on industry.

Significantly, every time we want to make a change, we have to take a step back and say, ‘is making a change worth the effort that has to be invested in order to make this change around the world in all the markets where it is affected?’ It is also quite difficult if you can make a change in a few markets, but not in all markets. It adds a lot of complexity.

So this lack of global harmonization is really quite a challenge. And as the slide says down below, it does hinder innovation and continual improvement. Because really the choices that we have to make are to make the changes that are must haves, but not necessarily the changes that are nice to haves. And a lot of those around innovation and continual improvement really fall oftentimes into that nice-to-have category.

Another reason that ICH decided that Q12 is important is because Q8, 9, 10, and 11, although incredible and important documents in and of themselves, when taken together had the promise of providing post-approval operational flexibility. Unfortunately that has not really been achieved. Perhaps one of the reason for that is that the main emphasis of ICH to date has really been on the early stages of the product lifecycle. And Q12 intends to address that by focusing on the later stages – in other words, the post-approval stages of the product lifecycle.

Background, Objectives, Scope, Issues to be Resolved, and EWG Makeup

Background

So just to give you a little bit of background on how Q12 came to be:

There was a quality strategy workshop last year in Minneapolis, and Q12 – in other words, change management – was identified as the top priority. A concept paper and business plans were drafted, and the ICH steering committee endorsed Q12 in September of last year. The EWG was formed, and in a little while, I will show you the members of the EWG. It is a very large and diverse group (see story on pp. 23-28). As you can imagine, there is an awful lot of interest in this around the world.

We held our first EWG face-to-face meeting in Lisbon in November. I am a member of the EWG. I am part of the PhRMA contingent to Q12. Our rapporteur is also from PhRMA, and that is Moheb Nasr.

Since then we have done a tremendous amount of work. We have had multiple phone calls. And in fact, we have drafted original sections of Q12. We will be getting together this coming week in Japan for our second face-to-face meeting.

Objectives

As I have said, one of the things that we are trying to accomplish through Q12 is harmonization, at least across the ICH regions, of change management.

Also, if we are going to accomplish this vision of having firms being able to make at least some changes without prior regulatory approval – more than we can do today – clearly regulators have to have confidence and trust in firms’ quality systems. That will be very important.

We also believe we have an opportunity to optimize the division of labor between assessors and inspectors in regulatory agencies around the world. It will be very important from a Q12 perspective that the role of each function is clear. And obviously we want to support continual innovation and improvement for the benefit of patients around the world.

Scope

The proposed guideline will apply to all pharmaceutical products. Importantly, it does not just apply to new products—in other words, products that are currently in development—but it is intended to apply to products that have been approved and are currently on the market.

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Issues to be Resolved

So just as [Q11 Q&A Rapporteur Tim Watson (Pfizer)] talked about[ IPQ July 10, 2015], our concept paper identified issues that need to be resolved. There are three listed here:

● The first has to do with the regulatory dossier itself, and some of Tim’s comments are quite relevant in terms of this as well. Really, a lot of times it depends on what you put into your dossier that determines how changes are made later on. This ties in to the definition of a regulatory commitment. Is everything in the dossier a regulatory commitment? Or are only certain elements a regulatory commitment? And can Q12 help to delineate that? If that is all we accomplish – although that is not all that we hope to accomplish – it should reduce some of the discussions that Tim was talking about earlier, because it will be very clear to firms as well as regulators what will need to be submitted for a regulatory change.

● I talked about the importance of the pharmaceutical quality system. Specifically, Q10 talks about the entire pharmaceutical quality system, but specifically risk management, change management, and knowledge management are critical to a firm’s ability to effectively and appropriately manage change and the risks that may be inherent in those changes.

● The third aspect that needs to be discussed and resolved is the use of post-approval change management plans and protocols. I am going to talk about this more in just a minute. This is a tool that is available, at least in the US and Europe to firms today. I believe that this is a highly underutilized tool. Q12 envisions enabling the use of this more effectively.

Expert Working Group

As I said, we do have quite a large expert Q12 EWG Participating Organizations working group, probably double the size of the one that Tim showed in his picture. ICH MEMBERS OBSERVERS Thirty or more folks are on the team, so ● EU ● WHO we do have quite a diversity of experience ● EFPIA ● APIC and expertise. I will say, however, that ● FDA ● BIO the team dynamics to date have been ● PhRMA ● DoH of Chinese Taipei outstanding and it is clear that everyone ● MHLW/PMDA ● IGPA is committed to achieving the objectives. ● JPMA ● DRA of Singapore Everyone is very invested in doing that. ● Health Canada ● WSMI The participating organizations are listed ● Swissmedic [in the box at right].

EWG Progress and Possibilities

This is our work plan. You can see where we are – June 2015. We do plan to have our Step 2 document finalized by the middle of 2016. This, for an ICH guideline, is a very aggressive time frame. But we are all committed to meeting it....

About the progress that we made at the face-to-face in Lisbon: Essentially that meeting was a brainstorming session – an opportunity for everyone to share the thoughts that they have about the different important elements as well as foundation building, so we could identify the pieces that we thought were important so that we could separately and collectively work on them to make good and rapid progress. I want to spend just a few minutes on this slide.

At this point, I want to make the same disclaimer that Tim did earlier and say that everything I am going to say is reflective of my own opinions, my thoughts, having been working on Q12 for some number of months now. It is not reflective of any consensus of the Expert Working Group or of PhRMA.

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Post-Approval Change Management Plans

When we think about Q12, what can Q12 accomplish? I think that Q12 can enable a couple of different pathways to change management.

The first pathway can be done, at least in two of the ICH regions today, and that is thepost-approval change management plan or protocol. Like I said, I think that industry does not benefit from that nearly as much as we could today. I think that what needs to be provided is clarity around how it can be used, probably from both a regulator perspective as well as an industry perspective.

Essentially, if you are not familiar with it, basically it is a document that would be submitted to a regulatory body that defines future changes that you want to make. It would delineate the criteria that you are going to meet in order to make those changes. And that document would be approved in advance – really before you start any of the work.

Once the regulator approves the plan or protocol, you would go about doing the work to demonstrate the benefit and the value of the change. The change can be made. And then you would inform the regulator that you had met all the criteria – you may or may not have to submit the data – and without additional approval you can go ahead and implement the change.

In order to do something like this, a firm really has to think about the future. They have to think and plan about where they want to go. So it does require a fair amount of investment. But once that work is done, implementation can be virtually immediate, so there is a lot of value in that. What Q12 can do here is to bring some clarity around how to do that more effectively.

Relying on the PQS

The second pathway that Q12 can enable, I think, is a bit more revolutionary than evolutionary. And I will use an example. Is it possible that a manufacturing site could be approved to implement the vast majority of their changes – certainly, not every change, but the vast majority – without prior approval? How could this be done even under the current regulatory constructs that are available to us?

One potential pathway, just thinking out of the box, is that a post-approval change management plan could be used for something like this.

So a manufacturing site that believes they have a very robust quality system, that they have all the elements that are necessary, could develop a post-approval change management plan where they list all the changes that they think they should be able to make within the confines of their pharmaceutical quality system. They would outline the robustness of their quality system, why they believe they are qualified to do this, and that could be submitted to a regulatory agency. Now clearly, under these circumstances, the bar is higher.

Certainly, an agency may want to come in and do a specific assessment of what is in this post-approval plan – specifically to look at risk management, change management, and knowledge management – to verify that the firm does have the proper systems in place to be able to accomplish this.

Once the regulatory agencies assess that, they could grant approval under that post-approval change management plan for this manufacturing site to make those changes. Sort of a different concept, but it does fit in to some of the thinking that we are currently having on the ICH expert working group.

I just wanted to leave that with you for you all to think about because it is something that we will be exploring – again, understanding that it does raise the bar. There would have to be some way for regulators to have that additional trust in the firm’s capabilities.

Also, in this sort of context there still has to be a lot of transparency with regulators in terms of the changes that are being made. One of the things we have talked about: Is it necessary, for example, to submit the changes as they are being made, maybe even those that historically would not have been submitted, so that the regulator has a full view of the current state of the manufacturing process, for example?....

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Desired Attributes

I would like to conclude by sharing the desired attributes of Q12. We want this to be a clear, comprehensive, and self- contained document. We want to learn from the previous ICH experiences. Our desire is not to have an IWG later on, but to really enable everything to be in this single document. We do not know if that will be possible, but that is certainly our goal.

We would like for this clearly to be a harmonized guideline that is useful globally in the future—at least initially useful in the ICH regions. It needs to be both forward-looking and pragmatic, and both conceptual and practical.

The EWG believes that if we come out of this exercise with something that is not practically implementable then we will not have succeeded in our objectives.

Finally, the ultimate goal is to support innovation, continual improvement, and to assure reliable supply of quality product to patients.

Q12 UPDATE BY RAPPORTEUR NASR AT END OF SEPTEMBER

We had a meeting in Fukuoka a couple of months ago. We had a lot of activities and drafts. We were able to compile a version of the technical document. I can advise you that it has not been made public because it is not readable…. But we have something that we can label as version one. And we got an agreement on how to progress moving forward with the guideline.

I am putting together the drafts we had from the work that was done this summer, and the outline [from Fukuoka] looked very different than this.

The Vision

Let’s try to step back and see what we are trying to do. I think we have a vision. The vision that the group has is, ‘what can ICH Q12 do in order to assure reliable supply of quality product to the patient?’ I think we all agree that, regardless of what we do – the regulatory system, the technical information, the development, the business and all of that – we all have an obligation that we should have high quality product available to patients. The development of drugs is not an academic exercise.

We have heard from Dr. Woodcock and the FDA for years that they have a vision. Dr. Woodcock’s vision that was presented in a workshop in October 2005 was that the industry should become, with regulatory help, more efficient, agile, and produce high quality products without extensive regulatory oversight. That was the FDA vision.

And now we have our ICH Q12 vision. I think you can see the connection. The connection is, how can we assure quality products? How can we assure that good science and risk-management principles are used? How can we get there?

In our view, if we achieve that desired state, most of the manufacturing changes…should be managed under the company’s pharmaceutical quality system. It is currently managed under the pharmaceutical system, but we are making the regulatory process part of the quality approach.

So we delink that. So how can we continue to manage manufacturing changes under the pharmaceutical quality system? There is nothing new there. What is new is, ‘without the need for regulatory approval prior to implementation’ – or the ‘do and tell.’ So in other words, if there is a need to make a manufacturing change, you make an assessment, based on science, based on product development knowledge, etc., and you have a plan, you start implementing the change, and you notify the regulator of the change….

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NOVEMBER / DECEMBER 2015 18 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

Progress in Fukuoka, June 2015

Established Conditions

One of the key aspects is the regulatory commitment/established conditions. So at the time we were getting together to start the drafting, FDA issued the draft guidance, May this year, on established conditions. The draft guidance, in my personal view, has some good stuff. I disagreed with a couple of things. But it was good that the agency took the initiative to put something on paper about established conditions.

The team agreed a month later in June that rather than reinventing the wheel, we could use the FDA draft guidance as a starting point to work on the development of established conditions. The drafting team did a good job determining how we could do that. They came up with working conditions. And the process is moving forward.

As a matter of fact, I can share with you that I am in the process of putting the different outputs into a single document now. I was working on it in the last couple of days and I continue to work on it. That section of the ICH Q12 guideline looks really good. So ICH Q12, I can assure you, will deliver on clarifying what established conditions are and how that will be translated into practical implementation.

I would like to thank my ICH Q12 colleagues. I am not going to name names now, who is doing what, so you do not go after them if things do not go well. You can come after me.

Frequent Manufacturing Changes

We are also working on frequent manufacturing changes. I think we realize that there are frequent manufacturing changes, and ICH Q12 could provide guidance about the expectations – with ICH Q12 and the tools and the enablers and all of that – about how you can manage the frequent manufacturing changes differently. We know what we did before Q12. How can it be done after ICH Q12?

We identified three types of changes – analytical methods, manufacturing processes, and manufacturing sites – and we are going to have some discussion on that in ICH Q12.

Lifecycle Strategy Section

There is a new section that we agreed to work on in Fukuoka and we continue to work on. It is not there yet. But here is where we are:

Many of us think that there is value in having a section in the guideline about how to link product development to control strategy, and use that linkage between product development and control strategy to identify the established conditions.

Why is that so important? Because having a discussion in ICH Q12 at a high level about established conditions is not going to be that valuable when it comes to implementation. In my view, and I think within ICH Q12 there is an agreement that the list of established conditions will depend on the level of development and the controls you have. If you have very empirical development and your control is only a list of testing that you do, the manufacturing process that you have and the list of testing that you have are your established conditions.

If you are doing enhanced development – quality by design development – you understand the impact of attributes and parameters on the quality of the product. You have fewer critical parameters. And many of these critical parameters and attributes you are controlling within your robust control strategy. Therefore, you will have a much shorter list of established conditions.

So established conditions is not going to be one size fits all. It will depend on the level of development, the controls, and the quality system. And this will be a value of what Q12 can do, whereas Q8, 9, 10, and 11 did not do. That is why it is important to link the product to the established conditions.

That section also could provide manufacturers with the opportunity to propose how to manage future manufacturing changes, rather than wait and submit and then you get back and forth discussions and so forth. You could also use that to develop and use comparability protocols and so forth.

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NOVEMBER / DECEMBER 2015 19 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

There is an agreement now within ICH that comparability protocols will be a part of ICH Q12. It will not be limited to only US and Europe – our Japanese colleagues agreed to that. I am going to use that discussion to share with you the involvement of countries outside of ICH. We have been working really hard. Because from an industry perspective, even though we have challenges within ICH, the majority of the challenges come from outside the ICH regions.

The question that I have that we can discuss: Would having that linkage and developing this product development lifecycle strategy be value added or not? Is it good to do it or not? How should we do that for a product? Can we use a similar approach for facilities?

This is a schematic description of the product lifecycle based on ICH Q10 and some of the industry and regulatory activities that are currently happening.

Issues Under Discussion

My reason for coming to talk to you this afternoon is not only to accept the kind invitation, but also to seek your feedback. And I think you have an opportunity – I am here, [FDA’s Bob Iser], other EWG members are here – to share with us your thoughts. This is more important to share now while we are developing the guideline rather than after it is public and you provide your comments through the docket and so forth.

I am summarizing on this slide some of the issues that are currently under discussion. I will try to explain why it is important to resolve these issues.

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NOVEMBER / DECEMBER 2015 20 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

ISSUES UNDER Q12 EWG DISCUSSION

Q12 Level of Detail: • High level similar to Q8-11, descriptive, or in between? • Is there a need to describe best practices for change management and knowledge management?

Product Development and Lifecylcle Strategy (summary of product development, control strategy, proposed establishment conditions, product lifecycle management strategy and proposed regulatory filing of future changes): • What is the value of developing an additional section in Q12 and inclusion into regulatory submissions? • Inclusion in CTD? Module 2 or Module 3? What about Japan Appplication Form? • Mandatory or optional?

Established Conditions: • What are the regulatory expectations for non-established conditions?

Legacy Products, Biotechnological and Biological Products: • How to assure the utility and benefits of Q12?

Level of Detail

The first one is the level of detail of ICH Q12. We recently developed some high-level guidelines – Q8, 9, 10, and 11. And I was part of that. I advocated for high-level principle guidelines, because when it comes to development, you lay the principles, and the development will depend on the product, business needs, and so forth.

The question is, should we have the same level of detail in ICH Q12? Or should we describe more about best practices – for example, for knowledge management and change management? Why is it important to have that discussion? It is because we need to provide regulators with the confidence that they need to trust our quality system and our change management process to manage the changes.

So we need to have an agreement about what their expectations are and what they are going to do for all manufacturing changes, regardless of the regulatory filing mechanism. Because right now the regulators do not pay as much attention, even though they should, to what we are doing in our quality system. They do it during an inspection, but the assessors don’t, because they see it in the file and they have an opportunity to review it and say yes orno.

Now, we are not going to do that. We are going to do it ourselves. And we are going to share the data with them after the implementation. That is the vision. So how can we have that agreement? How can we gain their trust? And how can we assure that we do as well as we do now or improve upon what we do now across all the sites and across all the products?

Product Development and Lifecycle Strategy

The second point is the product development and lifecycle strategy that I mentioned a couple of slides ago. And again, what is it? It is a summary of product development, control strategy, proposed established conditions based on the above, product lifecycle management strategy, and proposed regulatory filing for future changes.

Again, the question that I raised earlier, I will raise it one more time: What is the value of developing an additional section in Q12 and the inclusion of that section in the regulatory submission? It has to have a value, because we want to simplify. We do not want to make things more complex.

If we agree there is value – and some of us think there is considerable value – how can we word that in current CTD? Should it be in module two or module three? And how would that fit with the Japan application form, and so forth?

Should we make that section mandatory or optional? My thinking is…that there are some elements of that section that are

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NOVEMBER / DECEMBER 2015 21 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 currently mandatory – the product development and the control strategy. And I will argue that every company will propose established conditions going forward. So there are some mandatory aspects as well. The only thing that could be optional is a company proposal of making future changes if you know that at the time of filing.

Established vs. Non-Established Conditions

When it comes to established conditions, considerable progress has been made. But what about non-established conditions? What are we going to do with that? The company can propose established conditions for the product and the processes. What do you do with non-established conditions? Are they going to go away? Are they going to be left out? Are they going to be included in the file? How are you going to make that distinction? How can they be evaluated? What is the role of inspection, and so forth?

So, you see from the above, that there is a linkage between development and established conditions and simplification of lifecycle management.

Legacy and Bio Products

How does that apply for legacy products? Many of these products were developed before the QbD age. How are we going to do that? What would be the opportunities? And how can Q12 facilitate the majority of products we have on the market that were developed a long time ago? We need to have some discussion on that. And how can we assure their utility not only for chemical entities, but also for biopharmaceuticals and biological products?

Conclusions

In conclusion, as you hear in this meeting and other meetings as well, ICH Q12 is a priority for industry and regulators.

It is a challenging topic, because we need to balance industry and regulatory expectations and needs.

Saying that, I think it provides a unique opportunity to:

● enhance transparency and build trust

● facilitate product lifecycle management, including continual improvement if we adopt the ‘do and tell’ strategy. I want to be very clear how that is going to take shape.

● [use] Q12 tools [to] facilitate accelerated development, such as adaptive pathway and breakthrough therapy designations….

Because with these new initiatives coming from the US and Europe, where less information will be available at the time of the filing, the lifecycle strategy becomes even more important. So if you think we have problems with products now, where you are taking years and years to develop and get it through the review process, imagine if you have a very condensed time to get the product ready for review and approval to bring essential medicine to the patient. I think the lifecycle strategy and activities that you will be expected to do after launch will become more important.

● [address difficult regulatory issues such as regulatory commitments and improve compliance]

● harmonize technical and regulatory aspects within and outside ICH.

We have considerable participation, not only within the expert working group, not only within ICH, but also outside ICH, from Asia, WHO, trade associations, and others. As I said earlier, I think today’s discussion will be very helpful to me and others in the development of ICH Q12.

I end my presentation usually by trying to frame where this discussion and other discussions are. I hope you can agree that we all have a shared vision of making sure that we have high quality pharmaceuticals available to the patients who need them.

I believe that ICH Q12 is beneficial to the patient, the regulator, and the manufacturer, under the following understanding, if you wish: that manufacturers should be empowered and responsible for the quality of marketed products, and that has to be done with appropriate regulatory oversight to assure public health across the globe.

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NOVEMBER / DECEMBER 2015 22 ABSTRACT SUBMISSION DEADLINE: 18 December, 2015 for Oral Consideration 12 February, 2016 for Poster Consideration SYMPOSIUM CO-CHAIRS: Cari Sänger - van de Griend, Kantisto BV Hansjörg Toll, Sandoz GmbH

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REGISTER NOW! www.ISPE.org/2016-Aseptic-Conference MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 Broad Base of ICH Q12 EWG Supports Initiative’s Urgency and Viability, Its Members Affirm at GPhA Conference

The broadening of the ICH Q12 Expert Working Group (EWG) good working group. And I think we have a good opportunity to include parties not traditionally associated with the ICH to move forward.” process may be facilitating, rather than hindering, the effort to meet the tight timelines set up for the guideline’s completion He attributed the size and cooperative nature of the working as well as enhancing its global relevance, EWG members are group to the broad interest worldwide among both industry affirming. and regulators in achieving the Q12 goals.

The recognition across the different industry sectors and To “stimulate discussion” at the GPhA session, agencies involved in the EWG of the stakes in finding a moderator Webber outlined “some of the risks and more viable and harmonized approach to post-approval benefits” he sees with Q12 (see box after section change regulation is heightening the sense of urgency around below). completing the ICH Q12 project. The anticipated benefits include an increased focus on quality The Q12 EWG is the largest in ICH history, currently assurance, more flexibility, and streamlined post-approval including 34 individuals representing 15 different change implementation. The risks that will need to be organizations. understood and mitigated, he cautioned, include the potential for longer review times, more detail in drug submissions, and Along with the six traditional parties from the US, Europe, more questions from regulators. and Japan, the EWG includes representatives from new ICH members Health Canada and Swiss Medic and official EWG Aligned on Mission observers from the regulatory agencies of Taiwan and A panel discussion followed, which focused on how and why Singapore and from the World Health Organization (WHO). Q12 is different than previous ICH guidelines, the impact of Both the assessment and inspection components of the various broadening the EWG base, and the challenges involved in agencies involved are participating. implementation. Also representing a broad swathe of industry as observers In addition to the size and makeup of the EWG, key are: ● the International Generics and Biosimilars Association differences explored by the panel were that Q12: ● (IGBA) ● the Biotechnology Industry Organization (BIO) ● is establishing new regulatory science in addition to the Active Pharmaceutical Ingredients Committee (APIC), harmonization ● has both technical and regulatory and ● the World Self-Medication Industry (WSMI). aspects in the title ● requires long-term thinking about At a session on ICH Q12 at the Generic Pharmaceutical the product lifecycle ● focuses on the commercial Association (GPhA) Fall Technical Conference in early phase of the product lifecycle, and ● is looking to November in Bethesda, Maryland, Perrigo Regulatory harmonize terminology as well as practices. [Editor’s Affairs Senior Director Keith Webber commented Note: The panel discussion is included at the end of the on the positive impact that the broad participation story.] is having on the Q12 effort. He represents IGBA on Participating on the panel along with Webber were two other the EWG and served as moderator of the conference EWG members: ● Dr. Reddy’s VP/Head of Quality Nick session. Cappuccino, who has been involved with ICH for many Webber formerly held leadership positions in FDA’s Office of years and represents IGBA on Q12, and ● Bob Iser, the Acting Pharmaceutical Science and Office of Generic Drugs (OGD), Director of the Office of Process and Facilities in FDA’s Office and he helped craft the Generic Drug User Fee Amendments of Pharmaceutical Quality (OPQ). The fourth panelist, Mylan of 2012 (GDUFA). Global Regulatory Affairs Policy VP Dawn Culp, plays an advisory role for the generics contingent. Also representing His introductory remarks at the session encompassed the IGBA on the EWG are Graham Powell from Mylan’s UK current status, structure and function of Q12, examples of operations, and Takeshi Sugiura from Towa Pharma in Japan. how it may be used, and the intended benefits. Reinforcing Webber’s assessment, Cappuccino commented “This large expert working group is working together that the EWG is working “really well together. I think the cooperatively very well across the regulators and the industry more thoughts and people involved the better the product components, brand and generic,” Webber affirmed. “It is a will be.” WWW.IPQPUBS.COM

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Iser maintained that while there are a variety of different ‘we do not have a pathway for this right now but need expectations and regulatory frameworks represented on to find a way through.’ Everyone is at the table to get the large EWG, the group is aligned on the fundamental harmonization.” principles of established conditions and not established conditions, which he views as key to moving the effort During the discussion, Colorcon Global Regulatory forward. Affairs Director David Schoneker, who plays a leadership role in the International Pharmaceutical “This is very important,” he stressed. With that alignment, Excipients Council (IPEC), queried the panel on the it becomes “just a matter of how we work in the details possibility of IPEC participating in the EWG effort. of how to show that something is not going to be an established condition based on risk, the knowledge that you Schonecker pointed out that “many of the most important have obtained, your development work, and those types of post-approval changes that we have to do are with things.” reformulations or modifications of excipients.” He suggested that the EWG could be “missing a fair amount of Culp noted that in addition to having good expertise” that the excipient association could bring to the alignment, the general attitude of the EWG members table. is one of cooperation and rising to the challenge of making the effort successful rather than focusing on Schonecker cited IPEC’s previous involvement, by roadblocks. invitation, on the EWG for the ICH elemental impurities “Some of the countries that are missing pathways for some guideline, Q3D. “ICH realized that without having the of these bits and pieces are at the table and seem to be excipient guys at the table they would not be able to answer responding quite well to the fact they are going to need to a lot of key questions,” he asserted. find a way through this,” she commented. Cappuccino responded that IPEC’s involvement with Q12 “So far, no one has thrown up any barriers right now saying is “certainly possible” and “not a bad idea…. It is not like ‘it cannot be done in our country because of this.’ It is more adding a few more parties would disrupt it at all.”

EWG MEMBER KEITH WEBBER ON THE BENEFITS AND RISKS OF Q12

To “stimulate discussion” at the GPhA session, moderator Webber outlined “some of the risks and benefits” he sees with Q12.

The Benefits

The increased focus on quality assurance has been very valuable. If you are less focused on the specific recipes that you use in your manufacturing process and more focused on the control systems and quality assurance methodologies that you have in your application and the established conditions that you have agreed to with the agency that are critical to assure quality, then there will be a much better focus from the industry side and regulator side on really what is important for quality.

In that manner, there should be more flexibility and freedom to operate within your established conditions. You can make changes in manufacturing that do not impact those established conditions. Therefore you will be able to innovate and continue to improve your operations as long as you are maintaining your established conditions, which are critical to quality assurance.

Another benefit is streamlined post-approval change implementation, because you may be able to make changes that do not impact your established conditions very quickly. Or using comparability protocols, you can make changes in a more streamlined manner as well. This should lead to fewer prior approval supplements and more rapid innovation for manufacturing better quality products in the long-term.

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The Risks

There is a potential that if you are going to put established conditions or post-approval change management plans in your application that you need to provide justifications for those, which could lead to longer review times. That is something that we need to be cognizant of and watch out for. We need to find ways within the interactions between industry and regulators to avoid that from happening.

There may be more questions from regulators if there is more information in the application. So again, implementation will be critical to assure that we know how to present information as clearly and comprehensively as possible, so the regulators know very clearly what we are planning to do in our post-approval period.

Again, if you are getting CR [complete response] letters, it could mean that additional review cycles would occur.

The established conditions potentially could increase in detail rather than decrease. What industry would like to see is that established conditions would be a narrower component – things that are really focused on quality assurance rather than broader components within the application. I think we have seen in FDA’s guideline that they are looking to pare things down into a subset of the application regarding what established conditions are.

The other thing is whether we will see a shift from a CBE-30 type of submission requirement for submission into a prior approval supplement. If the agency is concerned about not seeing information before implementation, then there could be this transition. That is another thing we have to watch out for as well.

Carpe Diem Noting that the EWG has been given a “pretty hard” deadline for completing Step 1 of the ICH process Given the size of the EWG and how well the group is by the EWG’s June 2016 meeting, Cappuccino working together, the panel members view this is as a commented on the danger that deadline may present. unique opportunity to come to grips with the post-approval change problem internationally. “I just worry that if the group cannot come to an agreement, some of those issues will be tabled. I would hate to see that Culp asserted that “the beauty is that everyone is at the happen, because this is the one good chance to do this.” He table this time. So if we are going to be successful at added that “if the topic gets closed, it is not likely to get harmonization, this is our best shot.” reopened.” The guideline “hopefully will be the best one we EWG members are stressing the criticality of not can come up with and not just driven by time.” just meeting the aggressive timelines but also accomplishing the goals set out in the concept paper. Implementation Will Be Challenging

Drawing on his long experience with ICH efforts, The panel weighed in on aspects of Q12 that will be Cappuccino weighed in on how the current ICH structure challenging to achieve, including getting buy-in from and the tight timelines the EWG has been given could be at non-ICH regulators, changing post-approval regulatory odds with accomplishing Q12’s goals. paradigms, the rapidly changing regulatory environment, and the long-term thinking that is required regarding post- “My experience with these types of topics and working approval changes. groups is that when the tough questions start to get asked at the end, typically what happens are compromises that do not really accomplish the objective,” he emphasized. “ICH Webber noted that the Health Canada representative on has a much more business-oriented focus right now. That the EWG – Anthony Ridgeway – reminded the group that translates to hard timelines for the working groups to meet the guideline is being developed primarily by a handful their deliverables.” of regulatory bodies throughout the world, but it will be

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NOVEMBER / DECEMBER 2015 25 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

“hopefully” implemented and utilized by a number of non- Webber highlighted the importance of industry thinking ICH regulatory bodies. proactively about the product lifecycle, which he maintained is not currently the norm. A “critical” requirement to fully implementing Q12 in all countries is the ability to downgrade supplements, Webber “A lot of companies do not think about the long-term with pointed out. “You have no ability to use the pharmaceutical their products and, prospectively, what changes they are quality system and the post-approval change management going to need to make down the line,” he maintained. “We plans to get streamlined change unless you have that in tend to be quite reactive as opposed to proactive in that place.” regard.”

Another challenge, Culp pointed out, “that we cannot The EWG member pointed out that the technical aspects of ignore” is the rapidly changing technology and regulatory Q12 are intended “to stimulate more of that in industry – the environment globally. “I would suggest, not just for Q12, brand industry as well as generics – so that we can explain but anybody trying to develop a guidance right now better to the agencies what our long-term plan is, and also has a challenge of trying to stay up with the regulatory so that internally we have a better concept of what the long- environment and all the changing pieces in it.” term plans for our products are.”

GPhA PANEL DISCUSSION ON HOW Q12 IS DIFFERENT FROM PREVIOUS ICH GUIDELINES

The following interchange between panelists and audience members took place at the GPhA conference in response to the question posed by moderator Keith Webber (Perrigo) on how Q12 is different from previous ICH quality guidelines. The key differences explored were that Q12: ● has broader representation on its EWG ● is establishing new regulatory science in addition to harmonization ● has both technical and regulatory aspects in the title ● requires long-term thinking about the product lifecycle ● focuses on the commercial phase of the product lifecycle, and ● is looking to harmonize terminology as well as practices. Along with Webber, the participating panelists included Nick Cappuccino (Dr. Reddy’s), Dawn Culp (Mylan), and Bob Iser (FDA).

CAPPUCCINO: Well Keith, Q12, as you indicated, has a very broad working group. It is not just because there are a lot of people there, it is because they represent a lot of different constituencies….

In addition to that, as was mentioned, we also have the blend of assessors and inspectors on the working group, which is also something that has not been generally part of the ICH process, and which also complicates it.

And I will say this about ICH – and I have heard this a lot of times at the steering committee when new topics were being discussed – that ICH is about harmonization, and not about creating new science or new guidelines. It is really a stretch to say we are harmonizing anything here, because we are developing a novel approach. It is not just a question of harmonization. We are establishing new regulatory science. It makes it doubly tough trying to establish that science while at the same time harmonizing it with existing regulations. That is why this guideline is a different kind of beast.

WEBBER: If Bob or Dawn want to comment, another aspect of this is the lifecycle strategy that is a component of Q12, which is something new to the ICH world, and clearly in the post-approval realm.

CULP: Yes, I think that there is that aspect of it. I also think that this guideline is being formatted slightly different than the others. I think that Q8 to Q11 offered up a lot of opportunity for a science-based or risk-based approach to change, but maybe did not approach the actual operation, the actual implementation of that. Q12 is going to hopefully allow us that operational flexibility that was really the intention of the Q8 to Q11 documents. We hope to see that that is something that will be a little bit different with this one as well. WWW.IPQPUBS.COM

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ISER: I want to add that one of the challenges, but also one of the opportunities, with Q12 is that many of the Q guidelines were about harmonizing technical considerations. This is technical and regulatory in the title. And that is a real challenge because, as you brought up Keith, there are different regulatory agencies within this group that all have different processes and different expectations when it comes to lifecycle management and change management mechanisms and how you report things. So it is working within those restrictions of the legislation it is currently there, but also seeking opportunities with regard to how we harmonize in a regulatory way with regard to change management.

I could also talk a little bit about lifecycle strategy, which is really the overarching idea behind Q12: How do you look at the product from development through commercialization and on from a lifecycle approach? It fits really well from our perspective – the OPQ perspective – but that is a different concept than in many of the other regions that are contributing to this.

WEBBER: I think one of the things the regulatory lifecycle strategy is going to do is to simulate companies to think long range about their product development and how their product is going to change from the time the original application is prepared throughout the life of the product. So if there are anticipations of change with suppliers or the expansion of manufacturing, to really start thinking about how those all fit together in the future so they can coordinate the change throughout the process.

CAPPUCCINO: It is important to understand that this guideline – and it is mentioned in the concept paper – is focused more on the commercial phase of the lifecycle, while all of the other guidelines are focused more on the development phase and the registration phase. This one is more geared toward filling that gap in the lifecycle. What happens? How do you apply the knowledge and the learning that goes on during the commercial phase to product improvement? That is the intention of the guideline. It is filling a necessary gap in that respect.

Hopefully this working group can come up with the right formula to make that operational. That has been an issue with these guidelines – they have been very philosophical. This one needs to be something that everyone in the room understands how it can be used in an application. Because that is not so easy.

WEBBER: I think that one of the values of Q12 is that there is a much broader interest worldwide to develop this. It is not just one particular regulatory body that is trying to make this change. There will be examples within the guideline, which will help to ensure the concepts of implementation. They are very forward-looking examples, I think, at least as they are now, and will include concepts of implementation. Pushing the envelope, as I said before, will be a component of the guideline.

From a regulatory perspective, it is very positive in my mind that FDA has jumped out of the gate pretty quickly with their established conditions guideline, which is in the comment period. Actually, it closed and was reopened. Initially it lays out what parts of the application are established conditions and which ones are not. As we see future developments, there will be more about how established conditions are being described in an application.

ISER: One of the really exciting things about the working group is that we have these differences in terms of current expectations and regulations, but I would say that the working group has very much aligned on the concepts. Obviously there are details that need to be worked out….

So it is exciting to be on the working group and have this discussion. We went in after the draft FDA guidance on established conditions came out and expected stuff to be thrown at us. It went really well. I do not want to say that it was endorsed by the group, but some saw that as, ‘Ok, now we have something that can we can work with. Let’s see how that fits into Q12.’

AUDIENCE PARTICIPANT: The purpose of ICH Q12 certainly is very clear and I think it is a worthwhile cause. But I think certain terminology and concepts that have come along the way perhaps need to be harmonized and put into perspective.

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For instance, we have been saying ‘control strategy’ for quite some time under ICH Q8. And we have always said ‘design space,’ and that certain design parameters need to be locked in. And nowhere have we seen ‘established conditions.’ We have all along been saying ‘comparability protocols,’ and now I think the term is coming up ‘post- approval change management plan.’ I think where we are headed, that we need to find a way to put all these previous initiatives and guidances into perspective to make this whole document even more effective.

Starting from SUPAC [scale-up and post-approval changes], we talked about level 1, 2, 3, we talked about major impact, and so forth. Where do you think we are headed in this pursuit? How do you see what would be the best compromise between industry and regulators in terms of eventual regulatory flexibility that we are all seeking?

When I left FDA in 2008, we were struggling with the QbD initiative there. We went so much gung ho on all this design space, quality by design, process parameters, criticality, and everything. In the end, when it came to post-approval changes, everyone was going back to SUPAC. In my opinion, they are outlived. They are from the last century. And still today we are applying them. Why do you think all these things need to be revamped as we go forward with a risk- and science-based approach to post-approval management of CMC changes?

CAPPUCCINO: I would say that the whole idea of Q12 is to replace all of that and hopefully have a harmonized approach globally. As someone mentioned before, one of the issues for a multinational generic company is getting a change approved in the US and not getting it approved Europe for a product that is coming out of the same facility. That represents a problem for them operationally, if they have to wait two years to get it approved one place where they can immediately implement it somewhere else. That does not help the whole aim of continual improvement. That part of it is sort of left to the side right now.

The guidance right now, the way it is written, talks about regulatory variation schemes in each jurisdiction that must be considered. That is kind of the language that is in there now. It is one of those things that has to come out of it. It will not accomplish its purpose unless we are able to change the whole paradigm on the variation regulations in various places.

SAME AUDIENCE PARTICIPANT: Also I think the concept paper says that the applicability of Q12 to generate this be based on individual regulatory authorities…. The risk to product quality is the same for a brand name product as the generic, as long as you have a good understanding of process and controls. It is irrespective of that.

WEBBER: I am glad you asked that question because it was one I was going to initiate myself…. I was not sure how many people had actually seen that statement in the concept paper where it says that it may or may not apply to generic products depending upon the regulatory region. That caused a lot of angst in my mind when I first saw it as I joined the expert working group. In pursuing that, it really was because there are differences in some regions with regard to the use of eCTDs for generic products. This guideline is very much focused on the use of the eCTD for generic products and on eCTD submissions.

Japan was having some challenges because number one, it was a matter of using it with eCTD documents in Japan, and there was concern initially. They did not want to sign on completely from a human resource perspective until they had seen more of what the guideline was going to really look like. We have been continuing to discuss that in the expert working group. I would say we are anticipating that that will not be an issue by the time the guideline is finished.

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NOVEMBER / DECEMBER 2015 28 REGISTRATION OPEN 40th INTERNATIONAL GMP CONFERENCE MARCH 7-10, 2016 Athens, Georgia

Please join us for the 40th Annual International GMP Conference co-sponsored by the FDA and the UGA College of Pharmacy. Our speakers include many current and former high ranking FDA officials as well as many internationally renowned regulatory agency and industry REGISTER speakers. These distinguished speakers will provide NOW updates on the activities of many FDA Offices and discuss new policies like the new Quality Metrics Guidance. They will also cover such important topics as data integrity, risk modeling, combination products, biosimilars, and the top findings from 2015 domestic and international OR inspections. International topics will cover areas visit www.internationalgmp.com such as the EU Good Distribution Practices and for program and registration ICH Quality Initiatives. information

The post-conference tutorial will be a workshop on Risk Modeling: The Approach to Enterprise Risk Management, and is available for an additional fee. Continuing education credit will be awarded for this tutorial only. Details on the tutorial can be found here.

Keynote Speaker – Lawrence Yu – Deputy Director, FDA Office of Pharmaceutical Quality

Other notable topics include

• Quality Metrics • Data Integrity • Combination Products • Biosimilars • GMP Inspection Trends • International Inspections

Representatives from U.S. FDA, Health Canada, MHRA, Saudi FDA and industry

Workshop on Risk Modeling: The approach to enterprise risk management APRIL 4-5, 2016 DOUBLETREE BY HILTON HOTEL Silver Spring, Maryland USA

SCIENTIFIC APPROACHES AND REGULATORY STRATEGIES 2016

ABSTRACT SUBMISSION DEADLINE: MARCH 15, 2016 for poster presentation

TOPICS THAT WILL BE DISCUSSED: Bioassay Thinking for a New Modality Potency Assays: Cell-based vs. Non Cell-based Formats Bioassays for Complex Modalities Data Analysis and Automation Challenges www.casss.org MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 Industry Experts Shed Hard Light on Negative Impacts of Current Complex Post- Approval Change Regulatory Situation Globally, with ICH Q12 in View

The vast resource drain that the current post-approval complex challenges involved by Pfizer Global Regulatory change regulatory situation globally is creating on both Affairs, Global Established Pharmaceuticals, VP Lisa industry and regulators is in sharp relief at public venues Skeens ● an update on the ICH Q12 effort by its rapporteur, where the future of pharmaceutical quality regulation is GlaxoSmithKline (GSK) CMC Strategy VP Moheb Nasr, being discussed. and ● a review of PDA’s post-approval change initiative by Sanofi Pasteur Chief Quality Officer Anders Vinther, who is With the ICH Q12 effort opening the door on a more spearheading it. efficient and improvement-friendly post-approval change paradigm, hard light is being shed on the full dimension The track continued on Day 2 of the workshop with a session of the problem and the stakes in finding an international centered around “practical examples of best practices.” approach with enough power to address it. Novartis Pharma Head of Quality Alain Ruffieux was followed at the podium by Biogen Idec Regulatory Affairs The adage that a problem can only be dealt with when clearly Director Julia Edwards, who narrowed the focus onto the understood is motivating the pharmaceutical community to use of comparability protocols to facilitate manufacturing forcefully articulate the resource drain and lost opportunity site changes. cost of the status quo. Vinther then returned to paint a picture of the The testimony that has been forthcoming, in turn, is tangled web of problems that present themselves compelling a deeper probing into how medicines could be in managing post-approval changes globally for a regulated across their lifecycles in a way that would liberate Sanofi Pasteur pentavalent vaccine, in particular. technology and quality science to improve processes and products, lower costs, and better assure patient availability. Vinther also filled in at the final session of the track to give a presentation prepared by World Health Organization Among the venues where this open dialogue about Coordinator of Regulatory Systems Strengthening for the post-approval change problem and how to Essential Medicines and Health Products Mike Ward address it has been occurring was a “manufacturing on the WHO efforts to use its leverage to move toward a science workshop” held following the PDA/FDA more rationalized and scientifically based global regulatory conference at the end of September. [For more approach, and to offer his own comments on their insights on the PAC regulatory issues, see the IPQ importance. February 2014 Monthly Update.]

The concluding session of the workshop brought The workshop began with a plenary session at which participants back together for a readout report on the post- Mexico’s Secretary of Health Javier Toledo discussed the innovations his agency (COFEPRIS) is making to better approval changes track by Skeens and on the continuous regulate the product lifecycle, and Office of Pharmaceutical manufacturing track by Eli Lilly Senior Director Glenn Quality (OPQ) Acting Director Lawrence Yu delved into Wright, followed by a panel discussion. Included on the OPQ’s effort to encourage emerging technologies. Former panel were COFEPRIS Chief of Staff Ricardo Cepeda, GSK’s CDER microbiology expert David Hussong, now a senior Nasr, Novartis’ Ruffieux, and OPQ’s Yu. consultant with ValSource, followed with a review of the use of comparability protocols to facilitate post-approval Skeens Reviews Internal, External and changes in the US. Regulatory Complexities

The workshop then broke out into parallel tracks to Reflecting her intimate experience in her career asa explore the scientific and regulatory issues around lifecycle regulatory professional dealing with post-approval change management and continuous manufacturing, respectively. filings, Pfizer’s Skeens highlighted the internal, external and regulatory sources of the complexities in the current global Caught Up in a Tangled Web situation and the implications, including high filing costs, disincentive to innovate, and increased risk of drug shortage The first breakout session in the post-approval track and non-compliance. Skeens was Global Regulatory Affairs focused on the “state of product lifecycle management VP for Hospira when it was merged into Pfizer earlier this in the industry.” It included: ● a revealing look at the year. [Skeens’ full remarks are included below.] WWW.IPQPUBS.COM

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A particularly burdensome aspect of the current post- Given this complexity, “there are thousands of approval change environment results from various things that could change,” the Sanofi Pasteur VP countries having different/unusual regulatory commented. “And of course there are things that are requirements and approval timelines, she pointed changing, because after the first filing you want to out – particularly where they are not science-based. move to a new building, buy new equipment, etc. This is constantly going on.” As a result, pharma companies are required to manage multiple versions of the same product for the different He noted that the vaccine product is registered in 105 markets and build multiple inventories to insure against countries, all with varying specification levels, requirements, drug shortages. Having multiple versions of a product also and timelines for post-approval changes. In this example, increases compliance risk. for the year examined, the firm produced 83 batches and Internal and external sources of complexity, Skeens noted, had 36 open changes that needed to be managed in the 105 include a change in raw material supplier, which can be different countries. driven internally by a pharma company’s desire to reduce costs or improve quality, or externally by a supplier going Vinther provided details regarding changes that were out of business or having quality issues. Manufacturing made and the number of batches that were impacted. He changes made by suppliers also have to be evaluated and noted that conversations take place “monthly” with health reflected in the regulatory filings. authorities in which Sanofi Pasteur informs them that if they do not accept a proposed change, the vaccine may no longer Other internal sources cited by Skeens include process be available in their country. and facility changes, and manufacturing network or labeling changes. Additional external complexities include Both Skeens and Vinther concluded their talks with inspection commitments and multiple dosage forms, some thoughts on where pathways out of the current specifications, and marketing applications. post-approval change regulatory quagmire may lie.

Vinther Describes View from the Bio Quality Skeens cautioned that the opportunity that ICH Q12 offers Side needs to be used wisely. “We have to make sure as we go through this endeavor that we are simplifying the complex,” Vinther gave his perspective on the “nightmare” involved given the implications that complexity has on drug in making post-approval changes in the current global availability, quality, compliance, affordability, innovation regulatory environment from the different vantage point of and continual improvement. a career spent in biologics manufacturing quality, including: ● co-founder and Chief Quality Officer of the contract Regulators, like industry, “want safe, efficacious, quality manufacturing organization CMC Biologics ● Roche/ products,” Vinthers stressed. “They want sustained Genentech Biologics Quality VP, and ● his current position availability. They want innovation, and they want improved as Chief Quality Officer at Sanofi Pasteur, accountable for controls.” Since “everybody is interested in that…the cGMP compliance, quality leadership, and the quality of question is, how can we work together better? If these are the company’s vaccines worldwide. [Vinther’s complete common objectives, we need to find a regulatory process remarks are included below.] globally that works.”

The Sanofi Pasteur pentavalent vaccine on which he focused actually includes eight different antigens to vaccinate against five different diseases. The manufacturing process [Editor’s Note: See pp. 40-50 for a review of the ideas that takes place in ten different buildings at different sites, has surfaced at the PDA workshop on how the PAC regulatory 49 manufacturing steps, 141 raw materials, 222 analytical problems could be addressed at the global level, including methods, and 1,265 individual tests. those offered by Skeens and Vinther.]

[The story continues on p. 31 with Skeens’ full presentation.]

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NOVEMBER / DECEMBER 2015 30 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

TWO INDUSTRY EXPERTS ON THE COMPLEX PROBLEM OF POST-APPROVAL CHANGE

At the PDA/FDA workshop, Pfizer Global Regulatory Affairs VP Lisa Skeens and Sanofi Pasteur Chief Quality Officer Anders Vinther described the resource-intensive effort it takes to make manufacturing changes in the face of the regulatory complexities and constraints that manufacturers face globally. Skeens highlighted the internal, external and regulatory sources of the complexities and provided insights into the implications, including high filing costs, disincentive to innovate, and increased risk of drug shortage and non-compliance. Vinther painted the picture of the tangled web of problems that present themselves in managing post- approval changes globally for a Sanofi Pasteur pentavalent vaccine, in particular. Both concluded their talks with some thoughts on where pathways out of the current quagmire may lie.

PFIZER’S LISA SKEENS

I am very happy to be here this afternoon talking about post-approval changes. My 20-plus year career has all been in regulatory affairs, and it has always had some aspect of involvement with post-approval changes – starting off as a regulatory associate doing all the work associated with post-approval changes, to then leading teams, overseeing teams, and convincing organizations that this is an important aspect of my job. It is something that is near and dear to my heart.

As we look over that 20 years, there have been a lot of influences in the environment that have made post-approval changes more complex and more involved. Some of that has to do with the globalization of the pharmaceutical industry. Some of that has to do with the mergers and acquisitions that companies go through, when you inherit products and you need to lifecycle-manage those products. It also is that the regulatory requirements in the agencies around the world have become more sophisticated.

So all of these factors have really created quite a complex environment. And when you look up complicated in the dictionary, I think we qualify adequately in this category – ‘composed of elaborately interconnected parts.’

When you look at post-approval change and change management in industry, how many different functions have to be involved in post-approval management? Pretty much everybody in your company – manufacturing, R&D, quality, and regulatory – are a whole bunch of interconnected parts that have to come together to manage that, not including all of the different regulatory agencies that we have to work with. They are difficult to analyze or explain.

We are going to talk about ICH Q12 during the next couple of days…. I am not sure how many of you know this, but ICH actually tried to do post-approval changes and harmonization more than fifteen years ago. They actually had meetings and a draft, and that had to be abandoned. It was too complicated for the regulators and the industry at that time to reach consensus around post-approval changes. Since then, it has only gotten more complex.

I am really pleased that we have a new opportunity to look at harmonization of post-approval changes and a new ICH. We will see how this plays out. I actually think that as we look at this new opportunity, we have to use it wisely. And we have to make sure as we go through this endeavor that we are simplifying the complex, and that, as we go through the process, we are not making the burden of post-approval changes more complicated. So I think that is one of the things we have to have at the back of our minds as we go into this endeavor with ICH Q12.

As I mentioned, post-approval changes are complex, and this complexity has real implications. It has real implications because it impacts drug availability and because it can result in a shortage. If you are not innovating your manufacturing processes, as we heard from Lawrence Yu earlier, then that can result in quality problems and recalls. And that can cause drug shortage. There is no incentive to innovate and continually upgrade your processes so that you can address problems, etc.

Another reason is that the complexity actually can result in drug shortages because of the timeliness of regulatory approvals and the complexity involved in how you have to build inventories, etc. Even if you have the best processes and the best planning, it can still be so complicated that in some areas around the world you are not able to implement that change in time. And if you did not build in enough inventory, that can result in drug shortage. WWW.IPQPUBS.COM

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There is also an increased compliance risk. Having so many different multiple versions of a product because the timing has to be staggered can cause an increased compliance risk.

It also creates inefficiency and waste. As I mentioned, there is inefficiency and waste in the regulatory process. We have at Pfizer now regulatory people that all they do is post-approval changes. We spend millions of dollars administering, scientifically evaluating, and writing those. But in all of that work, when you combine it with all of the companies, is that creating value, or is that an opportunity to decrease complexity and increase efficiency?

As I talked about before, as we mentioned in the earlier session, [the complexity] is a disincentive for continuous improvement and creation of new technology. Instead of encouraging all of those changes, the complexity discourages it. If we all stay focused on ensuring availability of safe and effective pharmaceuticals and supporting patients around the world, and keep that as our goal – both regulators and industry – we should be working together to solve the complexity issue.

Sources of Complexity

There are multiple sources of complexity that I am going to talk about today:

● First is the product perspective and all of the different versions of products that exist, even for the same molecule in your company today. I am sure you have multiple dossiers of the same version of product that are a source of complexity.

● Also, regulatory requirements: how sophisticated they are today around the world, and how they are a source of complexity.

● Finally, the manufacturing and supply chains themselves are a source of complexity today. Some of our molecules are manufactured at three or four facilities around the world for the same product. There are advantages to that and also complexity to that.

The changes that we process come from a lot of different places through the lifecycle of a product. They can be internal or external, and they can be changes that you choose to implement. You may want to make a change that is optional for continuous improvements or for your cost of goods. There are also changes that are not optional – changes that must be made in order to keep the product on the market. Your organization has to process these changes.

Internal Sources

Some of the internal sources of changes include improvements to aspects of the drug or how it is manufactured, including process or manufacturing changes – maybe how you are doing things in the quality control lab or a storage, etc. There are a lot of process changes that people want to make or desire to make.

Also, expanding facilities or improving your facility with new equipment, such as building new lines. These are all internal sources of change. And you might want to change your product or change your container closure system. You might want to change the shelf life of your product voluntarily.

Companies are also always adding suppliers for a variety of reasons. You always want to decrease cost, you want to increase quality. One of your suppliers is having a compliance issue, so you need to change to another supplier. Those can be API suppliers, excipient suppliers, container closure suppliers, etc.

Then manufacturing networks, including the use of third party manufacturing or TPMs. Your laboratory testing sites create a whole bunch of drivers for why companies want to make changes, and it adds to the complexity of all the changes that have to come through that you have to deal with.

Then there are labeling changes. In regulatory, we process a lot of labeling changes. So even if you are in manufacturing, and have to keep up with all the labeling changes, that alone is a significant amount of work and a significant amount of complexity, especially if you look at all of the international country requirements for labeling and just how complex labeling itself is.

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External Sources

Then there are external sources of change – for example, new regulatory requirements. If you are doing business in China and you are dealing with the pharmacopeia changes that just happened like we are, we have to immediately drop everything and make sure that we are complying with those new changes.

But that is just one example. There are all kinds of new standards that are implemented around the world where we have to meet those new regulatory requirements, sometimes even for older products.

Then compliance: There are things you have to deal with in compliance. Perhaps there was an inspection site that got a 483 and there were commitments made, so you have to deal with post-approval changes that came out of that. There are also commitments from regulatory filings that you have to do from a compliance perspective. And there are changes that come from external sources such as suppliers or vendors and they pass through the changes.

You are lucky if they always tell you about it way in advance so you have a lot of time to plan and get the regulatory approvals before they implement them. Obviously, having good relationships with your suppliers can help.

At the same time you still have to deal with the magnitude of changes coming from your suppliers. That could be changes in the substance or the material itself, your container closure or delivery device, or other APIs or excipients. It also could be changes by suppliers making process or facility changes—moving something here to there—and it affects your products. As manufacturers, we are responsible for all of those changes and we have to process all of them.

Then manufacturing network changes – we have to process all of them. And labeling changes are an external source of change, not just an internal one.

Looking a little bit more at product complexity: Again, there can be many variables. You could have one drug or molecule that has multiple formulations and multiple different dosage forms and container closure devices and delivery systems. And some of these differences are for all good reasons, right? The pharmacists, the hospital all have a different requirement in a certain country. Some countries prefer pre-filled syringes, some countries prefer vials. We have made all ofthese different product configurations for a variety of different reasons. But it factors into the complexity that we are dealing with.

As I mentioned, manufacturing sites: Some products have three different manufacturing sites for the same molecule, in the same presentation. Or some will have the same presentation at different manufacturing sites, etc.

One of the big reasons for drug shortage is that there are issues with the API suppliers for generic drugs. That means that, for critical drugs, you probably need to have two API suppliers, so that if there is an issue with one, you have another approved – dual sourcing. Then again, you have to keep up with all the regulatory work to maintain multiple suppliers. And that is complex and a lot of work. For excipient suppliers, the same thing.

Often times we have different specifications for the same product because of regulatory requirements. One country has different levels of impurity specification during review that you have commitments with and something has happened, so it creates a lot of divergence in the regulatory filing. That means that it is maybe the same product, but it has different specifications, different labeling, etc. And all of this just adds to the complexity that we have to deal with.

Even though we may start with one molecule, you may have hundreds or thousands of presentations. You may have multiple applications, NDAs, or ANDAs, and marketing authorizations. For some countries, you can only have one strength in a marketing application authorization. You could have multiple marketing authorizations for the same molecule.

Regulatory Sources

Then there is the regulatory requirement complexity. Many large pharmaceutical companies are very global now. We are marketing our products in more than 100 countries. That is an opportunity. That is a choice that we make. We do not have to be selling products and registering products in all of those countries. It is a choice that we make. But it also adds complexity. That is part of the nature of this, right? Many pharmaceutical companies are that global.

The requirements and timing for submission of these changes varies drastically. They are not always scientifically based, these requirements. So how do you analyze, plan, prepare, and assess for changes? All of the regulatory requirements play into that. WWW.IPQPUBS.COM

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Then the timing….the first part of the slide, the first bullet, emphasizes the timing, because the timing can be different. If the manufacturing site wants to lifecycle-manage something and they want to decide and then implement, they do not want to wait four years to implement a change. But that is the reality of it. Some regulatory agencies take two-plus years to approve a change.

And sometimes you cannot even start the registration in one country because it is dependent on the people in the more sophisticated country. First you have to submit and get approved, and you can only submit in some of the emerging markets after you get approval in a more sophisticated market. That is where this timeline gets extremely long, and it causes the manufacturing facility or your organization to have multiple staged approvals over time. Then they probably start manufacturing products with that halfway in between, and you are building inventory hoping that it will carry you for the rest of those products. Again, it takes significant complexity.

The content of dossiers is different…. The actual content is based on regional requirements. What you are submitting is different. How to do post-approval changes is also very different. The regulatory professionals in our companies have to understand all of that nuance and be able to accommodate all of that.

It also varies greatly country to country, in some cases. In the U.S., there is an annual report. Most countries do not have annual reports, so you do not have that option. But others will allow notification. Others will require nothing, and you never have to update your dossier except for very major changes. But the regulatory complexity that that adds to implementation of even one change, let alone multiple changes across multiple facilities, is significant.

Again, the data required to support these changes is very different, and it is not always science-based. A lot of regulatory agencies are becoming more sophisticated and are becoming more scientific. Some of the questions we get from regulators in Asia are more scientifically advanced than the questions we get from FDA today.

However, there are also agencies out there that are asking questions or making requirements or demands that are not scientifically based. That can add to the complexity. Because if you have already put together a package to submit, and then you have additional strange requirements on top of that, it can really add additional burden to implement the change.

Then cost – obviously there is a cost to all this complexity. And the regulatory variation fees alone to support these changes are continuing to increase and increase. Brazil just doubled their fees for post-approval changes. The same with China – it just quadrupled.

When I am trying to plan my variation budget, these variation fees are not insignificant. In fact, when we do an assessment of whether we should do a change or not, if it is an optional change, we are actually trying to do an assessment, especially because of our cost-improvement initiative. The cost of filing all these regulatory variations may outweigh and outnumber the actual cost savings you are going to get with the change.

For centralized change procedures in Europe, it is $100,000 for a change. These are large numbers that can really add up and be significant. It also adds complexity, because now we have to be really strategic about bundling the changes and making sure that we are being super smart about how we are filing all of these post-approval changes.

There is another complexity in some countries, because they will not accept multiple changes at the same time. You have to submit them sequentially. And you have to make sure that you are planning from a priority perspective—which one is more important. If you have multiple changes coming through at the same time, that can delay implementation and approval of the change.

There is also complexity from manufacturing and the supply chain. Inventory builds are required for markets that have longer approval times. You have to estimate these, and it is not always easy to predict. You do not always get first-cycle review. We like to get first-cycle review. But if it is extended, and you have to go through questions and answers and multiple periods, the timelines can be longer than you anticipate. If that happens, drug shortage can occur, because the approvals are taking longer than expected and you did not build sufficient inventory. As I mentioned, the approval times can vary very drastically country by country. Often the changes have to be implemented in a staggered way. If you are a manufacturing facility, you have to build inventory of all these different versions of a product and make sure you are only releasing to the markets where it is approved. It is extremely difficult to manage that complexity.

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Opportunities

As I mentioned, ICH Q12, which we are going to hear about from our next speaker, is a great opportunity to revisit post- approval changes and how we can simplify things. The hope is that now that most of industry has implemented the ICH Q8, Q9, and Q10, and our quality systems are more robust, our change management is more robust, we can manage more changes through the change management system with the quality system and not have prior approval of as many changes.

It is only the ICH regions that agreed to that. It is not enough. Some of the most difficult situations are in the rest of the world’s emerging markets. How can ICH influence the other regions to implement that? We are going to hear about WHO more tomorrow. But having that really international agreement and alignment of post-approval changes is important. That includes standardization of established conditions. FDA released their guidance on established conditions. And that is a start. If we can all agree on what are established conditions, that would be helpful, and then move on to the rest of the regulatory requirements.

Finally, the use of global change management protocols. Many of us have used comparability protocols. In fact, in my experience, the best comparability protocols have been those that we used for multiple products at the same site or even products across sites. The question is, how can we leverage that? How can we have industry-wide comparability protocols or change management protocols?

That kind of standardization is where we will really gain a lot of benefit and try to simplify the complex. We also have to convince other regulators to use these comparability protocols or change management protocols. FDA, maybe Europe, is open to using them—the rest of the world, not so much. Unless we can really influence the regulatory environment globally, we are not going to see the kind of results that we are all hoping for.

I am looking forward to engaging on the discussions this week, and I hope this gave an appreciation for part of the reason why we are here and what we need to achieve.

SANOFI PASTEUR’S ANDERS VINTHER

I am going to present a story on the post-approval change complexities from the perspective of a vaccine manufacturer…. Sanofi Pasteur is a vaccine manufacturer. Probably all of you have had our products help you present diseases.

This is an example vaccine. It is pentavalent, which means that it treats five different diseases with one shot. It is very simple. It is easy to take your child to the doctor and get the shot and everything is fine. It looks simple.

What is in it are vaccines against five different diseases. But it is not just one drug substance each. Pertussis has two different antigens, and polio has three. So when you have this one vaccine, it is actually not just one, it is eight different antigens. Generally in manufacturing, one drug substance becomes one drug product. This is eight drug substances that become one drug product. And there might be conjugation and other kinds of things that make it more complicated. So maybe it is not that simple.

Let’s look at a few numbers. There is one vaccine. There are two different ways of administering it. There are eight antigens. To produce this product, there are 49 different manufacturing steps. These are performed in ten different buildings at different sites. There are 222 analytical methods that we are using along the way, with 1,265 individual tests from start to finish. And we have 141 different raw materials. There is a lot that all needs to fit together and work really well.

It is still the case in the vaccine business that every batch produced is also tested by the authorities. So we test a batch and get it ready for release, and then the health authorities test it as well. One thing that is a challenge in the vaccine industry is

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NOVEMBER / DECEMBER 2015 35 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 that there are lots of biological tests – lots of in vivo tests. And you know in vivo tests are not plus-or-minus 2%. It is plus- or-minus a lot more than that.

That means that, in terms of established conditions, or things that you have agreed with the authorities about in the filing, there are thousands of things that could change. And of course there are things that are changing, because after the first filing you want to move to a new building, buy new equipment, etc. This is constantly going on.

This is an example (see boxes at right). You might have one change, Impact of Vaccine Changes ‘A,’ that actually impacts all of the In this and the figure below, the impact of changes to the multivalent vaccine different antigens. It also impacts are shown. This figure shows how individual changes affect each of the active the formulation, QC, filling, and substances, formulation, QC activities, filling and packing. The figure below packaging. Then there are other shows the 83 lots involved in the left column, with each change color-coded examples – changes like ‘E,’ that only across the top showing which of the lots was impacted, leading to multiple impacts one of the antigens and the versions of the same product. filling. It is a matrix of what changes ANTIGENS (ACTIVE SUBSTANCE) impact what areas. That is the first FORM QC FILL PACK layer that you have. This is an actual CHANGE A x x x x x x x x x x example: CHANGE B x x x x x x x CHANGE C x x x You have the lots produced in the first CHANGE D x x x x column. I think it is 83 lots produced CHANGE E x x in one year of this pentavalent CHANGE F x x x vaccine. And the specific changes CHANGE G x x x apply to only certain lots. I think one CHANGE H x of the most challenging jobs in the CHANGE I x x vaccine industry is dealing with the CHANGE J x x logistics. CHANGE K x x x x x x x x

In itself, vaccine manufacturing is complicated. It is great for healthy individuals, children, so they can get one shot and that is it. But behind that is a lot of complexity.

Another dynamic is the filing. This one is registered in 105 countries. All of them, of course, have varying specification levels, requirements, and timelines for post-approval changes. Usually every single change takes years. Therefore, we had 36 open changes at some point in the year for this example.

We had 83 batches produced, and 36 open changes that we had to manage in 105 different countries.

One-third of the changes impacted more than half of the batches. There were no more than seven batches that were identical, in terms of

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NOVEMBER / DECEMBER 2015 36 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 the changes. 55 batches were Post-Approval Change Complexity completely different from one another. And 81 of the 83 batches In Vinther’s case study on 36 open changes impacting 83 consecutive were impacted by an autoclave vaccine batches, he pointed to the following list of changes and the change. number of batches they impacted:

When you talk about examples that • 81 batches impacted by new autoclave make no sense in our regulatory complexity, this is an example. • 78 batches impacted by new reference standard The autoclave is very important. • 43 batches impacted by updating analytical method If it does not work, you have a to new pharmacopoeia version problem. • 36 batches impacted by change from pyrogen to LAL But this is basic stuff for people endotoxin testing working with this – putting a new • 26 batches impacted by new raw material supplier autoclave in. Why is it that 105 countries need to approve this? • 55 batches totally different from one to another • 1/3rd of the changes impacted more than 50% of the Why isn’t this something that we batches can handle in our quality system? That is one example. • No more than 7 batch ‘versions’ identical

The next example is 78 batches that were impacted by a new reference standard. In the vaccine world, every time you put in a new reference standard for your test methods, it needs to be approved by the regulatory authorities. You cannot just put in a new standard. It requires prior approval.

And we have examples where we know if we are not changing something that we cannot produce any more. We might see tests where we start to see a trend, and you have to put a new standard in. This is an example where we have to go to the authorities and tell them that if they do not accept this new reference standard they will no longer have vaccines available. It is not a big deal. It is good science.

Then there was a change in the European Pharmacopeia. Of course we need to meet the pharmacopeia requirements. So we updated the methods. But that needs to be approved by all the authorities, including in Europe. So that is kind of funny – the European Pharmacopeia changes its test method, but we still have to apply and say, ‘we updated our analytical methods so they meet your requirements in Europe,’ and they say, ‘yeah, we will evaluate it.’

We had 36 batches impacted by a change from pyrogen to LAL endotoxin testing. I can understand that they would want to evaluate that.

And then we had 26 batches that were impacted when a raw material supplier went out of business and we had to find a new one. We had to say that we needed to move to a new raw material supplier, and if the authorities do not accept that, we will have to cut off supply of the product. These are real-life examples. And this is just one out of many. But I thought it would be good to share with all of you.

It is a nightmare. We can send a batch here but not there. Then another sponsor all of a sudden wants more vaccines, but we are not sure we have enough for them. We stockpiled a little bit. But it is very difficult.

So the number of possible changes in what you have filed – what is called established conditions – times the number of different regulatory processes is very high. I did not even put a number on it. It is high. And the question is, is it really sustainable?

Common Goals and Possible Solutions

This is my personal view: If you look at us as an industry, we want globalization – the same vaccine everywhere. Kids all over the world need the same vaccines, in general. Then there are certain diseases in certain parts of the world that need vaccines that are not needed in other places. But the basic combos are the same around the world.

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NOVEMBER / DECEMBER 2015 37 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

So we like to be globalized. Plus you always want to be more efficient in your operations, in particular with the cost pressures on prices you need to be better at being efficient.

You would like to improve your processes all the time. If you start with processes that vary and you can make them more predictable and improve your process capability, the better it is.

You have as a company vaccines to improve public health globally. It does not matter if it is a person in India or Australia or Nigeria or wherever, the mission is to improve public health. And then of course you want to ensure that what you send out is safe and efficacious.

You want to make sure that you can sustainably provide the product. It is not that you can only provide it for the next three months and then maybe we can make some more next year. It should always be available. That is really the challenge – always being available. Because we have to say that if a change is not approved within the next three or six months, you will no longer have any product in this country. It happens every month. Every month we have a conversation with health authorities somewhere in the world about this….

What if you are a regulator? You want to make sure that you optimize things in your country. You want to look at what works in your country. You have to safeguard the public health locally. If I work for the US FDA, it is not my accountability to make sure that this product used in Germany works in Germany. I only need to think about the US. And you want also to ensure a sustainable supply to your country. And you want to make sure that the GMPs are met.

But I think the regulators also want safe, efficacious, quality products. They want sustained availability. They want innovation. And they want improved controls. That we can always talk about. I have never had a health authority say that they are not interested in those things. Everybody is interested in that. So then the question is, how can we work together better? If these are the common objectives, we need to find a regulatory process globally that works, I think.

To me it is finding the balance between the regulatory controls and timely access. And it is not there now. The timely access is the problem. What is it that holds national governments back? You want to introduce a new product where the approval time takes two or three years. You could have treated people for those two or three years. You could have put a vaccine out two or three years earlier. What is it that holds them back?

Of course you do not want your regulatory controls to relax so much that something gets sent out that should not have been sent out. I understand that there has to be this balance. But right now, it is not the right balance in my view.

We also want to make sure that we reduce the regulatory burden. Everybody agrees on that. Even the governments say that it is too difficult.

I think that if we change the dialogue to be much more about sound science and what it is technically that we want to achieve, and really focus on that as companies and have health authorities in that conversation with us, I think we can achieve more. That is where the global change protocols come in….

We need to have a conversation about what really needs to go into the quality system. It is not in Q10 today. The whole regulatory assessment of change management is not in Q10 today. There is something about change control, but it is more about standard things, it is not in relation to submissions. So we need to think about that.

And then from the regulator side, there has to be a convergence of processes. And I think what you will hear the first thing after lunch – I think it is a very good guidance, or resolution in WHO language – is about convergences of regulatory processes. I think when you see that presentation you will agree that it is very forward-looking.

I think we need to move upstream. Instead of submitting reports that say we are submitting a change and here is the data, that is too late. I think we need to communicate earlier and tell them what we are planning to do. That is where the lifecycle management plans and protocols would come in. We need to have a conversation and say, ‘if we are changing this, you have to accept it as well.’ It does not make sense to do all of this work and then have a health authority say that they want you to do the validation differently. That is too late. We need to move it upstream.

And I think the controls should shift from the review to inspections. We all have inspections. In fact, we probably have way too many. Everybody wants to come and visit companies. WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 38 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

And then we need to think about regulators relying on each other more. WHO does it a lot. And actually that is the case in the European Union right now. There is one country that takes the lead. Then other countries may say that they actually want something else looked at as well. And it sort of works. In the developing countries there are also examples. But that to a large extent is because some countries do not have a regulatory system, or it is very poor. That is something to think about.

I think it is about time that we as an industry find ways to help move in that direction and how we can get regulators to speak more with each other….

So let’s get back to the vaccines again. We now have a hexavalent vaccine on the market. So that is six. And it just adds more complexity. It also gives more convenience for kids and grownups around the world. They can get one vaccine to protect against six diseases.

You could do the same thing in your company and find something very similar. I do think that vaccines are good examples, because combo vaccines are super complex, there are so many things going on.

IPQ wishes to thank the following sponsors:

For subscription and sponsorship information visit IPQpubs.com or contact Wayne Rhodes — [email protected], Tel: 202-841-9470.

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Global Change Protocols Proposed as Part of a More Standards-Based Approach to Regulating Life Cycle Management Internationally

Globally standardized change management protocols But requirements vary significantly from country to country that would clarify the expectations internationally for in terms of reporting levels, amount of documentation, and implementing various types of manufacturing changes is approval timelines. This represents a significant barrier to among the proposals that are now on the table as industry and continuous improvement and a challenge in maintaining regulators explore what a more scientifically-based, efficient compliance – ultimately, potentially impacting the capacity of and harmonized quality regulatory paradigm could look like. the industry to deliver products to patients.”

The global change/comparability protocol (GCP) concept is During his talk, Ruffieux explained how Novartis is using being advocated in the international lifecycle management more sophisticated IT systems to address the variability of discussions in the wake of the positive experience companies the process. However, he noted at the end of his remarks, have had in the US with the use of protocols for making the they “do not remove the regulatory complexity, and are not same changes to multiple products. enough by themselves.”

The standardization of these CPs and their adoption broadly “We can only make serious differences,” he stressed, “if we across regulatory agencies would help reduce the complexity move away from a pre-approval control-based system to that is causing major problems for the pharmaceutical science-based knowledge where changes are implemented industry, the advocates are proposing, pointing to a similar on a ‘do and tell’ basis and we have a mechanism through standards-oriented approach that is taken in the medical inspections for regulators to check that it has been done device arena globally as a model. properly.”

The GCP idea is among those that have been During the Q&A, the Novartis quality head reiterated that “the receiving the attention of a team PDA has set up key point is to have one concrete standard.” He recognized on post-approval change (PAC) issues and was that achieving this “will take time. But it is where we need to vetted by team members at a PDA workshop at the go, because we cannot sustain the current system.” end of September focused on exploring the current regulatory problems and potential solutions in ECPs Put QbD and Risk Management to Work the PAC arena. [See story on pp. 29-39 for a fuller Setting the stage for the breakout discussion of the GCP description of the workshop.] concept was a review by Biogen Regulatory Affairs Director After taking a hard look at the problems firms currently face Julia Edwards of her positive experience with CPs and the globally in trying to make manufacturing changes (ibid.), the broader-based “expanded” CPs. Edwards was formerly workshop participants explored where solutions may lie and with Genentech and was involved with the biotech firm’s what a different regulatory paradigm could look like. exploration of the use of CPs and its pioneering of the eCP concept. Standards vs. One-Off Negotiations She explained that a change protocol is “a prospectively The global comparability protocol concept received workshop defined regulatory agreement or contract between a sponsor backing as part of the need underscored by participants and a health authority that has a defined scope and acceptance to move the pharma quality regulatory paradigm in the criteria, which results in a regulatory submission category direction of universally agreed to and auditable standards and downgrade” for the change. away from a system based on one-off negotiations between Building on a quality-by-design (QbD) foundation, companies and reviewers at individual agencies. the expanded protocol extends the concept to In concluding his presentation, entitled “Managing encompass multiple products and changes – Post-Approval Changes: Yesterday, Today and incorporating quality risk management principles in Tomorrow,” Novartis Pharma Quality Head Pierre- addition to the acceptance criteria. Alain Ruffieux provided a terse summary of the The eCP concept, in turn, could evolve into a standardized, current situation and why standardization is scientifically-based GCP, accepted internationally for making necessary to move forward. particular changes across products, sites and companies – with Post-approval change, he said, “is a relatively simple process. monitoring done during inspections to assure that individual WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 40 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 companies are making the changes in compliance with the regions beyond the US and EU, she said, “would provide protocol and overall quality system change management significant benefit to setting appropriate and globally expectations. relevant regulatory strategies.”

Genentech submitted the first eCP as a prior approval Asked after her presentation about the acceptability of the supplement (PAS) as part of FDA’s quality by design (QbD) eCP model outside the US, Edwards explained that while pilot (IPQ October 3, 2014). The protocol addressed site Genentech had “a lot of discussions” with EMA about its transfers, allowing Genentech to do them when meeting its use in the EU, “what it came down to was because we were terms by submitting only a 30-day changes-being-effected working across products, procedurally they couldn’t do it. supplement (CBE-30), without the need for real-time stability The strategy there would be to do it product by product.” data. The result includes about a five-month saving on bringing the new site on line. [For a review of Genentech’s In turn, the bar on trying to get the eCP approach approved approach to assuring comparability during site transfers, see globally would be “extremely high. I think just getting heads IPQ September 30, 2015.] around the stability requirements would be difficult to do.”

“If you think about an emergency situation – Genentech is in One way that global firms like Genentech and Biogen California, with earthquakes and those sorts of things – this are exploring to “turn up the crank” is to put a change sort of time saving could be hugely important to patients,” implementation date in global submissions. Edwards stressed. “Unfortunately,” she added, “it is just “We are saying that we are going to make this change by patients in the US that can benefit from this at the moment.” this date. It is a very reasonable date – it is not six weeks. Beyond the time savings from the filing downgrade, We are saying that at some point if it has been 18 months or Edwards noted other “substantial wins” for both two years, we have to move on and make this change and the company and FDA that flow from the increased potentially look at the risk of being out of compliance and transparency and collaboration. some other things in some of these territories. We are being transparent.” The expanded protocol allows FDA “to get pieces of paper off of their desks, too,” she pointed out. “One thing to review is Simplifying the Complex going to be better for them in the long run.” To date, this approach has been used for minor changes. “We In turn, the site transfers become planned and predictable. have not looked at some of the bigger ones and what that Genentech “now has very defined submissions – they are would really mean,” Edwards explained. almost cookie-cutter.” What has to be done is “all defined, all At the workshop, Pfizer Global Regulatory Affairs, Global understood, all endorsed by the agency,” which is “hugely Established Pharmaceuticals, VP Lisa Skeens painted the beneficial regardless of the five-month time savings.” picture of what the current complex PAC situation looks ECPs also become a “very useful tool” in the accelerated like and its impact from the vantage point of her career as pathway context, Edwards noted. “If you are deferring a regulatory affairs professional wrestling with the filing work until post-approval, they are a great way to set up the challenges (see story on pp. 29-39). contract with the agency in terms of what you are going to do In concluding her presentation, and during the to enable breakthroughs.” discussions at the final plenary workshop session, Skeens fleshed out what a standards-based PAC While the CP approach has been applicable only in the regulatory system might look like, citing the device US and Europe, Edwards does see the potential for the and other industry approaches as potential models concept to be leveraged in helping address the PAC (see box below). issues on the broader global regulatory submission context. In her experience, “the best comparability protocols have been those that we used for multiple products at the same “I do not think we have even gotten to the tip of the iceberg in site or even products across sites. The question is, how terms of how much this sort of pathway could help us as an can we leverage that? How can we have industry-wide industry in making changes,” she stressed. comparability protocols or change management protocols?”

Currently the regulatory submission complexity “continues Simplifying the complex through that kind of standardization to require balancing supply and compliance risk” – resulting “is where we will really gain a lot of benefit.” The challenge in stockpiling, expiration date pressures, and juggling pre- is convincing regulators outside the US and Europe of and post-change materials. Extension of a CP approach to their value, Skeens said, stressing that unless we can really WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 41 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 influence the regulatory environment globally we are not The challenge is to reach the world beyond ICH, going to see the kind of results that we are all hoping for.” where more difficulties lie, and have “that really international agreement and alignment on post- ICH Q12, she affirmed, “provides a great opportunity to revisit approval changes.” post-approval changes and how we can simplify things. The hope is now that most of industry has implemented the ICH Having standardization around established conditions Q8, Q9, Q10, and our quality systems are more robust, our would be an important starting point, the Pfizer regulatory change management is more robust, that we manage more VP affirmed. “If we can all agree on what are established changes through the change management system with the quality system and not have prior approval of as many conditions that would be helpful, and then move on to the changes.” rest of the regulatory requirements.”

PFIZER’S LISA SKEENS ON ECP, DEVICE AND ISO APPROACHES AS GCP MODELS

The following are Pfier P eens’ comments during the worsho discusssions on why a globabl change rotocol and PAC insection aroach built on the eanded CP device and models could wor in the harma regulatory contet.

I think that a lot of us have successfully implemented comparability protocols that are similar to what we are talking about. They are across products for a specific type of change that has been approved by FDA. So that same concept can be applied more generally and scientifically. I think that is one of the reasons that [the PDA PAC team] thinks this can add value in scientifically creating regulatory examples, almost like a standard.

And the reason I am optimistic is because I also have medical device experience. And when you look at medical device companies, they use these. There are ISO standards that say if you are making a particular type of change, then this is the testing that you need to do. And you need to meet the standard. So all of the different products can use the same standard.

I do not understand why we cannot do something similar on the pharmaceutical side, where we create the standards and the types of tests that you have to do and the type of acceptance criteria. Then that could be the standard for all of industry to use for a specific type of change. That is the vision. The more that we do things case-by-case where you have to negotiate something on an individual basis with a regulator vs. having them standardized, the less likely it is to achieve [the intended result]….

The device industry did not create the concept of a quality system – they took it from ISO. Devices are not perfect. But they certainly knew a good idea and implemented it around quality systems back in the 80’s including design controls, etc. And they took it from other industries. I would say the same is true for how they have adopted a lot of standards.

One way a lot of other industries have gotten to international harmonization is through the use of accredited standards. And I think that is also something we might want to look at. Look at how other industries – even those that are regulated – are able to manage the complexity that we are dealing with. It could be through the use of standards.

We are trying to perhaps standardize change management protocols, etc. But we should think about whether there is a use of standards, maybe ISO standards, which could help the pharmaceutical industry – because they are part of things that every country recognizes, and it would make it easier for regulators around the world if companies are following a recognized standard.

So as we look at different things, we should not be looking only at devices, but across industries for other ideas for how they are solving these problems and what we can learn from them – whether it is the auto industry or the aviation industry, etc. WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 42 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 Moving the Global Dialogue to Science As in the Q12 case, driving the PAC team effort is the quagmire that companies find themselves currently in Sanofi Pasteur Chief Quality Officer Anders Vinther, who trying to make changes, which de-incentivizes innovation is playing a leading role in the PDA PAC initiative, also and jeopardizes sustainable supply (see story on pp. 29-39). cited the GCP concept in stressing the need to “change the dialogue” between companies and health authorities “to be Vinther pointed out that PDA has participated in this area much more about sound science and what it is technically previously, including with PDA Technical Report TR 68 – that we want to achieve.” “Risk-Based Approach for Prevention and Management of Drug Shortages” – which includes sections on post-approval Regulators, like industry, “want safe, efficacious, quality changes and approaches to consider for expedited PACs. “It is a very simple, easy-to-use, triage model,” he commented. products. They want sustained availability. They want inno- vation. And they want improved controls.” The challenge ISPE’s Drug Shortage Task Team has also been taking is to work together to find a regulatory process globally that a hard look at the current PAC regulatory situation as works better in achieving these objectives, and has a better part of its multifaceted effort to better understand the balance between regulatory control and timely access. causes of shortages and what can be done to prevent them. Vinther asserted that the conversation needs to “move upstream” in the form of lifecycle management plans and ISPE released a white paper in late 2014 explaining how protocols. “It does not make sense to do all of this work and aseptic equipment and facility upgrades are delayed or then have a health authority say that they want you to do the prevented by the lengthy timelines involved in getting PACs validation differently.” approved around the world, and the dual operations that result with their increased risks and technical complexities The conversation should deepen about “what really (link provided below). needs to go into the quality system,” he said, pointing out that “the whole regulatory assessment of change As part of its PAC effort, PDA submitted comments to the management is not in Q10 today.” In turn, with docket on FDA’s draft guidance on “established conditions” clearer quality system standards on change control, released in June (IPQ June 30, 2015). regulatory oversight “should shift from the review to inspections.” The team has been working on a template for a lifecycle management plan (LCMP) with practical examples, and Also needed from the regulator side, is a “convergence of is considering how such a template would be of benefit processes” and more mutual reliance, Vinther said. He and made available for industry and regulator reference. pointed out that the European Union currently has a system In addition, the association put together a survey asking based on one country taking the lead, with other countries members to submit post-approval change examples that having the opportunity to review additional elements. There worked well. are similar examples among developing countries, but that often reflects their having poor regulatory systems of their How the role of the quality system could be enhanced is another area of focus, Vinther explained. “How would you own, he commented. actually incorporate into the product quality system how to manage post-approval changes? In which sections? And “I think it is about time that we as an industry find ways what are some good examples?” to help move in that direction and…get regulators to speak more with each other,” the Sanofi Pasteur quality leader The PDA PAC team is also looking at how to facilitate maintained in concluding his remarks. alignment on common technical improvements and innovation that can benefit from global change PDA Team Weighs In on Post-Approval Changes protocols.

In a separate presentation at the workshop, Vinther described In the case of moving from a conventional line to an isolator, the PDA PAC team effort that he is leading intended to for example, Vinther commented, instead of firms creating provide practical support for the ICH Q12 initiative. individual PAC filings and protocols, the GCP approach would entail having industry experts and regulators “sit Along with himself, Skeens and Edwards, the team currently down as scientists” and agree on the considerations and includes Emma Ramnarine (Genentech), Melissa Seymour approach that would be acceptable globally. The PDA (Biogen), Ursula Busse (Novartis), Franck Chassant (Sanofi team is targeting developing eight or ten of these GCPs for Pasteur), and Denyse Baker (PDA). different changes to advance the process. WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 43 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 “In shaping the future of post-approval changes, we are Along with global change protocols, breakout groups really well linked in to what the Q12 group is doing,” the focused, in particular, on lifecycle management plans and Sanofi Pasteur official stressed. “We are not trying to step the role of the pharmaceutical quality system (PQS). on any toes. We are trying to take a practical approach to see how we can help each other.” As in the GCP context, the “overriding theme” in the discussion on lifecycle management plans was that Lifecycle Plans Need Common Template industry should align on a plan template, Skeens reported. The breakout discussions at the workshop were set up to explore the concerns that the PAC initiative is targeting “If we allow every company or every change or product to and provide input on its agenda. At the concluding plenary have a different lifecycle management plan, it will become session, Pfizer’s Skeens provided a summary of the breakout messy in terms of whether we are managing elements of the discussions. plan in a consistent manner.”

The discussion on global change protocols included what Integral to the discussion was the importance of product types of changes they might be used for and what elements they should contain (see box below). knowledge management over the product lifecycle and ensuring transparency of the information to regulators. Also “The key takeaway,” Skeens explained, “is that we should key to a lifecycle management plan, the breakout group felt, be aligned on what elements a global change protocol is how the process and product are going to be monitored – should contain.” The PDA team, she said, “will be looking for example, by the use of continuous process verification. It at developing specific examples of global change protocols” was brought up that the annual product review (APR) could that could be used “almost like a standard.” be leveraged as part of the process.

Break Group Recommendations on Global Change Protocols

reaout session members roduced the following lists of the tyes of changes they felt would benefit from having a global change rotocol left column and the elements that should be included for a site change and euiment change GCP right column.

TYPES OF CHANGES FOR GCP Site Change GCP

Site changes and tech transfers Tech transfer protocol Comparison of equipment, facility, processes Process validation (isolator, Equipment changes Aseptic area qualification newbioreactor, Raman for ID Container closure integrity testing Stability Requirements CMO vs. internal site Raw material changes Regulatory status/inspection status Proposed regulatory strategy API manufacturer changes Process side-by-side comparison Comparison of API, RM, components Test methods Equipment Change GCP (e.g. isolator Container closure systems Operating principles of equipment Equipment capability vs. processs requirements Process changes, e.g.lyo cycle,- Qualification plan (IQ/OQ formulation changes Acceptance criteria for qualification Equipment side by side comparison Stability commitment vs.part of AR Proposed filing category

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Expanding the Role of the PQS to explore as a precedent. “We can ask how that works and how can we use it to assess the strength of a pharma PQS.” The breakout discussion on how the pharmaceutical quality system can be used to implement post-approval changes Medical Devices as Inspection Model? began with a discussion of the more high-risk changes that may need continued upfront filing review such as changes During the panel discussions that concluded the workshop, with a high safety impact and paradigm changes such as Skeens commented further on using the device model to batch to continuous processing. create a more harmonized, trans-agency inspection approach that would be capable of handling the extra quality system Session participants proposed creating an “escrow account” PAC oversight. for non-reportable changes. The escrow account would contain an index of all the risk assessments that are done She pointed to the Medical Device Single Audit for a non-reportable change. A percentage of the risk Program (MDSAP), in which accredited third-party assessment records would be reviewed periodically, along auditors perform inspections of medical device with inspection outcomes, resulting in “some sort of companies that are accepted by FDA, EMA, Health Canada, and Brazil’s ANVISA. rating” of the PQS, and eventually a review of all of the risk assessments. “They send third party auditors or inspectors who are trained on the basic quality system that is common to all “Essentially, the higher the rating for the PQS, the more of the regulators, and then they add some additional items the confidence that you can manage the changes asnon- specific to each of the regulatory agencies,” she explained. reportable through the PQS,” Skeens commented. “So when they do an audit, they satisfy the requirements for all of the regulators that have signed up for this program.” The group felt that the PQS inspection and evaluation approach used in the medical device arena would be good Skeens suggested that the same model could work for pharmaceuticals, and would have the added benefit of reducing the number of inspections that regulators perform Workshop Participants Suggest Key and companies receive. She further suggested that the focus Questions Needing to be Addressed of the inspection could be on change management and the quality system, perhaps resulting in an “accreditation” The following are some of the key questions that that the systems are “robust enough” to allow some post- workshop participants suggested need to be approval change management. addressed by the pharmaceutical community in evolving the PAC regulatory process. “The regulators that are involved could define exactly what that criteria is,” she proposed, “but then it would be ● Could we rank the established conditions by criticality something that could be leveraged by all of the regulators.” and be clear on which ones need to be submissions vs. which ones can be managed in the quality system? GSK VP and Q12 rapporteur Moheb Nasr agreed that there are learnings to be garnered from the device arena, but ● How do we assure and get the regulators’ confidence expressed doubt that a similar third party approach would that the quality system could be used to manage changes? be viable in the pharma context, suggesting that reducing inspections and sharing of workload may be a more feasible ● Could an annual report in the US list the changes to approach. Nasr, who had provided an update on the Q12 established conditions that were managed through the effort earlier in the workshop, participated in the final panel. PQS instead of making a submission? A central theme in the workshop presentations and ● How do we demonstrate the strength of the PQS? Could quality metrics be used to show the strength of discussions was the vast resource drain and lost your PQS? opportunity cost that the current PAC regulatory situation globally is creating on both industry and ● How can we assure reliance on a CMO’s PQS? regulators, and the stakes in finding an international Through the quality agreement? approach with enough power to address it (see story on pp. 29-39).

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NOVEMBER / DECEMBER 2015 45 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 At issue at the workshop was how medicines could be so, fostered by international networking, collaboration regulated across their lifecycles in a way that would liberate and regulatory convergence. [Vinther’s full remarks on the technology and quality science to improve processes and WHO effort are included below.] products, lower costs, and better assure patient availability. The presentation encompassed WHO’s view of: ● the Pointing to “the amount of money in play here that is not various regulatory scenarios and how maturity levels can being used efficiently,” one participant noted that “if we be assessed ● why strengthening regulatory frameworks is take a fraction of that and create a more efficient system, important ● the elements needed, and ● the role played by everybody wins.” information and work sharing internationally.

Some of the current resources, for example, he suggested, The resolution recognizes the challenge of finding the right could be redeployed to create the standards needed and balance between the degree of regulatory oversight to potentially to fund a trans-agency government body like ensure safe and effective health products and the barriers to WHO to oversee/audit industry’s change management timely access to those products. programs – possibly resourced on a user-fee basis. Judging from the successful deployment of user fees in the generics Underscored by Vinther was WHO’s emphasis on the context in the US, the return on investment from a streamlined potential to share the scientific evaluation of quality, safety regulatory process could be substantial, he pointed out. and efficacy – decoupling that scientific evaluation from “all of the national laws and regulations, and how it all WHO Opens Pathway to Better Regulatory Systems works with pre- and post-market surveillance,” and then leveraging that with work sharing and information sharing. Enriching the larger conversation on where the global pathway lies toward a more harmonized, efficient, scientific “It is a scientific evaluation, and whether I live in the and risk-based regulatory process was a presentation during Netherlands or Austria or Japan, it should not look different. the workshop on what WHO was doing to advance the It is technical experts talking together,” Vinther commented. cause. Vinther filled in for WHO Coordinator of Regulatory “What it this element could be shared amongst national Systems Strengthening for Essential Medicines and Health health authorities?” Products Michael Ward, who had prepared the presentation but was unable to attend – adding his own comments on the significance of the WHO effort.

The main focus of the talk was the substance and impact of DOWNLOADS FROM THE STORY: resolution 67.20, endorsed by the World Health Assembly in May 2014. The resolution encourages countries to strengthen ● ISPE Drug Shortages White Paper their regulatory systems and provides a roadmap for doing

[The story continues on p. 46 with Anders Vinther’s full presentation.]

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SANOFI PASTEUR’S VINTHER ON WHO’S REGULATORY SYSTEM STRENGTHENING EFFORT

In the post-approval change management track of the PDA Manufacturing Science Workshop, Sanofi Pasteur Chief Quality Officer Anders Vinther described the substance and import of resolution 67.20, endorsed by the World Health Assembly in May 2014, which encourages countries to strengthen their regulatory systems and provides a roadmap for doing so aided by international cooperation. Vinther filled in for WHO Coordinator of Regulatory Systems Strengthening for Essential Medicines and Health Products Michael Ward, who had prepared the presentation but was unable to attend. Described is WHO’s view of: ● the various regulatory scenarios and their maturity levels ● why strengthening regulatory frameworks is important ● the elements needed, and ● the role played by information and work sharing internationally. Vinther also offered his own comments on the significance of the WHO effort in moving globally toward a more harmonized, efficient, scientific and risk-based regulatory approach.

The plan was to have a guy named Mike Ward, who used to work for Health Canada and now works for WHO, give this presentation. WHO is doing some cool stuff in the area we are talking about. The vaccine business is a lot about the developing countries and countries outside the ICH region, so I started to learn a lot more about it. There are so many interesting things going in the WHO. And this one I am going to show you, I am going to put my own spin on it….

What I am going to talk about is resolution 67.20. The way it works is the World Health Assembly, WHA, meets on a regular basis. This was their 67th meeting, and this is resolution 20 from that meeting. It is on regulatory system strengthening. So in a nutshell, it is saying that every country should have a good regulatory system. And many countries in the developing world do not have it. Some have very low levels of it. So it is encouraging countries to have a good regulatory system.

At the same time, [67.20] is saying that when you get that regulatory system, there is a risk that you will prevent product from being on the market. They may [have been saying that] ‘it is all good. We rely on a WHO pre-qualification of a facility for certain products.’ Now you are going to look at it and come out and do an inspection and ask all of these questions as well. And instead of dealing with 60 countries, we now have 20 more to answer to.

So strengthening regulatory systems and fostering networking, collaboration, and regulatory convergence is what we want to talk about….

The vision is that all member states have regulatory systems to ensure that all medical products and other health technologies meet internationally recognized standards of quality, safety and efficacy. And the mission is to strengthen capacity of regional/sub-regional and/or national regulatory systems in order to contribute to improved access to medical products and other health technologies of assured quality, safety and efficacy.

Global Regulatory Scenarios

This one is interesting in that SRA means ‘stringent regulatory agency’ (see box below). That is like the US FDA, EMA, and so on. And you heard [COFEPRIS Secretary of Health Javier Alcantar Toledo’s] presentation yesterday about all of the fantastic things they are doing with changes in COFEPRIS in Mexico. It said on one of his slides that that they have now been qualified by WHO and PAHO as a functional agency.

For an SRA, the first thing is that they have a robust registration system – a ‘full-service’ regulator that can serve as a reference for emerging systems. So for example, they may say, ‘this one has been looked at by FDA, so maybe we will just piggyback on their approvals.’

The functional aspect is that they have a technical registration system in place – independent systems that may be challenged to balance responsibilities, resources and experience. And it includes a mix of local and reference body authority and may be developing approaches for harmonization and collaboration. WWW.IPQPUBS.COM

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And then you have elements of a functional system, and then you have a non-functional system.

One of the conversations I had at the reception yesterday was what if we had that for our quality systems? If you were at the best level up here with your quality system, could you then lower your reporting category? Whereas if you were lower down, you would have to report more. Just a thought. It is not really related to this talk. But it is an interesting concept.

Here is the dilemma: You have to find the balance between the degree of regulatory oversight to ensure safe and effective health products and the barriers to timely access to those products. That is right there in the resolution.

With very limited regulatory capacity there are low barriers to access, but insufficient oversight to pre- and post- marketing activities. As capacity increases so does oversight, but at a potential risk to timely access. And the stringent regulatory authorities have a strong oversight, but it might be that all countries do not have adequate resources to do this.

Why Build a Regulatory Framework?

If we have a weak regulatory system, it is not really in the interest of consumers, patients, industry or the health care system.

And here is one I think is really good: Some elements of regulatory oversight can be shared. That is what we talked about earlier today as well. What if the evaluation of quality, efficacy and safety is something that could be shared across different countries? Because it is scientific. It is a scientific evaluation. And whether I live in the Netherlands or Australia or Japan, it should not look different. It is technical experts talking together. What if that would happen? What if this element could be shared amongst national health authorities?

The other elements of regulatory oversight must be local – for example, the licensing decision, because we cannot say, ‘if you do everything that is OK in EMA, you should just be able to put it on the US market.’ The final decision needs to be local.

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You also need to have local oversight on: ● manufacturing ● pharmacovigilance ● distribution controls, and ● product security.

I think that if we think about multiple changes like that as well and try to separate it into two different things, that might be a way forward. It might be a way of thinking about it.

Enhancing regulatory maturity while managing capacity and timely access can be fostered through development of best practices that minimize redundant work, divergent requirements, and poor flexibility.

Elements of a Good Regulatory Framework

How do you put up a good regulatory framework? The resolution says that it should be: ● science-based ● risk-based ● flexible and adaptive to evolving needs ● streamlined and efficient, and ● harmonized and aligned with international standards. I do not think that we can disagree on that. Are we meeting it or not meeting it?

Efficiency comes in by leveraging the work of other regulatory agencies. And that is exactly what Javier talked about yesterday. That is what they are doing.

I spoke to his boss a few months ago in Mexico City and asked him how they do that. He said they just borrow it. They have a product that is registered in another country, and they say, ‘OK, we have gone through our established conditions. We have some questions. We just call them and ask.’ He said that very often instead of asking the company ten questions, they only had one. The other nine they got from EMA or US FDA. He said it is very fast now doing it that way.

And of course it all starts with a good strategy. And maybe that is one of the things we in PDA should help with. We should talk about that….

Development of an effective regulatory framework can be facilitated through development and adoption ofaset of guidelines – the ‘tools’ to building a strong framework. Effective tools are a set of principles that can fit national realities. They should: ● permit sovereign decision making ● be implementable across the spectrum of regulatory capacities, and ● cascade local regulation and guidance tailored to the local environment.

So now on to flexibility. Regulatory oversight must be risk-based to achieve a balance between appropriate controls and timely access to medical products. There will be cases where there will need to be accelerated access, such as with emergencies of public health concern, drug shortages, and innovations in treatment of critical illness. You will need to be able to push it through the system faster.

Increase in regulatory oversight is vulnerable to the implementation of overly rigid constraints. That is a natural thing. When you put in a new system you need to make sure you have good controls and so on. But it might actually defeat the purpose. This can be exacerbated by existing legal frameworks.

Information and Work Sharing Continuum

This is what they are saying about how it could be. If you take again a well-resourced stringent regulatory authority, it has: ● established harmonization agreements ● transparency among participants ● work sharing, and ● ratification of centralized recommendations.

When you are functional: ● national decisions may be informed by decisions of trusted reference national regulatory authorities ● there is information sharing among cooperative endeavors ● work sharing is developed within a participant group, and ● harmonization initiatives are in progress.

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There is a general thing about work sharing vs. information sharing. There is more tendency to do information sharing, but not necessarily the work sharing. And it is not going to be effective and efficient until you do the work sharing as well. But what are the rules for work sharing?

● Take account of one another’s work with a view to improving the efficiency of the global regulatory system.

● Commit resources to form cooperative networks based on uniformity of standards and inspection systems.

That is one of the things we talked about. There are so many resources used already. What if a certain percentage in a national agency was given to international collaboration? What would you get back out of it? What is your return on that investment?

● Engage with regional and international initiatives promoting harmonization, information sharing, and use of data generated by other regulators as a tool for improving timely access to medicines and medical products.

WHO is very good, I think, about using things they find that are good, and bringing people and agencies together.

All models can serve to promote the efficiency of review processes, strengthen regulatory capacity, build trust, facilitate convergence, and reduce unnecessary duplication of effort and requirements.

Concluding Remarks

National regulatory authorities around the world are under mounting pressure to improve performance and facilitate timely access to safe, effective, and quality medicines and other health technologies.

WHA Resolution 67.20 on regulatory systems strengthening endorsed in May 2014 reinforces WHO and member states’ commitment to strengthen regulatory systems worldwide.

WHO has focused efforts on increasing regulatory capacity and efficiencies by promoting innovative information and work sharing arrangements as one of the main functions.

WHO pre-qualifies companies for certain products. Then countries with less-developed regulatory frameworks will buy the products from that facility. WHO wants to phase that out, but they need to be very careful about how they do that.

It is a shame that Mike could not be here and do the presentation himself. I really would have liked for him to be here. But it was not possible. But I hope you agree with me that there are some really great suggestions here. There might be bright spots here.

I personally like the thing about splitting out the assessment of quality, safety, and efficacy, and making them all scientific across countries. If that can be decoupled from all of the national laws and regulations, and how it all works with pre- and post-market surveillance and those kinds of things, maybe that is a way of doing it, and leveraging what WHO says here about this, including the work sharing and information sharing. You are giving up some sort of control without giving up full control. I think that is what they are talking about here.

There is also a resolution, 67.22, which is sort of related. If you want to read that, it is also well-written.

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2795 NSF PB Industry Expertise Quarto Ad.indd 1 27/05/2015 14:14 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 More Structured, Interactive Process To Drive Convergence in Latin America Advocated by Biotech Product Regulators and Industry at CMC Strategy Fo- rum in Brasilia The need for a more structured, interactive process to drive the harmonization of their policies. She noted the point made convergence and resource sharing among the regulatory by Chilean regulator Fabiola Espinoza that the absence of agencies of Central and South America – potentially drawing a permanent CMC working group among the regulatory on elements of the European model – was a dominant theme authorities in the region is hindering progress and should be among the industry and regulator participants in the second created as quickly as possible. annual CMC Strategy Forum Latin America held again in late August 2015 in Brazil’s capitol city Brasilia. Convergence, Predictability, Transparency in Focus

The two-day forum, sponsored by CASSS with the support The opening session of the forum focused on “regulatory of the key regulatory agencies in the region, brought convergence, predictability, transparency and priority together industry and regulator CMC experts to review: ● reviews in Latin America.” It included presentations by the the significant progress that has been made in recent years regulatory agencies of Brazil (ANVISA), Peru (DIGEMID), in strengthening the biopharmaceutical regulatory capacities Chile (ISP) and Mexico (COFEPRIS). Updates and comments in the region ● where the shortfalls remain, and ● how the were also provided related to the themes of the session by region can move into closer alignment with the US, Europe representatives from the EU and FDA, and from Grupo Farma and Japan, and keep pace with their evolving processes. Brasil and the Latin America Federation of the Pharmaceutical Industry (FIFARMA). An extended panel discussion In her summary of the presentations and discussions followed. presented at the forum’s conclusion, industry consultant Nadine Ritter (Global Biotech Experts) Regulatory Panel at Brasilia Forum highlighted the consistency among the participants in wanting to strengthen the foundation for increased regulatory convergence and resource The following is a list of the panelists who gave presentations and participated in the discussions at the sharing – a desire heightened by the challenges that opening regulatory session of the 2015 CMC Strategy biotechnology presents and the limited resources Forum in Brasilia. EFPIA LATAM Network Chair Ana available at the individual agency level to address Padua (Roche) served as a moderator for the session them. [Ritter’s in-depth summary is provided in full along with ANVISA’s Marcelo Moreira. below.] • Edith Roxana Vásquez Alayo (DIGEMID, Peru) Pointing to the increased involvement of countries in the • Reginaldo Braga Arcuri (Grupo Farma Brasil) region with international organizations like the World Health • Niklas Ekman (Finnish Medicines Agency) Organization (WHO), the Pan American Network for Drug • Sarah Kennett (FDA, USA) Regulatory Authorities (PANDRA) and the Pan American • Marcelo Moreira (ANVISA, Brazil) Health Organization (PAHO), Ritter noted the desire echoed • Fabiola Muñoz (Public Health Institute, Chile) across the agencies represented to have more permanent • Thomas Schreitmueller (FIFARMA) interactions at that international level. • Esenbeckia Yureri Torres Guzman (COFEPRIS, Mexico)

“A really strong message came from everyone that they wanted to promote increased interaction among their agencies Following the pattern of the foreign CMC Strategy Forums, to advance their understanding and even to advance internal the opening regulatory session led into targeted sessions with training on technical issues specific to biotech and biosimilar industry and regulator presentations and panel discussions products,” she stressed in her summary. exploring some of the key technical challenges in the biotech arena. Heightening this desire is the recognition that “these are definitely different products. They require different complex In focus, respectively, at the two-day Brasilia forum systems, and they require different CMC considerations to were: ● the characterization, control and regulation support their safety and efficacy and stability.” of protein glycosylation ● technology transfer, and ● cold chain management and product transportation In her summary, Ritter reviewed the regional and global qualification.[Editor’s Note: See IPQ September 29 and collaborative efforts that the Latin America regulatory IPQ September 30 for a review of the presentations and agencies presenting at the forum were engaged in to further discussion at the tech transfer session.] WWW.IPQPUBS.COM

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CMC Strategy Forums are also held annually in Europe in May In his presentation, Roche Biologics Regulatory Policy and Japan/Asia in the late fall. Next year’s Latin American Head Thomas Schreitmueller, who heads up FIFARMA’s. forum will be held in Mexico City. Regulatory and Biologics Working Group, explained the association’s concern, in particular, with the current lack of a A pair of forums are held in the US in conjunction with the harmonized risk-based approach to biologic product lifecycle CASSS Well Characterized Biotechnology Product (WCBP) management and outlined FIFARMA’s thinking on the conference in late January and another during July. The WCBP pathway to achievement (see story on pp. 69-74). conference will again be in Washington, D.C. with forums scheduled on January 25 – the day before the WCBP conference During the panel discussion, Schreitmueller begins – on the “technical and regulatory considerations reemphasized that convergence is “in the interest for pharmaceutical product lifecycle management” and of everybody,” with the potential to bring resource “production cell line development and control of product spending down by mutually recognized decision consistency during cell cultivation,” respectively. making based on similar regulations.

Panel Probes International Opportunities He cited the biosimilar example of how the convergence process can start from the global organization WHO, flow The panel discussion at the opening regulatory session in down through PAHO and then spread out to individual Brasilia gave the presenters the opportunity to explore further countries. how the goals of transparency and convergence relate to each other, why they are important to pursue, and how their The key ingredient is the building of trust, which can realization can be furthered. only happen through transparency, the Roche FIFARMA representative stressed. He cited the European Public Assessment Report (EPAR) as an example of the transparency/ Key Questions for Regulator Panel at trust relationship at work. Latin America Forum Finnish Medicines Agency biologics quality assessor The following were the important questions driving Niklas Ekman, who updated the forum on the EU’s the regulatory panel discussions at the opening adaptive pathway and transparency initiatives, agreed session of the CMC Strategy Forum Latin America with Schreitmueller that transparency “is a crucial on “regulatory convergence, predictability, thing for harmonization and convergence.” transparency and priority reviews.” Ekman noted that the content of the EPAR, which provides • Predictability: What are the measures planned and the basis for the regulatory decision and has the company’s implemented to enable the correct estimate of evaluation review buy in, continues to increase. “To be transparent and come deadlines? out with information that the regulatory decision is based on,” he maintained, “is a win-win situation for all.” • Convergence: Considering the Latin America regulatory environment, what are the barriers for development of It was noted during the transparency discussions that the integration and cooperation among national regulatory agencies Asia Pacific Economic Cooperation (APEC) initiative has a (NRAs) in order to promote regulatory convergence? What are the main hurdles and how could they be overcome? working group that is looking at developing a guidance for international product review summaries based on the EPAR • Transparency: In the context of regulatory convergence, it is model. evident that transparency is required. How could transparency be provided? What tools could be used? How could Seeding Convergence with Training transparency in regulatory decision be ensured? CDER Office of Biotechnology Products (OBP) Division of • Priority Reviews: Are there priority review programs in place Monoclonal Antibodies Review Chief Sarah Kennett, who or under implementation in your country? What has been the provided the FDA update at the session, suggested that, experience and timelines achieved? rather than “100% convergence,” the initial focus should be • 2015 Priorities: What have been the top three priorities on “regulatory consistency,” which in itself would be “very, established in your regulatory agencies and industry very beneficial.” organizations for 2015? What about the evolution of these priorities during the past months? Different laws and regulations create convergence hurdles that take time to cross and there are different risk benefit/ • 2016 Priorities: What are the most important regulatory tolerance levels and intellectual property sharing concerns Inperspectives his presentation, for 2016? Roche Biologics Regulatory Policy Head Thomas Schreitmueller, who heads up FIFARMA’s that factor in as well, she noted. WWW.IPQPUBS.COM

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A key to making progress is training, Kennett the mutual recognition pathway, followed by transparency emphasized. She noted that knowing how to do around the registration approval process. While mutual efficient and consistent application reviews and recognition is a worthwhile goal, “we have a long way to write them up is a concern on which FDA has been go” to reach it, he said. focused internally – having the training systems in place “so people know what is expected of them and PAHO and the ASEAN/APEC Models they start doing things the same way every time.” In presenting FIFARMA’s recommendations during his Ekman concurred that product assessment is increasingly presentation and again in the discussions, Schreitmueller challenging, and commented that the EMA has been pointed to the need for PAHO to be more actively engaged expanding its international training efforts, in which in driving the convergence process “to the next level” in assessors from Latin America have participated. Latin America.

He pointed out that Europe is dealing with the resource What is needed is more “political will” behind the effort in constraints through its harmonized assessment system and Latin America, he said, equivalent to what is taking place in mutual recognition. With its four biotech reviewers, the the Asia Pacific region under the Association of Southeast Finnish agency “could never handle all the applications that Asian Nations (ASEAN) and through APEC (IPQ July 27, are going around in Europe. Our agency would need to be 2014), where countries are working to harmonize through a at least ten times bigger than it is currently.” “top-down approach,” which could lead toward a EU-type collaborative system. Peru DIGEMID’s Edith Alayo highlighted the challenge faced by the seven regulators at her agency involved with Schreitmueller cited a suggestion made publicly by CDER biologic evaluations in handling the divergent products. Director Janet Woodcock that with all the disparate Training is important, she stressed, adding that the more initiatives going on globally around convergence, what senior people in the agency should also be attending may be needed now is a global umbrella steering committee these types of meetings and that video conferences could to minimize duplication of efforts and provide strategic help promote mutual understanding and regulatory direction. advancement. ANVISA’s Moreira noted that it is usually the same Mexico COFEPRIS ‘ Esenbeckia Guzman commented that academic and industry experts should be involved along subject matter experts involved in the different regional/ with regulators to advise and collaborate on new approaches international groups, resulting in more harmonization and help streamline the convergence process. among the various initiatives than their diversity would imply. ANVISA’s Marcelo Moreira offered a more general comment on the ability of Latin America to address The regulatory session concluded with a review by its individual agency resource constraints by moving the various panelists of their top priorities during directly to the mutual recognition-type system 2015 and how they would evolve in the coming year. established in Europe. Increasing regulatory efficiency and effectiveness through Europe has shown that language issues can be dealt with. more transparency and international collaboration on However, Moreira stressed, harmonizing around the guidelines, inspections, and pharmacovigilance appeared technical criteria and requirements is a necessary first step on high on the priority lists.

DOWNLOADS FROM THE STORY:

Peru (DIGEMID) Chile (ISP) ● Legal and technical development of biological products ● ISP commission meeting proceedings ● Registration of chemical and biological products Europe (EMA) ● Regulation of biological products ● Adaptive licensing ● Review of similar biological products ● Transparency ● Review of biotech products ● Publication of clinical reports Brazil (ANVISA) ● Comparability exercise, heparin, and interferon alpha guidelines

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CLOSING SUMMARY OF 2015 CMC STRATEGY FORUM LATIN AMERICA BY INDUSTRY CONSULTANT NADINE RITTER

At the conclusion of the 2015 CMC Strategy Forum Latin America, industry consultant Nadine Ritter gave the following summary of the four sessions comprising the two-day forum. The opening session of the forum, focused on “regulatory convergence, predictability, transparency and priority reviews in Latin America,” included presentations by the regulatory agencies of Brazil (ANVISA), Peru (DIGEMID), Chile (ISP) and Mexico (COFEPRIS). Updates and comments were also provided related to the themes of the session by representatives from the EU and FDA and from Grupo Farma Brasil and the Latin America Federation of the Pharmaceutical Industry (FIFARMA). An extended panel discussion followed. “Technical” sessions were then held focused on three challenging areas in the biotech arena: ● the characterization, control and regulation of protein glycosylation ● technology transfer, and ● cold chain management and product transportation qualification.

General Observations

In the first part of this, I am going to talk about my general observations – what I heard and what I saw from the Latin American regulatory authorities’ presentations. And there was actually amazingly a lot of consistency in some of the points.

It is very clear from everyone’s presentation that since around 2009 this region has been undergoing significant regulatory adaptations, specifically for biotech and biosimilar products. And these are not only changes in technical guidances that are being issued, but also the legal framework for these products in terms of their registration processes.

There has been an amazing amount of work that has gone on in this region just within the last six or so years. You guys have been extremely busy. And many of the initiatives have required updated regulatory guidance documents that separate historical registration pathways of chemicals from biologicals and establish specific processes for biosimilar products – the emerging class of biotech products, which of course are global.

And while we do not have full convergence across all of the regional agencies in this area, most align closely with WHO, EMA, and FDA guidance for biosimilars, and ICH guidances on things like the common technical document [CTD] format and the specific ICH guidances, especially the Q5 series for biopharmaceutical products. And so even though there were some regional logistical difficulties, the philosophies and strategies are actually very similar for many of the elements.

We just learned a minute ago in the last session that there were still some significantly different practices in a few elements like shipping. But by and large for the development of these kinds of products, a lot of the CMC elements are very similar.

We did learn that there is increasing involvement with a lot of other agencies in this area – other organizations like PANDRH [Pan American Network for Drug Regulatory Harmonization] and PAHO [Pan American Health Organization]. And you will see that there has been an increase in requests for more involvement with PAHO.

Each of the agencies and many of the audience members really desire to have more permanent interactions at that level. And one of the comments made about the ASEAN [Association of South East Asian Nations] countries is that they became very strong when they began to collaborate on their practices – not necessarily mutual recognition, but certainly in getting a permanent working group together to converge and harmonize for efficiencies.

There will still be some differences. And one of the issues that is most difficult is interchangeability extrapolation. But that is not unique to this region – it is a global concern. There is still not harmonization on this globally.

Also priority reviews are not necessarily possible logistically in every region and every authority in this area.

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And then there are traceability requirements, where there are some differences between what the proposals are from WHO and what the requirements are regionally for labeling of products.

A really strong message came from everyone that they wanted to promote increased interaction among their agencies to advance their understanding, and even to advance internal training on technical issues specific to biotech and biosimilar products. These are definitely different products. They require different complex systems. And they require different CMC considerations to support their safety and efficacy and stability.

One thing I am going to note here for myself because, as I mentioned, the notes from the slides here will be put up on the CASSS website, and ultimately they will be transcribed into the publication International Pharmaceutical Quality. I have a note here that each of the regulators did a fantastic job, I thought, of putting the detailed links to their websites and specific regulatory guidance documents in their slides.

And so what I am going to do is work with [IPQ Editor-in-Chief Bill Paulson] and make sure that those things are put into the IPQ article, so that we can all have access to them (links are provided above). Because one of the hardest things sometimes is knowing that you do not know where to find something. And having these all available at this time and current was really an achievement and we really appreciate that.

Now just a couple of notes: I am not going to summarize anyone’s slides. It was mentioned that the individual speaker slides, where permission was granted, are going to be put up on the CASS website. So I am not going to reiterate any of the slides here other than to say a couple of points that stuck out for me.

Key Points from Regulators

One point was from ANVISA – this is just something that popped out as being unique: They were not necessarily agreeing with all of the elements of the WHO proposal for naming conventions. In fact, they made the comment that even regions are not harmonized on what to call the things – that they are ‘biosimilars,’ ‘follow-on biologics,’ ‘similar biological products,’ or ‘subsequent entry biologics.’ So getting down to the level of granularity of an INN [International Nonproprietary Name] is perhaps a bit premature now if we cannot even call them the same things as a class of product.

From Peru, they have indicated some major updates in their regulatory approaches for biotech and biosimilar products. And now they have two different registration options for dossiers for a de novo product or a similar bioprocess product. They encourage us to look at their reference documents. They generally reflect the WHO guidance. But they also consider elements of EMA and FDA guidances in there as well.

Chile was indicating that all of their biological products are registered as new products. They do not have the CTD format yet. But they do emphasize the value of a well-organized dossier in their review process. And certainly, having worked many times with other health authority officials, having a well-organized dossier is not to be underestimated. We can debate about the value of CTD document. But the organization of information is important.

Chile also indicated that they are collaborating with other regional health authorities like WHO and PANDRH to be able to further harmonize and converge policies. They indicated that the absence of a permanent CMC working group in this region is hindering progress. They really advocated a permanent working group among the regulatory authorities in this region to advance these issues as quickly as possible.

They emphasized the deficits that occur in training, and that having trained reviewers to be available to look at these complex products is a very important element. So having staff is good. But having trained staff is essential.

Mexico is also working in a very collaborative way with other health authorities like Health Canada, EMA, FDA, the Swiss and Australia – the TGA. They are trying to move toward better predictability via emergency equivalence agreements with these regulatory authorities. So there are a lot of very positive things going on in our sector in this region of the world that we have heard in the last couple of days.

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And also in Mexico, priority review is currently limited to disasters and emergencies. But they are working to get that high priority status for high demand products. However, they do have to go through their federal executive, which is a legal process that is out of their control.

Now some of the things that we have heard from the EU, from the EMA representative, is that the centralized procedure for a market authorization through a centralized review is necessary for biotech and biosimilar products. The review is actually done by regional representatives, but it is authorized through the EMA.

And there is a new innovative approach – the adaptive licensing model – which is being piloted now. It is in the middle of its pilot process. Initial authorization is given followed by a progressive staggered review approach before final authorization. The details about this are still being worked out. But it involves multiple iterative phases of data gathering of the CMC elements. And that combines with iterative license adaptations according to the stage that you are in.

It means that you will likely provide them with a limited package at the time of first authorization, which will involve a rolling review of CMC data as it comes in. However, CMC could be a gating item if there are deficiencies in data sets that are related to patient safety. So they have to have enough CMC data to at least understand that the material you are making is not going to risk the patient safety in a period between initial approval and full approval.

FDA had a couple of notes from their representatives. They know that most of the US products that they work on are globally produced. Even though their jurisdiction is the US, they are not unaware of the fact that almost all the sponsors are globally producing the products. And they are in fact heavily involved in global convergence discussions, which I did not realize until Sarah showed it. It goes back to the original FD&C Act about the expectation of working with global regulatory agencies.

But as she said, it is easier said than done, because there are only a certain number of people, and you have stressed resources. You want to get your reviews and inspections done. But the global interactions are valuable activities. And so they do provide for that in their plans.

They just recently signed on with PIC/S for inspections. They have worked forever with ICH and ICDRA [the International Conference of Drug Regulatory Authorities] to be able to exchange information. However, there is no formal mutual recognition agreement yet. In other words, they still have to review their dossiers individually because of jurisdictional requirements. They cannot just sign off on someone else’s approval or someone else’s inspection. I have to say that probably from my experience the inspection side is a little closer to that, although it is not there yet.

There are expedited review processes in place, but there are no major CMC shortcuts for either breakthrough or biosimilar products. Some orphan products do have flexibility in rolling CMC information, but that is based on the risk to patients and the type of product. But there are no major CMC shortcuts that are allowed, because CMC is what drives decisions on product quality and process control.

Both the EU and US said that they have heard from the industry and they have heard from patients, and they really have tried to implement the priority review status or rolling review status to be able to meet the demands of industry and patients. So the policies and procedures are in place that are facilitating this, but they have to have data.

So the good news is that the logistics are present, but the bad news is that you still have to get data. They cannot possibly approve a dossier, even a breakthrough or adaptive dossier, unless they have enough information to convince them that your production capabilities are in control, and that your product is sufficiently characterized, consistent, and stable for the intended use that it is going to be approved for in whatever legislation it is going to go through.

This means there is increased responsibility on the sponsors to understand these expectations and know how to get the right data at the right time to fulfill what the regulatory agencies need to conduct their reviews effectively.

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Industry Groups on Post-Approval Changes

We had some notes from presentations by two industry groups that were really quite excellent – Grupo Pharma Brazil and FIFARMA. And some general things that I have pulled up are that they were quite laudable about the progress that has been going on globally for the preapproval requirements for biotech and biosimilar products. However, the next challenge is closing gaps on the post-approval changes.

And this is a theme that echoed through that whole session. The good news is that we have a lot more harmonization and understanding of preapproval requirements globally. The bad news is that once we get them approved it goes into a nightmare scenario of multiple iterative changes that are not in parallel.

They are mindful of the fact that there are legal jurisdictions that are constraining regional registered products – that you cannot violate the laws – but they still encourage discussion on the mechanisms of at least the convergence of CMC requirements for post-approval changes to be implemented as rapidly as possible worldwide for approved products.

This is not just a benefit for industry, obviously. The point remains that it will also minimize the burden on regulators by harmonizing the nature and amount of CMC data that they need to see to support approval of a post-approval change.

This means it will also streamline the assessment of those filing packets. If you have some consistency in the data sets that are expected, then like with the CTD for preapproval, you can go through and see what you are expecting to see to efficiently review the post-approval changes.

And something that came out during later discussions – it seems like such a system would also minimize the burden on the regional public facilities that are engaged in tech-transfers where global licensed products come in and they undergo changes during the time of the tech-transfer.

So it seems like there is a dual benefit there – that the public facilities that we heard from that are trying to affect these tech transfers would also have a significant benefit from a harmonized post-approval change, in that they can minimize the number of gaps that occur while something that is being tech-transferred in.

FIFARMA had a recommendation to WHO and PAHO to prepare and update guidance documents for this purpose, and harmonize or at least converge the data requirements for changes to biotech products. Currently, we have guidance documents on what can be done, but not how to do it globally. I think that the issue is not the technical part. It is, ‘what are the data sets that have to be submitted to the regulatory authorities for their review and approval?’

So we know what we have to do, like comparability protocols. We do not know how to actually get it through regulatory affairs logistics in each region easily. And the goal is to be sure that we can do this most effectively and efficiently.

They even went so far as providing a title for a guidance document just in case there needed to be a little bit more prompting. It would outline the change classification concept, the documentation required for regions for individual changes, and the procedures including timelines for post-approval changes. These are meant to be complementary to the existing technical guidance on what studies you do to do comparability, like analytical studies for process changes. This is one of the logistics of it.

Agency Transparency

In terms of transparency, which is one of the major issues, we saw very common statements.

ANVISA indicated that all of their applicable regulatory statutes and guidances are on their website. Plus they have now made their drug approval and refusal letters available for people to review. Peru indicated the same thing – that their regulatory statutes and guidances are now on their website.

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Chile was the same way, and include commission proceedings and evaluations from their debates and discussions.

Mexico indicated that their statutes and guidances are available.

EMA has had them on the website for a while. And EPARs [European Public Assessment Reports], which are summaries of the approvals, are available on the website. And they indicated that there is a considerable amount of detail available, because those are published in cooperation with sponsors so that any confidential information is negotiated before it is published.

Similarly, FDA has all their statutes and guidances published on their website. And they also publish their ‘Summary Basis of Approvals.’ However, those are heavily redacted, so they are generally a little smaller than the EPARs. But they are still quite valuable if you know what you are looking for.

So all of these agencies are using the Internet and using their websites to be able to make these documents available to us, if we can just mine them ourselves.

One little problem that has come up, and this came out in the CMC Forum in Japan, is that of course the documents are in their regional languages – they have to be. But to really facilitate global transparency for those who want to use them outside of the region it would be of great benefit be able to have access totranslated copies of some of these documents.

And when we had the CMC forum in Japan in 2012 – this is an editorial comment that we did not talk about, but I want to put it out here – it was noted then that the Japanese guidance documents and regulations are all available, but they were only available in Japanese, obviously, because those are the people that wrote them and need them.

But a proposal was made at that forum that like the ICH and WHO documents, it would be very nice to have access to these documents in English. Could a regional industry group provide support? Because regulatory bodies cannot do this as they are stretched already.

And in fact that seems to have happened. I just noticed this morning that we have some provisionally translated documents that are available. And you can see the note – it says that the English version is only for reference. If there is a conflict between the original and this one, then the former prevails.

So I would like to just set it out there that maybe something can be done here. It would be nice to have just for an increased transparency of all the regional documents that have been so carefully and dedicatedly written.

Okay, let’s talk about interchangeability, extrapolation, and the naming convention. ANVISA did a very good job of overviewing what is currently the status of interchangeability.

Health Canada does not declare interchangeability for biosimilars. EMA has individual countries with different policies. FDA law permits FDA to designate a product as interchangeable. But the decisions do not occur at the FDA level, they occur at the pharmacy level, which is ruled by state laws.

ANVISA indicated that they consider interchangeability if there is sufficient clinical data to support that purpose.

Extrapolation is currently under discussion. There is a working group that is proposing a reflection paper that hopefully has enough information to support scientifically when extrapolation would be allowable.

And the internal rule for INN is in conflict right now with what the WHO is doing, and so that is something that they are discussing right now.

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International Integration and Cooperation

Now let’s go to a couple of questions: What are the barriers for development of integration and cooperation among the national regulatory agencies to promote convergence? What are the main hurdles? What are some of the comments that we had?

How can each agency maintain what is best for its own region? If the European Union could do this, so could this region. That was one of the comments that came out of the discussion.

It is recognized that each agency cannot formally recognize each other’s dossier approvals. But they could review what other agencies approved and what considerations were taken by those agencies. A comment was, ‘a mutual acceptance of a dossier, I mean the legal ability to sign off on else’s review, is not the same thing as using the converged guidance documents to inform more consistent review outcomes.’

And so I think that the message there for us is that we will certainly, hopefully, get more consistent reviews, more predictable reviews. But I think it is a bit premature to expect legal mutual recognition of registered products based upon one review in one region.

It was noted that even though EU has an EMA review process, it is driven by one member state that takes the lead. And if that lead gets it approved, the other member states agree to follow it. And there is contribution to the lead review from other scientific advisory panels and other entities within the regions.

The US FDA does not have a formal mechanism for partnerships and reviewing CMC. There is an office of international programs at FDA that may have some other information available. But that is the preclinical and clinical side, not the CMC side.

FDA noted that they also struggle with staff versusworkload , and that training is an issue, especially in crosschecking the CMC elements to other sections; that reviewing a BLA is quite complicated; and that the CMC has to tie to other elements.

Some of the hurdles: Everybody seemed to be uniform across the board that regulatory authorities need resources, time, training, and communications. And the national regulatory authorities here need more resources. They cannot just implement good ideas without adequately trained reviewers. Even if that training has to be done by videoconferencing, it is better than nothing.

EMA has workshops that have had participation of Latin American health authorities, but they do not have formally shared reviews.

Mexico indicated that they are attending more APEC [the Asia Pacific Economic Cooperation group] meetings as they move towards manufacturing and marketing in Mexico. And Peru is attending meetings on data protection for biotech products and similar biologic products. But there is no agreement yet on how that is going to be done internally.

And Chile is also engaged internationally with APEC and Korean health authorities for imported products that are going into Chile. So you can see that there is an enormous amount of interaction going on internationally from this region and other parts of the world.

In fact, a comment came out of the discussions: With all the industry and regulatory groups working on so many meetings, is it really convergence or is it divergence? The comment was made that it is usually the same people taking part in the same topics in the various regions. So it is more harmonized than it would appear. You have a lot of the same subject matter experts – [Finnish regulator Niklas Ekman], [Office of Biotech Products reviewer Sarah Kennett], and those kind of folks – who are perennials in our CMC hall of stars for these discussions. So it is more harmonized by their consistent participation.

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In fact, Janet Woodcock of FDA noted that there are numerous parallel organizations working on convergence such that it almost begs some kind of global umbrella steering committee to minimize duplication of efforts.

It was also noted that APEC has sent out surveys to the field on how their guides are being used. And at this point they seem to be used as a checklist by the countries that use them, and not so much on how to improve convergent discussions. That could be an area for improvement.

And FIFARMA had kind of a bold statement: In the Latin America region, there has to be a stronger political will behind formal harmonization of the health authorities, like the ones that have occurred in Asia with ASEAN and APEC. And that those two agencies have had a great impact on biopharma development and approval logistics. So it is possible to do here.

The national regulatory authorities said there is not much local production of biopharma products yet. But that is changing with the tech-transfer of manufacturing of products here.

The political will for patient access to new and cost-effective drugs is definitely there. But they must educate the politicians about the need to have good regulatory review. It is not enough to say you are going to have new cost-effective drugs to the patients. The pipeline has to go through regulatory authorization. And maybe there are some folks within the political system that really need to understand that better.

And they need to be made aware of the critical link between their political initiatives for faster entry of products, the need for good regulatory policy, good regulatory practices on review, and approval of post-approval changes, if they really want to get them into the hands of the patients who need them.

We talked about transparency and some of the issues that are related to improving transparency and what tools would be available. In the EU it is a collaborative process with the health authorities and the individual firms on what is published in the EPARs. This could possibly be a model for other regions that want to open their decision-making process to review from other people, with of course protection of confidential information.

APEC has a working group on a guidance for EPAR-like review. I think they are called IPARs. This might lead to the public consultation on a draft soon for international product review summaries.

Also ANVISA is tackling transparency with many different things. They have analysis rankings and abridged versions of approval letters that are available to us. And companies do get to see a draft of the summary before it is published to redact any confidential information.

They are also working to reduce what is considered confidential information. But they do expect that firms will resist a bit. Their goal is not to expose a firm, but to share whatever is valuable and what elements factored into the regulatory decision so that everyone can see what that predictability will be like for similar application.

The IPARs that are within the working group now would ideally have a harmonized format and much more common information that could possibly even be copied and pasted for each regional authorization letter. I think the timeframe for that was in the next one or two years. There are no official plans to disseminate this in Latin America. But it might be available for consideration once it becomes available.

ANVISA has launched the CTD format, and has found it very useful. I have another comment later where it is not being used.

Oligosaccharide Analysis for Glycosylated Proteins

Now lets’ jump to the state of art of oligosaccharide analysis. We had some really spectacular presentations that gave us a snapshot on the current technology and applications of oligosaccharide analysis for glycosylated proteins.

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The take home message is that it is not one technology. It is a slate of technologies. In fact, it is a massive slate of technologies that have to be used for complete analysis of carbohydrates, because carbohydrates are very complex structures and there are many biomolecular elements that can be interrogated.

In order to be able to provide an adequate data set on characterization of carbohydrates and for glycoproteins, FDA would expect a combination of methods to be used for comparison of two products for biosimilarity. They would expect to see many more features than what we would characterize in a novel product. Why? Because the purpose is to compare the features that are similar or different between the originator product and the biosimilar product.

The originator product is characterizing it for its own molecular entity. The biosimilar is characterizing it for the purpose of claiming comparison. And so it could require a drill down on things that the innovator did not do.

Also it was noted that different methods for carbohydrate analysis have different purposes. Methods used for clone selection – which turned out to be an extremely valuable aspect of biosimilar product development – may be different, and should be different than process optimization methods vs. methods that are used for comparability and similarity. They are all considered carbohydrate analyses. But they have very different intended outcomes in the data sets.

The EU said the same thing. In fact, they said methods usually are not the problem when it comes to comparability, especially in glycan starches. That most companies do a very good job of characterization and assessing similarity of glycans. But the challenge is that when they see differences, what do they mean?

So the good news is they are getting a lot of good data. The bad news is that if they see differences you have to figure out if that has an impact on the safety or efficacy of the product.

The paper that was used, and I do recommend it, was a 2006 paper.

Have there been any updates to that since 2006? And the answer is that, in fact, these are still the tools that we use. The difference is that the paper was academic. And what typically happens in the evolution of analytical methods is they arise in an academic environment and ultimately get adapted into applied biotechnology. And so the tools that are there are still the same. It is the application that has changed since 2006.

What if any limitations exist with these technologies? Well, some technologies are not yet amenable to QC applications. We know that it could take a decade or more for an academic technique to practically move into applied biotechnology, usually from the R&D side of analytics. It could possibly move into a QC environment if it is determined to be robust enough, can be validated, and is demonstrating that it is measuring a product characteristic that is critical for the control of product quality.

But when the method does get into a QC lab, it is expected that it will be validated and maintained in a state of operational control with no excessive number of invalid runs. Anecdotally in the break – this was not a public conversation – we were noting that in some QC laboratories it is kind of a rule of thumb that you should have less than 10% invalids for your validated methods. Whether that holds true or not across the globe has yet to be seen.

What high throughput methods are there for carbohydrate analysis? There are a few that can be reasonably high throughput, but noted was that oftentimes in those cases it is the sample prep that is the gating item. Once you get the sample prepared and the extraction performed, loading it up on the auto sampler is not the problem. It is the sample prep that is usually the slow part of those kinds analyses, especially those that use auto samplers.

But in any event, it is not going to be high throughput if it keeps breaking down. You have to have good method development and optimization, including sample prep steps, that make the method more vs. less cumbersome to execute routinely. And so it is not inherent to the technology, it is inherent to the procedure that is utilizing the technology.

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What strategies are used to define the criticality of glycosylation? EMA indicated that they expect comprehensive assessment in cell culture models based on the understanding of the mechanism of action for each type of product.

Efficacy is not the only parameter to consider. You need to look at things like PK and immunogenicity that could be different if different glycans are present. It is easier to assess the criticality of efficacy than it is other of these things because they require animal systems or complex testing systems that are not just the in vitro potency assay.

How do you correlate no clinically meaningful differences in glycosylations and in vitro assays based only on real world reports? Part of that requires good pharmacovigilance reporting in all regions. The only way you can really do this is with head-to-head trials of products. So when looking at historical or literature reports of post-marketing surveillance pharmacovigilance, you can only infer that there is no impact of glycosylation or bioassay differences when there are no adverse events reported between, say, a biosimilar and an innovator product.

It was critical in terms of when to start doing glycosylation analysis of a reference licensed drug. Comments that were made there were that you really want to do a pretty thorough characterization of the target reference license drug first, and then use that information to select the clone that you are going to use that matches the glycan range of the target product as well as possible.

It is much more challenging to select the clone and discover that it is not in the same glycan range, because you can only do minimal things to try to fix it. And so there is a drive for more biosimilar companies to do a lot of assessment up front in clone selection, especially for glycan patterns.

In fact, FDA commented that they have seen problems when the wrong clone is picked. Even a 2% change in fucosylation can lead to large differences in vivo that can affect the approvability of the biosimilar candidate. And also mentioning immunogenicity and PK, that sponsors do tend to forget when they talk about critical quality attributes, it is not just critical quality to efficacy, it is critical quality to everything it is doing someone’s body.

A question about different expression systems, specifically NSO-zero to CHO between an originator and biosimilar product: The agencies indicated that this could be risky depending upon the kind of product being reproduced. So it is important to understand what the differences are in glycosylation based upon the biology of the system to determine if you are going to be able to mitigate those risks some other way.

What should be considered in designing a control strategy for glycosylation? Look at the critical quality attributes for all of the elements that they consider. And recognize that it is not just end product testing that is a part of this, it is a total control strategy, which is a concept that has been in the industry for a quite a while for biotech products.

How do we use sophisticated methods, like mass spec, for emerging markets and import testing?

Well, compared to the rest of the technologies needed it is complex, but it is transferable. It is just an instrument. You push the button and prepare some samples. It does require good training of analysts and well-validated methods.

You have to get good vendor support on instruments for the user laboratories. And there were a couple of meetings that were brought up where you tend to have a good interface with vendors who are providing these instruments. And we can talk to them about things like invalid rates and method suitability for its intended use in its operating environment.

One thing that was noted: However you get there, it is expected that methods to be used under GMP will be validated to be robust in the lab operation environment. So that is a quality requirement. And there are many different ways you can get there.

What happens to interchangeability if a post-approval change causes changes in the glycan structure? The European agency indicated that their principle is that once a similar biologic product is authorized, it is now its own stand- alone product with no tie to the originator. So if one or the other changes, it is managed through a post-approval change

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How would you notice if there was an adverse event reported in pharmacovigilance? How would you know if they were related among products unless someone drills down into the lot-by-lot assignment of what product batches have been attributed to the adverse events?

And the notation there was that the traceability of batches requiring lot numbers and sources would be a way that you could get those signals out of the data set. And the European agency indicated that Eprex is one of those cases where the signals were detected based on tracking specific lot numbers of the product. So this kind of puts pressure on the INN question: How do you know what the product is? And what is the lot number it came from to be able to do this pharmacovigilance that we need?

One question that came out was based upon a case study that was shown where the sponsor drilled way down into dissecting assay performance differences between the similar and the reference product. And when they found differences, they had to go back and make the assay less sensitive to determine what the functional differences were.

And the answer that we got from the regulatory bodies is that it is a challenging question, because you really do need to look at the totality of data and how it relates to the mechanism of action. And the sponsor indicated that they actually were asked by the regulatory body to add additional bioassay data and then to dissect the differences, and then later had to figure out the strategies about why those differences did not matter.

What FDA indicated, and what we were talking about, is that you do look for the most sensitive methods to see what the differences are. You cannot assess the differences unless you can see them. Then when you see them you determine how to do a risk assessment and determine what effect it could possibly have on product safety and efficacy.

It is the same question during post-approval changes for comparability for one product in the same company or between products. And you have to judge the impact of the differences or no impact of the differences on the clinical indication. So it is a body of data that goes out into great granularity, but then also has some less sensitive techniques to assess what the meaning is of some of these differences.

Biotech Product Tech Transfers

Then we went to tech transfer of biotech products. Some of my observations from those discussions were that: ● Regional public agencies have extensive experiences in biological products like vaccines and serums. ● In this region, there is a significant growth of the transfer of biotech products from local production of these complex protein products. ● Tech transfers that are occurring right now from private entities to public entities here require detailed discussions of all elements of the transfer activities including those for quality systems and quality agreements.

We had a lot of discussions about roles, responsibilities, liabilities, and lengths of time that these occur under quality agreements that were quite informative. The take home message, and this is from the public laboratory presentations and the industry presentations, is that it is highly critical to design and execute a comprehensive, systematic plan for generating the appropriate data to assess the material being produced at the recipient site against its intended characteristics to know whether or not that recipient entity is going to be able to make the materials it is supposed to make.

There were great case studies that were presented that can show what can go right and wrong in tech transfer projects, with specific points to consider. I do recommend that you look at the slides for all of these because they were far more detailed than I can summarize here. But here are a couple that caught my eye:

● Operational disconnects: This was actually from the public entity – that there were disconnects in testing capabilities. In one case the bioassay did not perform the same, the in vivo assay, because the animal food lacked iron, and the animals had different responses. In another case they had a mass spectrometer that was setup with the tech transfer partner. The brands were the same, but the models were different. So they had to negotiate how to manage those

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differences in that technology, which might not have been as subtle as you might expect, just because the models were different.

● At the analytical level, Mary was talking about the use of stress stability studies to reveal possible differences in pre- vs. post-transfer materials. She presented some very interesting case studies – three different case studies – where the two-stage statistical model that they had developed was extremely objective and highly sensitive to hidden differences, which saved them a lot of time – and I have to believe a lot of money – in chasing products that needed to have some remediation before they were ready to go.

● And then even culturally: [Biologics Consulting Group Senior Consultant Christina Vessely] pointed out some cultural differences that can affect successful transfer of technologies, including language. And I got it down, ‘Do notuse Google Translate for SOP’s.’ I got it Chris. I will not do that.

And even when the tech transfer does occur smoothly and everything does finally get established in the recipient location, you have change management. And this was a part of the post-approval change discussion that we had. This is a major challenge for tech transfer of products into regional facilities, because the staggered global approval process can generate the need to run parallel products in the facility.

So they are really strongly pushing back not to tech transfer things until all the changes are approved globally, because they will get stuck in the middle where changes are in various places around the world. And actually even sponsors deal with this all of the time in their own facilities. They have to run parallel processes sometimes until all the approvals are globally concluded.

What are the most time-consuming and costly aspects? We had two perspectives:

● From regional entities perspective, it was the cost of investment in infrastructure at the site. And we discussed what capital input and financial aid they can get from the sponsor vs. the government sector. Add to that the cost of the drug substance for the tech transfer.

Also they have issues regionally with the timing being less predictable, because they have a requirement from the government sector on the delivery of services and material. And any delay they have gets magnified. This happens in the private sector as well. It is just that we can usually yell louder and throw more resources to make it go away.

Anytime there is a lag in infrastructure it is going to have problems and have a domino effect on project timelines. That is definitely true. And they indicated towards the end of our discussions that even something as simple as getting enough drug substance by continuous harvesting can be a challenge to timelines and to costs.

● From the sponsor side, some of the costs were noted. The cost of the drug product transfer, which requires a lot of bulk API, can be very expensive. So they try to use surrogate materials in order to validate production processes, [such as] form/fill processes for drug product. Having to make that much API – not only does it cost a lot just for the API itself, but it takes production time away from API that you could be using to supply markets that are looking for the product.

Another comment was that tech transfer failures are extremely costly. Consecutive batches must pass or it would jeopardize the claim for success in tech transfer. And that is why there is so much attention paid to the design of the comparison study. The comparison can fail comparability – not because the products are different, but because the methods were not used appropriately or the data were not structured correctly for the analysis.

Analytical Considerations

How can sponsors and partners balance cutting edge technologies in emerging countries and markets?

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One comment was made that the instrument choices should factor in what the unusual lag is going to be. Does it have to be the cutting edge technology because of the sensitivity of the measurement that is being made? Or are there standard techniques that are still just as suitable for use without the most high-end piece of equipment that you can get?

There are challenges in old vs. new equipment in QC. It is not that they are not compliant. Old equipment, simple equipment, can very much be compliant to GMP. But when it comes to being able to get the information for the product quality, they may not be sufficiently sensitive or specific.

One approach was that when you build a new lab, that is a good time to get new instruments. And you can bridge between technologies. It was indicated from the industry side that often they add new technologies when they license a new product and then slowly retrofit that into legacy products by bridging to the old methods once they get experience in what that new technology is doing for them. If it is an advantage, then they will bridge it back to their existing legacy products.

In one of the product development partnership agreements it was noted that there are annexes specifically in terms of putting together a matrix based on each technology needed. They have these discussions with the private partners so that resources are available to be able to make sure they can accomplish the testing that they are supposed to accomplish by having the instruments they need for the project.

What are some of the practices in deciding whether to engage with multiple or single partners for manufacturing?

The cons were: ● Multiple costs: Costs are increased because multiple sites increase cost. ● You have to manage multiple streams of work. ● There is the potential for divergent practices, and ● Stability studies are a big cost for tech transfers, especially for those required for validating shipping stability, with large regional differences and requirements.

But there are some pros, and some of those are: ● being able to improve supply chain robustness ● being able to have access to things if you have an issue, and ● it is more risky to be limited to a sole site or sole provider, especially when you have the potential for environmental disasters like wildfires, floods, and earthquakes. So there are some very practical reasons to want to have multiple sites in your product stream.

One of the questions from the audience was: What does FDA and EMA see in terms of reviewing post-approval changes and tech transfers in dossiers?

EMA said there was not a specific problem. All of them are possibly problematic depending upon the product and the sites. But they do not see much problem with stability data. It really depends on the data sets, the product, etc.

Most problems that they do see are actually in the comparability data sets when they get results that are not comparable. And then sponsors have to find out how to justify that the differences are acceptable.

FDA said that the biggest problem they see is that there is not enough data oftentimes to support the change or tech transfer that is being conducted. Of course the agencies indicated that they do not see what did not work. We tend to keep those under wraps. And we do not tend to share with the agencies all the things that we found that were problems and that we fixed. We only tend to submit to them what worked.

But even still, they see deficiencies in data sets, particularly in not directly correlating the changes that you are making, and then the studies that you are designing to assess those changes. Make sure that you are measuring the right parameters to cover the nature of the changes.

One of the things that is a mantra out there in biotechnology is that the further upstream in a process a change is made, everything downstream is subject to comparison. And if you do a tech transfer, that is considered the ultimate upstream. Everything is transferred. And so the nature of those comparability studies is not as simple as just saying the release test for the drug substance are adequate. It is changing everything in terms of that process. We had some good examples from industry about what they did to assess those things.

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What are the pros and cons of staging and testing stability samples at satellite sites? It is always risky for a lot of reasons. It is not just stability samples, it is release testing as well.

Small differences in analytical methods can generate different results. We had examples of integration differences, and that is a subtle one. LIMS systems and stability protocol computer systems may not talk to each other between the sites. And you may not be able to get all the raw data you needed from the site to ensure that the results are accurate.

This is my own note. I did not add it in discussion, but I will add it here. This is specifically for stability. There could be different local practices on how they hold samples after they come from ICH conditions. In other words, in some labs it is their practices to always freeze everything when they get it from a stability station. Well, is that okay or not okay?

Or they hold it at 5°C. Well, that is fine. But it was frozen when it was stored. Or do they hold it at the ICH temperature in their laboratory? There is no guidance on how to do that. It is a matter of what the lab will do. But when you have two different laboratories doing it, that is a source of disconnect that can occur very easily.

Different ranges in the temperature of the stability chambers could impart different rates of degradation. Amgen had an example that was quite intriguing. It was a slight change in temperature that affected the stability rate.

Another note was that the sample containers used for drug substance stability studies between the two sites can be slightly different. The drug substance is often sub-aliquoted into smaller versions of the container closure, and those have to be matched as much as possible to the bulk container. And there are some subtle differences in those that can be different.

Shipping Considerations and Cold Chain Management

Then the shipping stability came into its own in the next session. There were just a lot of issues. And the comment here was about shipping test samples. The shipping excursions that we were talking about in this section were all about shipping materials that were to be used for product. But even shipping test samples from one location to another is not a trivial issue, because you want to be sure that the results you get out the test sample is accurate for product quality, not based upon some excursion that that sample had that does not reflect the overall batch.

It was even noted that it is not a matter of two different entities – a single entity can have two different physical locations. So if you call it one site, it is a site, but they can be forty kilometers apart. And there is still shipping that has to occur of the test articles between those two locations before they get the results for the stability pull point.

The last section that we had was on cold chain management. These are my seat of the pants observations from that.

We had excellent highly detailed presentations on specific strategy studies and international vs. regional regulatory requirements, including a discussion of a major new guidance from Brazil and an annex from Chile, and the discussions that are necessary.

I would strongly refer you to the speaker slides that are going to be available on the CASSS website, because they had some really terrific detailed information about the designs of these studies.

It was recommended that you follow good distribution practices. It was also noted that there are several good PDA technical reports on shipping studies. Also discussed was the ANVISA guidance that clarified the expectations for Brazil. And I will note that [Bernardo Moreira’s] presentation had thirty individual references associated with it for your information (see below). So you cannot say after this presentation that you did not know what was going to be expected.

There are still some regional differences that are currently experienced by global companies – for example, the type and nature of the product stress stability studies throughout shelf life for all possible environmental scenarios including pharmacy and patient handling conditions. All possible real-world conditions must be factored into one study design.

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And you have to be concerned about terminology – warm does not mean microwave. There are also requirements to validate all aspects of shipping conditions for both the packaging and the product, agitation, dropping, heat, light, water, and all seasonal variations in both hemispheres. This was reiterated several times in the presentations.

References Used by ANVISA to Create GDP Guideline Currently Under Development

● AMMANN, C. (2011). Stabilly Studies Needed to Define the Handling and Transport Conditions of Sensitive Pharmaceutical or Biotechnological Products. AAPS PharmSciTech, pp. 1264-1275 ● ANVISA. (12 de julho de 2013).http://portal.anvisa.gov.br/wps/content/Anvisa+IPortal/Anvisa/lnicio/Medicamentos/Assunto+ de+lnteresse/Produtos+Biologicos ● BADURINA, G., MAJIC, Z., & PAVLIN, S. (2011). Evaluation of Air Transportation under Controlled Room Temperature for Pharmaceuticals. Traffic & Transportation , pp.121-130. ● BISHARA, R. H. (2006a). Cold Chain Management—An Essential Component of the Global Pharmaceutical Supply Chain. American Pharmaceutical Review, pp. 1-4. ● BISHARA, R.H. (2008). Good Cold Chain Practices for Clinical Trial Materials/lnvestigational Medicinal Products. American Pharmaceutical Outsourcing, pp.1-4. ● BISHARA, R. H. (2005). Qualfication Versus Validation and Good Cold Chain Management Practices. Pharmaceutical Manufacturing and Packing Sourcer. ● BISHARA, R. H. (2006b). The Application of Electronic Records and Data Analysis for Good Chain Management Practices. The Journal of Pharmaceutical & Biopharmaceutical Contract Services. pp. 1-5. ● BRASIL (2010c). RDC n° 17. Estabelece os requisitos mlnimos a serem seguidos na fabricação de medicamentos. ● BRASIL (17 de agosto de 2005). RDc n°234. Dispõe sobre a importação de produtos biológicos em sua embalagem primária e o produto biológico terminado sujeito ao regime de vigilância sanitária. ● BRASIL.(18 de agosto de 2010b). RDC n° 3B.Alter a a RDC n°234, de 17 de agosto de 2005. ● BRASIL.(20de setembro de 2011). RDcn° 49. Dispõe sobre a realização de alteracções e inclusões pós-registro, suspensão e reativação de fabricação e cancelamentos de registro de produtos biológicos e dá outras providências. ● BRASIL (16 de Dezembro de 2010a). RDC n° 55. Dispõe sobre o registro de produtos biológicos novos e produtos biológicos e dá outras providêcias. ● DUTTA, S., SENGUPTA, M., DAS, S. K., & KUMAR, S. (2009). Importance of Cold Chain Management in Stability of Pharmaceutical Product. lnternational Joumal of Pharma. Research & Development, pp. 61-63. ● EUROPEAN UNION INSTITUTIONS, BODIES, OFFICES AND AGENCIES. (2013). Guideline on Good Distribution Practice of Medicinal Products for Human Use. Official Joumal of the European Union, pp.1-14. ● FORCINIO, H. (2013). Seeking cold-chain efficiency: medication safety and efficacy depend on maintaining products at the proper temperature. PharmaceuticalTechnology. ● GOFF, R. (2012). What Happeened On The Way to Your Costumer? Pharmaceutical Outsourcing, pp. 1-3. ● HAWKINS, J. (s.d.). Moving to Electronic Temperature Monitoring. http://www.worldpharmaceuticals.net ● HEALTH CANADA. (2011). Guidelines for Temperature Control of Drug Products during Storage and Transportation. pp.1-9. ● IRISH MEDICINES BOARD. (2011). Guide to control and monitoring of storage and transportation temperature conditions for medicinal products and active substances. pp. 1-20. ● LUCAS, T., BISHARA, R., & SEEVERS, R. (2004). A Stability Program for the Distribution of Drug Products. Pharmaceutical Technology, pp. 68-73. ● ORGANIZA AO MUNDIAL DA SAUDE. (2006). Good Distribution Practices for Pharmaceutical Products. pp.180-202. ● ORGANIZA AO MUNDIAL DA SAU DE. (2011). Model guidance for the storage and transport of time- and temperature-sensive pharmac eutical products. pp. 324-372. ● PARENTERAL DRUG ASSOCIATION. (2007). Guidance for Temperature-Controlled Medicinal Products: Maintaining the Quality of Temperature-Sensitive Medicinal Products through the Transportation Environment. PDA Journal of Pharmaceutical Science and Technology. pp. 1-20. ● REDDY, C. M., MALLIYALA, S., NARESH, Y., RAGHUNANDAN, H., &JINADATHARAYA, H. (2012). Good Cold Chain Management Practices. Journal of Pharmacy Research, pp. 5043-5047. ● SIMONNOT, 0. (2012). Monitoring Value. Parenterals: Cool Chain , pp. 34-36. ● TAYLOR, J. (2001). Recommendations on the Control and Monitoring of Storage and Transportation Temperatures of Medicinal Products. The Pharmaceutical Journal, pp. 128-131. ● TAYLOR, J., & HOLLOWAY, I. (2007). Transportation of Biological Products: European Regulations and Guidance. American Pharmaceutical Outsourcing, pp.1-4. ● TREDREE, R. (2007). The Supply Chain for Biopharmaceuticals: Maintaining the Correct Temperature. Official Journal of the European Association of Hospital Pharmacists, pp. 52-54. ● UNITED STATES PHARMACOPEA 35. (2012). (1079) Good Storage and Shipping Practices. pp. 1-6 ● (2012). FDA & ICH: Regulations and Standards for Temperature-Controlled Supply Chains.

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And although there are mechanical engineering standards for typical shipping test conditions, human factor studies, and even though it was mentioned in the question and answer portion, user surveys, are increasingly important for anticipating what should be tested in those studies. And the comment there was that it was just a continuous improvement element that you deal with from practical field experience. You just say, ‘I did not know you could do that. I guess we have to plan for that next time.’

And excursions have varying regulatory feedback. It is undoubtable that the impact on a protein product can be far more significant for excursions than on a chemical drug. So it is a very high-risk event for protein therapeutic products.

Some agencies even expect anticipatory data, including the robustness of shipping conditions to the hold temperature range that has been stated. Or whether or not there is support of stability brackets at the beginning of shelf life, at the end of shelf life, etc.

What are the main challenges? Planning all possible scenarios in advance. As was mentioned, use existing guidance documents and tech reports, but improvise as needed to support your own chain of custody and user practices. And remain vigilant to field reports about what is being done with your product.

Another challenge is navigating and coordinating all the regional variations required for importation of products. Geographical issues are very relevant to each regional agency, as are the data packages that are required for them to review to get your products into their sites.

Can multiple factors be combined into assessing shipping conditions and excursions?

And the answer was ‘possibly,’ if in the end the data can prove that the product will be stable throughout all of the shipping and handling conditions that it can experience throughout all of its shelf life. So the burden of proof is on the manufacturer to be able to get data sets that are meaningful enough to be able to make that assessment.

And [Amgen Contract and Product Quality VP Tony Mire-Sluis] mentioned that Amgen uses chamber robots where they can actually build in DOE studies with factorial designs and hundreds of replications with slight variances that can at least look at some physical conditions that they can model there.

So it might be possible in some regions. But there are still substantial gaps in the data sets required for shipping validation studies.

And then the last one that I have – this is an intriguing one, and I have a personal note for it too – How much can the shipping conditions vary from the ICH stability conditions that have been established?

These are the harmonized conditions around the world for stability data, right? So shouldn’t they exactly match what we do for shipping? And the answer is that they actually do not. It depends upon the degree of excursion. Time and temperature is a factor for what impacts a protein product. And there is no harmonized approach across the agencies of how much difference there can be from these carefully controlled ICH conditions and the stated label conditions.

I have a footnote here to tell you that I inspected a laboratory in Japan where their control room storage temperature of the reagents had a sticker that said from zero to 30° C. Because the JP says room temperature is zero to 30° C. It may have changed. That was three years ago.

The concept was hopefully that these things would get reconciled eventually. But even the USP has it at 15° to 30°. There is not a relationship between what is label claim allowed by the pharmacopeias and what ICH has harmonized so carefully for stability data.

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6731 NovaPure Advert.indd 1 3/29/2012 8:46:01 AM MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 Industry is Urging Latin American Agencies to Cooperate in Filling Lifecycle Management Regulatory Gaps for Biologics

The Latin America Federation of the Pharmaceutical Industry maintained that most of the guidelines are “high level,” and (FIFARMA) is advocating the need for the agencies in the “silent” on specifics that are required for implementation. region to extend the progress they have been making in regulating the approval process for biologics and cooperate During the panel discussion after Schreitmueller’s talk, Fabiola on filling the regulatory gaps for their life-cycle management. Muñoz from Chile’s Public Health Institute also asserted that more specific guidelines are needed across Latin America – As more biologics and biosimilars are approved in the region, for example, in the area of manufacturing changes. She noted what is “urgently” needed, the federation of associations that some discussions have taken place regarding setting up is stressing, is a common agreement on a viable risk-based a regional group to address the topic along with other CMC approach for regulating the post-approval changes of these issues warranting harmonization attention. products.

In his presentation at the opening session, Grupo Farma At the opening regulatory session of the CMC Brasil’s Reginaldo Arcuri explained that formulating Strategy forum, focused on “regulatory convergence, guidelines clarifying registration and post-registration predictability, transparency and priority reviews in expectations is among the main recommendations Latin America,” (see story on pp. 51-68) the head of that the association is making for improving the FIFARMA’s Regulatory and Biologics Working Group regulation of biotech drugs in the country. Grupo Thomas Schreitmueller took the opportunity to direct Farma Brasil represents nine innovator companies, attention to the consequences of the current lack of a and has a mission of strengthening the framework for harmonized coherent approach to biologic life-cycle innovation, manufacturing, and patient access. management and outlined the pathway that FIFARMA

is advocating for achieving it. Another Grupo Farma recommendation is to create the opportunity for companies to discuss their developing plans Schreitmueller is the Biologics Regulatory Policy Head for biotech drugs with ANVISA, which would help guarantee for Roche. FIFARMA includes the Federation of Central “more legal and regulatory certainty” for pharmaceutical American Pharmaceutical Laboratories (FEDEFARMA) and investment. Arcuri also cited creating and regulating GMPs the Association of Pharmaceutical Laboratories Research and Development (AFIDRO) among its members. specific to biological drugs as a further step needed to improve ANVISA’s regulatory process. Representing FIFARMA, Schreitmueller explored why a commonly adopted risk-based approach for post-approval Peru DIGEMID’s Edith Roxana Vásquez noted that her agency change regulation for biologics is important. His remarks has two technical documents in internal review covering further underscore the need for the ICH Q12 effort. The biotech products, which establish specific requirements for dialogue that took place at the forum shed additional light, registration and post-approval changes. The guidelines also in particular, on the challenges that will be on the table in establish two pathways for approval of similar biological implementing the ICH guideline globally. [Editor’s Note: products. see stories on pp. 3-50 for more on the global post-approval change landscape and the potential impact of the Q12 effort.] Mexico has been working over the last five years to update biotech product regulation, COFEPRIS’ Esenbeckia Guzman Existing Guidelines are High Level reported. In 2014 it published general operational rules for the assessment of technical information submitted for registration While “many” Latin American countries are harmonizing of biotech products. “Opportunity areas” the agency intends around international guidelines – such as those from the to focus on include new bilateral equivalence agreements and World Health Organization (WHO) and ICH – Schreitmueller priority review for high demand biotech products.

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High on FIFARMA’s list of areas where it would FIFARMA recommends that WHO and/or PAHO write a like to see clarification and harmonization for post- post-approval change guideline, and has even proposed a approval changes are predictability of approval title – “Guidelines for Procedures and Data Requirements timelines and agency expectations regarding for Changes to Approved BTPs.” The federation suggests change categorization, documentation, and data that the guideline outline the change classification concept, requirements. the documentation required for individual changes, and the procedures including timelines for their clearance. It The Roche exec pointed to a World Health Organization explains that the guideline is meant to be complementary to the existing technical guidance such as that from ICH. (WHO) guideline for recombinant DNA products, which recognizes the need to implement changes after In her summary of the Brasilia forum presented at approval. Among those referenced are improvement of its conclusion, industry consultant Nadine Ritter the manufacturing process, increase in scale, a site change, (Global Biotech Experts) noted that while industry improvement of product stability, and compliance with groups were “quite laudable about the progress changes in regulatory requirements. that has been going on globally for the preapproval requirements for biotech and biosimilar products, “Nevertheless,” he maintained, “the guideline is silent the next challenge is closing gaps on the post- on how to do this.” WHO references “some international approval changes.” guidelines like the ICH one on comparability. They also reference the comparability guidelines from EMA and “The good news is that we have a lot more harmonization FDA. These guidelines are also silent when it comes to and understanding of preapproval requirements globally. categorization of changes and timelines.” The bad news is that once we get them approved it goes into a nightmare scenario of multiple iterative changes that are ICDRA Charts Global Reg Course not in parallel.”

Schreitmueller explained how FIFARMA’s assessment No Need to Reinvent the Wheel of the gaps and its proposal how to fill them align with the recommendations of the International Conference of During the panel session after Schreitmueller’s presentation, Drug Regulatory Authorities (ICDRA) for improving the a discussion took place regarding the roles that ICH and the regulatory processes for biotherapeutics globally. Pan American Network for Drug Regulatory Harmonization (PANDRH) could play in harmonizing post-approval ICDRA provides the drug regulatory authorities of WHO change requirements in Latin America. member states with a forum to meet and discuss ways to strengthen collaboration and provide recommendations. ANVISA General Manager of Biological Products, Blood, Tissues, Cells and Organs Marcelo Moreira commented that the fastest way for Latin American Coming out of a 2014 ICDRA meeting were a set of countries to further harmonize would be for all of recommendations to the WHO Director General, including them to adopt the ICH guidelines. one to “strengthen the capacity of national regulatory authorities to assess and monitor the quality, safety and He noted that they were written with input from a large efficacy of biotherapeutics during the complete life-cycle group of experts and have been agreed to by the US, Europe, of the product.” Another recommendation encourages and Japan. As such, they have been tried and tested, he WHO to “update norms, standards, and tools to facilitate said, and can be adopted “without prejudice” to individual further development of expertise for regulatory evaluation country requirements. of biologicals.” Schreitmueller agreed, but noted that ICH documents tend “Having the word ‘lifecycle’ in there clearly demands that to be high level, and “for certain things you would need we should work on proper regulation driving this issue more detail.” He pointed to a central tenet emerging from a forward,” Schreitmueller asserted. “To me, this is a call for 2013 PANDRH conference he attended in Ottawa that “we WHO as well to come up with a global guidance on post- should not reinvent the wheel. If there are documents out approval changes for biotech products.” that can be adopted, let’s do it.”

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NOVEMBER / DECEMBER 2015 70 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 CDER Office of Biotechnology Products (OBP) Pharmacovigilance Also Needs Coordinated Division of Monoclonal Antibodies Review Chief LATAM Attention Sarah Kennett, who provided the FDA update at the forum, commented that she agreed “very much with A third FIFARMA priority is improving pharmacovigilance, what has been said here.” an area where empirical data indicates that the Latin American region is lacking. The need for strengthening She suggested that, rather than “100% convergence,” the the reporting process in Latin America was cited by other initial focus should be on “regulatory consistency,” which forum panelists. in itself would be “very, very beneficial.”

Kennett commented that the ICH documents have been Schreitmueller referenced a presentation by Malin Fladvad agreed upon by “a few” regulatory authorities in Latin from the WHO Uppsala Monitoring Center, given at a America and “are followed a bit by a number of others.” meeting in Brasilia on biosimilars a few weeks prior to the CMC Strategy Forum, in which she compared adverse event Harmonize Around ICH and its CTD reporting in Latin America to the rest of the world. Fladvad is responsible for development and management of WHO The lack of agreement in Latin America on common drug dictionaries, adverse drug reaction terminologies, standards such as the ICH CTD received attention during and ensuring mapping of drug adverse event reports at the the panel discussions, and the agency representatives cited the problem in outlining their priorities at the session’s Uppsala Centre in Sweden. conclusion. She noted that while the global reporting numbers over the Chile’s Fabiola Muñoz noted that the national regulatory last several years have shown a drastic increase, the numbers authorities in the region have differing requirements for the in Latin America were low and had shown no increase. information requested for product registration, the format of the information, and review timelines. She commented “I think everybody agrees that this is a big issue,” that using the CTD as a common design for submissions Schreitmueller commented. “It is not related to the agencies. and the formation of a work group to interact with industry Really it is an educational thing – that physicians and on submission requirements would be beneficial to both industry and regulators. patients are reporting the events. And obviously in other countries you have a bit of a different culture on that and ANVISA’s Marcelo Moreira emphasized that a top priority this is why we get more reports.” for his agency for the coming year is to settle on the use of the CTD as a way to produce cleaner applications and make He suggested that a strong pharmacovigilance review timelines more predictable. system is needed within each country as well as on a regional basis. FDA’s Kennett commented that among FDA’s priorities is pulling together information requested by the ICH eCTD The Roche official cited a presentation he saw from the working group, which is again active and considering what pharmacovigilance committee at EMA, which cited numbers revisions are needed. showing that on an annual basis they are getting one million FIFARMA’s top priority, Schreitmueller emphasized, adverse event reports. Out of these one million reports, is to help facilitate the implementation of common approximately ninety potential signals are expected. Out guidelines across the region. of these approximately ninety signals, forty label changes result. A second priority is to encourage regulatory agencies in the region to become more transparent in their drug approval “Think about it on an individual country basis,” he said processes. – “how many reports you will have and to what extent at the very end you will be able, in fact, to detect a signal.” “I think ANVISA absolutely made the first step in the very right direction with the approval letters” that it is now Schreitmueller suggested that, as in the post-approval posting to its website. “But we have many other countries change arena, PAHO and WHO could be instrumental in in the region, and it might be helpful to have this, or to have shoring up pharmacovigilance efforts in the Latin American something like this in other countries as well.” region. WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 71 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

FIFARMA REP THOMAS SHREITMUELLER ON ADVANCING LIFECYCLE MANAGEMENT REGULATION IN LATIN AMERICA

At the opening regulatory session of the 2015 CMC Strategy Forum in Brazilia, Roche Biologics Regulatory Policy Head Thomas Schreitmueller presented FIFARMA’s view of: ● the gaps in the regulation of post-approval changes for biologics in Latin America and how they can be filled, and ● how the federation’s proposal for a harmonized risk-based approach aligns with the recommendations of the International Conference of Drug Regulatory Authorities (ICDRA) for improving the regulatory processes for biotherapeutics globally.

I am speaking on behalf of FIFARMA. This is the regional industry association we have here in Latin America, representing most of the local industry associations…. We have a biologics and regulatory working group that I am chairing. When I saw the topic we had for this session, I thought, ‘well, let’s focus on a specific topic really around convergence.’ So this is really a call for a risk-based lifecycle management approach, which I think we really need for biologics.

Lifecycle Management Gaps

Here to a certain extent you see a bit of a problem statement. We see – and you have seen it before in the other presentations – a lot of progress around the establishment of regulations for biopharmaceuticals, for biotherapeutics. But we see gaps in the regulatory approaches governing the life-cycle management of these products, specifically for this broader class.

This is getting more important now over time, because as you have heard, we will see more and more biosimilars coming to the market. We will also see more new biotech products coming to the market. Getting them approved is just the first step. Then you will see manufacturing changes. How can we have more predictability in handling these changes?

Here is what we at FIFARMA see as the situation in Latin America (see box below). As I was saying before, we have more and more countries promulgating regulations according to WHO standards, but still manufacturers are struggling with the implementation of post-approval changes….

I think it is clear to everybody that there is a need for manufacturing changes for biologics. This is true for biosimilars as well as for originator products, because to a certain extent you have to continuously drive improvement of these processes. Also, you have to maintain high quality.

I think as new technologies are popping up you should implement them to keep your processes state of the art. Also – and this is true of course for innovator products as well – you have to do label changes when you get new indications and stuff like that. Here, very often, you lose a lot of time until you get those approved (see box next page).

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NOVEMBER / DECEMBER 2015 72 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

I also will not go into details because I think everybody is Schreitmueller used the followlng graphic to illustrate that “any change in aware that there is guidance the manufacturing process of a biotech product is a multiple-year endeavor out on how to introduce when executed globally.” manufacturing changes, how to generate the respective data packages dependent on the change, how to introduce the risk categorization, etc. All of this in principal is available. Nevertheless, to implement a change it really would take years for the regional and global changes.

As you know, we have the WHO guideline for recombinant DNA products. The guideline, in fact, recognizes that there is a need to introduce manufacturing changes.

Here you see the citation directly coming from the guideline: ‘Changes to the manufacturing process of an rDNA-derived biotherapeutic often occur both during development and after approval. The reasons for such changes include, for instance, improvement of the manufacturing process, increase in scale, a site change, improvement of product stability, or compliance with changes in regulatory requirements.’

Nevertheless, the guideline is silent on how to do this. They reference some international guidelines like the ICH one on comparability. They also reference the comparability guidelines from EMA and FDA.

These guidelines are also silent when it comes to categorization of changes. What, if you really look in detail, is a major change? What is a moderate or a minor change? How do you classify those?

These guidelines are also silent when it comes to timelines – for example, how much time does an agency need in order to evaluate a minor change versus a major change? This is really what industry is struggling with, because there is not that much predictability if we look around, including here in Latin America.

Also there is no clear definition when it comes to documentation and data requirements for certain changes. Having all of this available of course would really make life at the agency as well as on the industry side much easier.

Luckily enough, we see that biotech products over the recent years have gotten more and more attention. You see this in many important meetings. Here you see the resolution that came out of the WHA [World Health Assembly] – last year or the year before – when they were talking about regulatory systems strengthening for medicinal products where they specifically mention that we need to ‘strengthen the capacity to regulate increasing complex biological products.’ In the World Health Assembly, all the members from WHO are there and they are behind that resolution.

ICDRA Recommendations

You also may remember our CMC strategy forum last year was just before the ICDRA [International Conference of Drug Regulatory Authorities] meeting that took place in Rio de Janeiro. I am referencing this meeting because from the ICDRA meeting are coming some very important recommendations that I strongly believe should also drive the lifecycle management of biotech products.

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NOVEMBER / DECEMBER 2015 73 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

Here you see some of these recommendations: One recommendation is that we should ‘strengthen the capacity of NRAs [national regulatory authorities] to assess and monitor the quality, safety and efficacy of biotherapeutics during the complete lifecycle of the product.’ This is an important recommendation. In fact, from my perspective this really should trigger the work on having post-approval change guidelines for biotech products available.

Another recommendation coming from the ICDRA meeting says ‘NRAs are encouraged to explore possibilities to promote convergence and harmonization of regulatory processes and use joint collaborative assessments.’ Well, think about it. Again, I am focusing on post-approval changes. We could envision agencies really working together if there is a common basis.

If, for example, we would have a regional or a global document that is really laying out what should be done when a certain change for a biotech manufacturing process is introduced, this would help agencies to work together or eventually to recognize each other’s regulatory decisions.

Another recommendation also coming from the session at ICDRA dealing with biosimilars: it is also quite nice to read this, because here the recommendation is ‘to ensure the regulatory oversight throughout the lifecycle of biotherapeutic products, including similar biotherapeutic products, to assure quality, safety, and efficacy of these products,’ and to ‘improve efficiency of regulatory evaluation of biotherapeutics, including biosimilars in order to improve access of care to products of assured quality, safety, and efficacy.’

I think this is really great recommendation. And again, having the word ‘lifecycle’ in there clearly demands that we should work on proper regulation driving this issue forward. It also asks WHO to ‘update norms, standards, and tools to facilitate further development of expertise for regulatory evaluation of biologicals.’ To me this is a call for WHO as well to come up with a global guidance on post-approval changes for biotech products.

So clearly, based on this ICDRA recommendation, I think it will be extremely important in the future that WHO and also PAHO come up with global guidance, eventually similar to what we have seen for the biosimilars. First there was the WHO guidance, which has been translated into a technical document from PAHO and was actually driving the regional convergence we see now in Latin America for these products.

We would really envision something similar for post-approval changes for the region. I think it does not make sense now that each and every country is developing their own guidance. Because at the very end we may end up with even a higher complexity than we are facing now. But really it would be great to have a regional or global standard and that individual countries could converge on.

Conclusions

In conclusion, our recommendation really would be that WHO and PAHO should work on a post-approval changes document. This is also a call to the regulators we have here in the room, perhaps to engage in discussions with PAHO and WHO and really help us in driving regulations on that level for those products.

I think also here it is recognized that both biotherapeutic innovator products as well as biosimilars have their own lifecycle. This is recognized in practically all of the guidelines. So it will be important for both products, for both biosimilars as well as for originator products. I think having this guideline in place would extremely facilitate the collaborations between the agencies from different countries, and at the very end may also really help to overcome certain resource problems you are facing.

We have heard this from everybody: Resources are limited. But really working along the same lines can help that a lot. This is why we recommend for both PAHO and WHO to come up with a guidance for procedures and data requirements for changes to approved biotherapeutic products where we clearly have outlined the change classification concept, the documentation requirements for individual changes, as well as the procedures, including timelines, for approving these changes. I think this would really help everybody.

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Updates in Brief

UNITED STATES

CMC/REVIEW

Woodcock 2016 Priorities for CDER

In mid-December at the FDA/CMS Summit in Washington, DC, CDER Director Janet Woodcock discussed her center’s 2015 achievements and 2016 priorities. Among the 2015 achievements were: ● meeting and exceeding GDUFA performance goals ● “stabilizing” the new Office of Generic Drugs ● putting in place the new Office of Pharmaceutical Quality ● issuing multiple draft and final guidances on pharmacy compounding ● issuing multiple draft and final guidances ● putting in place the Panorama IT system for workflow management, document and data access, which now hosts the generic drug review process, and● responding to Congressional requests on “21st Century Cures” legislation. Woodcock divided 2016 priorities into “front burner,” “important,” and “continuing” categories. Among the “front burner” priorities are: ● negotiating PDUFA VI, GDUFA II, and BSUFA II ● continuing to implement new and clarified statutory provisions on drug compounding and outsourcing facilities ● continuing implementation of the track and trace program ● continuing to plan for and build out Panorama for the new drug review process and other regulatory functions, and ● filling more than 600 vacant CDER staff positions.

Emerging Technology Draft Guidance

In late December, FDA released for comment an eight-page draft guidance titled “Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base.” In the draft, FDA invites companies to participate in a program involving the submission of CMC information containing emerging manufacturing technology to FDA – specifically, those with “elements subject to quality assessment for which the agency has limited review or inspection experience, where the technology has the potential to modernize the pharmaceutical manufacturing body of knowledge to support more robust, predictable, or cost-effective processes.” The program is open to companies that intend the technology to be included as part of an investigational new drug application (IND) or original or supplemental new drug application (NDA), abbreviated new drug application (ANDA), or biologic license application (BLA) reviewed by the Center for Drug Evaluation and Research (CDER). The agency notes that “while the implementation of emerging technology is critical to modernizing pharmaceutical manufacturing and improving quality, FDA also recognizes that innovative approaches to manufacturing may represent challenges to industry and the agency. By the very nature of an approach being innovative, a limited knowledge and experiential base about the technology may exist. Pharmaceutical companies may have concerns that using such technologies could result in delays while FDA reviewers familiarize themselves with the new technologies and determine how they fit within existing regulatory approaches. Through [this program], the agency intends to encourage the adoption of innovative approaches to pharmaceutical manufacturing.” Comments are due by February 22.

HCT/P Public Meeting

FDA announced a public meeting to be held for feedback on four draft guidances relating to the regulation of human cells, tissues, or cellular or tissue-based products (HCT/Ps). The meeting will be held on April 13, 2016 at FDA’s White Oak Campus. Electronic or written comments will be accepted after the public hearing until April 29, 2016. The meeting will focus on stakeholder input regarding three draft guidances published in 2014 and one published in late October, 2015. The 2014 guidances are: ● Recommendations for meeting the minimal manipulation criterion, 21 C.F.R § 1271.10(a)(1) ● FDA’s current thinking as to how the four criteria in 21 C.F.R § 1271.10(a) apply to HCT/Ps produced from adipose tissue, and ● Recommendations for meeting the “same surgical procedure” exception from Part 1271. The October draft guidance is on recommendations for meeting the homologous use criterion in 21 C.F.R § 1271.10(a)(2). In its announcement, FDA explains that it is “seeking feedback, both general and specific, from a broad group of stakeholders, including HCT/P manufacturers, tissue establishments, biological and device product manufacturers, health care professionals, clinicians, biomedical researchers, and the public.” In particular, the agency is interested in comments regarding scope, clarity and consistency, particular topics covered, the particular questions posed, and additional issues needing guidance.

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NOVEMBER / DECEMBER 2015 75 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 IND Communications Draft Guidance

FDA announced in early December the availability of a draft guidance on “Best Practices for Communication Between IND Sponsors and FDA During Drug Development.” The purpose of the guidance is to describe best practices and procedures for “timely, transparent, and effective” communications between IND sponsors and FDA at critical junctures in the drug development process. A mandate for the guidance was contained in the latest re-authorization of the Prescription Drug User Fee Act (PDUFA V, 2012). CDER and CBER gathered review staff best practices and sought input from interested parties via a Federal Register notice in October 2014, which were used to inform the writing of the guidance. In addition to the introduction and background sections, the draft includes sections on: ● FDA’s philosophy regarding communication with IND sponsors ● scope of interactions between the sponsor and the review team ● types of advice that are appropriate for sponsors to seek ● general expectations for timing of communications ● best practices and communication methods, ● resources for sponsors ● additional contacts, and ● resources. Comments are due by February 9.

Combining ANDAs

In early November, the CDER released a “manual of policies and procedures” (MAPP) describing how multiple abbreviated new drug applications (ANDAs) for the same strength of the same drug product may be combined into one “parent” ANDA. Historically, ANDA applicants submitted a separate, original ANDA for each strength of a particular generic drug product for which they sought FDA approval. This practice, the MAPP notes, “resulted in multiple ANDA numbers for different strengths of the same drug product.” Under the new scenario, the combined parent ANDA is the one associated with the strength upon which all in vivo bioequivalence (BE) studies were conducted and serves as the basis for BE waivers for the remaining strengths. Once these ANDAs are consolidated, the applicant may submit one prior approval supplement (PAS) or changes being effected (CBE) submission to the parent ANDA for any subsequent change to all strengths of the drug product and one annual report.

Biosimilar Meeting Guidance

FDA has announced the availability of a final guidance on “Formal Meetings Between the FDA and Biosimilar Biological Product Sponsors or Applicants,” which finalizes the April 2013 draft. The guidance provides recommendations to industry on formal meetings between FDA and sponsors or applicants relating to the development and review of biosimilar biological products regulated by CDER and CBER. It is intended to assist sponsors and applicants in generating and submitting meeting requests and the associated meeting packages to FDA for biosimilar products. The Federal Register announcement notes that “as a result of the public comments, information has been added to provide clarity on the process for requesting meetings, including identifying the appropriate meeting type, and the data expectations to support the appropriate meeting type.”

Designated Medical Gases Draft Guidance

In late November, FDA issued a draft guidance on “Certification Process for Designated Medical Gases,” which revises a late- 2012 guidance of the same title. The 2012 draft was issued to fulfill a requirement in the 2012 FDA Safety and Innovation Act (FDASIA) Title 11 for a designation system to be put in place and overseen by FDA (IPQ October 8, 2012). The 18-page draft, out for comment until January 25, 2016, includes sections on: ● the statutory certification process ● the current list of designated medical gases ● requesting a certification ● evaluating a certification request, and ● enforcement of the certification requirement. It also includes a draft certification request form. In the Federal Register notice announcing the 2015 draft, the agency notes that in response to the comments it received on the previous version, revisions were made to the discussions of labeling for final use containers and documentation by a person or entity that markets a designated medical gas but is not the original manufacturer or marketer of the gas. The December 2012 draft also contained a detailed implementation timeline, which has been removed in the revised version because the dates listed in the implementation timeline have all passed. FDA also made “small revisions to improve readability and address minor technical issues.” No revisions were made to the draft certification request form (Form FDA 3864) or form instructions.

OTC Sunscreen Draft Guidances

FDA has released four draft guidances covering over-the-counter sunscreens as required by the Sunscreen Innovation Act (SIA) of 2014, which amended the Federal Food, Drug, and Cosmetic Act to establish a process for the review and approval of over-the- counter (OTC) sunscreen active ingredients. Among other things, SIA established new procedures and review timelines for FDA to determine whether a nonprescription sunscreen active ingredient or combination of active ingredients is generally recognized as safe and effective (GRASE) and not misbranded when used under the conditions specified. The four draft guidances were released on November 23 for a 60-day comment period, and cover: ● format of submissions by the sponsor to support GRASE status ● withdrawal of a sunscreen application ● requesting an advisory committee review, and ● safety and effectiveness data to determine whether a sunscreen active ingredient is GRASE. WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 76 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 Fixed Combination Drug Regulation

In a December 23 Federal Register notice, FDA is proposing to revise existing regulations on prescription fixed-combination drugs and establish new provisions applicable to prescription and nonprescription fixed-combination and co-packaged drugs and combinations of active ingredients under consideration for inclusion in an OTC monograph. Fixed-combination or co-packaged drugs are intended to provide greater effectiveness – either by having a greater effect for a single indication or by treating more than one indication – than either ingredient alone, or by having one active ingredient enhance the safety or effectiveness of another active ingredient. For purposes of the proposed rule, the term “drug” includes biological products but does not include medical devices. Under the proposed rule, fixed-combination and co-packaged drugs will be generally recognized as safe and effective when three criteria are met: ● each active ingredient must make a contribution to the effect(s) of the combination, enhance the safety or effectiveness of an active ingredient, or minimize the potential for abuse of an active ingredient ● the combination of the active ingredients does not decrease the safety or effectiveness of any of the individual active ingredients, and ● the dosage of each active ingredient must be such that the combination is safe and effective and provides “rational concurrent therapy.” Comments can be submitted to the docket until March 22, 2016.

Biosimilar Substitution

New Jersey is the latest US state to pass a law that will allow the substitution of biosimilars at the pharmacy level, the Generics and Biosimilars Initiative (GaBI) is reporting. New Jersey Governor Chris Christie signed Assembly Bill 2477 into law on November 9, 2015, following unanimous passage in the New Jersey Senate and Assembly earlier in the year. The New Jersey bill authorizes a pharmacist to substitute a biosimilar for a prescribed biological product if the biosimilar has been approved by FDA as interchangeable and the prescriber has not indicated “do not substitute.” To date, 15 states have passed legislation allowing for substitution of biosimilars: ● California ● Colorado ● Delaware ● Florida ● Georgia ● Indiana ● Massachusetts ● New Jersey ● North Carolina ● North Dakota ● Tennessee ● Texas ● Utah ● Virginia, and ● Washington.

GMP/INSPECTION

Deviation Reporting for HCT/P Products

In late December, FDA released a 16-page draft guidance on deviation reporting for non-reproductive human cells, tissues, and cellular and tissue-based products (HCT/Ps) that are regulated solely under section 361 of the Public Health Service Act (PHS Act) and Title 21 of the Code of Federal Regulations (CFR) Part 1271. The guidance describes scenarios to illustrate who must report, what must be reported, and when such reports must be submitted to FDA. Also provided are examples of both reportable and non-reportable events, including examples chosen to illustrate the most frequently reported HCT/P deviations that have historically been submitted to FDA’s Center for Biologics Evaluation and Research (CBER). The deviation examples are divided into five categories: ● donor eligibility ● donor screening ● donor testing ● processing and process controls, and ● receipt, pre- distribution, shipment, and distribution.

Contaminated API from China

FDA alerted compounding pharmacies in early December that certain lots of baclofen active pharmaceutical ingredient (API) manufactured by Taizhou Xinyou Pharmaceutical and Chemical Company in Taizhou City, China, may be at risk for contamination with particulates and should not be used to compound sterile injectable drugs. FDA contacted Taizhou through its US agent, and the company confirmed that, due to the level of controls in the manufacturing process, the baclofen API it manufactures is not suitable for use in injectable drugs, as it may contain particulate matter. The use of baclofen API contaminated with particulate matter can result in serious injury if injected directly into the spinal column and may also clog pumps used to administer the medication. There is also a potential risk that the baclofen API may be contaminated by endotoxin or microorganisms.

Chemical Contamination in Chinese Drugs

In late December, FDA alerted drug compounders and manufacturers that drug shipments from Tianjin, China may be at risk of chemical contamination from two massive explosions at the Tianjin Dongjiang Port Ruihai International Logistics Company chemical warehouse in August 2015. FDA has found hydrogen cyanide contamination in two shipments of drugs from Tianjin Tianyao Pharmaceuticals Company located in Tianjian, approximately 30 kilometers (18 miles) from the explosion site. Two other shipments from the company were found not to contain hydrogen cyanide. FDA notes that the shipments appear to have been intended for use in pharmacy compounding. The announcement reminds drug manufacturers and compounders that source finished drug products, active pharmaceutical ingredients (APIs) and excipients from the Tianjin City region to that it is

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NOVEMBER / DECEMBER 2015 77 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 their responsibility to ensure that all shipments they receive “are free from contamination associated with the explosion and not contaminated in any way.”

NIH Pharmacy Compounding Report

A National Institutes of Health (NIH) task force released a report with the findings of its investigation into its Clinical Center Pharmacy Department compounding operations that was initiated after a ten-day FDA inspection in May 2015 that discovered a number of deficiencies related to facilities, personnel training, and standard operating procedures in its Pharmaceutical Development Service (PDS) and Intravenous Admixture Unit (IVAU) labs. PDS is the compounding laboratory that formulates and packages batches of investigational drugs and other research products for use in research protocols at the NIH Clinical Center. The IVAU formulates and packages sterile products on a case-by-case basis to fulfill medical prescriptions for individual participants and patients while they are at the Clinical Center. NIH suspended sterile operations of PDS upon receiving FDA’s inspection report in May. However, because the observations in the IVAU were less serious, NIH has been able to maintain IVAU operations during the course of ongoing remediation efforts. The FDA inspection occurred after the report of fungal contamination of two vials of albumin in the PDS in April, 2015. FDA’s observations and the NIH Task Force’s assessment revealed that the underlying problems “were widespread and longstanding,” the report maintains. A consulting firm employed by the task force reported that “the extent of the problems would necessitate significant facility construction for both the PDS and IVAU to meet modern requirements for cGMP compliance.” To respond to FDA expectations, the NIH Clinical Center submitted an interim corrective action plan for the PDS and IVAU in late June, 2015. Subsequent updates have also been provided on short- term remediation activities and the changes that have been implemented to enable ongoing operations in the IVAU.

Dietary Supplement Indictments

In mid-November, FDA announced the results of a year-long sweep of dietary supplement manufacturers and distributors, which resulted in civil injunctions and criminal actions against 117 firms that produced or distributed dietary supplements and tainted products falsely marketed as dietary supplements. Led by the U.S. Department of Justice, the initiative included FDA, the Internal Revenue Service’s Criminal Investigation Division, the Federal Trade Commission, the U.S. Postal Inspection Service, the Department of Defense, and the U.S. Anti-Doping Agency. Prominent among the criminal actions was an 11-count indictment against USPlabs, a Dallas, Texas-based company. The defendants were arrested/surrendered to the U.S. Marshal’s Service. Along with the arrests, FDA and IRS special agents seized assets in dozens of investment accounts, real estate in Texas, and a number of luxury and sports cars. The indictment alleges that USPlabs engaged in a conspiracy to import ingredients from China using false certificates of analysis and false labeling and then lied about the source and nature of those ingredients after it put them in its products. It further alleges that USPlabs and its principals told FDA in October 2013 that it would stop distribution of OxyElite Pro, once the product had been implicated in an outbreak of liver injuries, but that despite this promise, USPLabs engaged in a “surreptitious, all-hands-on-deck effort to sell as much OxyElite Pro as it could as quickly as possible” at dietary supplement stores across the nation.

Hikma Pharma Close-Out Letter

Terrugem, Portugal-based Hikma Farmaceutica has received a close-out letter from FDA indicating that the agency believes the firm has successfully addressed the violations contained in its October 2014 warning letter that resulted from a March 2014 inspection. The close-out letter was based on the firm’s responses to FDA. The agency notes in the letter that “future inspections and regulatory activities will further assess the adequacy and sustainability of the corrections.” Violations cited in the letter were related to EM excursion investigations and the associated CAPAs, and the firm’s quality SOPs( IPQ “Monthly Update” November 2014, p. 39). Hikma develops, manufactures and markets a broad range of both branded and non-branded generic and in-licensed drugs.

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NOVEMBER / DECEMBER 2015 78

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MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

EUROPE

CMC/REVIEW

Ph. Eur. Draft Chapter on Co-Processed Excipients

The European Pharmacopeia (Ph. Eur.) has released for comment a draft chapter on co-processed excipients. A co-processed excipient is defined as any combination of two or more excipients obtained by physical co-processing that does notleadto the formation of covalent bonds. It notes that the individual components of a co-processed excipient must comply with the requirements of any corresponding individual monographs and of the general monograph on substances for pharmaceutical use. Sections are included on: ● production ● characteristics ● identification ● pharmacopeial tests ● labeling, and ● functionality- related characteristics. Comments are due by December 31, 2015. The draft can be viewed here after logging into the EDQM site.

EMA Type IB Variation Checklist

EMA has released a checklist for Marketing Authorization Holders (MAHs) to use to facilitate the submission of complete and correct Type IB variations. Type IB variations are considered minor and do not require formal approval, but must be submitted to EMA 30 days prior to implementation to allow the agency to review the application and deem it acceptable. The four-page checklist notes that the submission must be in eCTD format, and includes requirements for: ● the cover letter ● the application form ● supporting documentation ● product information ● changes to the risk management plan, and ● changes to an active substance master file. The agency “strongly recommends” that the checklist be used in advance of submission of any Type IB variation.

UK Human Factors Guideline

The UK’s Medicines and Healthcare products Regulatory Authority (MHRA) announced the results of its second of four meetings with stakeholders to get input on a guideline the agency is working on that will cover human factors analysis related to medical devices and drug/device combination products. The guideline will include sections on the regulatory framework pre-market and post-market, human factors standards, and simulation/usability. The working group includes representatives from notified bodies, academia, the National Institute for Health and Care Excellence (NICE), trade bodies and professional associations as well as representatives from the devices, licensing and vigilance and risk management in medicines divisions at MHRA. It is chaired by MHRA Devices Expert Advisory Group (DEAC) Chair Peter Nightingale. A draft guideline, which initially will be shared with a larger group of stakeholders, is targeted for a mid-2016 release.

MHRA Baseline Guideline

Britain’s MHRA has released a guideline covering “baseline submissions.” A baseline submission refers to submission of all current valid documents along with a statement that the content has not changed, only the format. “For transparency reasons and ease of process, it is recommended that baselines are applied when there are no pending regulatory activities for the product,” the guideline states. Baseline submissions are usually required when converting the format used for submission of procedures and/ or correcting technical issues relating to previously supplied documents in the current submission format.

EMA Interaction Framework

The European Medicines Agency (EMA) has published a “framework for interaction between the EMA and industry stakeholders,” which aims to formalize and structure its interactions with industry and industry associations to facilitate and streamline communications. EMA notes that as it has grown in size and the scope and complexity of its responsibilities under EU legislation have increased, “its approach to stakeholder management has become fragmented,” as communications in the past were managed by various operational units. The framework seeks to build a centralized, consistent approach to communication, by: ● providing a platform to exchange views and promote dialogue with stakeholders on topics ● improving communication and providing efficient, targeted and timely information in a proactive manner ● enhancing stakeholders’ understanding of the EU medicines regulatory framework and the role of the regulators and enriching the EMA’s understanding of issues that are pertinent from the industry perspective for product development and licensing ● building on existing interactions between industry, academia and other stakeholders, and ● increasing transparency of stakeholders engaging with the EMA. The effort will be gradually implemented beginning in Q1 2016.

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NOVEMBER / DECEMBER 2015 79 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 EMA Labeling Review

At an early-November EMA “industry stakeholder platform on the operation of the centralized procedure for human medicinal products” held at the agency’s headquarters in London, EMA Medical Information Sector Administrator Monica Prizzi gave a presentation on product labeling reviews. The label review for a new product runs in parallel to the scientific evaluation of the marketing application, with the review of the first label mockup taking place at 120 days after the application is submitted. “Problematic areas” the agency has seen during labeling review include: ● logos and pictograms interfering with the readability of the information ● available space not used to enhance legibility/readability of information ● poor contrast between text and background ● too much prominence on one element, which can impair visibility of the rest of the information ● small font size, and ● too many colors, which the agency maintains can be “confusing.”

EMA Five-Year Plan

EMA and Heads of Medicines Agencies announced their strategic goals for the next five year period, titled “EU Medicines Agencies Network Strategy to 2020.” The new plan, announced in mid-December, includes 16 objectives around four themes: ● contributing to human health ● contributing to animal health and human health in relation to veterinary medicines ● optimizing the operation of the network, and ● contributing to the global regulatory network. Among the GMP/CMC goals are further strengthening pharmaceutical supply chains to exclude falsified medicines and addressing data integrity concerns in applications. “The integrity of the data in the studies used to support market authorization is fundamental to trust and confidence in the products themselves,” the report notes. Also planned are continued efforts regarding regulatory convergence in collaboration with WHO, EDQM, FDA, Japan’s PMDA, the International Coalition of Medicines Regulatory Authorities (ICMRA), the International Pharmaceutical Regulators Forum (IPRF) and the International Generic Drug Regulators Program (IGDRP).

MHRA Submission Format

UK’s Medicines and Healthcare products Regulatory Agency (MHRA) announced that beginning February 1, 2016, it will no longer accept regulatory submissions on physical media (CD/DVD). The agency explained that it had completed a consultation with industry trade associations in which there were no “unresolved objections” to its phasing out the acceptance of physical media and instead requiring all submissions to be performed online.

EMA Variation Deadlines

EMA is advising marketing authorization holders to submit any transfer of marketing authorization applications or type IA variations for 2015 by the end of November to enable the agency to acknowledge the validity of the submissions before its closure between December 24, 2015 and January 3, 2016. Marketing authorization holders are also advised to submit any type IB variations or groupings of type IBs and type IAs by December 1, 2015. For submissions received after that date, the assessment may not begin until January 2016.

GMP/INSPECTION

French Manufacturing Plant Suspended

In mid-November, France’s National Agency for Medicines and Health Products Safety (ANSM) suspended operations at contract manufacturer Catalent’s softgel manufacturing facility in Beinheim, France. The suspension relates to the occurrence of out-of-place softgel capsules in several product batches that were detected during quality control procedures and removed prior to distribution to patients. Based on its preliminary investigation, Catalent believes “it is highly unlikely that the capsules could have been misplaced through unintentional human error or from failure of a control process, and that the incidents could be potentially related to a deliberate malicious action by one or more individuals.” The firm reports that it has notified the appropriate French law enforcement authorities of the incidents, and that it is “cooperating fully” with the ANSM during its inspection and investigation. Catalent reported the suspension and related information in a Form 8-K filingwith the US Securities and Exchange Commission (SEC).

French API Plant Non-compliant

France’s National Agency for Medicines and Health Products Safety (ANSM) has issued a statement of GMP non-compliance for a Cargill manufacturing site in Lannilis, France. The release of the report from a July inspection follows a previous decision by the French agency to “suspend the manufacture, packaging, the marketing, distribution, export and use of raw materials produced by the company.” In the inspection report, Cargill received 14 observations, including one deemed critical and four that are WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 80 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 major. The critical observation was regarding “deficient” mixing operations, claiming that “conformity of the final batches to specifications, notably Ph.Eur. specifications, could not be guaranteed.” The major observations were around: ● manufacturing an active substance without ANSM authorization ● a change control related to the suppression of one filtration step in the active substance manufacturing process deemed “deficient” ● a lack of master production instructions and batch production records for API manufacturing, and ● a lack of review of batch production records of critical process steps before release of the active substance for distribution.

Italian Radiopharmaceutical Plant Non-Compliant

An Italian Medicines Agency (AIFA) inspection of an Iason Italia radiopharmaceuticals plant in Rome has resulted in a GMP non-compliance statement, published in the EU’s EudraGMDP database. The October 2015 inspection reported three critical deficiencies, eleven major deficiencies, and five minor. The report notes that the “main deficiencies” were related to sterility assurance and risk of contamination/defects of the final product. The critical deficiencies included: ● failure to fully investigate and document out-of-specification results for microbiological environmental monitoring in class A isolator and class B/C surrounding areas ● use of an expired reagent in manufacturing, and ● incomplete master batch records with inadequate QA review.

AstraZeneca API Import Ban

An inspection conducted by Sweden’s Medical Products Agency (MPA) of an AstraZeneca active pharmaceutical ingredient (API) plant in Bangalore, India has resulted in an import ban for all lots the API terbutaline sulfate manufactured at the plant in 2014. Terbutaline sulfate used for the manufacture of non-sterile and sterile finished products, and is exported from the Indian plant to Sweden and China. During the inspection, 24 deficiencies were found. None of the deficiencies was critical, but four major deficiencies were found, including two regarding documentation routines and data integrity, and one each in the areas of design and maintenance, and validation. The EudraGMDP report cites four failed validation runs executed between February and November 2014 that included “several OOS results, adjustments, test batches and inappropriate root cause analysis.” After a fifth validation run “the company stated that the process was successfully validated, despite a specification change (exclusion of a melting range) that was necessary to approve the validation. After the validation the rejection rate was very high (approximately 40%) and for this reason the company stopped the production in December 2014,” the report states. One week prior to issuance of the EU non-compliance report, AstraZeneca announced that it would close the site due to “low demand for the API in its export markets.” The site’s GMP certificate, issued by MPA, expired in February 2015.

Wockhardt Indian Plant GMP Certificate

Indian drug firm Wockhardt announced in early December that its Chikalthana plant at Aurangabad in Maharashtra received a GMP certificate from the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) after an inspection of the plant, the Economic Times of India is reporting. In January, MHRA expanded its import ban on products coming from Wockhardt’s Chikalthana plant that began in 2013 (IPQ January 20, 2015). The plant received a warning letter from FDA in July 2013 (IPQ April 28 2014).

EDQM/EMVO Agreement

The European Directorate for the Quality of Medicines (EDQM) and the European Medicines Verification Organization (EMVO) have announced the signing of an agreement on how they will work together to perform periodic conformity assessments of the European Medicines Verification System (EMVS). The purpose of the conformity assessments will be to determine whether the EMVO European Hub and blueprint systems are designed, managed, and operated in accordance with the standards described in the “Delegated Act on the Unique Identifier” supplementing the Falsified Medicines Directive 2011/62/EU, whose purpose is to secure the legitimate supply chain and to prevent falsified medicines from reaching patients. The EMVO non-profit organization is made up of pharma trade organizations, including; ● the European Federation of Pharmaceutical Industries and Associations (EFPIA) ● the European Generic and Biosimilar medicines Association (EGA) ● the Pharmaceutical Group of the European Union (PGEU) ●the European Association of Pharmaceutical Full-line Wholesalers (GIRP), and ● the European Association of Euro- Pharmaceutical Companies (EAEPC).

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NOVEMBER / DECEMBER 2015 81 Upcoming Workshops:

In-vitro Testing for Future Challenges for Veterinary Dosage Forms March 14, 2016 - March 15, 2016

Storage and Transportation of APIs and Finished Drug Products: Developing Standards May 23, 2016 - May 24, 2016

Single Use Systems: Development of a Compendial Standard June 20, 2016 - June 21, 2016

12th Annual International Symposium on Pharmaceutical Reference Standards Co-sponsored by: EDQM, Council of Europe and USP November 3, 2016 - November 4, 2016

Third Peptides Workshop November 14, 2016 - November 15, 2016

www.usp.org MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

INTERNATIONAL

CMC/REVIEW

ICH Reorganization

The International Conference on Harmonization (ICH) announced organizational changes following the inaugural meeting of its new Assembly and Management Committee in late October. In addition to changing “on” to “for” in its name, a new operating structure was established which includes the creation of an ICH association, a legal entity under Swiss law. The association establishes the new Assembly as the over-arching governing body that will facilitate broader regulatory agency membership.

Restructured ICH Convenes

At its meeting in Jacksonville, Florida, in early December, the newly-restructured ICH Assembly met in person for the first time, bringing together regulators and industry members, including observers from WHO, other regulators, and industry associations. In addition to reviewing a new application process for new members and observers, the Assembly also encouraged members of the former Global Cooperation Group to take the opportunity to automatically become observers before January 23, 2016, as allowed under the new membership process. The Southern African Development Community (SADC), the Gulf Cooperation Council (GCC), Brazil’s ANVISA, the Pan American Network for Drug Regulatory Harmonization (PANDRH), and the Asia- Pacific Economic Cooperation (APEC) were welcomed as the first observers under the new rules. In a press release, ICH also provided updates on the progress of several safety and efficacy guidelines. The next ICH meetings will be held June 11-16 in Europe, and November 5-10 in Japan.

China Drug Approval Process

Following an announcement by China’s State Council in August on its intention to speed up drug and device approvals in China (IPQ “Monthly Update” July/Aug. 2015, p. 51) the China Food and Drug Administration (CFDA) has published its implementation plans, Ropes & Gray is reporting. The plans are contained in the November 11, 2015 release of the “Circular Concerning Several Policies on Drug Registration Review and Approval (CFDA Circular [2015] No. 230) and several draft implementation measures. These documents aim to transform China’s drug approval system by implementing the following initiatives: ● piloting the European Marketing Authorization Holder (MAH) system ● expanding the fast track approval pathway ● changing the classifications for new drugs and generics, and ● simplifying the approval process for clinical trials. Of note is the policy change that categorizes a new drug as one that has not been approved anywhere in the world, as opposed to the current definition of not yet approved in China. While the new definition, which goes into effect on December 1, applies primarily to new applications, sponsors with applications in process that meet the definition can apply for expedited approval, Biocentury is reporting.

TGA Biosimilar Regulation Update

Australia’s Therapeutic Goods Administration (TGA) has updated it regulations regarding the registration of biosimilar medicines. The agency has adopted a number of European guidelines that outline the quality, nonclinical, and clinical data requirements specific to biosimilar medicines, along with the ICH guideline on the assessment of comparability (Q5E). In addition, the update includes details around the reference product – which much be sourced in Australia – and data requirements for the CTD application. CTD Module 3 of the submission will require “significant modification” from the EU dossier, as it will need to include: ● information on the in-house standard ● bridging comparability studies ● shipping stability, and ● labelling.

TGA OTC Registration Process

Australia’s TGA announced an updated process for registering over-the-counter (OTC) drugs in Australia. The instructions: ● help applicants identify the regulatory process that should be followed, and ● navigate applicants through the process step- by-step. Also included are links to relevant guidance and forms. Successful completion of the process gets the product listed in the Australian Register of Therapeutic Goods (ARTG). The process was originally published in November, then updated in December to include instructions regarding payment of registration fees that go into effect on January 1, 2016. TGA also published instructions on how to change a listing for a product that is already in the ARTG.

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NOVEMBER / DECEMBER 2015 82 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015 GMP/INSPECTION WHO Draft Data Integrity Guidance

The World Health Organization (WHO) has released a draft guidance on “Good Data and Record Management Practices.” The background section in the 35-page document notes that “implicit in the assessment and review process” of drug application data “is a trust between the regulator and the regulated that the information submitted in dossiers and used in day-to-day decision-making is comprehensive, complete and reliable.” It further notes that “in recent years the number of observations made regarding good data management practices …has been increasing,” pointing to the need for further industry guidance. In addition to the background and an introduction, the draft includes sections on: ● aims and objectives of the guidance ● glossary ● principles ● quality risk management to ensure good data management ● management governance and quality audits ● contracted organizations, suppliers, and service providers ● training in good data and record management ● good documentation practice ● designing systems to assure data quality and reliability ● managing data and records across the data lifecycle ● addressing data reliability issues, and ● references and further reading. The comment period ends on November 30, 2015.

PIC/S Update

At its meeting in Indonesia in October, the Pharmaceutical Inspection Cooperation Scheme (PIC/S) elected a new chairman, new officers, and announced a new member. Paul Hargreaves from the UK’s Medicines and Healthcare products Regulatory Agency (MHRA) will be the chairman for 2016 and 2017. Office holders were also elected for the following seven sub-committees: ● Training (SCT) ● Expert Circles (SCEC) ● Strategic Development (SCSD) ● Compliance (SCC) ● GM(D)P Harmonization (SCH) ● Budget, Risk and Audit (SCB), and ● Communication (SC COM). PIC/S also approved Croatia’s Agency for Medicinal Products and Medical Devices (HALMED) to join the scheme beginning January 1, 2016. HALMED will become PIC/S’ 48th participating regulatory authority. It was approved after a paper assessment and a five-day inspection in June. Agencies from Brazil, Iran, Mexico, Thailand, the Philippines, and Turkey have applied to join PIC/S, with Belarus, Chile and Kazakhstan in the pre- application phase.

India Adding Lab, Inspectors

India’s Central Drugs Standard Control Organization (CDSCO) has announced that it will set up a Central Drug Testing Laboratory (CDL) at Indore in Madhya Pradesh, India, PharmaBiz is reporting, based on an announcement CDSCO west zone deputy drugs controller Bengaru Rajan made at the Pharma Tech Expo 2015 in Indore in early November. Rajan noted that the site has been identified and construction is scheduled to begin soon. In addition, the central regulatory agency plans to have offices in all Indian states. Currently, he said, CDSCO has six zonal offices, four sub-zonal offices, and 12 offices in various ports. Pharmabiz also reports that CDSCO has recruited 85 additional drug inspectors. 50 are already on board, with 35 others to begin soon, bringing the total number of CDSCO drug inspectors to 155.

Managing Vendors and Quality Agreements

The international supply chain consortium Rx-360 has released a white paper on “Managing Critical Vendors” and a “Best Practices Quality Agreement Guide” on quality agreements. The Rx-360 “Supplier-Led Working Group” produced both documents, which can be downloaded here. The white paper covers the key aspects of vendors that supply manufacturers of regulated products, focusing on first tier vendors, best practices in handling the management of a critical vendor that is under scrutiny, and minimizing the impact on the supply chain. The process and best practices discussed are focused on regulatory areas of scrutiny, but may be applied to other areas of quality concern. The “best practices guide” is intended to assist both customers and suppliers in efficiently managing the initiation, negotiation, implementation, and ongoing maintenance of quality agreements. The consortium notes that both are considered “living documents,” and will be “updated as needed based on the most current industry and regulatory practices.”

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NOVEMBER / DECEMBER 2015 83 ABBVIE • AMGEN • AMPAC FINE CHEMICALS • ASH STEVENS • ASTRAZENECA • AURISCO PHARMACEUTICAL CO. LTD. • AVANTOR • BASF • BAXTER • BAYER • BEND RESEARCH • BIOGEN IDEC • INGELHEIM BOEHRINGER •

We the undersigned members of Rx-360 YORK CONTAINER • • fully support the mission of Rx-360 which is to: SQUIBB BRISTOL-MYERS WEST • WATSON • VWR • • PROTECT PATIENT SAFETY BY LABORATORIES MAJOR CAMBRIDGE UCB • TEVA • SHARING INFORMATION AND TEMPTIME • •

DEVELOPING PROCESSES RELATED HEALTH CARDINAL TAKEDA • TO THE INTEGRITY OF THE • CODEXIS CODEXIS • DAIICHI SANKYO SANKYO DAIICHI SPECTRUM CHEMICAL MFG

• HEALTHCARE SUPPLY CHAIN AND •

THE QUALITY OF MATERIALS INTERNATIONAL DKSH SIGMA ALDRICH •

SARTORIUS WITHIN THE SUPPLY CHAIN. • • We support our suppliers and colleagues who share our support of Rx-360 and its critical INGALLS & DOE SANOFI • mission to protect patient safety. And, recognizing the power of leadership by example, we invite others who share our patient safety goals to join us in this important endeavor. • DSM NUTRITIONAL PRODUCTS PRODUCTS NUTRITIONAL DSM ROCHE/GENENTECH • Wes Schmidt Ashley Readshaw Richard Spoor Allen Welsher Matt Anderson Thomas Paust VP, Quality Systems Chief Procurement Offi cer SVP Procurement Global Head QA VP Quality VP Supply Chain Management AbbVie Astrazeneca Bayer HealthCare Daiichi Sankyo Co., Ltd. Merz North America, Inc. Sartorius

Jennifer Finnegan Tom Beil William Reis Peng Zhien Debra Katter McCafferty Patricia M. Latzo VP, Quality and Regulatory • VP, Global Strategic Sourcing President VP, Corporate Quality VP External Quality SVP Global Quality and Strategic Affairs LILLY ELI Amgen Inc. Aurisco Bend Research GlaxoSmithKline Sourcing Sigma-Aldrich Mylan Inc. OSO BIOPHARMACEUTICALS • • FOREST LABORATORIES LABORATORIES FOREST Martin VanTrieste Richard M Siberski Melissa Stoutt Seymour Luisa Paulo Tom Tyner SVP Quality Global Director of Quality Sr. Director, Corporate Quality Compliance Director Michael Cohen VP Quality & Technical Service Amgen Inc. Avantor Performance Materials Biogen Idec, Inc. Hovione Managing Director Spectrum Chemicals and PFIZER • Myoderm Laboratory Products Vincent Antle Sr. Director of Technical Gary A. Baker Jaspreet Gill Robert Pantano Operations and Quality VP, QARA VP, Global Quality & Compliance SVP, Warehouse Operations and Assurance Michael Hoffman Steve Feldman •

Ash Stevens, Inc. Baxter Healthcare Corporation Operational Excellence Ligand Pharmaceuticals, Inc. VP Global Procurement VP Quality & Regulatory Affairs FUJIFILM Cardinal Health Pfi zer Inc. Temptime Corporation PROCTER & GAMBLE • • Dr. Paul Heiden Robert Nass Angélique Klootwijk HEALTHCARE GE SVP QHSE John Nicols VP Quality and Regulatory Heiko Hackel Director Quality Management & Bayer HealthCare President and CEO Management Merck Millipore VP Global Sourcing Quality Assurance Codexis, Inc. Merck KGaA Sartorius VWR International PERRIGO • • GLAXOSMITHKLINE GLAXOSMITHKLINE Protecting Patients Worldwide® +1 (202) 230-5608 • [email protected] • www.rx-360.org

• • NOVARTIS • MYODERM • MYLAN • KGaA MERCK • . CO & MERCK • MERZ • LIGAND • TECHNOLOGIES LIFE • LIFECONEX • LABOCHIM • JOHNSON & JOHNSON • HOVIONE • HOSPIRA • NOVOZYMES BIOPHARMA HIKAL MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

WARNING LETTERS

The following are the drug GMP warning letters posted by FDA during November and December, categorized into U.S. and International. The main areas of concerns are listed along with links to the warning letters themselves. Included is a review of the letter’s salient features.

UNITED STATES

Company Name Location Letter Date Product Type Areas Cited Triangle Cary, NC Nov. 2, Compounded ● failure investigations ● in-process testing and Compounding 2015 control ● container closure systems ● aseptic facility and equipment cleaning and disinfection

Inspections of Triangle’s NC facility took place from September 8-22, 2014 and from January 12-16, 2015. The first was an initial inspection of the facility after Triangle had applied to be an outsourcing facility to see if it met 503 (B) outsourcing requirements, as well as to perform an investigation into adverse events reported after the use of sterile drug products it had produced. In January 2015, a re-inspection was performed to determine whether compliance had been achieved after the September inspection, to obtain further information regarding sterility failures and complaints, and to collect sterile drug product samples for testing. A form 483 was issued after each inspection.

In addition to the GMP findings, the letter informs Triangle that it “failed to meet the conditions…necessary for drugs produced by an outsourcing facility to qualify for exemptions from certain requirements under the FDCA.” The letter also maintains that Triangle had failed to submit to FDA upon initial registration a list of the drug products that it compounded during the previous 6-month period as required in the outsourcer application. The reports that it submitted subsequently, the agency asserts, failed to identify all drugs compounded at the facility, but did identify chlorhexidine gluconate, a compound that appears on an FDA list of drugs that have been withdrawn or removed from the market because they have been found to be unsafe or not effective.

In the letter, FDA “strongly recommends” that Triangle management “immediately undertake a comprehensive assessment of its operations, including facility design, procedures, personnel, processes, materials, and systems. In particular, this review should assess aseptic processing operations.”

Company Name Location Letter Date Product Type Areas Cited Advanced North Nov. 3, Compounded ● maintenance of aseptic conditions ● Compounding Hollywood, 2015 stability program ● aseptic and sterilization Pharmacy CA process validation ● EM ● aseptic facility and equipment cleaning and disinfection ● testing for conformance to drug product specifications

During a January 12-16, 2015 inspection, investigators observed “serious” GMP deficiencies, as well as noting that drugs were not being compounded in response to “valid prescriptions for individually-identified patients for a portion of the drug products” being produced. Accordingly, the drugs compounded without valid prescriptions for individually-identified patients are not entitled to the exemptions in section 503A of the FDCA, and are also considered misbranded.

During the inspection, investigators observed compounding of 17-hydroxyprogesterone caproate (17-P). 17-P is the active ingredient in an FDA-approved product, and thus cannot be compounded except in response to a prescription for an individual patient who requires a “significant” change from the marketed product.

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NOVEMBER / DECEMBER 2015 84 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

From a GMP perspective, observed deficiencies include: ● an external air conditioning unit installed on the cleanroom wall across from the hoods where aseptic production occurs, with no data to indicate that a HEPA filter was installed in the air conditioner and no assessment to determine if airflow from the air conditioner affected operations within the hoods ● non- sterile cleaning wipes being used to apply disinfectants to ISO 5 work surfaces, and ● a lack of studies to show that hoods used for aseptic compounding are able to provide adequate protection of the ISO 5 area in which sterile drug products are produced.

The letter states that the firm notified FDA that it had “discontinue[ed] business as of April 3, 2015” and that “there are no plans to perform sterile compounding.” FDA provides guidance as to what steps the firm will need to take should it decide to resume sterile compounding.

INTERNATIONAL

Company Name Location Letter Date Product Type Areas Cited Sandoz Maharashtra, October APIs and ● contemporaneous completion of batch records ● India (two 22, 2015 finished data integrity ● equipment maintenance records ● sites) (posted dosage forms training ● OOS investigations ● computer system by FDA in security ● microbial contamination prevention ● November) media fill practices ● EM

Inspections were conducted at two Sandoz sites in Maharashtra, India, from August 25-29, 2014 (Kalwe API and finished dosage form facility) and August 12-28, 2014 (Turbhe finished sterile dosage form facility) and addressed in the same warning letter. The primary concerns at the Kalwe plant were around data integrity, while those at the Turbhe plant focused on the potential for microbial contamination of aseptically-produced products.

Kalwe:

At the Kalwe plant “uncontrolled Excel spreadsheets” were used to record discrepancies and certain in-process drug quality data. “This data was initially missing in the batch manufacturing record. Your firm later entered this data into batch records and backdated them,” the letter asserts. The firm admitted to the practice, which the agency termed “unacceptable.” FDA investigators found original preventive maintenance work orders in trash bags, and a partially-completed document retrieved from a waste receptacle “included handwritten notes about the condition of equipment observed during preventive maintenance.”

Data integrity concerns also included laboratory computer systems that “lack necessary controls to prevent data tampering and to detect data that may have been compromised.” Also at issue was contract employees who do not speak English, but were provided training materials only in English.

Turbhe:

Regarding the Turbhe site, the warning letter emphasized that while the agency is aware of the firm’s plans to shut down and/or divest the Turbhe facility, it noted that “CGMP violations” at the site related to aseptic process controls are similar to violations cited in a November 2011 letter issued to Sandoz’ parent company, Novartis.

At issue were procedures and practices designed to prevent contamination of sterile products, including: ● “inadequate” smoke studies ● a lack of procedures for removing units following interventions, periodic adjustments, set-up, and end of fill ● rejected units with intact container/closure systems from media fills without written justification or explanation ● rejected vials that were not incubated as part of the media fill, and ● “inadequate scientific justification” for environmental monitoring sampling plans in manufacturing areas for aseptically-filled injectable drug products.

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NOVEMBER / DECEMBER 2015 85 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

Company Name Location Letter Date Product Type Areas Cited Dr. Reddy’s Telangana November APIs and ● data integrity ● computer system security and Andhra 5, 2015 finished ● contemporaneous completion of batch Pradesh, dosage forms records ● documentation revision system ● India (three OOS investigations ● CAPAs ● storage of sites) intermediates ● sterile processing equipment and manual interventions ● validation of aseptic and sterilization processes ● visual inspection

The ten-page warning letter addresses inspections at three Dr. Reddy’s sites, respectively: ● November 17-21, 2014 at CTO Unit VI in Andhra Pradesh (APIs) ● January 26-31, 2015 at CTO Unit V in Telangana (APIs), and ● February 26 to March 6, 2015 at Unit VII in Andhra Pradesh (finished sterile dosage forms).

Units VI and V:

Of primary concern at both the Unit VI and Unit V API sites was data integrity, including computer system security. Cited at Unit VI were raw laboratory data missing from lab records, information recorded on uncontrolled sheets rather than in official log books, entries in batch records that were not recorded at the time performed but were added later and backdated, and HPLC lab systems that do not require passwords to access them, and allow any user administrative privileges to change or delete data with no audit trail. The computer system issue at Unit V was the allowance of QC personnel to release final batches without QA oversight, which was purportedly both acknowledged and denied in two separate communications by the firm to FDA.

Unit V:

At Unit V, investigators discovered a “custom QC laboratory” previously unknown to the agency that was performing CGMP analysis of APIs with a pattern of disregarding failing results and continuing to retest until a passing result was obtained. Also noted were photocopied, pre-filled labels for API found in the trash that included the name of the product, material code, batch number, drum number, net weight, batch quantity, signature and date. Also observed were drums of intermediates that were not recorded in batch records, and no controls to prevent mix-ups of the intermediates.

Unit VII:

At the sterile product site, Unit VII, CAPAs, sterile processing equipment issues, media fill practices, and visual inspection practices were of concern. During the inspection, the FDA investigator documented a malfunction in sterile filling equipment and notified quality and operations management. However, according to the investigator the “management failed to intervene, and allowed the filling process to continue uninterrupted.” The letter emphasizes that “even though your senior management was notified of this failure, you did not initiate an incident report to investigate the equipment malfunction or determine the effects of this discrepancy on the quality of the product until we concluded our inspection and issued a Form 483.”

Also observed were poor aseptic practices by operations personnel, including manual interventions that potentially compromise the sterility of the product and represent deviations from the firm’s SOPs. Inadequate investigations and medial fill accounting and reconciliation were also cited, and both were noted as repeat observations from a February 2008 inspection. The firm’s training of inspectors who look for visible particles was of concern, as the training kits “were inadequate because particle size in the kits is not specified. There is thus no way to determine if the kits themselves are sufficient to qualify inspectors under the essentially-free standard.”

In addition to responding to specifics in the warning letter, Dr. Reddy’s management was instructed to provide supporting documentation to include a comprehensive third-party evaluation “of the extent of inaccuracies in recorded and reported data,” including “a detailed action plan to fully investigate the extent and root causes of deficient documentation and data management practices.”

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NOVEMBER / DECEMBER 2015 86 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

Company Name Location Letter Date Product Type Areas Cited McGuff Santa Ana, Nov. 13, Compounded ● a lack of valid prescriptions for individually- Compounding CA 2015 identified patients Pharmacy Services

In a December 15-31, 2014 inspection of Santa Ana, California-based McGuff, investigators noted a lack of valid prescriptions for individually-identified patients. As such, these products are not entitled to the exemptions in section 503Aofthe FDCA, and are also considered misbranded. No GMP manufacturing deficiencies were noted. In an April response to FDA, McGuff stated that it has completed its “conversion to 100% Patient Prescription Orders” and “will no longer take orders for ‘office use.’”

Company Name Location Letter Date Product Type Areas Cited Medisca Plattsburg, November APIs ● adulterated and misbranded drugs NY 25, 2015

A ten-day inspection of Medisca’s Plattsburg, NY facility was prompted by adverse event reports in patients who were administered drug products compounded using its active pharmaceutical ingredient (API) labeled as L-Citrulline. During the inspection, investigators collected six samples of APIs labeled as L-Citrulline that had been repackaged for distribution to pharmacies for use in compounding. Subsequent FDA laboratory analysis of these samples determined that two of the samples were N-Acetyl-Leucine, a different amino acid. Medisca subsequently recalled eight lots of the L-Citrulline product after its own testing indicated that they did not contain L-Citrulline. The subsequent warning letter deems the product adulterated and misbranded. The letter requests the firm to provide details concerning its investigation regarding the extent of the product mix-up and any assurance other APIs that have been or will be distributed are not impacted.

In addition, the letter notes that the agency has received information that the firm may be repackaging and distributing domperidone API to pharmacies for use in compounding drugs. Domperidone can only be manufactured under an approved application as it is not the subject of an applicable United States Pharmacopeia (USP) or National Formulary (NF) monograph, is not a component of an FDA-approved drug, and is intended for conditions that are not amenable to self-diagnosis and treatment by individuals who are not medical practitioners. The letter instructs the firm that if it is repackaging and distributing domperidone to “stop immediately.”

Company Name Location Letter Date Product Type Areas Cited Sun Pharma Halol, December Sterile ● microbial contamination control ● validation Gujarat, 17, 2015 finished of aseptic and sterilization processes ● media India products fills ● facility maintenance ● stability program ● CAPA ● cleaning validation ● lab method validation ● computer validation and security

Sun’s warning letter was based on a September 8-19, 2014 inspection. Of primary concern is the validation of aseptic and sterilization processes, including a failure to perform “adequate” unidirectional smoke studies under dynamic conditions and an indication that the studies that were performed indicate that the aseptic processing equipment “is not properly designed.”

Facility maintenance was also found lacking, with buckets with water collected from ceiling leaks and other leaks in the manufacturing area observed by investigators. The firm investigated the reported leaks during the inspection, but “failed to address environmental control in the parenteral manufacturing area during the period of concern, or to determine how leaks in this area could compromise the quality” of the aseptically-filled products, the letter asserts.

CAPAs for out-of-specification results, unknown peaks in batch analyses, and an extraneous peak discovered during cleaning validation were either not performed, or did not get to the root cause, the investigators maintained. Analytical method validations and calibration of laboratory instruments and equipment used in manufacturing were also deemed inadequate, as was lab computer security, in which passwords were shared and audit trails provided “no way to verify that individuals have not changed, adjusted, or modified equipment operation parameters.” WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 87 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

Company Name Location Letter Date Product Type Areas Cited Cadila Healthcare Ahmedabad, December Tablets and ● root cause investigations ● com-plaint India (two 23, 2015 APIs investigations ● computer system security ● sites) uncontrolled lab notebooks ● data integrity

2014 inspections of two Cadila Healthcare facilities in Ahmedabad, India – August 28-September 5 at the Moraiya tablet facility, and December 1-6 at the Zyfine API facility – resulted in an FDA warning letter posted in late December. The Moraiya facility is one of four Cadila finished dosage plants in India, and the Zyfine plant is one of three API operations.

Moraiya:

Of primary concern at the Moraiya facility were OOS investigation reports associated with potency and content uniformity specifications for warfarin sodium, a narrow therapeutic index drug. The same problem had been identified in an August 2013 FDA inspection that resulted in a recall of one lot of warfarin tablets because of failed assay and oversized tablets. The letter notes that “the recurrence of product quality failures following the completion of your investigation indicates that your CAPA was ineffective. The recurrence of these failures is apparently due to inadequate identification of root causes and lack of action to resolve this manufacturing problem. These persistent failures indicate that your manufacturing process is not in a state of control. Nevertheless, at this time, drugs from this facility are being released to the market.”

Also cited were complaint investigations. The agency maintains that over a three-year period the firm received nine consumer complaints related to potential mix-ups, but did not complete a root cause analysis or submit an FDA field alert report (FAR) in eight of the instances. As a result of the inspection, Cadila re-opened its investigations of the complaints, which identified manufacturing deficiencies that could have led to the product mix-ups. In addition, it submitted FARs and initiated a product recall of several lots.

Zyfine:

Failure investigations were also found lacking at the Zyfine API facility, where root cause was not determined for failing analytical results, but the firm “reprocessed the failed batches without scientific justification.” Also found were QC lab computer systems that allowed the lab manager to delete files without an audit trail, and on which passwords were shared among several analysts. Inspectors discovered that a file containing the moisture content results for an API batch had been deleted, and noted that the deletion “was not identified and reviewed as part of the batch release decision.”

In addition, data integrity issues were discovered in the form of “rough or unofficial notebooks” used to document various CGMP activities. In one case, an “unofficial” notebook contained an entry stating thatPseudomonas was found in the water system. However, the letter maintains that the firm “was unable to provide the investigators with any documentation regarding Pseudomonas sp. found in the water system.” In another case, investigators reviewed AHU/HVAC filter cleaning records and duplicate records in the engineering office that company personnel said had been “rewritten for clarity.” A comparison of the original and rewritten records “found discrepancies in cleaning dates and cleaning personnel.” The letter notes that the record keeping findings “raise serious concerns about the effectiveness of your manufacturing controls, the integrity of your computerized records, and the accuracy of your CGMP records.”

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NOVEMBER / DECEMBER 2015 88 PAREXEL® Consulting: Strategic C ompliance and Risk Management

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© 2014 PAREXEL International Corporation. All rights reserved. MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

RECALLS

The following is a listing of the drug product recalls included in FDA’s weekly “Enforcement Re- ports” issued during November and December. Included are the generic names of the products, the dosage form, the manufacturer, the number of lots involved, FDA’s classification, and the spe- cific reason provided by FDA in the Enforcement Report. The recalls are grouped by the general category of problem that caused them. The categories are: ● compliance with NDA/monograph requirements ● contamination/lack of sterility assurance ● dissolution ● GMP/GDP ● impurity ● labeling/packaging ● foreign product ● particulate ● potency/content uniformity, and ● other spec nonconformance. Within the categories, the recalls are organized by class, with the most serious, Class I recalls at the top.

COMPLIANCE WITH NDA/MONOGRAPH REQUIREMENTS

Product Recaller Lots Class Reason Erectile The One All lots I Marketed Without An Approved NDA/ANDA: Miracle dysfunction Minute Miracle through Rock 48 was found to contain undeclared thiosildenafil, caps expiration an analogue of an FDA approved drug for male erectile date dysfunction making this product an unapproved drug. 06/01/2018 Weight loss The One All lots I Marketed Without An Approved NDA/ANDA: Miracle Diet caps Minute Miracle through 30 was found to contain undeclared phenolphthalein, expiration a drug product once contained in over-the-counter date laxatives but was taken off the U.S. market due to safety 04/15/2018 concerns, making this product an unapproved drug. Weight loss Blue Square All lots I Marketed Without An Approved NDA/ANDA: presence of caps Market undeclared sibutramine and phenolphthalein. Erectile Blue Square All lots I Marketed Without An Approved NDA/ANDA: presence of dysfunction Market undeclared sulfoaildenafil. strips

CONTAMINATION / LACK OF STERILITY ASSURANCE

Product Recaller Lots Class Reason Various Moses Lake >900 II Lack of Assurance of Sterility: all sterile human compounded Professional compounded drugs within expiry. products Pharmacy Various Park 4 II Lack of Assurance of Sterility; all sterile compounded compounded Compounding products within expiry. products Pharmacy Various The 66 II Penicillin cross contamination compounded Compounder products Various B&B Pharmacy 80 II Lack of Assurance of Sterility: FDA inspection identified compounded GMP violations potentially impacting product quality and products sterility. Various US 252 II Lack of Assurance of Sterility: The firm is recalling compounded Compounding all sterile preparations that are within expiry due to products deficient practices which may have an impact on sterility assurance. Various Essential 115 II Lack of Assurance of Sterility: A recall of all compounded compounded Wellness sterile preparations within expiry is being initiated due products Pharma to observations associated with poor sterile production practices resulting in a lack of sterility assurance for their finished drugs. WWW.IPQPUBS.COM

NOVEMBER / DECEMBER 2015 89 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

Product Recaller Lots Class Reason Various Downing Labs All II Lack of Assurance of Sterility. compounded products C-budesonide Solutions Rx 16 II Penicillin Cross Contamination: Possible presence of caps Pharmacy penicillin in bulk budesonide powder used to compound prescription nasal rinse/nebulizer capsules.

DISSOLUTION

Product Recaller Lots Class Reason

Fenofibrate tabs Valeant One II Failed Dissolution Specifications: Failed 24 month dissolution testing.

IMPURITY

Product Recaller Lots Class Reason Rifampin for inj. Akorn One III Failed Impurity/Degradation Specifications: Out of specifications result obtained for a known impurity.

Meclizine HCl Par Pharma 27 III Failed Impurities/Degradation Specifications: Out of tabs specification for impurities.

Meclizine HCl UDL Labs One III Failed Impurities/Degradation Specifications: Out of tabs specification for impurities.

LABELING / PACKAGING

Product Recaller Lots Class Reason Doxycycline C. O. Truxton One II Labeling: Wrong Bar Code; bar code incorrectly scans hyclate tabs as phenobarbital tablets.

Hydrocortisone Akorn One III Defective Container: Product missing safety seal and acetic acid around the neck of the bottle. The product label sol. indicates, "Tamper Evident: Do not use if printed seal around cap is broken or missing." Because the product is missing the approved component and is not consistent with the labeling, the lot is being recalled.

FOREIGN PRODUCT

Product Recaller Lots Class Reason Duloxetine Breckenridge One III Presence of Foreign Tablets/Capsules: One foreign delayed release Pharma capsule identified as omeprazole 10 mg was found in caps the bottle.

PARTICULATE

Product Recaller Lots Class Reason Hydrochlorothiazide Qualitest 3 II Presence of Particulate Matter. caps

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NOVEMBER / DECEMBER 2015 90 MONTHLY UPDATE - NOVEMBER/DECEMBER 2015

POTENCY / CONTENT UNIFORMITY

Product Recaller Lots Class Reason Alprazolam tabs Pfizer One II Subpotent drug

OTHER SPEC NONCONFORMANCE

Product Recaller Lots Class Reason Ranitidine oral Qualitest 3 III Failed Stability Specifications: Out of Specification sol. results obtained for preservative butylparaben.

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