INTERNATIONAL PHARMACEUTICAL QUALITY IPQ Inside the Global Regulatory Dialogue IPQPUBS.COM VOL. 8, NO. 1
MONTHLY UPDATE - JANUARY 2016
UNITED STATES
CMC/REVIEW
● FDA’s Generics Office Overcomes Tough Challenges to Meet Year 3 GDUFA Goals, p. 4 OGD’s Uhl Reports at GPhA Fall Tech Conference
● FDA’s API DMF Assessment Timelines Improve as eCTD Use Increases and OPQ’s p. 25 New API Review Structure Takes Hold
● Starting Materials Remains a Challenging Issue for Both Regulators and Industry; p. 33 FDA DMF Assessments Show SM Gaps
● Drug Product Quality Dashboard Taking Shape at FDA in Wake of OPQ Integration p. 43 and Expanding Knowledge Base
● IPEC-Americas Continues to Urge Family Approach in Dialogue with FDA on p. 48 Improving Inactive Ingredient Database
INTERNATIONAL
GMP/INSPECTION
● Challenges of Implementing U.S. and Global Serialization Mandates Compel Industry p. 65 Cooperation
UPDATES IN BRIEF p. 81 U.S CMC: ● CDER 2016 Guidances ● Vet Drugs ● Bioequivalence ● USP Protein Standards ● USP Packaging ● USP Plastic Packaging U.S GMP: ● Compounder Consent Decree ● Tainted Supplements ● ER Drug Shortages
EUROPE CMC: ● EMA Active Substances ● EP Raman Spectroscopy
INTERNATIONAL CMC: ● WHO in India ● Canada Biosimilars ● TGA Sunscreens INTERNATIONAL GMP: ● India Track/Trace ● India Inspector Training ● China Inspections ● WHO Drug Shortages ● ISO Cleanroom Standard
FDA DRUG GMP WARNING LETTERS, EMA GMP NON-COMPLIANCE REPORTS, AND FDA DRUG RECALLS POSTED IN JANUARY p. 85 MONTHLY UPDATE - JANUARY 2016
INTERNATIONAL PHARMACEUTICAL QUALITY provides in-depth coverage of emerging drug, biologic and combination product CMC and GMP issues and developments with a mission of helping advance and harmonize the quality regulatory process globally. Headquartered in Washington, D.C., IPQ is read by regulatory agencies, manufacturers, suppliers, consultants, law firms, and universities around the world.
IPQ tracks the industry/regulator dialogue at key international forums along with the developments, initiatives, regulations, guidances and standards in the quality regulatory arena to create a uniquely valuable resource for the intelligence gathering and knowledge management needs of the pharmaceutical community.
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The “Monthly Updates” organize the stories that went online during the previous month by region (US, Europe, and international) and topic area (CMC/review and GMP/ inspection) and are an easy way for subscribers to keep up with the current critical developments impacting the quality regulatory process worldwide. Included are "Updates in Brief" on recent developments in the CMC/ GMP global arena with links to the referenced documents and to our related in-depth analysis. Also included are an annotated listing of FDA drug GMP warning letters and recalls as well as EU GMP non-compliance statements posted during the month.
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EDITOR’S NOTE ON THE ISSUE: FDA’s vision of a quality regulatory process that would be more efficient, science-based, review/inspection coherent, and process improve- ment and product supply friendly took more concrete shape during 2015. In the January Monthly Update, we explore some of the dimensions of that transformation across CDER’s Offices of Generic Drugs and Pharmaceutical Quality. While the focus of these stories is FDA-centric, the agency’s effort to put theory into practice has significant ramifications on the global regulatory stage.
Bill Paulson, Editor-in-Chief The first story focuses on the generics office “State of the Union” address traditionally delivered by the OGD Director at the beginning of the GPhA Fall conference – in this case, presented by the office’s current leader Cook Uhl. She explained the significant hurdles OGD had to cross en route to successfully meeting the 2015 GDUFA mandates, how the office is transforming itself with the user fees as fuel, and how industry can help.
Integral to OGD’s review process is the role of CDER’s new Office of Pharmaceutical Quality. OPQ’s responsibilities include overseeing the quality of APIs across the NDA/ANDA spectrum. The next two stories explore how the API regulatory process is evolving with OPQ at the helm.
The first of the two focuses on the impact on Type II DMF reviews – the timelines and results, and where the prob- lems lie. The next story probes deeper into the issues around a particularly thorny aspect – the designation and control expectations for starting materials. Both stories offer valuable insights from the OPQ management on the agency’s expectations and how companies can help make the review process go more smoothly.
We then broaden out onto the role OPQ is playing in better integrating the review and inspection processes, and cre- ating a more knowledge-rich foundation for how they function and what they focus on. On that foundation, CDER’s vision of a drug product quality dashboard is now taking shape. The dashboard will provide a comprehensive sum- mary of the current state of quality for NDAs and ANDAs for a particular drug product. Our story offers insights from the head of OPQ’s Office of Lifecycle Drug Products on how the expanding knowledge base is key to improving lifecycle management – both for companies and for the agency.
The Monthly Update continues with an in-depth review of the effort in which industry and CDER are engaged to improve the agency’s inactive ingredient database (IID) – with significant implications for what is viable in drug product formulation. The story builds off a session on the IID effort at the November GPhA conference and a work- shop focused on excipients held a few weeks later at USP. At the GPhA session, two IPEC-Americas leaders reviewed the discussions that the excipient association and GPhA have been having with FDA and where industry and the agency are now focused in bringing the needed improvements to fruition. The coverage includes insights from the CDER head of the IID improvement project. The story sheds a lot of light on the challenges involved and the stakes in addressing them.
Our concluding story moves into the complex web of challenges that a global drug distribution system presents in trying to identify and trace products and what regulators and industry are trying to do to deal with it.
The U.S. Congress has mandated that a robust electronic serialization system for Rx medicines be fully functional within a decade of the signing of its Drug Supply Chain Security Act (DSCSA) in 2013 – with significant milestones needing to be met in the intervening years. While a decade may seem like a long time, the challenges involved are not to be underestimated, and the old adage “he who hesitates is lost” is fully applicable. “E pluribus unum” also has relevance, with industry realizing that the problems can only be solved by close cooperation between all those involved in the manufacturing and distribution process.
Our story explores the dialogue that took place among a panel of experts at a GPhA conference session in November on the progress and learnings to date on the DSCSA implementation challenges and the issues that remain to be ad- dressed as industry moves into the next phase in 2017. Also receiving panel attention was the impact of the emerging serialization and traceability requirements elsewhere in the world, and the role of pilots in the U.S. and international- ly. Cognoscenti as well as relative novices in the track-and-trace arena should both find a lot to chew on in our story.
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JANUARY 2016 3 MONTHLY UPDATE - JANUARY 2016
UNITED STATES
FDA’s Generics Office Overcomes Tough Challenges to Meet Year 3 GDUFA Goals, OGD’s Uhl Reports at GPhA Fall Tech Conference
A significant increase in controlled correspondences, Filing Backlog Eliminated in FY 2015 easily correctable deficiencies, and information requests, along with a major reorganization, were among the tough The OGD leader noted that, during FY 2015, her office challenges that the Office of Generic Drugs (OGD) overcame eliminated the filing backlog and approved a record number to meet the Year 3 goals of the Generic Drug User Fee Act of prior approval supplements (PASs). The generics office (GDUFA) – the first year that goals came into play. met or exceeded the GDUFA goals in Year 3 of the program for actions on PASs as well as controlled correspondences. Developing the interface with the newly formed Office of Pharmaceutical Quality (OPQ) and a hiring and training In addition, OGD is already narrowing in on its Year 5 goal blitz that brought more than 1,000 new staff members into of acting on 90% of the GDUFA backlog of Abbreviated OGD were among the other hurdles that the office faced in New Drug Applications (ANDAs) and PASs – having dealt pursuit of the GDUFA goals in place for FDA’s fiscal year with 82% of them by the end of Year 3. (FY) 2015, which ended September 30. Uhl commented that “we built this machine, and we are At the GPhA/FDA Fall Technical Conference in now cranking it up. This was a heavy lift. And it produced Bethesda, Maryland in early November, OGD a huge benefit.” Director Katherine “Cook” Uhl commented that In the current fiscal year – Year 4 of GDUFA – tighter GDUFA implementation has required “a deep goals kick in. And while challenges remain with foundational restructuring of everything related to increased communications, a new organization the generic drug review program. We had to build structure, and dealing with the backlog of ANDAs an entirely new infrastructure. We had to not only and PASs, Uhl expressed her confidence in OGD’s define our business processes, but improve them ability to meet and exceed its goals. and create efficiencies along the way.”
“In Years 4 and 5 we will maintain a strong focus on target In her presentation, Uhl discussed the challenges the action dates” for incoming submissions and the backlog of generics office faced in GDUFA Year 3 and its achievements, pre-Year 3 applications, she emphasized. “And we will and what her office will be doing to further enhance the hold the first generics in tender loving care so that we avoid review process and meet the Year 4 and 5 targets. any forfeitures and that we continue to pursue timely first generic approvals.” She highlighted how GDUFA creates more predictability for industry and what actions the agency and industry need She pointed to a new IT platform that went into operation to take to further the goal. in October 2014 as a key to OGD’s productivity gains and faster review times. The platform now includes information The OGD director then delved into her office’s productivity on about 39,000 submissions, 3,000 products, and 24,000 and output – providing the data through GDUFA Year 3 on ingredients, and is accessible to all OGD employees. ANDA/supplement approvals, controlled correspondence, complete response letters, and GDUFA backlog, and the “So you are seeing improved numbers of approvals and progress on product-specific guidances. tentative approvals. It makes it easier to collaborate and communicate with industry. It improves review consistency, Uhl concluded her talk with “helpful hints” on “controlling and also the ability to identify and study precedent your destiny,” which included a review of the common applications. And it makes review times and completion deficiencies the agency is seeing related to application times more predictable.” review, and how they can be avoided. She addressed issues involving the cover letter, the point of contact, the facility Commenting that “we could not have done it without establishment identifier (FEI), bioequivalence, clinical data, you,” the OGD director stressed the importance of labeling and controlled correspondence. FDA and industry continuing to work together to
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JANUARY 2016 4 MONTHLY UPDATE - JANUARY 2016 ensure that the ultimate aims of GDUFA are met – The presentations by Uhl and Yu were followed by i.e., safety, access, and transparency. a panel session that explored the challenges industry faces in implementing the identification and tracing In addition to fulfilling GDUFA commitments, the generics requirements of the Drug Supply Chain Security Act office implemented additional program enhancements as they unfold through 2023 (see story on pp. 65-80). related to target action dates and information requests to improve output and communication with industry. These Also receiving the attention of the experts on the panel was changes, along with continued industry cooperation, will the impact of the emerging track-and-trace requirements help build “a robust, modern generic drug regulatory elsewhere in the world, and the role of pilots in the U.S. and program that is sustainable and predictable,” Uhl asserted. internationally. [Uhl’s complete remarks at the conference, along with a number of key charts and graphs that she presented, are provided below.] GPhA Biosimilars Council at Work
USP Holds Pre-Conference Workshop The last session of the first day focused on the efforts of the GPhA Biosimilars Council. Presentations were given by The morning of the first day of the GPhA conference Momenta Senior VP/General Counsel Peter Sullivan and consisted of a half-day pre-conference workshop hosted by Amneal Biosciences Director of Professional Affairs and USP. Speakers from the pharmacopeia addressed topics of Medical Information Bruce Leicher, also an attorney. interest to generic drug manufacturers. The council’s mission is to “support the broad components of The workshop began with an overview by USP Compendial the biosimilar industry, and enable patients increased access Affairs and Executive Secretariat Director Mario Sindaco. to safe, effective and affordable biosimilar medicines.” The resolutions that were passed at USP’s 2015 convention for the next five year cycle, he noted, include: ● an increasing Sullivan and Leicher discussed the council’s focus on the relationship with FDA ● international ongoing efforts in four areas: ● naming ● medicare harmonization, and ● quality standards for compounding reimbursement ● labeling, and ● “patent dance” and dietary supplements. [A link to the USP’s 2015 – 2020 litigation. resolutions is provided below.]
Also receiving attention at the USP workshop were its On the labeling front, AbbVie has filed a Citizen’s Petition ongoing work on elemental impurities, reference standards, with FDA regarding the content of labels for biosimilars USP-NF excipient specifications, and standards for biologics that is at odds with GPhA’s position on the issue. The and biosimilars. association will file comments with the agency in response to the petition, Sullivan emphasized. Emerging Technology and DSCSA Draws Attention The council has also been engaged in active litigation regarding the requirements created for applicants under the The GPhA conference began in the afternoon with Uhl’s abbreviated 351(k) pathway that creates a complex system presentation, followed by an update from OPQ Deputy for settling patent disputes for biosimilars – commonly Director Lawrence Yu on his office’s first year. called the “patent dance.”
Yu highlighted, in particular, the impact of OPQ’s Emerging The Biologics Price Competition and Innovation Act Technology Team and the approval of the first 3-D printed (BPCIA) includes provisions whereby biosimilar applicants drug and the first continuous manufacturing process can choose to disclose the contents of its application to the as emblematic of OPQ’s effort to support technological original BLA holder in order to engage in a “patent dance” to advancement. [A full review of Yu’s presentation will be determine what patents will be covered by any infringement provided in IPQ’s February Monthly Update.] action prior to approval. “A lot of companies are actively pursuing continuous manufacturing” due to its flexibility and robustness, Yu However, GPhA believes this disclosure is not mandatory, commented, urging the generics industry “to pay attention as the BPCIA specifically considers litigation alternatives for to this emerging technology” because “eventually” it will BLA holders when the biosimilar applicant does not provide impact that industry as well. their application as contemplated by the statute.
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JANUARY 2016 5 MONTHLY UPDATE - JANUARY 2016 Pharmacovigilence, Integrated Quality The interactive session featured over 70 FDA staff personnel Assessments Discussed along with GPhA and industry leaders answering questions on topics ranging from the role of the Regulatory Business The second day began with a “state of the association” Process Manager (RBPM), what is new in OPQ, and user presentation by GPhA President and CEO Chester “Chip” fee management and budget formulation, to product launch Davis. preparation.
Following Davis were two presentations on pharma- API DMF Reviews Spotlighted covigilance in the generics industry. They provided an overview of: ● the regulations ● the spectrum of The final day of the GPhA conference consisted of two parallel pharmacovigilance practices in the industry ● and FDA tracks, one of which focused on active pharmaceutical pharmacovigilance inspections and the triggers for ingredients and API drug master files (DMFs). enforcement action. OPQ Office of New Drug Products (ONDP) Deputy The last morning session included presentations by Director Scott Furness opened the session with a review OPQ staff and a panel discussion on its integrated of his office and its functions, and provided insight into its quality assessment initiative (IPQ October 25, 2014). API review initiatives, including: ● the construction of a more formalized drug substance risk assessment platform Included were: ● an overview by OPQ Office of Lifecycle for NDAs/ANDAs ● devising a new review template that Drug Products Acting Director Susan Rosencrance; and ● will facilitate the most efficient and concise assessment of a discussion of the benefits and challenges of the integrated drug substance quality, and ● development of new starting assessment from the Regulatory Business Process Manager material selection criteria. and Application Technical Lead vantage points. ONDP chemist Jayani Perera followed with a Q12 and 505(b)(2) Pathway Also in Focus discussion of completeness assessments for Type II DMFs, including the agency’s CA timelines and In the afternoon, a session on how to get an ANDA approved metrics, what a “Refuse to Receive” is and how to included presentations by OGD Office of Regulatory avoid it, and common deficiencies she has seen in Operations (ORO) Division of Project Manager Leader DMFs (see story pp.25-32). Kevin Denny and OPQ Office of Program and Regulatory Operations (OPRO) Acting Branch Chief Craig Kiester. The DMF theme was continued by Office of Program and Regulatory Operations (OPRO) Lifecycle Business The presentations focused on: ● recent developments Process Manager Truong Quach with a discussion of how affecting approvals, including a new IT platform and new RBPM manages and integrates DMFs into the team-based hires becoming more productive ● the disciplines involved integrated quality assessment, including a review of the in the approval process, and ● areas where the agency is communications and logistics that occur in the review. asking for industry assistance. [See Ulh’s presentation at GPhA, included in full below, for “helpful hints” on getting Following Quach, FDA Drug Master File Expert Arthur an ANDA approved.] Shaw probed more broadly into the DMF system, including The second part of the afternoon shifted to a panel discussion the laws and regulations covering DMFs, the five types on ICH Q12, which addressed the impact of its having a more of DMFs, what they are and how they are useful, and the broad-based Expert Working Group, including generics challenges the current system presents for both industry and industry representation. EWG members participated on the the agency. He concluded by noting that the problems can be panel. (IPQ December 18, 2015). minimized if DMF holders understand their responsibilities, adhere to the regulations, follow the recommendations in The Q12 panel was followed by a session on the 505 (b)(2) the guidances, and communicate with each other. approval pathway, with presentations by Foley and Lardner Partner David Rosen and Camargo Pharmaceutical Services The logistics and requirements for electronic submission President and CEO Kenneth Phelps. of DMFs and a new guidance covering them was then discussed by CDER Office of Business Informatics Division Held simultaneously with both the Q12 and 505 of Data Management Service Director Ginny Hussong. The (b)(2) sessions was a three hour “project manager requirement to file DMFs electronically becomes mandatory exposition.” in May 2017.
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JANUARY 2016 6 MONTHLY UPDATE - JANUARY 2016 ONDP Division of Lifecycle API Acting Quality The statistical models that may be used for evaluation of Assessment Lead Ronald Michalak turned attention potential genotoxic impurities are discussed in M7. CDER to the selection of starting materials for Type II Office of Translational Sciences Chemical Informatics DMFs. Program Lead Naomi Kruhlak gave a presentation on how the models may be used, noting that they can provide a He maintained that all of the general principles in Q7A and high-throughput means to assess the mutagenic potential of Q11 for selection of starting materials should be considered impurities. rather than applying any individual one in isolation. These principles include consideration of: ● commercial Kruhlak emphasized that prediction transparency and availability ● complexity of the process and structure ● interpretability are key, and that comprehensive reports that impurity fate and purge ● significant structural fragment, include documentation of the software and model names and ● adequate SM specification. and versions reduces the need for follow-up by the agency.
Michalak also noted that deficiencies for inadequate starting IID and Biopharmaceutics in Focus materials are common during DMF reviews “and can be costly.” These costs can include extra review cycles, more The second parallel day three track included presentations on work, such as validation and method development, and the FDA’s Inactive Ingredient Database (IID), biopharmaceutics, risk of receiving an RTR for the referencing ANDA. and labeling.
DMF Reviews Take M7 Into Account In the IID session, Ashland Global Regulatory Affairs Manager Priscilla Zawislak – who is the Chair-Elect for Presentations on risk-based reviews for drug substances, the IPEC-Americas – reviewed the discussions that the trade ICH M7 guidance on mutagenic impurities and its impact associations have been having with FDA since 2011 on the on DMF reviews, and the use of quantitative statistically- excipients database and the progress to date. derived models to evaluate potential genotoxic impurities rounded out the afternoon in the API/DMF session. Colorcon Global Regulatory Affairs Director David Schoneker, who chairs the IPEC-Americas maker & OPQ ONDP CMC Lead Stephen Miller discussed the distributor relations committee, followed Zawislak to the scope and content of M7, the implementation timeframes, podium to discuss the importance of the family approach and current FDA perspectives. Miller served as an FDA for excipients and the work done to date to get FDA’s buy representation on the M7 Expert Working Group. [See IPQ in along with: ● IPEC-Americas’ evaluation of the changes October 31, 2014 for an earlier presentation by Miller on M7 to the IID made in August ● the association’s response to an implementation.] FDA docket opened in July to solicit industry input on the IID, and ● next steps (see story pp.48-64). Miller emphasized that it applies to both new drug products and marketed products when certain post-approval changes Providing an update on how his office has been are made. He also provided cautions regarding some types impacted by becoming part of OPQ, ONDP Division of mutagenic impurities that can in some cases persist of Biopharmaceutics Acting Director Paul Seo through a surprising number of reactions and purge points. compared the “markedly different” responsibilities, timelines, and deliverables for biopharmaceutics How M7 will be integrated into DMF reviews was evaluations under the PDUFA and GDUFA addressed by ONDP Acting Quality Assessment programs. Lead David Green. Seo noted that, historically, the approaches for evaluation of The key steps the DMF reviewer will follow in implementing new and generic drugs have been different. Now that both M7, Green explained, will be to: ● calculate the Threshold product types are being evaluated in OPQ, there is a need to of Toxicological Concern (TTC) for the API based on the find “some parity” in the approaches, he said. He stressed Maximum Daily Dose (MDD) of the reference ANDA and the importance of using clinically relevant specifications as the Daily Intake per Duration of Treatment (DIDT), and a way to achieve that parity. ● look at the firm’s synthesis and determine if there are any chemical compounds that contain structural alerts. If Clinically relevant specs, Seo commented, could: ● allow structural alerts are identified, the reviewer will follow the for wider in vitro release acceptance criteria ● provide DMF structural alert process to determine the appropriate more insight during post-approval changes, and ● provide response to the firm. increased confidence in release and stability data.
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JANUARY 2016 7 MONTHLY UPDATE - JANUARY 2016 He pointed out that while the thought processes are early October, 2015 (link provided below). It provides for evolving and flexible, his group would like to see more the labeling content of ANDAs to be approved in draft as early development data submitted in support of QC in vitro long as any outstanding labeling deficiencies are minor and release tests, and the use of computational modeling when editorial in nature. larger data sets are being examined. A new USP General Chapter <7> on labeling becomes official Spelling Matters May 1, 2016. All information pertaining to labeling has been moved from other chapters to Chapter <7>. Golson noted In an in-depth presentation on labeling requirements, OGD that until it becomes official, labeling information can still be Division of Labeling Review (DLR) Acting Deputy Director found in current chapters. Lillie Golson addressed: ● the reorganization of DLR ● changes and current trends in labeling ● “insider’s tips” of Also in the day three track were sessions on the regulatory best practices to improve the quality of labeling submissions, science efforts related to GDUFA and bioequivalence and ● recently published guidances impacting labeling. inspections.
To meet the DRL commitments in GDUFA, her division LINKS: is streamlining review efforts and working to ensure ANDA labeling remains consistent with the labeling of USP 2015 – 2020 Resolutions the reference listed drug (RLD). In addition, an effort is being made trying to ensure more consistency in labeling FDA on Refuse-to-Receive standards: review recommendations across the division and reduce the ● Final guidance (May 2015) number of review cycles. ● Pre-recorded webinar
Golson’s “insider tips” were related to best practices FDA on Controlled Correspondence: regarding: ● insert labeling ● injectable drug labeling for expiration and beyond use date (BUD) ● ANDA labeling for ● Final Guidance (September 2015) the reference listed drug (RLD) ● safety labeling changes for ● Pre-recorded webinar discontinued products ● the formatting of hyphenated or compound words ● distributor labeling, and ● submitting FDA on Labeling: the same labeling change to both an NDA and ANDA that references the NDA. ● Acceptability of Draft Labeling to Support ANDA Approval
At the conclusion of her presentation, Golson FDA on Stability: pointed to two recent guidance documents regarding ● Final guidance (June 2013) labeling – one from FDA and the other from USP. ● Guidance Q&A (May 2014) An FDA final guidance titled “Acceptability of Draft Labeling to Support ANDA Approval” was issued in
OGD DIRECTOR COOK UHL ON GDUFA’S REVIEW PROCESS IMPACT As the opening presenter at the GPhA Fall Technical Conference in early November, OGD Director Cook Uhl discussed the challenges the generics office faces in meeting its GDUFA commitments and how the review processes are being transformed to assure the goals are met.
I am pleased to be here to give you an update on OGD and on GDUFA…. I am basically going to break my topic into three parts:
● I am going to give you an update on GDUFA – where we are with some of the changes, improvements, progress, and such.
● I am going to spend the bulk of my time talking about output and productivity, though, because I think that is what industry is most interested in – not just what we are doing, but how we are doing it.
● And then I am going to zip through very quickly some helpful hints for industry….
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JANUARY 2016 8 MONTHLY UPDATE - JANUARY 2016
Just a brief reminder to everyone about what GDUFA is and where we are: We just finished year three of the five-year GDUFA I commitment. The major program goals of GDUFA are that of metrics – so basically due dates on things like applications, the GDUFA backlog, and some CGMP inspection improvements. As well, some of the goals include efficiency enhancements – things like IT improvements, which I will get into more, and also regulatory science. And the basic tenets of GDUFA are a triangle of transparency, safety, and access.
GDUFA Update
I have talked to you before about GDUFA. This part of it is a transforming program. There is nothing about GDUFA that is just doing the same stuff that we did before GDUFA. So in addition to transforming this program, we still had work to do, and we still had to perform while we were transforming. I have talked to you over the last two years about what all these changes are and how we are doing. But I am really happy to report this part: We built this machine, and we are now cranking it up.
So this is what GDUFA required – a deep foundational restructuring of everything related to the generic drug review program. We had to build an entirely new infrastructure. We had to not only define our business processes, but improve them and create efficiencies along the way. We had to hire and train new staff: There were over a thousand new employees brought into the agency under GDUFA.
I mentioned this new IT platform. So, anyone who has even installed an update from Microsoft knows how destructive that is. Imagine if the entire thing that you were working with every day is new and changing. That is what we have had with our IT system. And, needless to say, we have had to improve communications with industry. We had to do all of this to prepare for Year 3 when goal dates went into effect. And that was necessary, but not sufficient, because we also have to hit the goal dates.
GDUFA Commitments
So I am happy to report that FDA is fulfilling its negotiated GDUFA commitments. We really feel comfortable with saying this and confident in saying this. We have also worked with industry on additional program enhancements, especially on things related to the pre-Year 3 group, which is a large group of applications. These include things like target action dates and information requests. And we did this to improve output and communication.
I would just like to pause for a second and say that this was a huge undertaking. This was a heavy lift. And it produced a huge benefit. This is not trivial, nor is it cosmetic. And we really thank our industry colleagues for working with us on this.
In addition, we are building a modern 21st century generic drug program. That is what we really need to do in order to implement GDUFA and really have GDUFA be successful. And in the end, what we are looking for here is significant, sustained increase in approvals, actions, and communications. And what you will see in my slides is our data that support that statement.
This is a busy slide (see Figure 1, p.10). We have shown this to you every year that we have been here since GDUFA implemented. In the first column are the applications for which there are goal dates. The middle column with the red arrow is where we are now, fiscal year 2016 – Year 4 of GDUFA, the second year with goal dates.
And goal dates are really very important because they are a powerful tool to improve the timeliness and predictability of review. One thing I want to point out here because I have heard this, or seen this misquoted in the trade press: Look at the first row – original ANDAs. The goal this year is that FDA will act on 75% of those submissions within 15 months. It does not say we will approve 75%. I would be thrilled if we could approve 75%. But it means that we will act – which means that you can get an approval, a tentative approval, or a complete response within that 15-month timeframe.
Predictability for Industry
This, again, is another busy slide (see Figure 2, p.10). It is a graphical depiction of what we are talking about regarding predictability for industry. We are in Year 4. Year 3 and Year 4 have 15-month goal dates for original applications. So OGD and OPQ are working hard and need to meet those 15-month goal dates.
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JANUARY 2016 9 MONTHLY UPDATE - JANUARY 2016
Figure 1
Predictability of Industry
Figure 2
This little graphical depiction (not shown) is what this will look like for Year 5, which is when there is a 10-month review. First the application comes in. Then there is filing. It gets assigned to the teams. There is a kickoff meeting. There are the reviews. Information requests go out to industry. They come back. Potentially, there is another information request that goes out and comes back. We wrap it all together. Throughout this whole timeframe everything is going on with inspections so that at ten months we can wrap it up, have the final assessment, and be able to communicate with you what our findings are.
So, we are confident that we can do that – now in 15 months, and next year in 10 months. And we are comfortable in saying and confident in saying that we anticipate that by Year 5 the first cycle of approvability will be improved. But this is achievable, again, if the submissions are high quality and complete upon first submission.
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JANUARY 2016 10 MONTHLY UPDATE - JANUARY 2016
This is a table here for you again about predictability (see figure 1). So, the previous slide is all the predictability for those applications that have GDUFA goal dates. A large chunk of work that we are working on does not have GDUFA goal dates. So this is how we are kind of, in parallel with the GDUFA goal dates, putting all of the pre-Year 3 applications in line similarly with what the goal dates look like for the Years 3, 4, and 5.
And this is a busy slide (see Figure 2). I am PREDICTABILITY for INDUSTRY going to walk you through this so you can see TADs for Additional Cycles (Pre-Year 3) where we are with what we have, specifically before Year 3. Right now – and this changes on a day-by-day basis – essentially, filing is all caught up. [Editor’s note: Uhl clarified that the data she was presenting at the conference would be “scrubbed” for formal reporting purposes.]
There are about 500 applications that have completed filing but have not been picked up by reviewers yet. There are about 2,100 applications for which at least one communication has been issued to industry but it is still under review with us. So right now there are about 2,600 applications for the pre-Year 3 cohort that are basically pending with the FDA. Figure 1
ANDA Workload as of 10/01/2015
Figure 2
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JANUARY 2016 11 MONTHLY UPDATE - JANUARY 2016
Industry Actions Needed
So what is sitting on industry’s plate? You have about 850 Projected vs. Actual Orignal ANDA Receipts applications for which we have issued a complete response. We cannot do anything with those applications. They are in your hands. You have to respond to us.
In addition, there are 267 for which we have issued tentative approval [TA]. Again, that is in your hands. When you are ready to convert that TA into a full approval, you then reach out to us.
So at this point there are about 1,100 applications in that pre-Year 3 cohort that are pending, but they are in industry’s hands. So this is kind of the current total – it is about 3,700. Figure 1 But if we look at this on a month-by-month basis – this is kind of the communication back and forth: There are about 100 complete response letters that we sent out. There are about 100 amendments that came back. There are about 550 to 580 information requests per month that go back and forth between the agency and industry. And there are tentative approvals on the order of about 10 every month.
So with this pre-Year 3 cohort, this is how it breaks down: We have approved 1,300 of those applications. There have been 100 or so of those that have been ‘refuse to receive.’ There are 400 and some that were withdrawn. And there are 3,700 that are still pending either our review or your action related to responding to CR or converting a TA to a full approval. So this is the big chunk of work that we are working on.
ANDA Receipts Jan. 2014 – Sep. 2015
Figure 2
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JANUARY 2016 12 MONTHLY UPDATE - JANUARY 2016 Output and Productivity
Let me move into output and productivity. Really simple and basic: What does my inbox look like? And what does my outbox look like?
So, our inbox is blown up right now. Thank you very much. There has been a record number of original submissions sent to the agency since GDUFA was enacted. And there is an increase in the number of controls – not just the number, but the complexity of the controls.
What does this look like? Let’s break it down. For every data point that I give you, I am going to break it down and show it to you, probably in more than one way. So here is what I am talking about – incoming submissions.
In fiscal years 2012, 2013, and 2014, there were a record number of submissions (see Figure 1, p. 12). When GDUFA was negotiated, it was projected that there would be 750 original applications per year. You can see that it has been well in excess of that – to the tune of about five-and-a-half years’ worth of work that came in in four years. Fiscal year 2015 actually dropped to 545, but that still does not average us out at the 750.
Here is what this looks like over the last year-and-a-half (see Figure 2, page 12). This is broken down month by month by month. On average, we are getting between 50 and 100 submissions a month, except for June of 2014, where we had 635 submissions in one month. So essentially an entire years’ worth of submissions in one month. That was due to the stability guidance and changes in stability – the expectations of what you have to submit about stability.
Controlled Correspondence and Productivity
This is data about controlled correspondence (see box below). The rightmost columns on this are the totals. Blue is Year 1 of GDUFA, red is Year 2, green is Year 3. So we went from 950 controlled correspondences the first year of GDUFA to over 1,500 just last year. So almost a 50% increase in just the last three years.
Controlled Correspondences Received under GDUFA (by discipline) FY13 -FY16
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JANUARY 2016 13 MONTHLY UPDATE - JANUARY 2016
The other two areas to point out are that they are different in complexity as well, because the controls that are being picked up by our clinical division have gone from a handful, 35, up to over 300 – a ten-fold increase. As well there was a large bump in the number of controls being handled by OPQ. So chemistry-related controls went from 70-something up to almost 270.
ANDA Productivity/Output
Here is our productivity and output…. Here are the originals (see Figure 1). This is the last 14 years’ worth of information about ANDA original application approvals. The little red arrow at the bottom is when GDUFA went into effect. So it is pretty obvious to see when you look at this across 14 years that we have definitely maintained productivity, at least similar to the pre-GDUFA levels.
ANDA Approvals FY2002 — FY2015 Number of Applications Number of
Figure 1
ANDA Approvals and TAs 2014 – Sep. 2015
Figure 2
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JANUARY 2016 14 MONTHLY UPDATE - JANUARY 2016
So, let’s break this down differently now. This is what approvals and TAs look like on a monthly basis over the last year- and-a-half (see Figure 2, p.14). Some months are higher than others. And obviously you can see over the last 6 months we are definitely trending to higher rates of approval and a sustainable number of higher approvals. And I can say that just this last month, which is not even on here, October, we had 51 approvals and 21 tentative approvals.
Here are some notable approvals in the last fiscal year: Aripiprazole, Testosterone topical gel, Glatiramer Acetate, Esomeprazole delayed-release, Ritonavir, Sirolimus, Linezolid, and Scopolamine transdermal – so many new approved ANDAs to provide for our patients affordable alternatives to the medications that they would have spent more on in the past.
Another component of our output is complete response letters. Complete response letters are required under GDUFA. A complete response letter is really complete if it includes inspectional information.
Here is what it looks like for complete response letters, again, over the last year-and-a-half. Approximately 100 complete response letters with inspections are issued every single month.
Here is that information for originals, composite across over the last fiscal year (see box below). This is what Year 3 of GDUFA looks like. We had 491 approvals – that is the mid-line, the blue line – increasing over the last 6 months. The topmost are complete response letters – over 1,100 complete response letters. And tentative approvals, 122.
ANDA Originals – Actions Taken FY2015
This is communication on the applications that we are reviewing (see Figure 1, p.16). This is easily correctable deficiencies [ECDs] and information requests [IRs] to industry. You can see a stark increase in the output of communication to industry, really sustained over the last 6 months – over 4,700 communications to industry on your applications in the last fiscal year alone.
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JANUARY 2016 15 MONTHLY UPDATE - JANUARY 2016
ECDs and IRs 2015
Figure 1
ANDA PAS - Actions Taken
Figure 2
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JANUARY 2016 16 MONTHLY UPDATE - JANUARY 2016
Another application type that has GDUFA goal dates are prior-approval supplements. This graph is how we did in Year 3 for prior-approval supplements (see Figure 2, p.16). There were 612 approvals – that is the topmost line. There were about 180 complete responses, and 360 easily correctible deficiency and information requests. We definitely nailed the prior-approval supplement GDUFA commitment for Year 3.
Control Correspondence FY2015 Cummulative GDUFA Performance by FDA Reciept Date-All Disciplines
Filing Backlog
Filing is always an issue that is brought up. There are no GDUFA goals for filing. But I do want to talk about filing, because every time I meet with you guys, you bring it up to me. There is no filing backlog. We are doing filing in real-time. So you have received communication on applications in the GDUFA backlog and in applications submitted in Year 1 and Year 2.
This time last year, there was a backlog of almost 1,100 applications awaiting filing review. This is what the Division of Filing Review has done in the last 12 months to that backlog. Johnny Young has led this group in an absolutely tremendous way. And I am proud to say there is no filing backlog.
They are also doing filing review in a way that you should be very happy about. The average filing is taking 31 days. So you are hearing back pretty much in real-time from us about a filing decision. Again, this division cleared away the pre-Year 3, and they did 1,200 filing reviews just last year.
Controlled Correspondence
Controlled correspondence is another type of submission for which there are GDUFA goal dates (see box above). The red line is the 70% GDUFA goal. And in fiscal year 2015, or Year 3 of GDUFA, we have exceeded the GDUFA goals for controlled correspondence.
There is a backlog of controls as well. These are controls that existed prior to Year 3. There were close to 900 controls, and we are working to eliminate that backlog as well. There are 175 remaining, and our goal is to get rid of that backlog of controls by the end of this calendar year.
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JANUARY 2016 17 MONTHLY UPDATE - JANUARY 2016
GDUFA Backlog
This is the GDUFA backlog (see box at right). There is lots to talk about GDUFA Backlog regarding what the backlog is. Defined in GDUFA itself, it is those applications that were pending as of the date that GDUFA went into effect. So there were 280-some original applications and 1800 prior approval supplements. And the GDUFA goal for that group was that 90% get action by the end of Year 5.
When I was here last year, I reported to you that we were at 65%. This year, we are at 82%. And that is at the end of Year 3. By the end of Year 5, we need to be at 90%, so we are way ahead of schedule on meeting this GDUFA goal.
Approvals GDUFA Years 1-3
I also want to point out the approvals of the originals is 584. This is more OverallOverall Actions than double the approvals than when I reported at this time last year.
And here is a different summary of the output of approvals, prior approval supplement approvals, tentative approvals, and complete responses (see box at right). The red line depicts the difference between pre-GDUFA and Years 1, 2, and 3 of GDUFA.
This is definitely output that was not seen prior to GDUFA. And again, we are maintaining productivity at least similar to pre-GDUFA levels. I think what you have seen in my last 20 or so slides is that over the last six months there is definitely increased and sustained output.
So for year 2015, the third year of GDUFA, let me just summarize again: We had 612 approvals. That is full approvals and tentative approvals. That is a 22% increase from last year, which was GDUFA Year 2, and a 14% increase from two years ago, which was GDUFA Year 1.
We issued over 1,000 complete response letters. We issued an additional 170-plus complete responses without inspection. Again, this is one of those additional communication tools with industry. And we have issued on a monthly basis hundreds of communications to industry with easily correctable deficiencies and information requests.
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JANUARY 2016 18 MONTHLY UPDATE - JANUARY 2016
Product-Specific Guidances
Another aspect are product-specific Product-Specific ANDA Guidances guidances. These are not required under GDUFA. But I want to show you the FY2013 – FY2015 increased output of guidances while we are as well maintaining our productivity (see box at right). New Guidance
You can see that every single year we have Revised Guidance more guidances, more draft guidances, and more revised guidances. We have doubled our guidance output in the last three years. And not only have we doubled in number, there are more guidances now being published that relate to complex dosage forms. There are a lot of different complex dosage forms – inhalational, ophthalmic, transdermals, etc. (see box below).
And there are two guidances I wanted to take a minute to talk about. One is the conjugated estrogen guidance. This product is a complex mixture. There was no previous ANDA pathway. The guidance has come forward specifically because of FDA Notable FY2015 Product Specific Guidances lab work on the analytical methods for this Recommendations on more complex dosage forms product. It took significant work across all of CDER. But there is now a draft guidance on how to develop this. ● 2 inhalation powders, 3 MDI, 4 nasal sprays
And another one is the size and shape ● 1 buccal tablet, 1 sublingual spray, 1 dental powder, 1 buccal film guidance. This was done between OGD and ● 8 ophthalmic solutions or suspensions OPQ. This published in June. The guidance is not being used for filing decisions. But this ● 9 topical semi-solids, 3 topical spray/foam guidance is useful to industry to understand ● 3 transdermal systems, 1 otic suspension, 2 ER injections what FDA is looking at and looking for during scientific and clinical review.
Communication Enhancements
In addition to that, there are a variety of communication enhancements for the pre-Year 3. So the pre-Year 3 was that very busy slide with numbers all over that represent 5,700 applications. Here we are doing complete response letters without inspection just so industry can have those deficiencies that were identified during review.
We are doing information requests. We are doing real-time communication. We have assigned target action dates to all of our applications. And we have communicated that to you.
For those applications that are pre-Year 3, they do not really have a goal date, but we needed to assign like a fake goal date of sorts so that all of the work could be coordinated together across the whole generic drug program. And the target action date is a method with which to do that.
In addition to that, we also have to do some TLC for the first generics so that the TADs align with patent and exclusivity-type expiry. And then we formalized and clarified all of these communication expectations in the communications with industry MAPP for those pre-Year 3 applications.
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JANUARY 2016 19 MONTHLY UPDATE - JANUARY 2016
Other Important GDUFA Updates
IT Platform
One important update is the efficiency enhancements that I mentioned to you, and that is IT. It is my opinion that the improved communication and increased productivity are the direct result of our improved IT system for the generic drug program.
For those of you who have been around for a while, and you’ve heard some of the agency’s systems like FAERS and DARRTS – those were home-grown systems. Those took years and years of development before they could even launch. And this IT platform for generics is basically… historic. And it is monumental, because it went from planning to launch in little over a year’s time. It uses off-the-shelf solutions that are configured to meet business needs in order to also to reduce development times.
This IT platform provides workload management and review management tools. And it also enables us to prioritize first generics, P4s, and any other type of exclusivity or patent issues.
The platform is basically three essential components: ● integrated data management ● integrated workflow management, and ● analytics search and reporting.
What this does is it supports faster review times. So you are seeing improved numbers of approvals and tentative approvals. It makes it easier to collaborate and communicate with industry. It improves review consistency, and also the ability to identify and study precedent applications. And it makes review times and completion times more predictable.
This is a busy slide, but I put this up intentionally to show you the complexity of the generic drug program (see box below). This is all the data that had to be migrated into this new platform – 39,000 submissions, almost 3,000 products, almost 24,000 ingredients, all of this in one IT system accessible to everyone in the generic drug program.
Data Migrated into New IT Platform
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JANUARY 2016 20 MONTHLY UPDATE - JANUARY 2016
We just launched this platform one year ago, so October 1st of last year. Since that time we have had a 21-22 percent increase in our approvals. There have been over 130,000 assignments that have been completed in this platform. We issued almost 4,300 communications to industry. We have completed almost 1,200 controls, and those met the GDUFA goal dates. There were almost 1,300 approvals. And the filing backlog was eliminated.
This overlays that approval chart that I showed you earlier with key milestones of the platform (see box below). You can see when the platform launched, there was a dip. That is due to issues of stability, data migration, data validation, employee training, and whatnot. After a major system upgrade, productivity bumped. One other tidbit number on this slide is that there are 1,400 users logged on to this platform every single week.
Impact of IT Platform
Regulatory Science
So another point of GDUFA is the regulatory science activities. This program backs the promise about generic drugs. It allows for advances in equivalence, and also the ability to have access to generic products across a variety or a full range of drug products that are tools for drug development and better tools for regulatory review and confidence in generic drug substitution.
We just released the 2016 research priorities report. And we just released the 2015 awardees for contracts and grants. You can find that on our website. And if you want more information about this, I highly encourage you to attend the session on Wednesday. Rob Lionberger and Larissa Lapteva from OGD’s Office of Research Standards will be presenting about our GDUFA regulatory science program.
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JANUARY 2016 21 MONTHLY UPDATE - JANUARY 2016
Helpful Hints
So, the last item I have here are helpful hints. As I said, I am going to zoom through this. But I do kind of like my little subtitle here about controlling your destiny. There will be an hour and a half presentation tomorrow by [Office of Regulatory Operations (ORA) Division of Project Manager Leader Kevin Denny and ORA Office of Program and Regulatory Operations (OPRO) Acting Branch Chief Craig Kiester] about how to get an ANDA approved.
My colleagues at OGD gave me all the slides that follow, and every single thing that they have highlighted here are recurring issues with ANDAs to the tune of many, many years seeing the same deficiencies. So, there is probably nothing new here. But the aspect of reducing cycles and actually getting first-cycle approvals is really going to be met by addressing some of these very common deficiencies.
General Housekeeping
So, a few things – these are general housekeeping. Issues with respect to the cover letter: Be sure everything is there. The 356-H form: All the sites have to be identified for 356-H. It is not uncommon that they are not all there, and some of them are hidden way down there, maybe in Module 4. They need to all be on the 356-H.
And another one worth pointing out here is, who is the point of contact for your application? So, it should probably not be your CEO. That would be akin to me being your RPM contact for your application. So, the point of contact needs to be somebody who is readily accessible, can give quick responses, quick turnaround, and rapid communication with the agency about your applications.
Another item worth mentioning are the FEI numbers, because there are obviously acquisitions and mergers going on actively. So you want to be sure that your FEI numbers are accurate.
And another thing to consider is electronic submissions. You can submit now and it not be electronic, but you just do not get a GDUFA goal date. But in spring 2017, it will be required that all submissions are electronic, and as well follow the eCTD format.
Filing Problems How to Avoid Filing Problems So, again, let me talk about filing. Filing is the first step of review. Historically, I think industry has thought of • Adhere to eCTD specifications and recommendations filing as, ‘we got it. If it is accepted for filing, we are going to be approved.’ And what ‘accepted for filing’ • Clearly identify new strength/new formulation requests (amendments and PASs) in the cover letter means is that your application is sufficiently complete to allow scientific review. • Abide by the stability recommendations implemented on 6/20/2014 So, now that the World Series is over, let me give • Place information/data/material in the appropriate you a baseball analogy here. If your application is sections/folders of the ANDA accepted for filing it means you got a homerun – it does not mean that you won the ballgame. But if • Conduct & submit all recommended comparative dissolution studies (test versus RLD) your application is getting approved, you won the ballgame.
The filing group has listed here a number of common deficiencies that they see on a daily basis in applications [see box above]. And there are a couple links here for you, the RTR guidance [links provided on p.8]. This is a final guidance. This was one of the very few guidances that was required under GDUFA, so there is the final guidance and there is a webinar that is available 24/7.
Bioequivalence: My colleagues in the office of bioequivalence say that they see these deficiencies all the time, and they have seen them for the last ten years, and not seeming to change much in their frequency. You will hear more about those tomorrow in Kevin and Craig’s presentation.
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JANUARY 2016 22 MONTHLY UPDATE - JANUARY 2016
So these are from the clinical division (see box below). And they point out issues related to excipient issues and related to drug device combinations as frequent problems, post hoc analysis…. So if the study failed and you are going to re-analyze it a different way, it is still a failed study. And then also variation from guidance.
Clinical Deficiencies Excipients • Novel excipients require safety studies outside the scope of an ANDA. Remember to ensure that DMFs do not introduce novel excipients. • Acceptable quantities depend on IID, prior use in approved drug products AND consideration of the indication, route of administration, chronicity, and population; e.g., an amount acceptable for adults may not be safe in children. • Avoid excipients that cause symptoms similar to the indication for which the product is given; e.g., sulfites in products used to treat migraines or osmotic agents in products used to treat diarrhea.
Drug/Device Combinations • Containers, devices, and patient instructions for use should be as close as possible to the RLD
• Differences complicate assessment of substitutability.
Post Hoc Analysis • Reanalysis of a failed study using different methodology should not be submitted in support of a new conclusion
Variation from a posted guidance • Failure to provide adequate justification may delay review or impact approvability
So, a guidance is not binding, and it is okay to vary from the guidance. However, you must provide the rationale – adequate justification for why you have deviated from that guidance. And failure to provide that may very well delay the review of your application.
Common issues related to labeling include both the labeling and as well the carton container. You are reminded to check drugs@FDA for a recent update. A guidance just published about draft labeling (link provided above). So we will now accept draft labeling to be able to approve a product. That is new and we think very beneficial to industry. If you want more about labeling, I encourage you to hear [ORA Division of Labeling Review Acting Deputy Director Lillie Golson] on Wednesday, where she will be discussing current trends in labeling and best practices.
And controlled correspondence: There are a variety of common problems that we are seeing with controls that come into us (see box below). You can read these at your leisure and you can hear more about these, again, tomorrow. One thing I do want to point out about controls is, controls have to come in via the generic drug email [[email protected]]. We do not receive controls by paper or by fax.
Common Problems in Controlled Correspondence
• Not indicating the existence of or including response to previous control as stated in the guidance - Needless effort spent on researching previous controls that should have been included in the follow-up request • Not submitting controlled correspondence through a US Agent - Any inquiry to the OGD email box should come through your US Agent even if you think it would not be a control • Not including full RLD information • Submitting questions related to a pending or approved ANDA and not making reference to that ANDA • Submitting a new Q1/Q2 request for formulation review when you have already been informed via a previous control that a proposed formulation Q1/Q2 is acceptable
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JANUARY 2016 23 MONTHLY UPDATE - JANUARY 2016
There is a guidance that we published on controls. This was not required under GDUFA, but we thought it was very important for us and for you that we clarify how we are going to deal with controls under GDUFA, and there is a link to the webinar that you can access (link provided above)….
Summary and Next Steps
The reason for significant and sustained increase is something that I said to you three years ago – GDUFA, GDUFA. We are implementing this program, and we are starting to see the benefits of this program.
We have just finished Year 3 [which] is the year that has metrics. So,how are we doing? For original applications, it is too soon to tell. Those applications that came in in October of last year have 15 month review goals of January of 2016, so we do not know yet.
What I can tell you though is that we are confident we will meet these goals. We have approved an application already from Year 3, and we have just tentatively approved an application about two weeks ago.
[Regarding] the amendments in Year 3: Again, too soon to tell. But we are very confident. For prior approval supplements in Year 3, we are exceeding the goals. For controls, exceeding the goals. The quality of submissions: Again, it is too soon to tell. But what I will say is, the metrics or the indicators that I think will help us understand the quality of submissions are: ● What is the refuse to receive rate in Year 3? ● How many RTRs? ● How many applications actually get approved first cycle in Year 3? ● How many cycles does it take to get approved? Those are the indicators for the quality of submissions. And then the GDUFA backlog – I already showed you that. We are way ahead of schedule for that at 82%.
So, what is next? We just started Year 4. So in Year 4 and Year 5, the metrics tighten. And just the data that I showed you, whether it is across 12 months, a year and a half, or even 14 years, there are obviously up days and down days, up months and down months, and that is exactly what I anticipated. You will still see in Years 4 and 5 that we will maintain a strong focus on target action dates with those related communications to industry for the pre-Year 3 applications. And we will hold the first generics in tender loving care so that we avoid any forfeitures and that we continue to pursue timely first generic approvals.
So, FDA and industry continue to work together to ensure that these ultimate aims of GDUFA are met – safety, access, and transparency. We could not have done it without you. And we thank you. I am happy to say our productivity is up. Our actions are up. Our approvals are up. Our communications are up. We have issued these target action dates. And we have a formula for success for all of the pre-Year 3 submissions. I showed you that table.
We are fulfilling our negotiated GDUFA commitments. We implemented additional program enhancements that I mentioned earlier – target action dates and information requests – to improve our output and our communication with industry. We are building a robust, modern generic drug regulatory program that is sustainable and predictable.
So, as my subtitle for my talk says, we are really reaping the benefits of this program. This is a direct result of the intensive agency and industry collaboration to get us to this point. So I used Rosie the riveter before, and I use her at work to inspire people. But I would say, it is not that we can do this: We are doing this. We are working together to provide affordable, high- quality generic drug medications for the American public.
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6731 NovaPure Advert.indd 1 3/29/2012 8:46:01 AM MONTHLY UPDATE - JANUARY 2016 FDA’s API DMF Assessment Timelines Improve as eCTD Use Increases and OPQ’s New API Review Structure Takes Hold
The increasing use of the electronic common technical Top Ten DMF Shortcomings Reviewed document (eCTD) for submitting Type II Drug Master Files (DMFs) has contributed to a significant reduction in the In addition to providing a detailed look at the CA timelines amount of time it is taking FDA to do DMF completeness and metrics, Perera addressed: ● how to avoid an ANDA assessments (CA), and a significantly higher percentage of refuse-to-receive (RTR) letter due to a DMF issue ● the most the electronic filings are clearing the CA review on the first common deficiencies her division has been seeing in DMFs cycle compared to the paper versions. in terms of the CTD section in which they occurred, and ● responses to common questions from industry regarding the During the first six months of the Generic Drug User Fee Act DMF process. (GDUFA) – October through April 2013 – about 20% of Type II DMFs were submitted in electronic format, compared to The sections of the DMF with the most shortcomings during 50% by the end of Year 3 (FY 2015). a one-year review were labeling, general properties, and container closure, Perrera noted. Meanwhile, the average number of days it took the agency to finish a full completeness assessment once the filing fee The issues with labeling centered on missing storage is paid dropped from 108 to 73 – well on the way to the temperatures and caution statements. Missing melting agency’s goal of 45 days. points or solubility in various organic solvents were among general property issues of concern. The container closure The time to do an “administrative” CA on a DMF for which a shortcomings usually involved information related to full scientific review has already been conducted has shrunk secondary and tertiary components. during the three years from an average of 20 to 9 days – seen by OPQ as about the efficiency limit. A completeness While issues with starting materials were not quite assessment either results in the DMF receiving a “complete” as frequent – starting material designation ranked designation or the issuing of an incomplete letter to the filer. sixth in the findings, and the vendor’s SM certificate of analysis (CoA) ranked tenth – Perrera stressed that In turn, data from the FDA’s Office of Pharmaceutical Quality they are significant due to consequences that unfold. (OPQ) is showing that about half of the CAs are being completed for electronic DMFs on the first cycle, versus only An inappropriate starting material designation “causes about 20% for the paper filings. delays,” she noted, as having to redesignate the starting material or reference another DMF “takes a long time.” The more efficient DMF review process flowing from eCTD use was highlighted by OPQ Office of New The common questions reviewed by Perrera covered topics Drug Products (ONDP) Chemist Jayani Perera during such as GDUFA fees, designating mixtures of components her update on the DMF assessment process and as APIs, stability requirements, and the concept of a “single” results presented at a track on active pharmaceutical manufacturing process.” ingredient (API) reviews on the third day of the GPhA/FDA Fall Technical Conference in November. ONDP Reviews All APIs
The eCTD “serves as a guide for what to submit and where ONDP Deputy Director Scott Furness opened the API/DMF to put the information,” Perera commented, resulting in session of the GPhA conference at which Perera spoke with better quality and better organized DMFs that facilitate the a review of his office and its functions, and provided insight CA process, and, in turn, allow ANDA applicants to better into its API review initiatives. plan and execute their submission strategies. ONDP’s specific functions include: ● conveying risk- Under GDUFA, in order to file an ANDA, all Type II DMFs informed recommendations on product quality to CDER for the drug substance must be available for reference. To offices and industry ● communicating product risk inthe achieve the “available for reference” status, the DMF holder pre-marketing stage of assessment ● collaborating with other must pay a one-time user fee, and the DMF pass the CA. The OPQ offices to conduct integrated quality assessments ● criteria is outlined in the agency’s draft guidance on DMF serving as quality liaison to the Office of New Drugs clinical CAs (link provided below). divisions, and ● participating in inspections as needed. WWW.IPQPUBS.COM
JANUARY 2016 25 MONTHLY UPDATE - JANUARY 2016 As part of the restructuring that created OPQ, “All indicators are that that has been a great success at cross- ONDP was tasked with the quality assessment training. This way we can rely on reviewers to work in both of Investigational New Drug (IND) submissions, PDUFA and GDUFA spaces.” original and some supplemental New Drug Application (NDA) submissions, and API Furness commented that “from a quality of work life information supporting all new and supplemental standpoint” the cross-training allows reviewers to NDAs and ANDAs. ONDP also assesses the experience “the best of both worlds, because they have a biopharmaceutics portion of INDs, NDAs, ANDAs, mix of both PDUFA and GDUFA products on their plate. and their associated supplements. They have unique, multi-disciplinary interactions that the new drug folks have with the clinical reviewing divisions With reviews of APIs for all application types brought as well as the variety of drug substances with the variety of together in the same office, the ONDP team sought to drug syntheses on the generic side.” improve the reviews with initiatives including: ● the construction of a more formalized drug substance risk Review Initiatives Underway assessment platform for NDAs and ANDAs ● devising a The ONDP deputy director also discussed API review new review template that will facilitate the most efficient initiatives in his office involving risk assessment and the and concise assessment of drug substance quality, and ● creation of a template to facilitate drug substance quality continuing to support development of new starting material assessment, respectively. selection criteria. Work will be starting “shortly on the construction of a much Furness emphasized that the Division of Lifecycle API, more formalized drug substance risk assessment platform where the GDUFA-driven DMF assessments take place, is spanning NDAs and ANDAs,” Furness reported, noting continuing to use a risk-based integrated review model in that “we already have a fairly formalized template for the place at the generic drugs office before the formation of OPQ drug product review.” (IPQ Oct. 25, 2014 and IPQ June 29, 2014). In contrast, the New Drug API Division – where the PDUFA-driven DMF The second initiative involves a team formed in the Spring assessments take place – did not start making assignments of 2015 tasked with facilitating more efficient and concise under the OPQ integrated review model until December of assessments of drug substance quality. 2014, and are “still very much in the process of mastering it.” The “CHOP” team produced a new review template, Furness said, “which has proven successful in pilot studies – both in Cross-Training Pays Off reducing the review time of the documents, and ‘chopping’ down their length and presenting the information in a much The ONDP deputy director went on to discuss the more concise format.” collaborative work his review staff has been performing, the training it has been undergoing, and the valuable experience Furness concluded his presentation by emphasizing its reviewers are gaining reviewing multiple application that ONDP is going to continue to support the types. development of new starting material selection criteria. “We are very pleased to announce that we have had a number of opportunities for workload backfill,” Furness “This is arguably the most controversial of all drug substance commented. “Last Fall and Winter, we had a number of regulatory review topics. We certainly are waiting along new drug reviewers that chipped in and helped on the with industry on what is going to come out of the ICH Q11 generic drug backlog for supplements. Those efforts really Q&A document that is going to be released fairly shortly.” made a big difference in eliminating a lot of that backlog.”
He noted that more recently the “lifecycle API” staff were LINKS: trained to do IND reviews. “We started off with a very small number of reviewers – just a pilot group – to try it out Draft guidance on initial completeness assessments and see how they liked it. The folks that tried out the new for Type II API DMFs review process with INDs really enjoyed it.” Final guidance on providing regulatory submissions The IND review training has now been expanded to in eCTD Format include the entire division. WWW.IPQPUBS.COM
JANUARY 2016 26 MONTHLY UPDATE - JANUARY 2016
OPQ’S JAYANI PERERA ON DMF COMPLETENESS ASSESSMENTS At the GPhA conference, OPQ’s Jayani Perera provided a review of the current state of Type II DMF completeness assessments. She discussed: ● CA timelines and metrics ● refuse-to-receive (RtR) decisions due to an API DMF and how to avoid them ● the most common deficiencies her division has seen in DMFs, and ● some clarifications on the DMF fee payments and CA expectations.
Under GDUFA, in order to file an ANDA, all Type II DMFs for the drug substance – that is the API – must be available for reference. To achieve the ‘available for reference’ status, the DMF holder must pay one time user fee, and the DMF must not fail the initial completeness assessment (CA).
The responsibility of the drug master file review staff…is to perform initial completeness assessments on all Type II DMFs once the DMF fee is paid. Then we develop and publish the criteria used for the CA. Those are in the draft guidance (link provided below).
We also publish a list of all DMFs that are ‘available for reference’ on FDA’s public website, which we update on a weekly basis. Because the availability for reference is linked to the ability to file the ANDA, the process and the timelines are very important and also of great interest to the industry.
CA Timelines and Metrics
In my next few slides I am going to show you our process flow and also give you an update about our timelines. I am going to walk through it very quickly.
CA Process Flow
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JANUARY 2016 27 MONTHLY UPDATE - JANUARY 2016
The CA process flow starts when the DMF holder pays the fee (see box above). We then generate the CA queue and prioritize our work based on the payment date. Next we determine whether the DMF is eligible for administrative CA. The DMF is eligible for an admin CA if there is a full scientific review on file after the cutoff date of November 30, 2007.
During the admin CA review, we actually consider the CA to have passed without going through the 62-item checklist. The rest of the DMFs are going through the full CA checklist. We call them the ‘full CAs.’ So we have the admin CAs and the full CAs.
If the answer to this question is yes, we are going to publish the DMF on the “available for reference” list. If not, then we are going to assign the CA to a review board for the full CA. If it is complete, it is going on the list. If not, we are going to issue an incomplete letter to the DMF holder.
At the same time, if the DMF has been referenced by a submitter and it is under a filing review, we also let the ANDA applicant know about the incomplete status of the DMF so they can communicate with the DMF holder regarding the best timeline to submit the response.
The DMF holder then submits a response, and at the same time they notify us using this email address [DMFOGD@fda. hhs.gov], which is actually on the fax cover sheet of the incomplete letter. I am going to mention that again a little bit later.
Once we receive the response, again we are going to assign it to a reviewer. If it is complete, it is going on the list. If not, the cycle is going to continue until we find the DMF complete.
Usually about 80% of the DMFs are found complete within two cycles. In rare occasions we have to go beyond two cycles to achieve the complete status.
CA Timelines
Before I talk about the timelines, I have to give you a little bit of an overview of where we were before. During the first two GDUFA years, the timelines were actually quite long and unpredictable. The reasons were actually due to large numbers of DMF fee payments that far exceeded the predictions, and also variable distributions from month to month including a couple of large boluses we had, and the limited review resources we had previously.
With the increased number of GDUFA hires over the last two years, I am happy to report that the average time from payment to completion for overall CAs – when I say overall, this includes the administrative and also the full CAs – is 53 days. The completion means that either it is complete or we have issued the incomplete letter.
We are going to break it down to administrative CA and also full CA. So for the administrative CA, the average time is about nine days. And let me show you some data from FY13, 14 and 15: During FY13, it used to be about 20 days. From FY13 to 15 you can see a gradual decrease. Actually, we do not expect this number to go down below nine days. This is as efficient as it is going to get. So this is the administrative one.
For the full CA, the average time from payment to completion is 73 days. So let’s look at some historic data. In FY13, this used to be about 108. You can see from this that we have a decreasing trend. We expect this to continue.
To ensure a smooth ANDA filing for the industry, our actual goal is 45 days. That is about six weeks. Based on the decreasing timeline you saw in the previous slide, this is both achievable and also sustainable. We believe that this timeframe will allow the industry to appropriately plan the fee payments and also submission strategies that reduce the risk of being not available for the referencing ANDA.
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JANUARY 2016 28 MONTHLY UPDATE - JANUARY 2016
DMF Fee Payments
Let me share some of the data on DMF fee payments. This is actually DMF monthly submissions with application fee paid. I am going to share with you the data for FY14 and also FY15. This shows the monthly numbers for the FY14. So the average was about 66 per month.
Also we saw about 43% of electronic submissions, compared to merely 20% in the first six months of GDUFA. You are going to see after a couple of slides why I am stressing [the importance of] electronic submissions.
This one shows the data for FY15. For the first 11 months, the average was about 45. Then we were hit again. Not the huge one like in September 2013, but we got about 180 in the last month due to the fee increase. But the good thing is that by this time we saw about 50% as electronic submissions. So it is about 50/50 electronic and paper.
The reason I emphasize electronic submissions is because in the next slide you will see the impact of the electronic submissions on the CA process.
The data here is actually for a two-year period, plotted semi-annually, for the first cycle CA complete rate eCTD vs. paper (see box below). If you just focus on the two years in total, you can see that the complete rate for electronic submissions is close to 50% when compared to paper, which is actually less than 20%.
First Cycle Complete Rate (eCTD vs. Paper) 1st Cycle CA Complete Rate (ECTD vs. Paper)
eCTD
Paper
There are a couple of reasons for this difference in the numbers. One could be that the DMFs submitted electronically are the recent ones, and the DMF holders have an awareness of our draft guidance, the published guidance on electronic submissions (link provided below).
Another reason could be that the eCTD – the electronic common technical document format – provides the backbone for this operation, which serves as a guide for what to submit and where to put the information.
And another good reason to submit the DMFs in electronic format is that with the eCTD format you do not have to provide the complete updates, because the electronic format always shows the current status of the DMF.
I have to stress here that there is no requirement to submit the DMFs in electronic format. But by looking at the data, you can see that the completeness of the submission has increased with the number of electronic submissions. So the increase in the number of electronic submissions is encouraging, since they improve the efficiency of the CA process.
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JANUARY 2016 29 MONTHLY UPDATE - JANUARY 2016
Avoiding an RTR Due to the DMF
This is the second part of my talk. These are some ways to avoid a refuse to receive [RTR] due to the DMF.
To avoid a potential refuse to receive due to the DMF, make sure the DMF is available for reference on the FDA public website prior to the ANDA submission. And also the ANDA applicants should communicate with the DMF holder so they know the ANDA submission timeframe and so the DMF fee can be paid ahead of time.
Our recommendation is to pay the fee six months in advance, before the planned ANDA submission date. This will allow us sufficient time if we need two cycles to achieve the complete status. I would like to emphasize that this six months is not a requirement – it is actually our best recommendation based on the data we have on file.
Of course, submitting a high quality DMF – preferably in the eCTD format – will enhance your ability to get the complete status in a shorter period of time, and also to avoid being RTR.
Another way to avoid being RTR is to be proactive: The DMF holder should be proactive to ensure a fast and smooth CA process. It is our expectation that the DMF holder will contact us for information and also CA status updates at the email address at the bottom of the slide [[email protected]].
Also know if the DMF is eligible for administrative CA. The admin CA has a short turnaround time. So if you have an ANDA submission with a timeframe, it is better to know if it is an administrative CA. Whenever you have a question about the status, you simply need to ask. We like to provide the information either to the holder or to your authorized agent.
Also make sure that the choice of starting material is appropriately justified. Because if you have to re-designate the starting material, then it is going to take a long time for the firm to respond. I am not going to talk more about the selection of the starting material, because my colleague [ONDP Division of Lifecycle API Acting Quality Assessment Lead Ronald Michalak] is going to be talking more about it later this morning.
Also know for an older DMF, normally you need to provide a complete update. If the DMF first submission is more than five years old, or you have more than five amendments sent to us since the last complete update, please submit a complete update. That way you are not losing your first cycle just to submit an update.
Another important thing: Make sure you have the current and the correct contact information with us. We use the fax number to fax the incomplete letters.
Try to respond as quickly as possible – within 30 days or less, if possible.
The next bullet point I have highlighted: Please provide the notification of amendment as instructed on the fax cover sheet. Whenever you send us the response for your incomplete letter, make sure to send us an email. Let us know. Because that is going to help us. If you fail to let us know, it may delay the CA process – sometimes by a few months. So it is better to let us know.
Lastly, contact us with CA status requests if the DMF is not on the list. If you do not see your DMF on the list, ask us. Wait about six weeks after the payment date and email us, and we will let you know. Then you can follow up with us to see when your DMF will be on the list.
Common CA Deficiencies
Before I talk about the common deficiencies we have seen in DMFs, let me show you how we came up with that list (see box below).
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JANUARY 2016 30 MONTHLY UPDATE - JANUARY 2016
First Cycle Incomplete Profile
May 13 - Apr 14
Oct 12 -Apr 13
*Completeness Assessment of Type II Active Pharmaceutical Ingredient Drug Master Files under Generic Drug User Fee Amendment: Review Metrics and Common Incomplete Items. The AAPS Journal, Vol. 16, No. 5, September 2014
We have two sets of data here, in red and blue. The data in red is for a six-month period. That data is actually published in the paper cited here. It discusses the common deficiencies and how to address them. So it is a very good paper to read for information.
The data in blue is for 12 months. And we plotted them together to show you that the frequency is pretty much the same. We have seen some improvement, but it is pretty much the same. So we have used the data for this period – the 12-month period – and compiled the ten most common deficiencies:
● Number one is the label. Most of the times we see missing storage temperatures – the numerical storage temperature range. We also see the prescription sign [Rx] and the caution statement missing.
● The next one is general properties – for example, missing melting point and solubility in various organic solvents.
● The third one is container closure – usually for the information related to secondary and tertiary components.
● The fourth one is the C of As for each reagent and solvent used in the manufacturing process.
● The next one is related to physical/chemical characterization data. Sometimes we see missing elemental analysis information.
● The sixth one is related to the starting material designation. Again, this is very important. Even though it came in as number six, this is one of the most important ones. It takes longer for the firms to respond because inappropriate starting materials always cause delays. As I mentioned before, you may have to re-designate. You may have to reference another DMF. So make sure you appropriately designate your starting materials.
● The seventh one is for the impurity standards.
● Eight and nine we usually cite together – the executed batch records and the yields and results of in-process controls. Sometimes we do not see any batch records. Sometimes we see batch records, but they are in a foreign language, and I can read only English. I do not think there are any DMFs published in my language. We have to have it in English. One thing we do during the CA review process is we check to see if the executed batch records are in English.
● Last but not least is the vendor’s C of A for the starting material. I think you have heard starting material too many times, so you get the picture.
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JANUARY 2016 31 MONTHLY UPDATE - JANUARY 2016
Responses to Questions from Industry
The last few slides are actually some clarifications on the DMF fee payments, and some CA expectations. These are the questions we actually get from the industry [in bold]:
● Do DMFs for manufacturing API intermediates pay GDUFA fees and undergo CA?
The answer is no. Only the DMF for the finished API itself is required to pay the fee and be available for reference.
However, there is one thing I need to mention here. If the DMF is referenced as an intermediate for the API, we actually do check to see if it is filed with the agency and is in active status.That is actually one checkpoint on our CA checklist.
● Can and when does a mixture of components qualify as an API?
This is actually kind of a complex issue. It is acceptable as an API when you have an API plus an excipient when the API itself is unstable for storage and shipment. At that time, we accept it as an API.
If the firms are not sure whether they have a mixture that can be considered as an API, we ask that you call us. And we ask that you provide a justification with your submission. You also need to know that these situations have important facility fee implications.
● What is the stability data requirement to pass a CA? Do the provisions of the new stability guidance apply?
No. The guidance requirements actually apply to the full scientific review. However, by the time you submit the initial DMF you need to show that the stability studies have started. And you need to provide a stability commitment and a post- approval stability protocol, as well as accelerated and long term stability data for initial and one time point beyond for one batch. We assume that you submit the actual data as they become available before we pick it up for the scientific review.
● The CA requires that a DMF be for a single API produced by a single manufacturing process. What constitutes a single process?
The DMF should be limited to one process. However, we do accept DMFs where you mention multiple manufacturing sites for the single drug process when the same process is utilized in each facility. That is acceptable.
Certain process alternatives/changes may be permissible with sufficient supportive information provided, for example: ● validated reprocess/rework procedures ● micronization leading to different particle sizes ● addition of a stabilizing antioxidant for stability purposes ● alternate crystallization procedure to produce a different polymorph, or ● a minor process variation that is the same chemical transformation with little to no risk to the impurity profile.
● What are the factors indicative of a second process?
Those factors include: ● a significant process alteration resulting in a completely different impurity profile and requiring different control strategy ● different starting materials, or ● different intermediates.
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JANUARY 2016 32 APRIL 11-13, 2016 | Renaissance Long Beach Hotel, Long Beach, CA
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REGISTER NOW! www.ISPE.org/2016-Aseptic-Conference MONTHLY UPDATE - JANUARY 2016 Starting Materials Remains a Challenging Issue for Both Reg- ulators and Industry; FDA DMF Assessments Show SM Gaps
FDA reviewers are reporting that firms producing active of Product Quality (OPQ) Office of New Drug pharmaceutical ingredients (APIs) are not always providing Products (ONDP) Division of Lifecycle API Quality adequate information on their starting material (SM) Assessment Acting Lead Ronald Michalak at the decisions or on the fate and purge of process impurities in GPhA/FDA Fall Technical Conference in November their Type II drug master file (DMF) applications. in Bethesda, Maryland (provided in full below).
Reviewers must determine the adequacy of the SM Michalak spoke at a track on API review on the third day designation as part of the DMF assessment – a job made of the conference. Also discussed in the track were DMF more difficult if the API manufacturer does not supply the electronic submission and completeness assessments, relevant information and the reviewer has to try to figure out the business process around DMF reviews, the ICH M7 a justification without the benefit of a deep understanding mutagenic impurity guidance and its impact on DMF of the process. reviews, and OPQ’s risk-based review process for APIs (IPQ January 26, 2015). Also an impediment are listings of impurities that include only those identified in the API specification, with very little discussion of the generation, fate, and purge of the impurities occurring upstream. SM Issues are Common and Costly
When the starting material or impurities information is Michalak emphasized that all of the general principles in missing or inadequate, the DMF completeness assessment Q11 and Q7 for the selection of starting materials should (CA) and the subsequent approval of the abbreviated new be considered rather than applying any individual one in drug applications (ANDAs) that reference them can be isolation. significantly delayed. The general principles are related to: ● commercial The issues that are surfacing around starting material availability ● complexity of the process and structure ● designations and applying the related principles in impurity fate and purge ● significant structural fragment, ICH’s API guideline Q11 were explored by Office and ● adequate SM specification.
Common Issues with Starting Material Designation
The following is an outline of the common issues FDA reviewers are seeing in industry starting mat- erial designations. The list/commentary was provided by OPQ’s Michalak at the GPhAAPI session.
• Proposing starting materials only one or two steps from the API in a multi-step synthesis –Justified by starting material contributing a “significant structural fragment”; by this logic even thefinal intermediate could be a starting material. Contradicts all other Q11 principles and Q7A • Proposing starting materials multiple steps from the API, however: –The steps are simple chemical manipulations e.g., esterification, removal of protecting groups –The “starting material” itself is synthesized by complex reactions, e.g., stereospecific reactions, complex ring systems, etc. –The process is telescoped: few or no isolated intermediates • Proposal of an advanced intermediate as a starting material and making a commitment not to change the manufacturing process for it without FDA notification –The ‘advanced intermediate’ should still meet all criteria for SM outlined in Q11 and Q7A –According to interpretation of regulations 21 CFR 314.70 and 21 CFR 314.420 (c), ‘any change’ could include starting material vendors with a new route of synthesis which results in the addition of tests to the starting material specification –These types of proposals are evaluated on a case-by-case basis
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JANUARY 2016 33 MONTHLY UPDATE - JANUARY 2016 The quality assessment leader noted that deficiencies “If my experience at end-of-Phase 2 meetings is any guide, for inadequate starting materials are common during then I would not expect to get a guarantee,” Michalak DMF reviews, and can be costly, due to the need commented. “But I think that you will get some valuable for extra review cycles, additional validation and input that will help you to make your decision.” method development work, and the risk of a refuse- to-receive (RTR) letter for the referencing ANDA. Japan’s SM Process Examined
Michalak explained that FDA’s key concerns regarding During the Q&A after Michalak’s talk, Aloka Srinivasan – SM designation revolve around: ● starting materials not a former Office of Generic Drugs (OGD) team leader who manufactured under GMP ● change control and vendor is now a consultant with Parexel – highlighted the starting qualification and ● changes to the manufacturing process of the starting material and impact on drug substance. material challenges the industry is facing and pointed to the Japanese model, which she maintained has more objective He noted that while outsourcing is common and provides criteria. a cost benefit to industry, it proposes an increased risk for regulators, which needs to countered with a good vendor “I remember in 2003 at FDA when we started talking about qualification program. In both the outsourced and in-house this issue,” she commented. “Now it is 2015, and we still production contexts, the quality management needs to be do not have a solution.” After leaving FDA, Srinivasan strong enough to understand how changes made to the SM explained, she began looking at how other regulatory manufacturing process can impact the API impurity profile – authorities deal with starting materials. including genotoxic impurities, regioisomers, chirality, and heavy metals – and have the appropriate control strategy. While characterizing the SM issue as a “huge quagmire” in Europe, she commented that the In a presentation given earlier in the same session, Japanese registration system for APIs is easier to ONDP Chemist Jayani Perera highlighted common deal with. deficiencies seen in DMF CAs, and commented on the starting materials issue in particular. In Japan, Srinivasan pointed out, the requirement is to On her list of the top ten deficiencies, issues with the starting include 60% of the significant bond-forming steps in the material designation came in at number six, and issues application. “This is a big help,” she affirmed, as opposed with the certificate of analysis for starting materials from a to the “vague” FDA guidance that a starting material vendor was number ten. Perera stressed the importance of be separated from the final intermediate by a “sufficient an appropriate SM designation and how a mistake in this number” of steps. She noted that even when she was at area can negatively impact CA timelines, since having to FDA, she did not understand how to interpret “sufficient redesignate the starting material or reference another DMF number.” “takes a long time.” Regarding the Japanese model, the Parexel consultant FDA Input Recommended commented that “people are not complaining,” and maintained that if FDA used a similar criteria it would be Michalak pointed to the importance of including in the DMF less burdensome on both industry and the agency. She a justification of why steps prior to the starting material, added, “it is kind of propinquity. But it is not propinquity. which are not carried out under GMP, are not likely to affect We are not saying three steps, because that does not make the quality of the API, and “strongly recommended” that sense. industry seek FDA input on a proposed starting materials justification before submitting it. She asked if FDA could consider a similar approach. He likened the SM communication to the “end-of- “As I say, for 12 years we have not been able to reach a phase-2” meetings that innovator firms have with conclusion. And it is a good time to start thinking about it FDA, and called it “a great opportunity to get a before GDUFA II.” preliminary evaluation.” ONDP Division of Lifecycle API Review Chemist The meeting request should include, “at a minimum,” the and Acting Quality Assessment Lead David Green, route of synthesis with isolated intermediates highlighted, a panelist at the session, responded that FDA’s and a proposed SM justification based on the Q7 and Q11 inclination has been in the direction of assigning the principles. SM based on risk. WWW.IPQPUBS.COM
JANUARY 2016 34 MONTHLY UPDATE - JANUARY 2016 “The first thought that popped into my head was that [the While the guide has not been made publicly available, suggested Japanese approach] would be sort of a reversion EDQM Certification Division Head Helene Bruguera to step counting or to the propinquity that you referred reviewed its contents at the APIC annual meeting held to. I think in general that our trend is toward a risk-based in Munich, Germany, in November, 2011 (IPQ March 21, evaluation of the route of synthesis. One of the major 2012). themes of Ron’s talk was ‘provide us sufficient information and sufficient justification so that we can do a risk-based A year later, at the November 2012 APIC conference in evaluation considering the fate and purge of impurities.’” Budapest, Hungary, Bruguera provided an update on the starting material topic, which, she said, remains, if not Noting that as a reviewer, he has not seen a “fate and purge” “hot,” still “very warm.” (IPQ September 22, 2013). table like the one Michalak showed during his presentation, Green suggested that “things like that would be helpful.” The following Summer, at a conference on the “Current and Emerging EU Regulations and He expressed support for the current risk-based review Inspection Trends” co-sponsored by PDA and the approach, which “gives firms a little more freedom” and Irish Medicines Board (IMB) in Dublin, Ireland in allows evaluations on a case-by-case basis. However, “that July 2013, EDQM Director Susanne Keitel discussed also puts additional burden on the firm to provide the how starting material designations can impact information to us. I think the type of review that we want whether a firm is chosen for an EDQM inspection to do is not always supported by the level of documentation (ibid.). firms are providing. I think this is especially glaring in terms of justification of starting materials.” The criteria used to determine whether a site will be inspected includes input from the CEP assessors, who will SM Issues Are Not New generally request an inspection when a starting material is close to the end of the process and not manufactured by the As Srinivasan pointed out, what is acceptable to propose as firm. a starting material in an API synthesis has been a significant topic of debate for over a decade in both the U.S. and “What we see clearly are more and more one-step syntheses,” Europe, and continues to be as regulators struggle to make Keitel pointed out. Since “everything after the starting the standards clear and industry is forced to cope with the material is subject to GMPs, there is, understandably, the uncertainty in their applications. wish from industry to have the starting material defined later if possible, compared to what regulators would like to Heightening the attention on starting materials were the see.” discussions around the implications for APIs of the QbD/ continuous improvement regulatory paradigm inculcated Reflection Paper Provides Clarifications in the ICH Q8-10 guideline series (IPQ Nov./Dec. 2007 Special Report). In September 2014, The European Medicines Agency (EMA) released a reflection paper on the selection and justification Additional guidance on the SM front was provided in ICH of starting materials. The paper aimed to clarify issues that Q11, released in 2012, (IPQ December 12, 2011) with more to have arisen in the wake of the implementation of ICH Q11 come in the form of a Q11 Q&A, due to be released in early (link provided below). 2016. The reflection paper problem statement notes that The European Directorate for the Quality of “disagreements between applicants and quality assessors on Medicines and Healthcare (EDQM) has been actively the suitability of proposed starting materials have become involved in the starting material discussions over the more frequent in recent times. This suggests that the current past decade and working to clarify its expectations guidelines, intentionally high level to allow application related to API CEP evaluations. to the wide range of chemical syntheses submitted to regulatory authorities, are open to interpretation.” In late 2011, the directorate approved an internal SM policy guide to provide clarification on issues that recur between The paper seeks to clarify the sections in ICH Q11 on regulators and industry and a framework to help reviewers selection of starting materials by providing the Q11 text and inspectors take a more uniform approach to their from those sections and appending them with “explanatory assessments. notes.” WWW.IPQPUBS.COM
JANUARY 2016 35 MONTHLY UPDATE - JANUARY 2016 At the APIC annual meeting in Amsterdam in The generics association would also like to see “an November 2015, European Generic and Biosimilar evolution” of EU quality assessors’ approach to the selection Medicines Association (EGA) Regulatory Affairs and justification of API SMs towards “a more pragmatic and Quality Manager Koen Nauwelaerts provided approach.” In addition, EGA supports a harmonized his association’s take on the current SM landscape. implementation of ICH Q11 at the international level through clarification of expectations, particularly regarding He noted that while there continue to be “a lot of problems API SMs. with regards to the interpretation of the definition of a starting material,” the situation has recently improved “to “Of course,” Nauwelaerts commented, “these kinds of changes should always be seen in relation to GMP oversight some extent” – in part due to the clarifications in the EMA of the whole supply chain.” reflection paper.
To further improve the situation, EGA would like to see a LINKS: move toward more centralized assessments of applications, EMA starting materials reflection paper as well as a separate assessment of API files, which it believes would “foster harmonization of interpretation of ICH Q11 what constitutes a starting material.”
OPQ’S RONALD MICHALAK ON STARTING MATERIAL REGULATORY ISSUES
At the GPhA November conference, OPQ ONDP Division of Lifecycle API Quality Assessment Acting Lead Ronald Michalak addressed the regulatory issues around starting materials and their selection.
My goal in the talk today is to give you guys some tips you can use when you are choosing the GMP starting point for your manufacturing process, so that you can minimize the risk of getting a deficiency for an inadequate starting material.
We will look at the starting materials statements in the ICH guidances Q7 and Q11, and then we will also consider the reviewer’s perspective on these starting materials statements and the guidances….
OPQ’s API Review Process
I will just summarize that all the CMC reviewers now for API and drug product – new drugs, generics – we are all one big, happy family now in OPQ. The two divisions in the office of new drug products for drug substance review are: ● the Division of New Drug API for review of NDAs and INDs, and ● the Division of Lifecycle API for DMF review – primarily for ANDAs. About 90% of ANDAs reference a separate DMF for their drug substance. We have about sixty reviewers in our division of lifecycle API.…
One thing I will point out is that the completeness assessment review can be done when the DMF is submitted to the agency. But no matter when the DMF is submitted to the agency, it must be referenced in a submitted ANDA for a full scientific review.
Once it is assigned for a scientific review, the primary reviewer typically, on average, [takes] two or three weeks to complete an in-depth examination of the DMF and write their primary review. Then it is forwarded to a secondary review for accuracy and consistency. The review cycle typically stops at that point, but it will be forwarded for a tertiary review if the ANDA application that references it is a first generic or if it is considered a high-risk DMF.
And Deborah Johnson has a talk later on that I encourage you to attend to see how we internally rate these DMFs as low- risk, high-risk. Some of the red flags for a high-risk DMF could include things like missing tests from an API specification, stability failures, and a deficiency for an inadequate starting material.
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JANUARY 2016 36 MONTHLY UPDATE - JANUARY 2016
Regulatory Starting Material and ICH
When you put the question in the title this way [‘What is a regulatory starting material?’], it has a pretty simple answer. The regulatory starting material is the starting point for the GMP manufacturing process. We have two published guidances with starting material sections in them: ICH Q7 and Q11.
The statements in Q7 are basically the last three bullet points, and I could summarize them as: ● you can make your starting material ● you can buy it, and ● it should be able to be characterized. But that does not really pinpoint where the start of that GMP process should be. So if we change the question a little bit to ask, “What is an appropriate starting material,” then it gets more interesting because of the different perspectives between industry and health authorities.
Regulators want to evaluate enough of the process so that they can understand the generation, fate, and purge of the impurities throughout the process, and to establish that the firm has the process under control, from a GMP perspective.
Firms should also want to show those things, but they have some extra considerations like supply chain flexibility – and by that, I mean the ability to change starting material vendors, to change the chemistry to make that starting material with minimum reporting requirements to global health authorities. And then there is the added cost of GMP – all of that extra documentation and control.
So, these industrial efforts to minimize the GMP part of their process sometimes leads firms to propose late-stage intermediate starting materials that do not really fit within the Q7/Q11 guidances.
Why Longer Synthetic Routes?
Why do regulators request longer synthetic routes? Information on earlier synthetic steps is necessary in order to understand the risk of impurity carryover. A sufficient number of purification steps needs to be documented.
So what do we mean by ‘step?’ How are reviewers counting steps? Basically, two conditions need to be satisfied. One is a chemical transformation as defined in Q11. That means covalent carbon-bond formation – so steps like recrystallization and salt formations are not considered chemical transformation steps.
And the other condition is a purge of organic impurities, which is typically, and best achieved, by isolation of a solid intermediate. There is nothing like isolating a crystalline solid from a reaction mixture to purge organic impurities from the process.
Sometimes firms telescope stages in their process. By that, I mean they carry their reaction mixture – or some solvent volume reduced reaction mixture – forward from one chemical transformation step to the next. That does not purge the process of organic impurities. It carries it forward.
Firms often break out their processes into multiple stages for various reasons. But no matter how many stages the firm presents in their manufacturing section, what reviewers are counting in their review are the actual number of chemical transformation steps and isolated solids.
Other Information to Consider
Besides Q7 and Q11, we also have some other information we can look at. For example, there may be published papers in the literature. There may be published patents on the API process or the impurity profile.
And remember, we are the Division of Lifecycle API, so there are always is at least one approved application with the drug substance in it. So, we can look at those prior approved applications to see what an adequate starting material is, and what the purity profile looks like, assuming the route of synthesis is comparable.
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JANUARY 2016 37 MONTHLY UPDATE - JANUARY 2016
Is the starting material complex? So, here is this idea of complexity. That word is not in the Q7 or Q11 guidances. But I think it makes sense if you consider the principle that enough of the GMP process should be included to demonstrate the purge of impurities. Because it just makes sense that the more complex chemical transformations that assemble the architecture of the drug substance, transformations that generate regional chemistry, that generate chirality – it is those kinds of transformations that have the most potential to generate impurities.
So when we see a GMP process that consists solely of esterification and de-protection type steps, there is a higher risk that the firm is going to be asked to re-designate their starting material upstream.
If you find yourself in that situation, or even if you do not, it is always good to provide information on how the starting material was made – route of synthesis, solvents, reagents… If you have a technical package from the starting material vendor, please include that in your DMF. It will help.
Q11 says that the firm should have an appropriate starting material specification. ‘Just’ is a synonym for ‘appropriate’ in the thesaurus. So, is the starting material justified? Are the impurity limits in that starting material justified based on observed impurity values during the process validation? Or, if the firm would like to have higher impurity limits in their specification, did they do spike and purge studies at those higher levels to demonstrate that the process can purge those higher levels of impurities?
Specification Example
I made up this fictional yet realistic example of a starting material specification. Some of the potential issues withthis specification are in the bullet points underneath (see box below).
Starting Material Specification Example
I am going to focus on the purity of not less than 90%. So, when the reviewer sees this specification, the next thing they are going to look at is a certificate of analysis from a starting material lot. If we observe a purity value of 99%, we are going to ask the firm about that. How do you know that when you get a starting material lot that is 90% pure, that it is going to perform successfully in your process?
And notice that there are not any identified impurities in the specification. Especially for a late-stage starting material, how does the firm track and demonstrate the purge of 2% of an impurity, especially in a short GMP process when they do not even know what it is?
And then what happens when they change the chemistry to make the starting material? How is the process going to perform with 2% of a new impurity that it has not even seen before? These are the kinds of questions that reviewers think about.
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JANUARY 2016 38 MONTHLY UPDATE - JANUARY 2016
Clarifications of ICH Q11
Coming soon is a question-and-answer companion document to Q11. I do not have a target date for its publication.
I am going to also verbally recommend another companion document that is on the Q11 page at the ICH website. The title is something like, ‘Reflections Paper on the Requirements for the Selection of Starting Materials,’ and that has pages of explanation for all of the starting material statements that are in Q11.
Here are these statements from Q11 (see box below). We are not going to read through these bullet points in the interest of time, but we will look at a few of these bullet points in more detail in the following slides.
ICH Q11 - Seven General SM Principles
● The manufacturing route begins from the starting material and GMPs apply from there onwards. ● The changes in material attributes and process conditions at the beginning of the manufacturing process have a lower potential to impact API quality. ● Manufacturing steps that impact the impurity profile of the API should be included in the process description. ● Enough of the manufacturing process must be disclosed so impurity fate and purge can be understood. ● Starting materials should be a substance of defined chemical properties, and non- isolated intermediates are not appropriate. ● Starting materials should be a significant structural fragment and should be distinguished from reagents and solvents. ● Commercially available commodity chemicals need not be justified as a starting material as long as these are available in the pre-existing non-pharmaceutical market.
Before I start in on this slide, I just want to read a quote from Q11. ‘The applicant should provide a justification for how each proposed starting material is appropriate in light of the general principles for the selection of starting materials.’ And the truth is that we do not always get justification for the starting materials in the DMF.
Reviewers must assess why that starting material was adequate in their review. So if the firm does not give us one, we just have to figure it out ourselves. I think it is better if the firm gives a justification to us because they know their process better than we do.
If we do give it justification, the most common one – at least the most common one I see, whether that is a statistically valid sample or not – is that the starting material is a significant structural fragment of the API. That is really a misinterpretation of that phrase. That phrase was never intended to justify the GMP starting point for the process. The intention of that phrase was to distinguish between raw materials and starting materials during the GMP process.
After you start your GMP process, if you were introducing a raw material that has several carbon atoms that go into the structure of the drug substance, then that, too, is a starting material and should be evaluated independently as a starting material. All reviewers know this. We train our reviewers so that when a firm gives us this justification for their starting material, it does not really help them.
The guidance is clear that commercially available chemicals, commodity chemicals, do not need further justification as a starting material. But it would be nice if the firm provided some supporting documentation for that non-pharmaceutical use for the chemical, just in case we cannot find it.
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JANUARY 2016 39 MONTHLY UPDATE - JANUARY 2016
Tracking Impurities
Manufacturing steps that impact the purity profile of the API should be included in the process description, and enough of the manufacturing process must be disclosed so impurity fate and purge can be understood.
When I was developing processes, I always knew where my impurities were coming and going, and I will bet that you guys know that too. So, please help us to understand the fate and purge of the impurities through your process, because many – at least DMFs – list only the impurities that are identified in the API specification with very little discussion of any upstream impurities. It would really help if somewhere in the DMF there was a narrative that described the generation, fate, and purge of impurities in the process.
I just made up this slide as a visual way to track impurities through the process (see box below). I have never seen anything like this in a DMF. It is certainly not required. But something like this could be used as part of the narrative that tracks the impurities throughout the process that would really make it easy for the reviewer to understand where these impurities are coming and going.
Fate and Purge of Process Impurities
This is kind of like a beta version. I can already see some room for improvement. So if I ever get to talk about any of this stuff again, I will have a better version.
SM Justification
The purpose of this slide is to consider where in this route would be an adequate starting material (see box below). So if we start at the end, it is pretty obvious that the unsalted form of the drug substance is not an adequate starting material. But another important point is that it would not be considered the final intermediate, either. Your classification of the final intermediate might not affect the adequacy of the initial review of the DMF, but it does have post-approval implications for changes in the route and the filing requirements for amendments.
The final intermediate is also rarely considered an adequate starting material. But there are exceptions. The final intermediate could be a commodity chemical, or the DMF under review might reference a secondary DMF for the synthesis of the final intermediate. In which case, it would then be adequate.
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JANUARY 2016 40 MONTHLY UPDATE - JANUARY 2016
What is Justified SM in This Route?
● Salt conversions not considered as chemical ansformations(Q11) ● FInal Intermediate rarely adequate as SM ● Unisolated intermediates (H) do not have defined chemical properties ● J is also a starting material as its structural elements are incorporated into the final API and should be evaluated by Q7 and Q11 principles
I put brackets around compound H, which is standard terminology for a non-isolated intermediate. Non-isolated intermediates are not usually adequate because they are difficult to characterize. It looks like the compounds in the box, A through F, certainly look like they might be adequate starting materials. But I just wanted to emphasize that it is the evaluation of these compounds by all of the appropriate criteria in Q7 and Q11 that will determine where the earliest point of this route is appropriate for the GMP process, whether it is A through F, or even D or G.
Another thing I wanted to point out in this route is that J is also a starting material in this route since it is going to contribute some carbon atoms to the structure of the drug substance. So J should go through an independent evaluation to determine whether it is an adequate starting material or whether more of its route of synthesis should be disclosed in the application.
Proposing Advanced Intermediates
Sometimes when firms propose advanced intermediates as starting materials, they give us some more information. They may make a commitment not to change starting material vendors or make any chemistry changes to the starting material without informing the ANDA holder, without informing the agency.
Sometimes the starting material vendor gives us a GMP statement. There are some problems with this extra information. These kinds of commitments – not to make changes in your starting material without informing the agency – are difficult to track in our system. And, as far as the GMP statement from the vendor, well, health authorities really do not have any enforcement capability before the regulatory starting material. That ‘reflections’ paper that I verbally recommended before – that has a really good answer about this kind of question.
These kinds of proposals are evaluated on a case-by-case basis.
Seeking FDA Input
I think this is an important slide because this gives the opportunity for generic firms to request some kind of preliminary evaluation as to whether your proposed starting material is an adequate starting point for the GMP process. This is something that innovator firms start to do at the end of Phase 2 when they meet with the agency.
I am not involved with this, so I do not know how much I can comment on it, how much it is used, but I would think this is a great opportunity to get this preliminary evaluation. If you make this request, I would certainly include at a minimum the route of synthesis, highlight the isolated intermediates, and provide the justification based on those principles in Q7 and Q11.
If my experience at end-of-Phase 2 meetings is any guide, then I would not expect to get a guarantee. But I think that you will get some valuable input that will help you to make your decision.
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JANUARY 2016 41 MONTHLY UPDATE - JANUARY 2016
Bottom Line
Okay, my penultimate slide (see box below). Just to wrap things up. Deficiencies for inadequate starting material are still common. About one out of five completeness assessments has a deficiency for either an inadequate starting material or inadequate supporting documents for starting material. I would think that would be a deficiency of major impact.
Starting Material Selection: Bottom Line
All the general principles in Q11 and Q7A for selection of starting materials should be considered rather than applying any individual one in isolation: ● Commercial availability ● Complexity of the process and structure ● Impurity fate and purge ● Significant structural fragment ● Adequate SM specification
Deficiencies for inadequate SM are common during DMF reviews (both CA and full scientific review) and can be costly: ● Extra review cycles ● More work (validation/method development) ● Risk of RTR for the referencing ANDA
I really think that if firms did a better justification of their starting material using all of the appropriate criteria that are in Q7 and Q11, that they are really going to minimize the risk of getting an inadequate starting material deficiency in their DMF.
2016 TRAINING SESSION: STRASBOURG European Pharmacopoeia Reference Standards 19 April 2016 Location: EDQM Premises, 7 allee Kastner, Strasbourg France Duration: 1 day; Working language: English
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JANUARY 2016 42 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 EUROPE 2016 Paris, France | 9-11 May 2016 | Marriott Rive Gauche Hotel
The CMC Strategy Forums focus on relevant CMC issues throughout the lifecycle of a biological product; and thereby, foster collaborative technical and regulatory interactions.
Forum Co-chairs: Regulation of Biopharmaceutical Products: Alistair Kippen, Ipsen Limited, United Kingdom Regulatory Perspectives Nanna Aaby Kruse, ICH Q12 Update: Danish Medicines Agency, Denmark Established Conditions / Approved Matters Jolanda Westerlaken, UCB Canada Inc. ICH Q12 Update: Post-approval Change Management Protocols Innovative Approaches: Tools and Technology Combination Trials and Combination Products Continuous Process Verification
For program updates, hotel and registration information scan the QR code or visit www.casss.org. MONTHLY UPDATE - JANUARY 2016 Drug Product Quality Dashboard Taking Shape at FDA in Wake of OPQ Integration and Expanding Knowledge Base
The vision of having a product quality dashboard that would The dashboard, she pointed out, will be part of a “product help guide the agency in regulating drug product lifecycles quality informatics system that will help us be efficient is emerging into more concrete form as FDA’s Office of and effective in resolving the routine quality issues we are Pharmaceutical Quality (OPQ) begins its second year. faced with as well as some of the more complex scientific challenges that we come across.” The dashboard is being designed to provide a comprehensive summary of the current state of quality for new and Rosencrance also advised the industry attendees abbreviated new drug applications (NDAs/ANDAs) for a on how they can help the agency in its efforts by particular drug product. coherent communication of risk management in product applications. At the IFPAC Forum on Process Analytical Technology in Arlington, Virginia in late January, She pointed to two quality-by-design (QbD) mock product development reports for ANDAs that FDA published in 2011 Acting Director of OPQ’s Office of Lifecycle Drug and 2012 – on immediate release (IR) and modified release Products (OLDP) Susan Rosencrance explained how (MR) dosage forms, respectively – for examples of how risk the dashboard is taking shape and how it fits in with can be communicated in the common technical document FDA’s evolving quality regulatory processes.FDA’s (CTD). [Links to the two mock reports are provided on p.44.] goal in putting together the ECs guidance was not to co-opt Q12, but, as the guidance explains, to clearly The examples explain that during initial risk assessments for lay out the relevant principles and expectations product development, the detailed manufacturing process inherent in the agency’s current regulatory approach has not been established. As development proceeds and and how they were arrived at. an optimized manufacturing process is established, the risk assessments should be updated to capture the reduced level OPQ, she said, is now actively working on developing a of risk based on their product and process understanding. “unified risk evaluation framework for brand and generic Both mock reports provide suggestions on how best to drugs that integrates the structured risk assessments with communicate the risk assessment in the CTD. the existing drug product knowledge base that we are building.” Dashboard Designed for Internal Use
The knowledge base is being enabled through the integration Following her talk, Rosencrance was asked if the agency’s in OPQ of review, inspection, surveillance, research, and quality dashboards would be provided for industry policy functions covering brand, generic, and over-the- reference. counter drugs, throughout their lifecycle, Rosencrance “Not likely,” she responded. “They would be for internal explained. use for our reviewers and investigators. But certainly if the firm really documents well how they are handling risk in The resulting drug product quality dashboard is intended their submissions, a lot of that would be captured when you to provide a risk profile and a ranking of a drug product’s do the risk assessment internally and when we see your critical quality attributes during the pre-marketing phase. application.” When the application comes in, it will go through a risk assessment and given a risk profile. The risk profile may She commented further on the NDA/ANDA also include information on the manufacturing site as well comparison component of the dashboards. as the firm’s quality system. “Currently when we see a new NDA or ANDA or when At the Mock Up Stage any new application comes into OPQ, it is assigned to an application technical lead as part of the team-based review Rosencrance provided a depiction of what OPQ’s drug process. One of the first things they do is a risk assessment product quality dashboard could look like in the context on the application in order to focus the team on the critical of a critical quality attribute (CQA) like content uniformity areas. So we are already doing the risk assessments. We mapped across an NDA and two ANDAs for a particular want to get the dashboard together so we can really utilize product (see p. 46). them.”
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JANUARY 2016 43 MONTHLY UPDATE - JANUARY 2016 She also clarified that the dashboard example she provided At a Generic Pharmaceutical Association (GPhA) CMC was not necessarily “how it is going to look.” Workshop in June 2014 in Bethesda, Maryland, OGD Chemistry I Division Director Andre Raw described the Dashboard Envisioned by CDER’s Woodcock risk-based review process that OGD had recently put in place for ANDAs. In a keynote presentation at the ISPE quality metrics meeting held in Baltimore, Maryland in April 2014, CDER In a natural progression from the office’s 2005 Director Janet Woodcock – at the time, serving also acting institution of quality-based-review (QbR) and its director of OPQ – discussed the desire of the agency to use publishing in 2011 of QbD examples, OGD turned to the dashboard concept (IPQ April 25, 2015). the risk management principles laid out in ICH Q8 and Q9 in an effort to solve the problem presented She explained that, while pharma companies have been by the shortened review timelines mandated under using dashboards for some time to look for trends and GDUFA and an increasing percentage of ANDAs gauge the health of their manufacturing facilities, CDER containing “an explosive amount” of QbD-related does not have a system it can use in a similar manner across information. the companies that it regulates. With resources divided relatively equally among the If the only information that a pharma company had applications it was receiving, Raw noted that some lower- on one of its manufacturing sites was from a brief risk applications with extensive QbD information were audit once every few years, the firm’s management taking an inordinate amount of review time. Conversely, would “feel very anxious,” Woodcock maintained. more complex applications that were higher risk may not She envisioned that an agency dashboard would include have been getting the proper attention in a timely manner. “a stable facility inventory with up-to-date information on The situation prompted Raw and other senior OGD officials facility status of products, inspections, and recalls – all the to develop a method to prioritize application review based different information that pertains to that facility – so that on an initial assessment of the potential risk of a product we can start to get a handle on it.” failing its critical quality attributes (CQAs) – taking into OGD’s Risk Assessment Algorithm Provides account the probability of failure and the severity of the Building Block harm it could cause.
Prior to the formation of OPQ, FDA’s Office of Generic Drugs (OGD) developed a risk assessment algorithm for LINKS: the review of ANDAs to help address the challenges of QbD example for IR dosage forms balancing more extensive QbD-based submissions with the foreshortened review timelines mandated under the Generic QbD example for MR dosage forms Drug User Fee Act (GDUFA) (IPQ June 29, 2014).
OPQ’S SUSAN ROSENCRANCE ON THE EVOLVING OPQ KNOWLEDGE BASE AND DASHBOARD
At the IFPAC conference, OPQ Office of Lifecycle Drug Products Acting Director Susan Rosencrance explained: ● how OPQ’s knowledge base is expanding through its integration of review, inspection, surveillance, research and policy functions, and ● how the expanded knowledge base is being used in the development of a drug quality product dashboard. She also advised on how industry can support the process.
Today I wanted to say a few words about OPQ – the Office of Pharmaceutical Quality. This is CDER’s and FDA’s newest office. It is a little over a year old now. It is made up of eight different sub-offices and has nearly 1200 people in it. It is distinguished by the fact that this office is focusing on drug product quality.
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JANUARY 2016 44 MONTHLY UPDATE - JANUARY 2016
When OPQ was set up, an eye was given to its organization, its integration, and a lifecycle approach to drug quality.
● In terms of organization, the people were strategically arranged in order to streamline regulatory processes and focus on quality.
● In terms of integration, functional areas were brought together – such as review, inspection, surveillance, and research – for more informed decision-making regarding both applications and inspections. The office really emphasizes a lifecycle approach to drug quality and risk-based knowledge management. And that is what I want to focus on mainly today in my talk.
● In terms of OPQ’s lifecycle approach, the office has been charged with bringing an overall, comprehensive approach to quality oversight that makes sure we look at product performance over the lifecycle of the products that we regulate.
Integrated Knowledge Base
Also, OPQ gives opportunities with the way it is strategically organized for building and using an integrated knowledge base that allows us to make quick, informed decisions during all stages – whether it is pre-approval or post-approval – and across all drug program areas.
In OPQ, we also want to have a product quality informatics system that will help us be efficient and effective in resolving the routine quality issues we are faced with as well as some of the more complex scientific challenges that we come across. I will say a few words about the current state of OPQ. In terms of the current state for lifecycle management, we are really actively working on building a knowledge base through the integration of all of these different areas, like I mentioned – review, inspection, surveillance, research, and policy. All of these have been brought together under the OPQ office, covering brand, generic, and over-the-counter drugs, throughout their lifecycle.
So the data and the information that we are collecting and communicating to each other is all going to go into the knowledge base. This knowledge base will allow us to have greater parity or equality in the regulatory oversight and the review of brand and generic drugs.
It will help us clearly identify where risks are for the products so that we can be more informed in our decision making. It helps us apply uniform quality standards for both brand and generic drugs. We can quickly address quality problems – get on top of them before we see some of the shortage situations that we have had over the past decade.
It helps us with overall efficiency improvements. And ultimately it is going to reduce regulatory oversight and increase operational flexibility in the commercial manufacturing phase. Our current state in terms of risk management and communication of that is that right now, we have a formal risk management process in place that helps us define the scope and the extent of the review. It focuses the reviewer on the critical areas to look at. It helps us as an organization to best allocate our resources given the product risk and the patient impact.
Also at OPQ we are maintaining structured risk assessments. What these do are focus on product failure modes and specific risks to patients. They balance the risk of a product with the risk of a patient getting that particular product.
We are using these structured risk assessments as a communication tool: We are sharing them with investigators who are part of our review team, so that when they go out on a pre-approval inspection or a surveillance inspection, they are well- informed in their decision making. We are also sharing them among the review sub-offices – the generic side vs. the new drug side – for knowledge transfer and overall good lifecycle management.
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Product Quality Dashboard
I will shift gears a little bit and talk about what this can provide for us – the potential for the future.
What we would like to develop is a unified risk evaluation framework for brand and generic drugs that integrates the structured risk assessments with the existing drug product knowledge base that we are building.
We are calling this our drug product quality dashboard. We are currently working on this. We are not there yet. But it is actively being worked on now.
The idea behind this drug product quality dashboard is that it will provide a risk profile and a ranking of a drug product’s critical quality attributes during the pre-marketing phase. When the application comes in, it will go through a risk assessment and given a risk profile. The information in the risk profile may also include information on the manufacturing site as well as the firm’s quality system.
In the product lifecycle, this could be used in the post-marketing phase to assess any proposed changes the firm wants to make and the risk of those changes on the product quality.
We also have the idea that this could be unique for each drug product and each manufacturer, allowing for individualized regulatory oversight of post-approval changes. I know that this is really visionary, and we are not there yet. But think of how this could incentivize a firm.
OPQ’s Drug Product Quality Dashboard Vision
ANDA x
NDA
ANDA y
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JANUARY 2016 46 MONTHLY UPDATE - JANUARY 2016
This will provide a comprehensive summary of the current state of quality for all approved NDAs and ANDAs of a particular drug product. This would be very valuable information for the agency to have.
This is a vision of how this could look (see box below). This is all the same drug product. This is ANDA X, ANDA Y, and this is the NDA for the reference listed drug for those generics. The idea here is this provides a snapshot – in this case it is focusing on the critical quality attribute of content uniformity. It also documents the risk mitigation strategy that the firm has in place. And it gives an overall grade.
If it is given a green grading, that would signify to the reviewer or the investigator that the firm has a good mitigation strategy in place – that it is well under control. And this particular aspect will require less emphasis when a review or inspection is performed. If it is given an orange or a yellow grading, that signals to the reviewer and the investigator that they need to give some more regulatory scrutiny to that particular aspect.
You can see in this example, ANDA Y very closely mirrored the NDA. In terms of ANDA X, they really had no strategy docu- mented in their application. So it was given the orange grading, signifying that the agency needs to take a closer look at that.
Again, we are not here yet. This is very visionary. But this is what we would like to work towards.
What Can Industry Do?
I would also like to point out some things that industry can do to help us.
● Number one, I would encourage everybody to invest in QbD.
QbD really offers a holistic approach to lifecycle management. It creates product and process understanding, which builds the knowledge base. It is the knowledge base that is really the key to successful lifecycle management of drug products.
Industry can leverage this knowledge base provided by QbD. And it can benefit both industry and the agency. In terms of the agency, leveraging of this knowledge base enables us to have increased confidence in a firm’s understanding of their product quality. It also enables us to have a decreased burden on our resources when we have to evaluate a change. Because if we feel confident in a firm’s ability, we are not going to put a lot of regulatory scrutiny on that aspect.
It benefits the industry, of course, because of the decreased regulatory burden. And it increases the opportunities for innovation and continuous improvement.
● The second thing that I would encourage industry to do is really communicate risk management in your submissions.
Look at the quality-by-design examples for ANDAs that were published a number of years ago. You can find them on the Internet. There were two of them. One was an example for immediate release dosage forms, and the other was for modified release dosage forms.
Take a look at these and see how risk is communicated. These are just mock product development reports that the agency put together. Look and see how risk is communicated in them with risk assessments that identify high risk formulation and process variables. Then the firm does the necessary studies. After the studies are complete, they update the risk assessments, after development, capturing the reduced level of risk based on their product and process understanding. I encourage you to look at these mock product development reports and see how risk is handled in those.
Conclusion
In conclusion, I want to emphasize that well-managed information from all stages of a product’s lifecycle results in greater transparency, understanding, and trust, between regulators and industry. It promotes enhanced regulatory flexibility and an environment where everyone wins. Industry wins. The agency wins. But ultimately the patient wins, because they are guaranteed quality drug products.
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JANUARY 2016 47 The right people. The right solution. The first time.™
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2795 NSF PB Industry Expertise Quarto Ad.indd 1 27/05/2015 14:14 FOOD AND DRUG LAW INSTITUTE EXPANDING YOUR MARKETPLACE: Guidance for U.S. Businesses Working Globally March 16-17, 2016 | Washington, DC
Are you interested in expanding your company or practice in Who Should the global marketplace? Attend this conference to: Attend: · Explore the cultural, legal, and regulatory · Understand business trends, opportunities, · Business challenges, and opportunities in food, drug, cultural challenges and growing markets in Development and device industries around the world. Asia, South America and Europe. Professionals · Discuss the pros and cons of global · Find out about pending and existing trade · Outside Counsel operations with an emphasis on agreements. · Compliance Office regulatory frameworks. · Identify opportunities in international mergers · Global Regulators Learn about the Foreign Corrupt Practices and acquisitions. · · Directors of Policy Act and the risks associated with doing Get tips and best practices in international · Consultants business with third parties. inspections and manufacturing. · · Inhouse Counsel Keynotes: Howard Sklamberg, Deputy Commissioner for Global Regulatory Operations and Policy, Food and Drug Administration (FDA) Jeremiah P. Kelly, Esq, MPP, Attorney for Medical Product Development & Regulation, O ce of the Sta Judge Advocate, US Army Medical Research & Materiel Command fdli.org/workingglobally MONTHLY UPDATE - JANUARY 2016 IPEC-Americas Continues to Urge Family Approach in Dialogue with FDA on Improving Inactive Ingredient Database
IPEC-Americas and the Generic Pharmaceutical Association In addition to comments on the family approach, (GPhA) are continuing their advocacy of FDA incorporating IPEC-Americas responded to the four specific a family approach in the toxicology assessment of excipients questions posed in FDA’s docket regarding the IID as they work with the agency on further improving the nomenclature, identification of excipient amounts, inactive ingredient database (IID) to support better drug updates, and structure. development and more efficient FDA reviews. Among the main recommendations were that the agency: In a session on the IID at the GPhA Fall Technical Conference ● strive for consistency between the IID and compendia in early November in Bethesda, Maryland, Ashland Global nomenclature wherever possible Regulatory Affairs Manager Priscilla Zawislak, who is the Chair-Elect for IPEC-Americas, reviewed the discussions ● express excipient amounts as the maximum daily that the trade associations have been having with FDA since intake (MDI) that has been used in an approved drug 2011 on the excipients database and the progress to date product for a specific route of administration rather than [Editor’s Note: For more on IPEC-America’s engagement the current per dose number. with FDA on the IID, see IPQ August 29, 2015, January 18, 2015, and December 3, 2013]. ● update the database at least quarterly in order to prevent a backlog of entries; include a change management Colorcon Global Regulatory Affairs Director David process that provides notification when something is Schoneker, who chairs the IPEC-Americas maker & changed and why; and improve its functionality by distributor relations committee, followed Zawislak to the immediately entering when a product is approved with podium to discuss the importance of the family approach a higher level of an excipient than currently listed, and for excipients and the work done to date to get FDA’s buy ● add data fields – specifically for maximum daily in along with: ● IPEC-Americas’ evaluation of the changes intake (MDI), and eventually for acceptable daily intake to the IID made in August ● the association’s response to an (ADI) – as well as a reference field that can be utilized FDA docket opened in July to solicit industry input on the to look at the associated toxicology data; improve search IID, and ● next steps. capabilities; and link to the various synonyms that might exist, including UNII codes and CAS numbers. IPEC-Americas used FDA’s July invitation as another opportunity to stress to the agency the importance In reviewing the recommendations at the GPhA of a family approach, in which similar polymers, conference, Schoneker stressed the need for all with similar physiochemical, toxico-logical, eco- excipient users and makers to communicate their toxicological and/or environmental fate properties desires and concerns regarding the IID to FDA, even are considered as a group of substances with similar outside the comment period for the docket, which safety profiles not needing individual evaluation. closed in mid-October.
“We want FDA to accept this family approach that we have “If you are in agreement with the IPEC docket response,” been talking to them about for years now in IID listings Schoneker emphasized, “get a copy of it, put your cover for families of related excipients,” Schoneker stressed. He letter on it, and submit it yourself, so that FDA knows characterized the requirement for tox data for each grade of that you are in alignment that all of these changes need to an excipient, as opposed to a family approach, as the “thing happen, and they see a serious response from everybody that creates more problems and controversy and waste of that we all believe these changes need to be made. We know time in this industry…than almost anything I deal with. many companies have done that.” That is where so many refuse to receive (RTR) notices that FDA’s Zuk Weighs In on the IID Issues make no sense have come from.” During the Q&A following Schoneker’s presentation, IPEC-Americas and GPhA will continue to push FDA for a audience member Susan Zuk from FDA’s Office of decision on the family approach, at least on oral solid dosage Pharmaceutical Quality (OPQ) Office of Policy for forms, over the next few months, Schoneker said at the early Pharmaceutical Quality (OPPQ) – who is in charge of the November session. “I cannot promise that will happen, but team that is updating and cleaning up the IID – commented certainly that is our goal. I do not know why it should not on some of the issues that Schoneker raised in his talk happen. I do not see any science reason for it not to happen.” (Schoneker’s complete remarks are provided on pp. 55-64). WWW.IPQPUBS.COM
JANUARY 2016 48 MONTHLY UPDATE - JANUARY 2016 Zuk discussed: ● record maintenance ● ADI ● change Regarding when the next revision of the IID would be control ● nomenclature, and ● the timing on the next published, Zuk said that her group had hoped to get it done IID update. by the end of October. “But actually we found problems that we needed to fix. We found inaccuracies. And we have “We do keep old records in the IID,” she said. “We do not our little mantra, ‘it is better to have it right than have it take any of the excipients out of the IID unless we find out fast.’ So, right now, the IT people are fixing some of those that the product was withdrawn for safety and efficacy problems.” The IID update was published in late November. reasons.” She noted that if industry identifies old records that it thinks should be deleted, it should inform the agency IID Clean Up Nearing Completion of those through the docket process. In mid-November, two weeks after the GPhA meeting, Zuk Regarding the ADI, Zuk explained that the levels that are gave a presentation at a USP “Focus on Excipient Quality, found in the IID currently are not necessarily based on tox Compendial Testing, and Regulatory Impact Workshop” at studies. “When you see that maximum potency based on USP’s headquarters in Rockville, Maryland. unit dose, it is what was approved in an application. It is not that that level is the upper limit that we would allow. It is Covering similar ground to Zawisklak and Schoneker at just what we have already approved in a product.” the GPhA meeting, Zuk reviewed the history of the IID, issues and limitations with the database, and the agency’s The approved levels, she pointed out, are taken from July solicitation of feedback on the IID. the composition statement in section 3.2.P.1 of the CTD. “Whatever the sponsor has sent us, we take that and people In addition, she highlighted the progress her group doing data entry just enter it exactly as it appears. So that is is making in its IID “clean-up project,” noting that the maximum potency per unit dose.” the effort will be completed “soon.”
Zuk next commented on Schoneker’s call for an The database “clean-up project” began in late 2014 as agency change control system that would inform a partnership between OPPQ’s IT staff, the Center for IID users whenever changes are made, and for what Drug Evaluation and Research (CDER) Office of Business reason. Informatics (OBI), and chemistry staff from the OPQ excipient working group. OBI, Zuk noted, is now responsible While her team understands the importance of change for maintaining the database. control for IID entries and notification of industry when changes are made, she categorized work in that area as The first step, which took place in early 2015, was to “secondary” to getting the database cleaned up. transfer “a huge master formula database from an old legacy system into a new, modern system that could speak “We have over 13,000 entries in the IID, and we are trying to other databases in FDA.” The next step was to capture to clean up the database right now.” While implementing the information from a ten-year backlog that had built up full change control will take a while, her team is currently during a time when no resources were assigned to perform “trying to find a way of at least informing users what is new data entry in the IID. in the database.” Zuk explained that there were about 4,000 formulas that On the nomenclature concerns, the IID leader needed to be added into the master database by the IT staff, explained that that responsibility resides with the who at the same time filled in missing potencies for old joint FDA/USP Substance Registration System (SRS) products as they were identified. function. She characterized the clean-up project as “really “When we prepare a report, which is going to become the chugging along.” next version of the IID, we involve the people that manage the SRS system,” she noted. “We ask them to go through To date, the IT staff has input 100% of all of the new drug our list and make sure that we are using preferred names.” applications (NDAs) that were approved between 2008 and 2015. The last two years of approved ANDAs and a “good Zuk noted that in the last version of the IID, she inserted a percentage” of the ANDAs between 2008 and 2012 have note directing users who could not find the excipient they also been put into the IID. were looking for to go to the SRS, enter the name they think the excipient should be under, find the preferred name, and Zuk explained that the input was “going backward because then go back into the IID to look for the excipient under that the newer applications tend to have the higher level of name. “We hope that in the future we can have a drop- ingredients. So we felt that we would get more bang for our down list of synonyms, especially the USP names. But we buck by having them enter the newest information first and do not have that functionality right now.” then work backward to fill in.” WWW.IPQPUBS.COM
JANUARY 2016 49 MONTHLY UPDATE - JANUARY 2016 Potency Listed Differently for Topicals and Also as part of the clean-up project, the team is Liquids working to address the issue of inaccuracies and to not create new inaccuracies. The chemistry staff is also changing the way potency is stated for topical and oral liquid products. “Our IT staff has implemented a very strong QC program where every single new entry is QC-checked by their staff. Topical products, for example, have traditionally had just a Then when we get ready for publication of the next IID, the percentage listed next to the maximum potency. “But if you chemistry staff does some checking to make sure there are do not know whether it is percentage weight per weight, no extreme, obviously incorrect values.” weight per volume, or volume per volume, you are kind of at a loss to try to understand what was actually in that The outcome of this QC project is that “the IID entries are formula and what FDA has approved,” Zuk pointed out. now more accurate and more reliable than they ever were,” “So you will see in the next publication that we now have Zuk said. changed that to reflect the proper units to give clarity.” “You will not see any outrageously extreme values, like The chemistry staff has also begun conversion of the oral those over 100%. And if you have used this system for a liquid products, which were also traditionally listed only long time you know that we have had all kinds of crazy, as a percentage. “For these products, that percentage was extreme values in the system. You can basically be sure that really a useless value,” she emphasized. “So we are trying the potency values have now been verified, at least for the to make the oral liquids consistent with oral solids in that most recent entries.” we are giving a weight per dose.”
In the next publication of the IID, the potency for “many” oral liquids will now have a weight – for example, 100mg of cellulose microcrystalline per dose, in a defined volume. “That is typically how oral liquids are dosed,” Zuk said. DOWNLOADS FROM THE STORY: The next project for the team will be to standardize the way that maximum potencies are listed for more complex dosage ● IPEC-Americas comments to IID docket forms – for example, transdermal and inhalation products and nasal sprays.
IPEC LEADERS PRISCILLA ZAWISLAK AND DAVE SCHONEKER ON IMPROVING FDA’S IID
In a session on the industry/FDA interactions on improving the IID at the GPhA Fall Technical Conference in early November in Bethesda, Maryland, Ashland Global Regulatory Affairs Manager Priscilla Zawislak, who is the Chair-Elect for IPEC-Americas, reviewed the discussions that the excipients association and GPhA have been having with FDA since 2011 on the database and the progress to date. Colorcon Global Regulatory Affairs Director David Schoneker, who chairs the IPEC-Americas maker & distributor relations committee, followed Zawislak to the podium to discuss: ● the excipient family approach ● IPEC-Americas’ evaluation of the changes to the IID made in August ● the association’s response to an FDA docket opened in July to solicit industry input on the IID, and ● next steps.
ASHLAND’s PRISCILLA ZAWISLAK
Thank you to Karen and to GPhA for asking Dave and me to speak today on a very hot topic – the inactive ingredient database [IID]. I think it is very relevant to the generic industry. We would like to give you a little bit of a background on the historical perspective. We have been meeting with FDA since 2011, and we would like to cover: ● some of the priorities that we feel industry has with the IID ● the progress we have made, and we have made some very good progress in cooperation with FDA ● what some of the recent changes have been in the IID that was published just back in August ● the FDA docket that is out there for comment, and ● next steps.
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So, let’s talk about some history. I am going to cover part of the history and where we are now, and then Dave is going to step in a talk about the information that we provided to the docket and where we would like to see things going in the future.
Historically, a lot of this started in October of 2010. FDA updated the Substance Registration System, or SRS, and that had a very significant impact on the inactive ingredient database – both in how it is managed, and how the information is utilized for product reviews.
SRS/IID Changes
Some of the changes in the IID that were related to SRS changes were inconsistencies in nomenclature. We found there were a lot of different terms that were being used – some were synonyms, some were not. Some listings of products were merged – for example, ‘un-like’ products polyethylene oxide and polyethylene glycol were merged into one chemical, and they are not.
Some of the listings actually completely disappeared. Things like ethylcellulose just came off the IID, and they had been there for years.
The maximum use levels also changed. And it went from generic listings, for example, like hypromellose at 680mg to then something like hypromellose five centapoise 2mg. That caused a lot of confusion.
Also the appearance of the UNII codes, which were starting to be assigned to a lot of listings. This also created a lot of confusion among makers and users, because a lot times there were no codes associated with these before.
Some of the impact of the changes were that sponsors were filing ANDAs and then they were coming to suppliers requesting UNII codes for mixtures, even though UNII codes were not assigned to mixtures. We were also seeing by way of our customers in the industry, unrealistic requests from FDA to the ANDA sponsors for data that either did not really exist or did not make sense.
Some additional information was being requested for safety data on very common excipients. As I mentioned, sometimes the listing changed – for example, hypromellose, generically listed at 680mg, in some of the other viscosity grades that were 5 maybe 10 centapoise, all the sudden the maximum potency was listed as two or seven milligrams. So we were being asked for tox data, specifically on that grade, that viscosity grade. This was creating a lot of questions. And we were questioning also whether this was really in the spirit of risk assessment, since these were tox studies done by families of excipients.
We were also getting urgent requests from our ANDA sponsors for data that we would not typically provide outside of a DMF. So, if FDA was asking for specific chemistry or tox data, and we had a DMF, we were not able to supply a lot of this to our customers directly because some of this is confidential information, particularly process related information. And of course if some of you were in the previous discussion with Art Shaw across the hall, you know that a DMF is not required. Sometimes you have common excipients, and you do not have a DMF for those, but yet you have questions coming from ANDA sponsors, or from FDA, asking for information that normally might be in a DMF. But if you do not have one, you are kind of stuck in the middle. What do you do to satisfy the questions being asked?
IPEC/FDA Collaboration
So what happened back in 2010 and 2011? There was a lot of confusion in the industry – particularly the generics industry, which really depends a lot on the information in the IID. This resulted in a higher number of deficiency letters and refuse- to-file letters.
And there was a lot of confusion about what excipients can be used, and at what levels, to submit in the ANDA information.
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How should excipient precedent-of-use be used in the time of filing? And then of course bringing in the questions around the SRS, nomenclature, and UNII codes, it left a lot of people with lots of questions. It was resulting in a lot of questions from FDA. And nobody really had a lot of good answers.
So IPEC Americas gathered the troops together, shared some war stories about the questions being asked, and said, ‘what can we do about this? We really need to get this addressed.’ So we put together information. We were using information from companies like yours. We put together a background document, and we submitted that to FDA. It outlined the issues that we felt were happening as a result of the SRS changes in October 2010. And we said, ‘what can we do? Can we meet with you to discuss some of these?’
So what resulted from that – and this actually started a little bit before we were aware of it – was that FDA was actually looking at it internally. In September of 2011, they put together their own excipient working group around the IID. And they were also looking at issues around data integrity – the completeness and accuracy of the IID – and the usability of the database. It went kind of from a flat file to an electronic file that was searchable.
They were looking at the search capabilities, and at how they could get input from users – both internal users at FDA as well as industry – what the needs were, and how they could improve the IID. They were also looking at linking back to the SRS system and trying to get standardization of the UNII code numbers, and incorporating synonyms and names.
So, while they were doing that, we had already submitted our background document outlining some of the issues that industry was having and asking for a meeting with FDA.
The first time that we met was in December of 2011, which was shortly after FDA organized their own group on this. And that actually kicked off a series of meetings that we have been having now for several years, between FDA – the Office of Generic Drugs at the time – and IPEC Americas. Somewhat into the process, back in June of 2014, GPhA became a member of the working group.
We have worked together to define industry concerns. We actually started our background document by proposing that we look at four very common excipients to get some of our hands around what some of the issues are, to at least put something down there as a place to start.
So we looked at things like hypromellose, polyethylene oxides, silicones, and carbomers. We felt that we had a lot of success in speaking with the FDA. In that first meeting, I think they felt that they got a lot out of meeting with industry. So we established, pretty much, a quarterly meeting schedule since 2012. Some of you, I am sure, are aware that the minutes have been posted on the FDA website.
And this is really a great opportunity to commend FDA on the transparency of this whole process. Our background document is posted. All of the meeting minutes are posted. The presentations that we have done at the various meetings have been posted. This is a great way for industry to see not only the cooperation, but also the progress that has been made on this.
Of course, with the reorganization of the FDA in 2015, we are now meeting with the Office of Pharmaceutical Quality, who owns the IID. And we have actually been told that this is a high priority project within CDER. So it is great to see that with the whole reorganization the IID issues still remain as one of the top topics for FDA as well.
IID Industry Priorities and Issues
So, what are some of industries priorities and issues?
● We mentioned nomenclature: There is a lot of confusion around that….
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● Maximum potency: Again, there is a lot of confusion. What does that really mean? And what do industry and FDA need?
● Policy and guidance: I am sure you are probably aware of some of the guidances that has been issued that may have some conflicting or contradictory information relative to getting information back and forth around IID question.
● Data integrity: The database itself.
● And then of course, the whole topic of toxicology and safety assessment.
Nomenclature
As we look at each of these individually, on nomenclature we found that the same excipient is often listed by different names, and sometimes even including trade names. The standardization of the ingredient names is really necessary in this. Everybody needs to be able to search on terms where they know they can find all the listings. And everyone needs to understand the synonyms that can be used for the different chemical compounds.
And it is important to be able to link the IID information with the substance registration system and the UNII codes. There should be a preferred name that is used, but then also a listing of the synonyms. And these might be generic names, common names, sometimes names might be [special] names for the cosmetic industry, brand names, and trade names. You should be able to find the compound that you are looking for in many different ways.
Data Integrity
In terms of data integrity needs, we know that the current database is not complete and has missing information. And as companies have identified these, we have tried to provide information to FDA saying, ‘we really think that this is missing based on our information.’ But sometimes it really depends on FDA being able to look into their records to see if everything has been included in there. We know there are some gaps there.
The IID team has requested the agency to help clean up the inaccurate, inconsistent, and missing information in the database and announce the changes prior to posting them in the database. A lot of times when it comes out, we have to search to see what has changed. It would be helpful to have a list of that those changes are each time it gets updated, highlighting the changes at the time of posting and providing a list of all changes under review for change prior to implementation.
What we have found in some of the cases where the next revision has been published is that there is some information there that was maybe not correct or maybe there are some questions, and it would be helpful to know in advance so we could review some of that. What we would like to see is kind of like the compendia do – they will put out a posting in the Pharmaceutical Forum, and you can provide comments before something becomes final. So if there are some glaring omissions, we might be able to identify those.
We actually identified some areas of concern this past August when the new list was published in August. And some of these are very urgent issues. I think [Dave Schoneker] is going to go into some of those later in the talk. When these come up we try to find them and bring them to the attention of FDA.
Overall, we are looking for the implementation of a change control process. It is something we all deal with a lot. And we are asking FDA if they would consider having some kind of a change control process for the IID, for the users that use it.
FDA has been extremely responsive. They have made some really good progress in these areas. We still have some work to do. But I think they have really focused a lot on the data integrity aspects of the database.
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Policy and Guidance
In terms of policy and guidance, for the two revised guidances – the Refuse to Receive, and Controlled Correspondence – I have actually created some questions. There is some inconsistent information in these, and some contradictory ones based on some of the meetings that we have had with our group at FDA. We would like to see if we can get some of those resolved.
We would also like to have some kind of question and answer document, which we were actually working on. I think that it made it up to the area of the policy department at FDA, but then it was not published. We did make a lot of progress on it until the reorganization started, which kind of derailed that a little bit.
But the good news out of this is the docket that was just recently posted to get user input for the IID. They have been listening to us for the last few years, and we really appreciate that. But there is a whole user community out there, both internally at FDA as well as externally, and it is important for them to get your input to the docket on the questions they are asking: What is important to you? How do you use the IID? And what can be done to improve it?
We at IPEC Americas have tried to get the word out, even globally, through our other IPEC counterparts to get companies aware that the docket is out there and it is open for comment, so that we can get as much collective input on this as we can. I think this really helping FDA validate some of the things that we have been talking about. In talking with a lot of you this week, we are finding that your concerns are very similar to the concerns that we have raised. So it is good that we are getting, I think, consistent input, but we really need that input to go to FDA.
There is also a big discussion about a mechanism for industry to provide information to correct missing or inaccurate listings that I mentioned. We were told in our last meeting that FDA is developing a mailbox for that purpose, which is great. That is a really nice development that we are really pleased about.
Maximum Potency
In terms of maximum potency, this has caused so many questions from our users, the ANDA sponsors. What everybody’s question really is, is ‘what is the maximum daily intake?’ That is a number everybody can sort of hang their hat on. The maximum potency is not very well understood. This kind of information is very important for the ingredients to be able support new drug development and to provide more efficient ANDA reviews. The current maximum potency, which includes a per dose level, based on the questions that we get, is not very well understood by a lot of users.
We are also recommending that there be an inclusion for the ADI [acceptable daily intake] based on the toxicology data available for the excipients.
Also, the limits are listed differently for different dosage forms for basically the same route of administration. So it leads to a lot of questions as to what limits should be used. For example, we are recommending a read-across listing where, for an oral dosage, it is that really different than sub-lingual or buccal? So when it is being adjusted orally, then you should be able to read-across based on the toxicology and the data we have on the excipients.
It is also unclear how families of materials should be handled. We have been having a lot of discussions with FDA about what we call ‘the family approach.’ When our companies do tox studies, or other organizations do tox studies, for example, on hypromellose or carbomer, it is not done based on the intended use, necessarily. We are generally chemical companies. We are looking at the safety and toxicology of the chemical. So, you are doing a lot of tox studies, but it is not with the intention you are going to put it in an injectable material, or a solid oral dosage, or for children. They are typical tox studies that are normally done on those chemicals.
These studies represent the entire family of that product. It does not matter, for example, whether it is a two centapoise hypromellose, or a fifty-thousand centapoise hypromellose – the toxicology is the same. So we are asking FDA to consider this family approach, which we think has been used in the past, and maybe has changed a little bit in the last few years.
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Can we go back to that approach and really consider these as families of excipients? Because the toxicology information is really the same.
FDA’s Progress
So, where are we right now? FDA has made tremendous progress in a number of areas, and we are really pleased with the group we were working with before, and the new group that has come to speed very quickly. We really appreciate their dedicated efforts in maintaining that continuity.
They have made some tremendous improvements in the IID website. They have been posting the IID files by quarter for the last three years. It did stop a little bit back in September of 2013, but they picked it up again last May. And the search capability has definitely improved.
There is still some work in progress on defining the preferred IID nomenclature. We have actually been working with some others who are working on that SRS database at FDA to try to give them a little assistance on how industry uses these names and what we have considered are some of the preferred names. The US Pharmacopeia has chimed in a little bit on the comments to the docket as well about using preferred compendial names. Select excipients have actually been revised to include preferred names, but they are not necessarily aligned with the compendial names. So we still have a little way to go, but there has definitely been progress made.
The IID cleanup has been in progress. Again, a lot of inaccuracies and inconsistencies have been corrected, including adding missing records. We also know that the data is being verified. FDA has gone back to the actual drug approval to verify the information. You may have seen some of those changes, particularly in the August version, where some levels went up and some levels went down. Dave is going to talk a little bit more about that.
We are also looking at the target date for completion of the backlog. We have heard some of the FDA people talking about that this week. Some of that is also tied to the progress that has been made on the IID.
Overall I think we have made some very good progress in the last couple of years. There are a few things that are still in progress and still being tweaked. And then there are some things that still need to be addressed, particularly the decisions around the ‘family approach.’
I am going to turn this over to Dave. He will give you an update on some of the comments that we provided to the docket and some of the information we had issues with since the last version, and hopefully where we see things going in the future.
COLORCON’S DAVE SCHONEKER
Priscilla gave us a good understanding of where we are and what we have built over the last several years. I am going to try to talk a little about where we are and where we are going. Where we are at is still an area of significant confusion throughout the industry. That is probably why we have so many of you here today. This is a hot topic. I can tell you that people like Priscilla and myself in the excipient industry and all of our friends within IPEC get phone calls daily on this issues with the IID from all over the world. And many people are very confused.
A lot of the improvements that we have been working on with FDA have come a fairly long way from where we started. But a lot of those improvements have not become visible to the public yet. They are sort of behind the scenes and have not gotten out there as a tool to help everybody yet. But I think what we are seeing now is a real rejuvenated effort on the part of FDA to move this forward. Things were put into a little bit of a holding pattern during the whole implementation of GDUFA and the reorganization of OPQ. There was simply not enough resources to go around.
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IID Cleanup
One of the things I will touch on here: You heard where Priscilla left off. She talked about the cleanup that is in process. Some of you may be aware of that, or maybe have heard some of the FDA presentations about this in the past. I am going to talk about some of the specifics about what we mean by ‘clean-up.’
First off, a lot of the information that is in the IID dates back how far? Who knows? It is information that was in an old paper spreadsheet that used to be there twenty years ago. And some of that information is still there today. Nobody quite knows exactly where that information came from in some cases.
One of the big issues is verification of the levels that are actually there that we are depending on, and whether they were actually ever used in an approved drug. Because one of the things that FDA has found, and we have also found in bringing things up to them, is that some of those levels do not make any sense. And as they have investigated these they have also found that, in fact, maybe there was a typo. Or a decimal point got put in the wrong place, and 1,000 milligrams was listed and it was supposed to be one milligram.
Well, these have tremendous impact on our drug development process when they are wrong. But FDA, as part of their current process, have put much of the resources that they are putting into this priority project into re-verifying and tracing back to see if there is a record of what really dictated that that level should be there on a per dose level. It is not a per day level. None of that information is available in the database today, although that is where we want to go.
So you have seen these updates coming earlier this year. It started in April. And then we had the one in August that I am going to talk about here. There is another big revision coming out very shortly. And they are expecting to finish the cleanup by April of next year.
But with that, there are all kinds of changes happening with both the nomenclature that they are trying to clean up and the levels that they are cleaning up. In some cases it is really good news. In some cases it is not so good news, depending on how you have been using this information.
August IID Revision
When the August 12 revision came out, many of us at IPEC spent a lot of time going through it trying to see what changed, because unfortunately we do not have that change procedure that Priscilla talked about yet that tells you what changed without going through it almost line by line.
We went through it and identified a lot of things that had changed. Some of them were very positive. Some of them were actually very significant concerns, where either it is information that is going to have a significant impact on industry that we are going to have to figure out how to deal with, or in some cases, we just think it is wrong. We think some changes are actually going to create more confusion or, in fact, may be a change that was made without understanding the whole background of the situation.
What we did is we assessed the current version – the August 12 version – and we put together a document that listed a lot of key question that we had on a lot of specific materials. We asked FDA to either explain why it changed, or to check into whether or not maybe it is not the right change that occurred.
So again, I do not have time today to go through everything that was in that document. But we have submitted that document, and it is listed in the minutes that was posted from our September meeting that is on the website, if you want to see the details of that document. We are still waiting on some answers from FDA about their investigation of all these topics. What are some of the key points I am going to stress today?
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Good news. There are quite a few materials for which the maximum potency levels that were there increased. That is good news for formulators, especially in the generics industry, because now you can utilize higher levels of these than maybe you were able to use in the past.
Here is a list of just some examples that are pretty important for a lot of drug products: ● polyvinyl alcohol went from 34.1 mg to 79 mg ● hypromellose from 2910 5 mPa.s went from 65 mg to 300 mg (see boxes below).
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It is great that we have data integrity. But if you are a drug formulator that was counting on that higher level during drug development over the last year, and now all of the sudden the level is a lot lower than it was, and maybe you are in that area between, what do you do?
This is one of the things that we asked FDA: If a company gets caught in that situation where they used the best information available to develop the product, and now all the sudden it exceeds the current level for that material, what sort of information is necessary to address that? What supporting information is needed? What do you need to do? We are still awaiting some answers on that. But it is a very important question for everybody in the audience.
If you look at some things like simethicone, it went from 36 mg to 7.5 mg. What if you are using 20 mg? You were fine on August 11. On August 12 you exceeded the IID. What do you do? These are important questions.
You will see other things like corn starch – it went from 1135 mg to 600 mg. Again, when you think of 1135 mg, for corn starch that would be an awfully big tablet. So, there is probably some typo that occurred way back when.
Another important one is magnesium stearate. How many products have that in it? It went from 400 mg to 256 mg. This may not impact you, it is a pretty high level. But it is a big change.
And you will see some other areas where there were removals that we believe are going to create some major problems – that we think are some mistakes.
For example, hydroxypropyl cellulose, a very commonly used polymer, used to be listed as hydroxypropyl cellulose. Now, it is listed with a Type H, or Type L, and those are viable types for hydroxypropyl cellulose. But all of the listings that exist today are either Type H or Type L, which makes no sense at all because the type of hydroxypropyl cellulose that has the most usage in the pharmaceutical industry is Type E. And Type E is not listed at all. And any of the references that anybody has ever used for Type E now say Type H or Type L, which makes no sense whatsoever. If you are using Type E, there is no reference anymore. What do you do? It does not make sense. We think it is a mistake. So, we are asking for that to be fixed.
Another area where we think there is a problem is the listing for colloidal silicone dioxide, which was removed. Now, there are only listings for silicone dioxide. Well, silicone dioxide and colloidal silicone dioxide are not exactly the same thing – they are different forms of silicone dioxide that are functionally and chemically quite different, and they should be segregated into grades. In this case it was combined, but it maybe does not make good sense. And we already have a lot of people who have been panicking because they cannot find a listing for colloidal silicone dioxide.
Pre-gelatinized corn starch was listed as starch, pre-gelatinized corn. Now there is a listing for pre-gelatinized starch, but all the listings that used to apply to starch, pre-gelatinized corn, are now listed under corn starch. Well, corn starch is not pre-gelatinized corn starch. They are totally different things. Again, we think there have been some mistakes in how nomenclature was applied, and we are asking for some things to be improved.
Microcrystalline cellulose: Well, there were always listings for PH101 and 102, the most common microcrystalline celluloses out there. All those grade determinations are now gone, and it just says, ‘microcrystalline cellulose.’ Now from a family approach we think that is a good idea, because in reality all microcrystalline cellulose from a safety perspective should be assessed as the same thing. And in this case, the level actually increased.
So you might think, great. But there is some confusion, because microcrystalline cellulose is now listed under different dosage forms. And under the capsule dosage form it has the same exact listing, with the same route, the same dosage form, the same CAS number, the same UNII code, with all different potency maximums. Why are there four listings for capsules, when in fact it is an oral route of administration, and the tablet is a lot higher? That is what you count, anyway. So again, confusion persists.
Now this is a good news situation: Polyelthylene oxide is one of the models we were discussing for the family approach.
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We do not think there should be a listing for all of the individual ones, because we think they should all be addressed together. But in the current version, a lot more grades are listed than used to be listed before. And what you will see is that some of the levels were increased significantly. Now this is used in modified release applications, and in many cases we needed much higher listings for normal uses. In this particular case, this grade used to be 81.43 mg and is now 345 mg. In another case it used to be 73.7 mg and it is now 393 mg. So the levels increased, which is good. We still think there are certain grades that are not listed that should be listed, and are covered by all the toxicology data. So, again, we will come back to that.
IID Docket Response
So, what is our FDA docket response? Given the August situation, and the fact that we have already submitted information on all the specific issues we had with the current version, we took all the things we have been talking about since 2011 that are not completed yet, or need further work, or things we have not even started working on yet that we believe ought to be included in a good IID that is useful for the industry, and incorporated them into our FDA docket response that I will summarize for you today. Again, it is publicly available so you will be able to see a copy of it on the docket site (link provided above).
One of the things we also did is we asked all of our member companies, and GPhA companies, and people around the world, that if you are in agreement with the IPEC docket response, get a copy of it, put your cover letter on it, and submit it yourself, so that FDA knows that you are in alignment that all of these changes need to happen, and they see a serious response from everybody that we all believe these changes need to be made. We know many companies have done that.
Unfortunately, the comment period ended October 19th. However, I would be willing to bet that FDA is so interested in this topic that if you have comments you want to submit, I will bet there are ways you can submit those comments yet. And I am sure FDA would be willing to accept those, because they really want to understand what the industry wants to see and how they need to improve the IID in the future.
The comments that we provided on October 12th are listed in the following slides…. I have limited time to go through this, but I want to hit on some of the high points.
There were five questions that FDA asked, where they wanted information from industry on these specific points.
Question 1: Nomenclature
● ‘How can we improve nomenclature in the IID? How can we use preferred ingredients names and synonyms in the database?’
We talked about the fact that we need to establish consistent, searchable nomenclature that uniquely identifies excipients that is consistent across all ingredient databases used for regulatory purposes. There are the SRS names, there are synonyms – it does not include all the synonyms – and we have compendial names that we have to use in labelling. We need some consistency, or at least cross-referencing that is easy.
We recommended that FDA seek industry input on the completeness and accuracy of the preferred names that are being set up, and the synonyms, in both the IID and SRS. What we have found in many cases is that they went ahead and made changes, and we would have told them right up front had they every asked us, ‘do not do that, that is the wrong name. It does not make sense.’ So there needs to be more upfront interaction before these changes get made, which goes back to the change control program that Priscilla talked about a little bit.
We want to strive for consistency between the IID and compendia nomenclature wherever possible. And wherever we see deviation from the compendia nomenclature, this causes significant confusion throughout the industry. Because if you have to call it what the USP calls it, and put that on your label, and then what is in the IID is a different name – if you want to create confusion, that will do it.
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I know one of the things that I have been after the SRS guys on for a while, on a topic near and dear to me, is they recommended something like FD&C Aluminum Lake be defined by saying FD&C yellow #6 dye, and aluminum. Well, nobody would ever call a lake, ‘dye and aluminum.’ It is a chemical entity. And the FD&C requirement is just called FD&C Aluminum Lake.
So, again, there are disconnects here that are creating more confusion, not solving problems. And we are trying to work with FDA to move this forward and be as consistent with USP and other compendial nomenclature, or CFR nomenclature, as possible.
The other thing that we have asked them in this section is to ‘define how mixtures that have compendial monographs, things like co-processed excipients, simethicones, and other non-compendial mixtures, will be addressed in the SRS nomenclature, and ultimately in the IID.’ There is a lot of confusion around how that gets addressed today, especially in the area of co-processed excipients, where they are not simple mixtures. But in other areas where they are, like simethicone, which is a USP name, it is actually a mixture. So, how do we deal with that? A lot of confusion.
Question 2: Excipient amounts
● ‘How should we identify excipient amounts listed in the IID?’
Well, first and foremost, as Priscilla said, the most important thing we all need is the maximum daily intake, theMDI , of the excipient that has been used in an approved drug product for a specific route of administration. That is the key number that we all need to determine how we have to put this in our formulation, and what we have to reference. That data does not exist today. What is there is a per dose number.
I think the question I have been asked in my 38 years since I started at ColorCon, more than any other question in my entire life, is ‘does the maximum potency stand for daily intake or does it stand per dose?’ Read the IID. It is per dose, absolutely. Unfortunately, because there is no MDI there. If that listing was driven by a product that was only dosed once a day, it could also be a maximum daily intake. But that is not the intent of it. Because there is no other information available, people tend to misuse that information and limit what they can use rather than do a controlled correspondence where they can find out through FDA research what the maximum daily intake is. So, we need this to be part of the database.
However, getting that information is a huge undertaking, because it does not exist in any database. When you do a controlled correspondence with FDA today and ask them, ‘I want to use this level that is higher than the IID, is it within what has been approved as an MDI?’ The only way that they can find that out is to actually to go manually and research through hundreds and hundreds of drug applications until they find somebody who used that material at a higher level than you are asking for.
Now they do not necessarily know what the maximum was, but they have to be able to say whether your level is okay or not. That is the only way they are going to be able to capture this information. And ultimately they have to do that research and put it into a new IID database in the future so that we all have access to that, since that is the critical information that we all need.
We are also asking that they consider publishing acceptable daily intakes, ADIs, on the excipient that is based on peer- reviewed toxicology data that is available in the literature. The ADI level is how every other toxicology review of these types of materials is done all around the world. You know the same materials that are excipients are typically also food additives in many cases.
Well, if you go to CFSAN, they live and die by the ADI. If you go to the cosmetic folks, they live and die by the ADI. If you go to Europe, to the EFSA [the European Food Safety Authority], they are going to live and die by the ADI. That information is what the tox studies say is acceptable. So if in fact there is a need to exceed an IID level, but it is still way below the ADI, there should be no concern.
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There has been a lot of talk about novel excipients – ‘do not ever use novel excipients.’ What is the definition of a novel excipient? This is one of the key things that we are trying to talk to FDA about, because this is a big concern. A higher level of use of material that you can eat by the pound, and you are talking about going from 2 mg to 3 mg, should not be something that the generics industry cannot use. And there needs to be a discussion about how to resolve that.
What if you are using a brand new chemical entity? That is another story. But if we are talking about something that has common acceptable safety data, we would limit our innovation tremendously in this industry if we say, ‘oh, novel excipients, under any circumstances, do not use them.’ I believe the FDA is wrong when they make that statement. I do not mind saying that. I am sure it will create controversy. I like to do that. We need to have that discussion, and resolve what types of novel excipients need to go into new drugs only, and what kinds have acceptability here.
Question 3: IID updates
● ‘How should we reflect updates to the current IID to ensure completeness and accuracy?’
We believe FDA should continue to update the IID at least quarterly in order to prevent a backlog of entries. Part of the reason they are doing the clean-up is due to workload constraints. Many people might not know this, but there was a period of approximately, I think, three years, where none of the NDAs or ANDAs that had been approved, none of the excipient levels that went into them, actually made its way into the IID. That is why you are seeing a lot of these things go up, because a lot of those things that got approved during that period are part of this cleanup. So, we believe there has to be, at a minimum, quarterly updates.
We believe in a new database. Ideally, it would be something where as soon as the product is approved with a higher level, it gets immediately listed in the database and updated rather than just quarterly, so that it is a real-time situation.
As Priscilla said, we need a published change management and notification process that really works and gives full transparency to everybody, and not only of what changed, but why it changed. If a level got reduced, we need to know why – not just that it got reduced. So that is one of the things we are asking for.
And then, collection of missing data: How can we have a better mechanism to capture and correct data that might be known by someone to be missing from the database? The mailbox FDA is talking about as a way to submit that information is a great start, but it may not be good enough to really allow us to continue to interact on this basis.
Question 4: IID structure
● ‘Should we restructure the IID, and if so, how?’
We believe that additional data fields need to be added, specifically for MDI, and ideally for ADI, as well as a reference field that can be utilized to look at what the toxicology data says.
We believe that the search capabilities need to be improved, and should be linked to the varied synonyms that might exist, including UNII codes and CAS numbers.
We want to ensure that the route of administration and the dosage form fields conform to standard definitions. And we want to see a collapse of similar dosage forms. It really is the route of administration, and this is the way they use it, even today: The highest levels for that route of administration is what is allowable for any dosage form in that route of administration. So, by having all these dosage forms listed with different levels, it just creates confusion.
If you had one number for oral routes, wouldn’t that be easy? Wouldn’t that be nice? One route for dermal levels? That is ultimately what we have to use anyway. But by having all these numbers in there, it creates lots of confusion. There is ongoing talk at FDA already about the possibility of collapsing these types of things in the IID to keep it simple in the future.
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We would like to provide IID mapping, as well, of similar or related routes of administration, where potency could be cross- referenced from one to another, with maybe an appropriate bridging discussion.
Priscilla talked a little bit about buccal or sublingual versus oral. It is going to be the oral data that is going to dictate, in most cases, what is acceptable. We may have to have some discussion on why you believe that data is relevant for buccal or sublingual based on membrane absorption, etc. But the data on oral is ultimately going to be where most of the data comes from.
Question 5: Additional comments
● ‘Are there additional suggestions or comments for IID approval?’
We had quite a few. For transparency purposes, we believe that FDA should issue a guidance, or a manual of policies and procedures [MAPP] that would better delineate the use of the database. The database is one thing, but how are they using it? Many people around the world are confused about the policies on how to use it and how safety decisions and considerations are being made related to the IID and the product development work that you are doing. And how do you deal with that on an IND basis, versus an NDA and an ANDA?
We believe that FDA needs to continue to work with industry and develop a template for specific types of toxicology data that are needed for different routes of administration. We have already provided a template that industry has developed that we think will give them everything that they need. We need to get some decisions on the possible use of that in the future. And we think that would facilitate consistency so that everybody would know what needs to be submitted and how to submit it.
We like to see a mechanism developed for industry to provide toxicology information on a confidential basis directly to the FDA – where in fact maybe a DMF does not exist – in a way that it will get looked at and stop some of the useless RTRs that are occurring today….
We want to allow for the use in regulatory filings of reference to publicly available,peer-reviewed toxicology studies that can be used to establish the safety of things like food additives and cosmetic ingredients, when in fact they are being used say in an oral or a dermal application where that data is relevant.
Finally, and most importantly, we want FDA to accept this family approach that we have been talking to them about for years now in IID listings for families of related excipients where the same toxicology data is available for all of those grades, and there never will be any more data. That is all the data that is going to exist for each grade, whether you ask for it fifty times or not.
We have to find a way to come to an agreement that within these families where we have demonstrated that the tox data covers the family, that we have one number that represents the whole family of grades. Because that one thing creates more problems and controversy and waste of time in this industry, I can tell you, than almost anything I deal with. That is where so many RTRs, that make no sense, have come from.
Excipient Families and Safety Assessments
So, what is an excipient family? They are structurally similar polymers, with physiochemical, toxicological, eco-toxicological and/or environmental fate properties that are likely to be similar or to follow a regular pattern that may be considered as a group of substances. These again are various related grades of an excipient. Especially polymers fall into this a lot, which differ primarily by molecular weight. Similar excipients can be derived from the same chemical backbone, and would be expected to have similar safety profiles. In fact, the data demonstrates that.
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And the examples that we use to model this approach, as Priscilla said, are hypromellose, polyethlylene oxide, carbomers, and silicones. Those four have created more controversy, more questions, more RTRs, and more people reformulating or designing their products in ways that do not create the best quality product that they could have because of worries about the IID and how it is going to be handled with those four materials.
Regarding safety assessment, how do we apply the maximum potency that is currently in the IID to related excipients in the same family? That is what we call the family approach.
And we need to define a process to allow a pharmaceutical company to use more than the IID limit when the safety data says there is no risk. We keep hearing about risk-based decision-making, so we need to use risk-based decision-making in this area. And saying we cannot use anything higher than the IID without assessing what the safety data says is not risk-based decision-making in my opinion, nor in IPEC’s.
So, the current FDA practice of requiring toxicology data for every grade of an excipient is simply not substantiated by scientific rationale. It is not aligned with risk-based approaches. And it creates redundant work for all of us. It also is not aligned with what they do in CDER and every other regulatory agency I am aware of around the world. We need to find a way to harmonize this.
The safety testing of excipients within a related family will almost always use a bracketing approach. There simply will not be data on every grade, and there should not be: It would be a total waste of animals, and the animal rights folks would be all over us if we tried to do that because it makes no scientific sense.
IPEC Americas has supplied significant pharm tox information to FDA to justify the use of the family approach. Detailed summaries with all the detailed safety data that exists in the world has been supplied to FDA on specific templates that we recommended to support the prioritized families of hypromellose, polyethylene oxides, silicones, and carbomers. We have a list of the next ten that we are ready to submit this kind of data on, as soon as we get a decision on the first four. Then we can move forward.
IPEC Americas and GPhA met with FDA policy and toxicology representatives back in December of 2014, and again in July of 2015, to try and accelerate progress on this topic. We met again in September.
In December and July, we brought with us some of the world-class toxicologists that are involved in doing these studies to explain why the family approach makes sense. In fact, one of them was Bob Osterberg, who in fact was the chair of the Excipient Safety Committee for CDER for 30 years, and who wrote the guideline on non-clinical safety assessments for excipients, to try to explain why this approach makes sense.
This is currently under review at FDA. We need to get a decision made on this in a way that we can move forward, because many of the other topics related to improvements in the IID cannot happen until we get this resolved.
One of the things that we just talked about with FDA, yesterday, Priscilla and I, is that we have a meeting that we are probably going to have in December, and we might take one little piece of this and just talk about the family approach on oral solid dosage forms, and talk specifically about what is needed to get a decision on that one piece. Stay tuned. Hopefully we will have some answers on that soon.
Next Steps
What are our next steps?
IPEC Americas and GPhA will continue to push FDA to get a decision on the family approach, hopefully at least on oral solid dosage forms, by year end. I cannot promise that will happen, but certainly that is our goal. I do not know why it should not happen. I do not see any science reason for it not to happen.
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We believe that the improved IID database that is being discussed and being proposed and the IT capabilities that are needed to support improved drug development and more efficient FDA reviews are going to take new software, a new system, more fields, more controls, and better change-control transparency.
Now, one of the things we have done to help: [GPhA Sciences and Regulatory AffairsAssociate Vice President Lisa Tan] has been involved in all of these discussions, and she had an idea that we have talked to FDA about: NIPTE already has a great excipient database related to functionality data for excipients. And we have put FDA in touch with them about whether there could be a way of taking an existing database like that, that already has the bells and whistles, and expand that to have the same kind of capabilities, but in the area of what we do with the IID. And that is something that there may be some future discussion on so that FDA does not have to build a new database from scratch. So again, stay tuned.
And finally, we believe at IPEC that the provisions to build and maintain a new and improved IID database are so important, and have so much impact on drug development in the generic industry, that this needs to be considered as part of the GDUFA reauthorization process, and should be funded by GDUFA fees.
I testified on this topic. Some of you might have been there, at the recent GDUFA reauthorization meetings. I had some interesting discussions with FDA after I testified on this point. And I know that GPhA is probably going to be pursuing this with some of the discussions with FDA as well. We are very much supportive of that, and we want to do whatever we can do, between IPEC and GPhA, to make that a reality, because it is going to take time to get all these important points taken care of that we have talked about.
So with that, I would like to finish, and acknowledge some of my colleagues who have worked very hard on thisIID presentation and on the topics we have been working on: ● Kathleen Ulman from Dow Corning ● Jeff Pitt from Dow, and ● Meera Raghuram from Lubrizol. Obviously, Priscilla and I have been dramatically involved in this. And certainly Lisa Tan from GPhA, who is your representative on our team, along with a representative from Teva who has been at the last several meetings, as well.
We would welcome further involvement from key players from GPhA to help us in moving this topic forward. We have been informed by FDA that they would like to hear more from the users, you guys, the pharmaceutical users, about the IID issues you are experiencing.
We have been a conduit to get a lot of your information to them, but they would like to hear it more directly from you guys, whether it is through the docket response, whether it is through conversations that you have with FDA, or through GphA. I strongly recommend that if this is an important topic to you, if you like the suggestions that we are making here, get behind them, talk it up, and push, push, push. FDA wants to hear what we have to say about this, and they are actively making improvements, certainly behind the scenes first. They want to do the right thing, but they have to hear from all of us about what that right thing is.
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IPEC-Americas: THE Authority and Resource on Pharmaceutical Excipient Quality and Safety Training www.ipecamericas.org
2016 Pharmaceutical Excipient Quality and Safety Training from Subject Matter Experts
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May 10-12: (Workshop) Excipient GMP Auditing to NSF/IPEC/ANSI 363 Reserve a space while waiting for approval to attend. You will be notified when registration is open.
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Learn More MONTHLY UPDATE - JANUARY 2016
INTERNATIONAL Challenges of Implementing U.S. and Global Serialization Mandates Compel Industry Cooperation
Pharmaceutical companies are reaching a clear verification requirements, and those that come into understanding that they will have to work closely together, play in phase 2 of DSCSA implementation through and with their supply chain partners, to address the 2023 ● strategies for dealing with the emerging serialization and tracing requirements of the Drug Supply serialization and traceability requirements elsewhere Chain Security Act (DSCSA) as they unfold in stages in the world, and ● the role of the serialization pilots through 2023. in the U.S. and internationally. [A full text of the panel discussions is provided pp. 68-80.] The need for industry cooperation in understanding and dealing with the complex web of implementation challenges What companies like Mylan have been learning, Gutmann presented by DSCSA was a key theme among the experts summarized, is that “we are not going to be able to solve participating in a panel session at the Generic Pharmaceutical this problem alone. In terms of implementing systems, or Association (GPhA) Fall Technical Conference held in implementing solutions on our packaging lines, if we go it November in Bethesda, Maryland. alone, I think we are probably almost guaranteed…to fail.”
The panelists explored where the DSCSA “The law is really forcing us as an industry to work together. implementation challenges lie, the progress and And that is not just manufacturers of pharmaceutical learnings thus far in preparing for compliance, and products. It is the wholesalers, and distributers, and it is the the problems that remain to be addressed as the dispensers – everyone working together to come up with second phase of the requirements come into play in what is the definition of an interoperable system.” the 2017 to 2023 period. Internal Preparation Also at Issue Leading the panel discussions was Leavitt Partners Collaborative Advocates Senior Director Eric Marshall. In addressing the first question posed by moderator Marshall The other four panelists were: ● Mylan Global Serialization on the serialization progress and lessons learned since the Program Senior Director Mark Gutmann ● Sagent DQSA was passed, the panelists stressed the importance of Pharmaceuticals Regulatory Affairs Director Mary Anne companies starting well ahead in preparing to comply with Anderson ● OmniMedia Associates Managing Partner the implementation deadlines to allow the time needed to Brian Rezach, and ● Allergan US Order and Fulfillment train, coordinate, and educate employees as well as their Management Executive Director Mary Woods. trading partners.
Marshall began the panel discussions with a review of DSCSA OmniMedia’s Rezach pointed to the Pharmaceutical and how the requirements unfold through 2023. The act is Distribution Security Alliance (PDSA) along Title II of the two-part Drug Quality and Safety Act (DQSA), with GPhA as valuable helpmates for industry passed by the U.S. Congress in 2013. DSCSA mandates the in determining “how best to satisfy the legal building of “an electronic, interoperable system to identify requirements of DSCSA in the most efficient way.” and trace certain prescription drugs as they are distributed in the U.S.” Title I of DQSA is the “Compounding Quality Gutmann commented that Mylan has seen enhanced Act” [The following stories represent a portion of IPQ’s connectivity throughout the supply chain – including extensive coverage of DQSA and its implementation: IPQ manufacturers, wholesalers, distributors, and onward Feb. 10, 2015, July 30, 2014 and Jan. 23, 2014. For more, type through the dispensers. in “DQSA” in IPQ’s word search function on the IPQpubs. com website.] He credited Electronic Data Interchange (EDI) as contributing to the result. Previous to DSCSA, Mylan had The moderator then guided the panel through under a dozen customers using the technology. However, a series of questions addressing: ● the progress the number has grown “to 60 or 70 customers,” and will and lessons learned to date ● the challenges of, continue to grow – “a great opportunity for the industry” and preparations for, the 2017 serialization and and a trend “that we really have not seen before.”
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JANUARY 2016 65 MONTHLY UPDATE - JANUARY 2016 Rezach emphasized that CMO compliance “is your DSCSA Guidances FDA is Expecting to compliance” and that the “coordination of manufacturers’ Release in 2016 whole ecosystem is critical for success and compliance to the 2017 serialization and verification requirements.” There are six DSCSA-related guidances expected to be released in 2016, according to the CDER guidance agenda. Another supply chain related Prepare for Verification Process Impacts guidance on the 2016 agenda will cover field As additional DSCSA requirements come into effect in alert submissions. the coming years, several potential issues remain to be addressed, including the impact on the verification process, ● Annual Reporting by Prescription Drug the panelists pointed out. Wholesale Distributors and Third-Party Logistics Providers Woods urged pharma companies to ensure ● Products Eligible for Grandfather Status appropriate staffing to respond to verification ● Standards for the Interoperable Exchange of questions, which DSCSA will require in 2017 to be Information for Tracing Certain Human, Finished answered within a 24-hour period and can be about Prescription Drugs any component in the standard numerical identifier (SNI). ● The Product Identifier for Human, Finished, Prescription Drugs Additionally, in 2019, wholesale distributors will be ● Verification Systems for Prescription Drugs required to verify the unique transaction identifier (UTI), unique transaction history (UTH), and serial numbers of ● Waivers, Exceptions and Exemptions from Product Tracing Requirements any saleable return. However, it is not explicitly required under the law for manufacturers to pass serial numbers to the wholesale distributors until 2023. Even if the serial numbers are sent, wholesalers are not required to receive them or to pass the serial numbers further down the supply 2017 Serialization Requirements Loom chain.
With the 2017 DSCSA deadlines looming, panelists Because of this, Rezach pointed out, “there is a certain discussed the preparations necessary to comply. The flexibility [in] the way verification requests will bemade resounding message at the forum was that companies need that is allowed for under the law.” Most manufacturers, he to communicate internally and with other companies in the claims, probably thought about a self-serve portal, where supply chain in order to prepare. someone could simply scan a barcode of a serial number, have that relayed back to a database as a query, and receive Sagent’s Anderson stressed that many of the company’s a verification. contract manufacturing organizations (CMOs) were not aware of DSCSA requirements when asked, while other Rezach recommends having several different avenues to CMOs have been aware of the requirements but have not send verification requests. “In addition to the folks who are begun preparing for the impending changes. capable of doing self-serve… you also need to be able to take requests on the telephone, into a call center… perhaps even She noted that GPhA posted a webinar series for CMOs in by email, and maybe by other means as well.” June to help educate those “who may not be aware of these requirements” and to make clear how the DSCSA affects Anderson noted that a work group composed of members them and their operations. from the Healthcare Distribution Management Association (HDMA), GPhA, and PDSA met and identified various models that work for serial number verification on saleable Gutmann stressed that companies that wait to begin returns – each having “different cost-risk-benefit profiles” preparing for 2017 may face hurdles in catching up. and operational paths. The work group “is currently identifying the methods for pilot testing on them.” “There is a supply and demand issue that is starting to develop,” he said. The demand for the solutions that are In addition to the change in verification processes, required to comply with these regulations “is starting to manufacturers are also required by November 2017 outweigh what the supply is in the industry” and may to provide electronic transaction information to create “a bit of a headwind” for companies looking for help trading partners, with everyone else in the supply in implementing their serialization programs. chain following suit in 2023. WWW.IPQPUBS.COM
JANUARY 2016 66 MONTHLY UPDATE - JANUARY 2016 Rezach stressed that this will be a very difficult transition Anderson urged companies to implement a flexible track- for customers because manufacturers will have different and-trace system that can take into account the requirements preferences for providing this information. Some trading of each country, and she stressed the importance of partners will prefer long advanced ship notices (ASNs), communication among trading partners. The “worst thing” while others may move immediately to an event-based companies could do is “make decisions in a silo” because protocol, such as the Electronic Product Code Information they would probably find it unworkable and be forced to System (EPCIS), in preparation for the 2023 requirements. create a new system.
Pilots Will Shape Future Interoperable System Gutmann pointed out that the 2023 DSCSA requirements are “less descriptive of exactly what” an interoperable In introducing the topic of pilots, Marshall maintained that system needs to look like. He urged drug manufacturers industry is at a “tipping point” in addressing serialization – to get involved with the cooperative efforts underway at a point at which it is moving from a “very reactive process” GPhA, HDMA, or PDSA, and to increase communications to seeing value in serialization and wanting to “get out with customers, in order to create a system that is functional front in some of these markets and actually shape and drive and seamless. harmonization.”
Varying Global Policies are a Sticky Wicket Due to the lack of explicit prescription in the DSCSA, the panelists pointed out, pilots are a significant and necessary Moderator Marshall began the discussion of how companies action in order to determine a viable interoperable model are dealing with the global landscape by pointing out the that businesses can implement in Phase 2 of the DSCSA. number of countries that are putting in place their own serialization and traceability requirements and the “tough Gutmann maintained that the pilots launched in the challenges” the divergent models create. near future will “be the vehicle that helps us define what 2023 looks like.” While the models differ, Rezach pointed out that In the past, he said, piloting had been used by industry as an a common thread is serialization, which is “the exploratory method to determine the best ways to serialize. enabling technology for any model.” Using global Future pilots, however, will be more focused on “volume” serialization standards such as GS-1, in turn, would and the “day-to-day” mishaps such as damages, returns, make the responsibilities of CMOs around the globe and chargebacks. more straightforward. Serialization Undercuts Need for Biosimilar The export requirements some companies are invoking Renaming are problematic, Rezach maintained, and could result in “otherwise good product being stopped at customs, and The Q&A that followed began with a member of the that would affect drug supply” in the importing country. audience commenting that the panel was the “best he had Another concern is the potential for pirating of U.S. serial ever heard on this issue.” numbers. A question that surfaced in his mind while listening, Underscoring the “astounding” amount of work it takes he said, is why there has been so much attention on to keep up with the international regulations, Gutmann adding qualifiers to the international nonproprietary highlighted the importance of “close contact with your name (INN) for a biosimilar, when “you could just point to the serial number.” companies’ in-country representatives and the local trade associations in those markets.” He pointed out that the European Generics Association has supported keeping the biosimilar name the same as the He believes the biggest challenge as an international company originator’s, while relying on “the track-and-trace system of is to build IT compliance that takes into consideration Europe to identify a product that is used by a patient and the large number of governments and customers and switches between individual biosimilars and a biological.” their different sets of requirements for serialization and track-and-trace. “The information you put on a product is Pointing to FDA’s recent approval of Sandoz’ filgrastim generally the same… but what we are required to do with it SNDZ, he asserted that “we don’t even need the SNDZ if is very different across the globe.” we have filgrastim with the serial number on it.”
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JANUARY 2016 67 MONTHLY UPDATE - JANUARY 2016 Mylan’s Gutmann expressed support for the point, noting The Q&A ended with an invitation by Rezach to join that he had not heard the two issues linked in any of the GPhA’s supply chain task force, “which really discusses DSCSA discussions he has been involved with. implementation issues around DSCSA…. It would be great to have everybody involved,” he said. Anderson commented that the issue had surfaced within GPhA a couple of years ago, “and we felt the exact same In summarizing the key points emerging from the panel way that you did – that it would be much more simplistic to discussions, Marshall stressed that there is a lot more work identify it that way. I think they are making it more complex to come in reaching the DSCSA goals and that “there is a than it needs to be.” great opportunity here to get involved and shape how this works both domestically and internationally.” The Sagent official recognized, however, that “the serial Companies also need to “start thinking about how you number structure was not completed at the time that they build a strategy that accounts for all of these things – that started doing the investigation into biosimilars. So I think stays nimble and flexible enough to account for the fact that might be where some of the complexity came in.” that new technologies are going to come along as the full interoperable system is taking shape. Marshall suggested that the “value add-ons for serialization” in general, particularly in terms of the patient, warrant LINK: consideration as the requirements move down to the CDER 2016 guidance agenda smallest packages sold to individuals.
Panel Discussion on Serialization at GPhA November Conference
The following is the panel discussion on the challenges of implementing the serialization requirements of DSCSA that took place at the GPhA Fall Technical Conference. Moderator Eric Marshall, Senior Director at Leavitt Partners, began the discussions by introducing the other four panelists and reviewing DSCSA and how the requirements unfold through 2023. He then guided the panel through a series of questions addressing: ● the process and lessons learned to date ● the challenges of and preparations for the 2017 serialization and verification requirements and those that come into play in phase 2 of DSCSA implementation through 2023 ● strategies for dealing with the emerging serialization and traceability requirements elsewhere in the world, and ● the role of the serialization pilots in the U.S. and internationally.
Introduction and DQSA Background
MARSHALL: I am going to bring out our panelists here today and do quick introductions for them:
● First on my end here, we have Mary Anne Anderson. Mary Anne joined Sagent Pharmaceuticals in 2008. She is currently the Director of Regulatory Affairs, where her responsibilities include the implementation of DSCSA and global serialization initiatives. Prior to joining Sagent, Mary held positions at Abbott, AbbVie, and Takeda in technical development, operations, quality assurance and compliance, clinical research, and sales operations compliance. Mary Anne graduated with a Bachelor’s of Science degree from the University of Wisconsin River Falls, and a Master’s in Business Administration from Lake Forest Graduate School of Management.
● Next we have Mark Gutmann. Mark is a Senior Director with the Global Serialization Program at Mylan. Mark has been with Mylan for twelve years in several IT and supply chain positions and has led the Mylan serialization program since 2010. Before joining Mylan in 2003, Mark worked with GE for fifteen years in various six-sigma and IT leadership roles.
● Next, we have Brian Rezach. Brian is a managing partner at OmniMedia Associates, working on technology applications and healthcare policy. Currently, and for the past nine years, Brian has been involved in supply chain legislation for the pharmaceutical industry, and specifically DSCSA implementation management, as well as monitoring and advocating global traceability models and implementation strategy for several drug manufacturers. In addition
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to individual manufacturer clients, Brian is a subject matter expert on DSCSA and serialization for GPhA. In 2010, Brian co-authored the GPhA endpoint authentication industry white paper. He has represented GPhA with PDSA [the Pharmaceutical Distribution Security Alliance] since its inception, and recently was one of the authors of the Rx-360 white paper, titled “Traceability Data Exchange Architecture.”
● And, last but not least, we have Mary Woods. Mary is the Executive Director for US Order and Fulfillment Management with Allergan, formerly Actavis, with over thirty years of customer relations and operations management experience in the chemical and pharmaceutical industries. Mary spent the last twenty years with Allergan managing customer relations…. She is responsible for day-to-day operations and strategic planning for several key business areas including customer master data and licensing, order management, private label business alliance, and DSCSA customer interface. Mary is an active contributor to the Allergan core serialization team and has been involved in the pedigree serialization traceability legislative requirements, and their overall operational impacts and workstream solutions for the last eleven years. Welcome to our panelists.
So we are here today to talk about the DSCSA, the Drug Supply Chain Security Act, and its implementation. So I want to take a few minutes here at the beginning just to step back and ask how we came here, how we got to be here, and what is this law that we are talking about.
The way this came to be is if you look at the years leading up to 2013 when the law was enacted, I think you have a recognition from industry and policy makers generally that there were some, although rare, very serious and significant threats to the security of the supply chain, and also a growing recognition nationally and internationally that serialization could help improve security and add some efficiencies to the supply chain.
At the same time, you had a very mixed and inefficient set of responses from the states as different states started to look at implementing different pedigree-type requirements leading to this patchwork of really almost, at best inefficient, and at worst maybe unworkable, set of requirements across the country.
The response was that industry came together. When I say industry, I do not just mean manufacturers, I really mean the entire supply chain – manufacturers, wholesalers, dispensers, repackagers, logistics providers. The whole spectrum came together, and the response was a single set of federal legislation setting forth some national set of requirements for serialization and the use of transaction data and enhanced supply chain security.
A few key things to note upfront about the DSCSA: The requirements in the law apply to prescription drugs in finished dosage form that are intended for human use. And what is probably most important about that are some of the requirements, or some of the types of products, that are not within the scope of the DSCSA.
It does not cover API. It does not reach back up the supply chain. It is really as product leaves the manufacturer’s dock down through the distribution chain. It is not OTC products. It is not animal products. And it is not devices, including most of your combination products that will be regulated as a device by the agency.
The law really sets out a pretty detailed set of requirements. With regard to the 2015 requirements that have come onboard this year – we will spend the first part of the day giving a presentation here, talking about really the four core requirements that we will talk through. Each of those really varies in detail. We will have slight differences depending on the sector you are in.
So, the first question I am always asked is, ‘What are you? Are you a manufacturer, a wholesaler, or a dispenser?’ As Brian will talk about probably, that is not always as easy a question as it may seem.
Phase 1 Requirements
So as I said, for 2015, coming online this year, there are really four core requirements that the law put in place:
[1] The first was the requirement that all companies must only work with what the law refers to as ‘authorized trading partners.’ This basically means whoever you are buying from and whoever you are selling to, you have to make sure those companies are valid, legitimate companies – meaning if it is a manufacturer registered with FDA under section 510, or if it is a wholesaler, or a dispenser, that they are properly licensed.
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[2] The second requirement is one that probably gets the most attention and probably you will hear about the most today, which is that every time a product is sold down the supply chain, every time there is what we call a transaction, a change of ownership – not possession but a change of ownership – you have to share and capture a set of information called the transaction information transaction history transaction statement – TITHTS, is what we call it for short. Basically, that is a set of data around the product, things like lot number, expiry, who the buyer is, who the seller is, and those kinds of things. The transaction history then is that set of data all the way back to the manufacturer, so you can piece together this chain of ownership all the way down.
So those were set to come online on January 1. There is some enforcement discretion exercised within the agency. Those deadlines were essentially pushed back to April 1. Dispensers were given an extra six months in this statute, so they were set to come online on July 1 for that requirement. That was delayed similarly through enforcement discretion through November 1. And just last week we got word that that would be further extended through March 1. So dispensers are not yet fully online with that requirement that is still coming down the line.
[3] The third requirement is that, if requested by the agency or by the Secretary, you have to provide that TITHTS…. The big thing to note there is that information has to be provided on request within one business day. So just start thinking about how this data gets stored and managed, that quick turnaround – that is important.
[4] And the last of those four core requirements is that companies also have to have systems and processes in place to identify, investigate, and respond to suspect and illegitimate products. The statute defines those as drugs that are potentially believed to be counterfeit, diverted, stolen, intentionally adulterated, subject of a fraudulent transaction, or otherwise appearing unfit for distribution. [You need] systems and processes in place to identify those, quarantine them, work with your trading partners to conduct an investigation, and then if you determine that they are actually illegitimate, then to notify the Secretary and immediate trading partners who may have that product within 24 hours.
All of this is stuff that came online in 2015, or is coming online in the very near future. It is really intended, if you really look at it compared to some of the state requirements, it may not be all that different – very much capturing at least the history as the product moves down the supply chain.
Phase 2 Requirements
But the real purpose behind the DSCSA was really looking out to the future a little bit, and saying in 2023, ten years out, we are going to move to, what we call in the law, Phase 2. So Phase 1 is all of this information sharing and passing as the product moves down as we talked about. Phase 2 is really looking out to 2023 – how do we build the technology that really moves away from just lot traceability down to individual serialized package-level traceability? And how do we build out a system like that?
As we start to do that, there are a couple requirements coming on in 2017 that hopefully some of you have started to hear about, that starts to enable that.
In 2017, manufacturers are required to start serializing their individual packages. It is probably important to note that a package is the smallest thing you intend to sell to a dispenser. So if it is a ten-pack of vials, it is the ten pack instead of the ten individual vials.
But serialization will come online in November 2017. Essentially, you will have to fix the 2-D data matrix to every package that carries the standard numerical identifier, which is the NDC plus the serial number, along with the expiry date and the lot number. And then, similarly, you will also have to have the ability to verify that serial number, that SNI, in the case of a suspect product or a saleable return.
That same verification requirement then starts to follow through the supply chain later insubsequent years – so repackagers in 2018, wholesalers in 2019, and dispensers in 2020 – all leading up, as I said, to 2023, when we move into a Phase 2 unit-level tracing system.
The statute itself is very vague and general on this point, and that was very intentional – a recognition that we do not really know what technology is out there yet. This gives us an opportunity in industry to work with the agency to figure out what that
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JANUARY 2016 70 MONTHLY UPDATE - JANUARY 2016 correct solution is. We will talk a little bit today about how we are starting that activity already. But moving to that place where it is away from this compiling and growing information as it moves down the supply chain, and moving toward more what we refer to as a one up, one back type of model – knowing that information about where the product came from and where it is going, so that, as you move through the supply chain, you can recreate that tracing of the product as it moves through.
Progress and Lessons to Date
So that is the scope of all that we are doing with that, and with that I want to go ahead and then turn to our panelists and then bring them in.
So, the first question is for Brian. Brian, you and I were up here a year ago now on this stage discussing the DSCSA, and at that time, it was very fast-approaching January 1 requirements. We talked a lot about several things like: resolving ambiguity in some of these sector definitions; the fact that we were hearing wholesalers saying we are getting radio silence from about 25% of our manufacturers; some concerns about vender preparedness; ambiguity around some definitions of suspect and illegitimate products. All in all I think it is probably fair to say there was a little bit of uncertainty in what was really going to come through, and what 2015 was really going to look like.
How would you characterize the progress that has been made, and what lessons do you think industry has learned along the way?
REZACH: I think to answer that question, to begin with, I would like to make some general comments on this topic. DSCSA has very far-reaching requirements for all manufacturers and really everyone in the supply chain. Because it affects all transactions, and generic manufacturers account for about 85% of the US unit volume, it is especially impactful to GPhA and its members.
Inside our companies, the requirements affect almost every business group in the organization. As such, one of the biggest challenges for those who have followed the development of the requirements and standards has been to educate others within their companies about how the different requirements and scenarios will affect them and their jobs, and how they will need to deal with the DSCSA scenarios going forward.
Even today, almost two years after DSCSA became law, it is surprising how much of this information is still in the margins about what this law does and does not mandate. And I am sure we will get into some of these issues on this panel discussion today.
To Eric’s question, in terms of the technical challenges that we faced to comply with existing 2015 requirements, there were many that had to be worked through by companies to become compliant, and no doubt they all had ramifications to existing systems and processes.
The authorized trading partner requirement, for example, seemed like a relatively straightforward thing upon first reading. But companies soon saw that this led to the development of a repetitive operating process that had to be rolled out and documented to make certain that all trading partners were actually ATPs on each and every transaction.
But I believe the major technical challenge of the 2015 requirements was of course the provision, as Eric has mentioned, of transaction information transaction history transaction statement to trading partners – and this is important – using the medium that those partners could receive and work with for their own internal processes. We have seen a big migration of trading partners over to EDI technology, specifically with respect to advanced ship nodes, ASNs, as an interim solution for sending TITHTS anymore than we are were using ADI prior to the passage of DSCSA. And as we lead up to the all- electronic requirements in 2017, we certainly anticipate seeing this trend continue.
I think one factor that became very evident through the process these last couple of years is the very high degree of complexity of the different business scenarios being used by the pharmaceutical industry to move products through the supply chain to dispensers. So the industry was tasked with, and importantly, has been able to achieve compliance to the requirements on even these most complex transactions.
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The Pharmaceutical Distribution Security Alliance, PDSA, of which GPhA is a member, has proven very valuable in providing a forum for trade associations and individual companies to work out detailed, specific business scenarios, and determine how best to satisfy the legal requirements of DSCSA on those transactions in the most efficient way.
GPhA, itself, has run educational programs, such as our recent webinar series for contract manufacturers. That was about contract manufacturer’s obligations to their manufacturing clients under DSCSA.
HDMA has also done a great deal of work on the ASN format, specifically, in order to facilitate a format that complies with the transaction information specification that is listed in the law. Because we all have requirements and timing issues, coordination among all trading partners is critical to success, and PDSA and trade associations have really driven that coordination.
Finally, PDSA, GPhA, and others in the industry have asked FDA for flexibility in allowing industry to solve DSCSA issues on business scenarios between trading partners. FDA has worked very well with industry in a partnership capacity to try to allow companies to comply with the law in a way that, where possible, leverages existing systems and processes. And we thank the agency for taking that approach. I am sure others on this panel will talk about the lessons learned in their specific companies in terms of complying with the existing 2015 requirements.
GUTMANN: Brian, I agree totally with what you just said there. For Mylan I think one of the things that has really come out of this law, and I think it is going to continue to come out of this, is just the connectivity that is happening right now in the supply chain – from manufacturers, to wholesalers and distributors, on through the dispensers.
As Brian mentioned, electronic data interchange, or EDI, is being used for that method. Previous to DSCSA, we had very few customers that used that technology. That has grown with the DSCSA probably from really just like 10 or 12 customers before, up to 60 or 70 customers that are using it now. And what is going to happen as we move through this law is that the level of connectivity that happens between manufacturers, all the way through the dispensers, and perhaps even to patients, is just going to grow. I think that is a great opportunity for the industry, and I think it is something that we really have not seen before.
WOODS: From the Allergan/Actavis side, I think one of the lessons that we learned before the 2015 implementation is that there is just that there is just never enough time.
You really need to start ahead of time to influence the amount of training and coordination for cross-functional teams. You really want to make sure you are bringing in your supply chain team folks, your security folks, your distribution, QA, IT, customer service, master data teams. There was a lot of coordination between our internal teams to make sure everybody was well aware of what their roles and responsibilities were with the new implementation in 2015 – the exchange of responsibilities, triaging, coordination for verification of ASNs, the new role that people would actually play inside of the organization. So we really spent a significant amount of time.
I would have to say a lesson learned inside of the organization that will also carry forth with all of the new enforcement dates for 2017, 19, and 2023, will continue to be the knowledge transfer, training, for all the internal teams to make sure there are no gaps in any of our processes.
ANDERSON: One of the lessons learned for Satient is that you really need to focus on very flexible processes and solutions. We had to work with our supply chain partners to develop processes for exception management. In the previous world, prior to the DSCSA, this was more of a financial situation. But now with DSCSA, it has compliance and regulatory implications….
Another area that we have seen some work in was the master data harmonization. An example of this that was very apparent in 2015 is manufacturers use a ten-digit NDC. But the downstream supply chain partners use an eleven-digit NDC, and we had to build systems that were able to speak to each other.
As we move into 2017, when we start distributing serialized product, it is going to be very important that we focus and work with our supply chain partners on building flexible processes that can be feasible.
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Preparing for 2017 Serialization
MARSHALL: So there has been a lot of progress over the last year, and it seems like we are just now getting through it. In fact, dispensers still have a few more months until we are confident that they are online as well, and yet we are already starting to hear all the talk about 2017 and the next set of requirements, when manufacturers now have to start serializing those individual packages.
What are the biggest challenges that you are seeing in preparation for serialization?
WOODS: Really, we just have probably another year before the 2017 implementation. I do not see a lot of commonalities between the 2017 requirements and what we had with 2015. So to me, the 2017 requirements to serialize is really a line in a plant issue with obviously a very huge capital investment, while what we were doing in 2015 requirements dealt with IT and internal company procedures.
The 2017 verification requirement will combine the line technology with additional IT projects. So for many companies, it is a very significant challenge, based on the significant number of lines that people are going to have to take into consideration. So, we are also scheduling production in lines that allow for significant time shutdown while line serialization is added. So there is a lot of coordination and complications in that.
I also think that there is a lot of complexity to what may appear today as a simple question to verify ASNs – where it is now going to be a much more complex inquiry with SNIs for verification. Organizations are going to have to really plan and structure significant emphasis on customer service training, so that we have new systems and new processes to correct errors or to resolve errors in exchange.
You also have 2017 where there is no paper ASN. Everything needs to be an electronic solution requirement, except for HCPs who can continue to use paper. And then you may also run into multiple technologies such as some people using ASNs where other people want to go EPCIS. So I think we are going to have a lot of complications that are going to be challenges where we do not have those complications right now in 2015.
ANDERSON: So as Mary mentioned, this is a very complex process, and we recognize this in our language. In 2015 while we were getting ready for the lot launches and all of the requirements, we reached out to all of our CMOs with a short survey just to assess readiness for the 2017 requirements.
We found that our CMOs ended up in three categories:
● The first category of CMOs are already serializing product or have their line installations well underway.
● The second category of CMOs are under the vendor validation process, so they are in the initial stages of line implementation. These CMOs were generally also getting ready for other markets this fall – for example, Korea or the EU – and they were pretty aware of what was going on in the US.
● The third category of CMOs had not started, and some of them were not even aware of the DSCSA requirements. And we started education of those CMOs.
GPhA actually recognized that need. They posted a webinar series for CMOs in June. It is a two-part series, and it is actually posted on the GPhA website. It is to help educate these CMOs who may not be aware of the requirements – what it means for them, what it means for manufacturers, so that they can get started.
I would urge each of you in the audience to check back with your company. See if you have engaged your CMOs. And if you have not, now would be the time to do so. It is a very complex process and lead times are getting longer with the vendors. Mark can speak a little bit more into that.
GUTMANN: Yeah, in terms of lead times, I think what Mary Anne was alluding to, there is really kind of two different kinds of companies that are engaged in serialization right now:
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● There are those companies that have been engaged with it for a while, that understand it, that have well-developed programs around it internal to their companies. Those companies are engaged in conferences like this, or working with PDSA or GPhA.
● And then there are companies that really have not engaged yet.
What is happening in the industry, is that there is a supply and demand issue that is starting to develop – that the demand for services, the demand for the solutions that are required to comply with these regulations, is starting to outweigh what the supply is in the industry.
So if you are in a company that has not started yet, you are kind of behind the 8-ball, but you are also going to have a little bit of a headwind when it comes to finding resources that know technically how serialization works and how to implement it within your companies.
REZACH: I think I would just like to add a couple of points to that. I certainly agree with everything that has been said here on the panel.
Just to reiterate a point that Mary Anne made about contract manufacturers. Coordination of manufacturers’ whole ecosystem is critical for success and compliance to the 2017 serialization and verification requirements, because as a manufacturer you are responsible for your ecosystem. So, in a sense, their compliance really is your compliance. So this is definitely something where, if your company is not actively putting specifications out and really organizing a CMO program, it is getting late and you probably need to do that quickly.
I think secondarily, aside from simply saying that we have to serialize packages and homogenous cases in November of 2017, there is a level of detail that is below that value. The markings themselves, where they go on packages, where… readible is in certain packages – all of these things.
So, here again, involved in it in GPhA and in our case, as a trade association, the PDSA, interacting with our trading partners really has been critical to understanding what really needs to be done in terms of a serialization project in 2017.
And serialization itself, certainly here in the United States but really globally, is the enabling technology for all of these authentication, traceability, track-and-trace – whatever the terminology you want to use – all of these initiatives from all around….
Verification Challenges
MARSHALL: Yeah, I think that is a good point, Brian. Serialization, itself, does not really add much in terms of value or supply chain security – slapping a number on the package. It is really when you actually start to use that serialized data that you mentioned [that you] add value and security to it. And you see that coming in 2017 along with serialization requirement. Again, manufacturers in 2017 have to have that ability to verify the serial number for suspect products and saleable returns. And again, following in subsequent years for the [other] sectors.
What do you see are the biggest challenges with that verification process, and what do you think industry is doing to prepare for it?
ANDERSON: It is interesting. The verification will impact manufacturers and [wholesale] distributors in 2019. There is an interesting area with saleable return verification. It is really an example where the decisions we are making in 2017 and 2019 are going to impact what it looks like in 2023. It is also a great example of how industry is really getting together, working together to come up with solutions to implement the traceability model for a secure supply chain.
Essentially, what is happening in 2019, is that wholesale distributors are going to have to verify UTI and UTH associated with any saleable return, and they will also have to verify the serial number with that saleable return.
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As we have been discussing, manufacturers are serializing the product in 2017. However, they do not have a requirement to pass serial numbers to the wholesale distributors until 2023. If the manufacturers pass the serial numbers earlier in the process, wholesale distributors do not have a requirement to receive them, nor do they have a requirement to pass them downstream to their downstream trading partners.
Since there is no clear requirement to pass the serial numbers for UTI until 2023, industry got together and started working on best practices for saleable return verification. An industry work group composed of members from GPhA, HDMA, and PDSA got together and identified about nine models that could work for serial number verification on saleable returns.
These nine scenarios have different cost-risk-benefit profiles, operational impacts, and compliance impacts, and technical complexities for the wholesalers and the manufacturers. They include manufacturers sending stuff on all of the product identifier data, essential repository, verification services, or distributors scanning all of the product inbound or scanning all of the product outbound. About five of these scenarios have [some] feasibility in the supply chain, and the work group is currently identifying the methods for pilot testing on them.
Again I just wanted to point this out as a great example of how industry is working together to come up with possible solutions to implement the secure supply chain.
WOODS: Thanks, Mary Anne. I just wanted to add one piece to that, which is making sure that you have appropriate staffing to respond to verification questions, because it is done at the SNI-level if you are a manufacturer. So if you have people who are calling out with questioning, you are at the verification process, they can be asking about any component in the SNI, and you are responding back to that question as opposed to just some general question on an ASN. So that all changes in 2017 at the manufacturer level.
GUTMANN: I think it is fair to say that in the coming years, there are going to be a lot of changes to returns in the industry. Right now, what we are talking about is, on a saleable unit, putting an individual, unique serial number on the unit. When that unit gets returned, you have to verify that that unique serial number is the serial number that came from your business.
So that is going to change the return process, I think, a lot. And it is going to remain to be seen exactly how that model works in the industry, but for sure it is going to change the way things happen today.
REZACH: I did just want to amplify some of the points that were just made. There is a certain flexibility in terms of the way verification requests will be made that is allowed for in the law. I know when the law was first passed, and perhaps even before that, when people talked about verification, I think most manufacturers probably thought about a self-serve type portal, where someone could simply do a barcode scan of a serial number, have that related back to a database as a query, and have a positive or a negative verification come back as something that, where the manufacturer could look at them and associate SNI or serial number information back to lot expiry data.
What actually ends up happening is you have to allow different kinds of requestors, if you will, of verification to do so on your own means. So as Mary was pointing out, in addition to the folks who are capable of doing self-serve from us, you also need to be able to take requests on the telephone, into a call center, let us say, perhaps even by email, and maybe by other means as well.
So there is a certain amount of flexibility and a certain amount of unknown with respect to how to staff up to meet those. And I also should mention there is [that] verification requests have to be answered in a 24-hour period. So, we have to be very prompt and ready with respect to how we are going to answer these.
I think the other point I wanted to make was on the third 2017 requirement under the law for manufacturers. And that really goes to the all-electronic requirement.
This is going to be a very difficult period of transition for our customers, actually, because you will have – I think in the 2017 to 2019 year period, you will have a large transition taking place. We mentioned in the opening about trading partners going to ASNs, for example. And you will probably still have even smaller trading partners going to ASNs at the time of November 2017, all electronic, simply because it is there, there is a specification for it, and you will be able to implement it.
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But you will also have, let us say, some manufacturers that may be further along in 2017. They may actually at that point transitioning away from ASNs and over to an event-based type protocol such as APCIS, which will probably be the protocol that gets used in the Phase 2, post-2023 model.
So it is going to be a time where working with your trading partners, working in these coalitions, becomes even more important to be able to make sure that everybody is getting the TITHTS’ they need to even as we work through the technology transition as an industry.
WOODS: One point I want to make on what Brian said: While we do have 24 hours to respond to a verification, many times people want an answer sooner than that because you are quarantining your product until you get a response back on the verification, and you are not allowed to sell it until you get that verification back from the manufacturer. So I know people would like to be that patient, but typically not as a customer.
I can tell you just even from today’s world and checking on the standard ASNs without the SNI, people are really critical about timing on getting those responses. So that is just something to keep in mind with everything that is going to be coming up, in addition to what we have today, is to consider the fact that people will be quarantining the inventory until a response is returned.
MARSHALL: Yeah, I think that’s a great point Mary…. For us, at PDSA, kind of sitting among all of the different sectors, probably one of the big surprises recently is just the volume of returns that are out there, and how big that impact is going to be.
REZACH: The number, actually, of saleable returns that was listed at a recent industry meeting was 58 million a year, I believe. That is a lot of verification requests.
Phase 2 Preparations and Challenges
MARSHALL: As you said, the serialization piece is really just kind of the first building block for what we are trying to get to in Phase 2, in 2023, when we try to move towards this interoperable, electronic, unit-level tracing system. In industry, we are already starting to discuss what that system is looking like as you guys have hit on.
What is your organization doing to prepare for those changes that are coming in Phase 2, and what do you think some of the biggest challenges facing industry are going to be as we move toward that?
GUTMANN: First of all, to kind of set the table on this a little bit. Eric, as you were kind of alluding to in the beginning, so far we kind of have been talking about the requirements up to 2017. I kind of think of that as Phase 1 of the law. The law was signed into law in 2013, and it gave the industry 10 years to implement a full track-and-trace, interoperable system. The first two years here, we have gone through a transformation and we are kind of collectively calling that Phase 1.
From 2017 out to 2023, we are kind of thinking of that as Phase 2. And, there is kind of good news and bad news about Phase 2, in that the law becomes a little less descriptive of exactly what an interoperable system looks like. So there is a lot of leeway in terms of the way the law can be steered in terms of meeting the requirements. That is probably good news, I think, for the industry, because it gives us an opportunity to work together to come up with a solution that is really going to benefit the patients and make our supply chain a lot safer than it already is today.
The one thing I wanted you to take away is, what we are doing at Mylan, and really what everyone is doing here on the stage is, early on, we learned that we are not going to be able to solve this problem alone. In terms of implementing systems or implementing solutions on our packaging lines, if we go it alone, I think we are probably guaranteed, almost, in a way, to fail.
The law is really forcing us as an industry to work together. And that is not just manufacturers of pharmaceutical products. It is the wholesalers, and distributors, and it is the dispensers – everyone working together to come up with what is the definition of an interoperable system.
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I think that number one, the most important thing that we are doing is we are getting involved in meetings like this. We are getting involved with the taskforce that GPhA has. We are getting involved with HDMA. We are getting involved with our customers, talking to our customers. This gives us a great reason to go and engage with our customers on something that is really important to us and very important to them.
PDSA is another way that we get together in a room and we talk about the issues, and we talk about some of the solutions. And I think for us it has been very, very helpful.
REZACH: Mark mentioned that the law is not very specific or prescriptive, really, about what post-November 2023 looks like. In fact, really, the information that is there says that after November 27, 2023: ● transaction information must include serialization data, SNI ● the transaction history part of it sunsets, and ● the model for interoperability gets decided from a regulatory point of view by pilots and analysis and reports, etc. So as Mark mentioned, there is a great opportunity there to kind of figure out what this looks like after 2023.
Now, the efforts, I would say, up until now really have gone back to the way that systems were being configured to meet the requirements that would be accepted state-wise that preceded DSCSA. As any of us – and all of us, I think, in this room probably – that have been involved in technology, the period of 2015 to 2023 is a long time for technology to develop.
So, what we would like to do, I think, as an industry, is to try to get to what the endpoint looks like, and then build verification and some of these other interim capabilities as building blocks, modules…so that companies don’t have to make these major investments in short-term hurdles, and then literally take what they have done and discard it for something else.
So this is a lot of the work that the coalition is now involved in in terms of trying to determine, maybe something that is a little bit different – that meets the requirements of the law, but that utilizes perhaps more advanced technology….
WOODS: Yeah, these are expensive systems and applications to be thrown away. So you definitely want to think strategically when you are putting them in.
Global Strategies
MARSHALL: Speaking of strategic decisions and interoperability and technical challenges, let us talk a little bit about the global landscape as well.
Over the last couple of years, we have seen a lot of other countries starting to pop up with their own serialization and traceability requirements. The EU system that has been under development for almost a decade now, seems to be pretty well down its path toward implementation. There are others like Brazil and India that I think have been, maybe putting it too gently, a little bit of a headache over the last year or two for industry.
What are your companies doing to approach this whole landscape? And specifically, how do you develop a strategy that balances this significant amount of lead time that we have talked about with both the uncertainty that we can see in some of these markets and the rate at which they are simply starting to pop up?
REZACH: I am going to borrow a phrase that one of our colleagues on the GPhA Supply Chain Task Force uses, which is ‘serialization is hot.’ And this is very true around the globe. Right now, by my rough count, over 25 non-US markets either have requirements for serialization and/or traceability and/or track-and-trace or our planning them, and we are tracking those.
As Eric mentioned, examples of these really kind of range. They are very diverse systems, one to another. Some examples would be Turkey, Argentina, and China, all of which feature government-built, centralized databases, where you are posting your serialization and commerce information into those government databases – to the European Union, which as Eric mentioned has been under development as a stakeholder model for more than a decade now, which is an endpoint authentication system – to other economies all over the world, choosing their own requirements based on their own scenarios and situations that exist in their own countries.
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So the common thread among all of these global requirements is serialization. Serialization is the enabling technology for any model. It is the sending of that serialized data that really creates traceability and creates track-and-trace.
So the differences among these models, and, frankly, the harmonization opportunities, really lay in two areas:
● One is the serialization markings themselves. Hopefully using a global standard – something like GS-1 – for serialization markings really makes a manufacturer’s job certainly a bit more straightforward in terms of meeting a lot of different markets’ specifications.
● And then secondly, the reporting requirements and data choreography – and by data choreography, what I really mean is where does the data reside, and how does it move from partner to partner in terms of meeting the requirement?
I would say for manufacturers, and for GPhA members specifically, concern about global markets really falls into two categories:
● First, obviously, if you were a generic manufacturer that does business in a certain market, you have to comply with those requirements to be able to keep doing business in those markets. And complying with maybe 25 or 26 globally is sort of where we came from prior to DSCSA here in the United States, where we had a lot of the so-called ‘patchwork’ of state-level requirements prior to settling on one set of federal requirements. Now, we have a similar situation developing all over the globe. That becomes a very rough challenge for manufacturers that are global.
● The second concern, though, hits a little bit closer to home here in the U.S, which is that there are markets that place requirements on products to be exported to markets like the United States. India is a very good example of this. They have an export requirement. Russia and other markets are actually considering similar requirements.
Why are the export requirements a concern for the U.S. market? Well, depending upon the enforcement in the country where the product is manufactured, it is conceivable that you could have otherwise good product being stopped at customs, and that would affect a drug supply in the export country.
For example, there is a great deal, as we all know, of CMO activity in India. And to extend that India example, the export requirement there may include a posting of serialization data intended for the exporter market, set up to explain, in the case of the US serialization data, to be posted to a government portal in India. Now, that same government portal may very well be used in the future to enable a domestic system in that country to include patient authentication. By doing this, it is conceivable that US serial numbers in this example could be exposed to perhaps bad actors accessing the government portal in another country, and those numbers potentially come back to the United States in illegal activity. Obviously, this is a big concern to the entire supply chain – to manufacturers and their products, specifically.
To answer Eric’s other question, I think keeping up with global requirements requires an awful lot of diligence. An organization similar to PDSA here in the United States called Rx-GPS has started, and it is designed to kind of do that. Certainly, there are a lot of folks here that probably belong to GS-1 Global.
In addition to joining these kinds of groups, keeping in close contact with your company’s in-country representatives and the local trade associations in those markets is also critical on this issue to get clarity. A lot of requirements at times get lost in translation, and we do not quite understand exactly what they refer to. So, keeping in contact with your local folks and their trade associations is important.
WOODS: The thing I wanted to mention is, I know it sounds like it is a very difficult situation to try and have any synergy. As Brian said, there are a lot of differences between the US and global requirements.
One thing you can do, however, is look at what the global requirements are, pick up synergies where you can, which is what we did at Actavis/Allergan, between anything that we could strategically overseas, as far as knowledge, equipment, service providers that you utilize, that operate in both our U.S. and global locations. Try to put as much synergy into it as you can where you are able. Obviously there are a lot of requirements that you cannot do that with, but where you can, and as feasible, just to get some cost savings between the US and your global partners.
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GUTMANN: I would agree, first of all, with everything that was said. I just want to reemphasize what Brian said in terms of the amount of work that it takes to keep up with these regulations on an international level is astounding, I think.
There is a lot of groundwork that has to go on from a corporate standpoint. It is really important to have people on the ground in the different countries that can work with the local agencies to understand what the requirements are, what the intent of the requirements are. Getting that rolled up into your global program, and then getting an implementation plan ready to roll out, is a challenge, at least for us.
The good news is, what we are putting on the product, as Brian said, is generally the same. We are putting a 2-D data matrix on there. Way back when, we never had a barcode or a linear barcode on any products and now it is on every product. So, we are putting that on there, we are putting serial numbers on there, and a couple other pieces of data, depending on what country it is.
The challenge, I think, for us as international companies, is to build an IT appliance, if you will, that can plug in to all of these different governments, or customers, or whatever is out there. Because as Brian said, the information we put on a product is generally the same, but what we do with it, and what we are required to do with it, is very different across the globe. So, that is the challenge for an international company or a global company – making your systems be able to plug and play really with a bunch of different requirements.
ANDERSON: I think flexibility is the big key to this, and really understanding the requirements in each country. We are building this system that will be able to take all of them and pass the data onward to all of your supply chain partners in the different countries.
I think communication is a key part of that. Get involved with your partners in all the countries. Talk to them. The worst thing that you could do is make decisions in a silo, because that would probably mean a rework. So, get out there, communicate, understand the requirements, and build a solution that can be flexible.
Significance of Pilots
MARSHALL: I do want to pull together a couple of the points. Mark’s prior comment to get involved, and Brian’s point that serialization is happening. I have been kind of preaching this message the last few months when I have gotten the chance.
I think that industry is really at a bit of a tipping point and shifting point in the global landscape. Up until now, I think it has been a very reactive process. A country puts out a set of requirements, industry reacts and says, ‘Oh we don’t like these pieces of it. What can we do to try to work with this?’
There is also now been more of an acknowledgement that serialization is happening. There is value in it. Let us do it right. I think industry is shifting now to how do we start to get out in front of some of these markets and actually shape and drive harmonization in some of these ways? And it is starting to take form and starting to happen in several ways as Brian mentioned.
We are trying to do it through Rx-GPS. And another place we are starting to see it is with pilots in the international landscape. Similarly, we have a lot of pilot activity going on here in the U.S. It is starting to take off. We have mentioned HDMA’s pilot activity…. FDA is moving forward with their pilot activity.
So, I want to ask one last question on pilot activity before we do open it up for those of you who may have questions:
Why has there been so much interest in these pilots, and what is industry looking to achieve with these?
RIZACH: Well, Eric, I think that the reason for all of the interest is the lack of prescription in the law. You do effectively have, let us say, some freedom as industry to determine what the traceability model looks like, so long as it meets the requirements set forth in the law.
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JANUARY 2016 79 MONTHLY UPDATE - JANUARY 2016
I would say, kind of harkening back to some of the pilots that were done let us say three and four and five years ago on specifically the California e-pedigree law, which predated DSCSA, many of them were very, very small in scale. AndI think one of the things that as an industry, and even with regulators, we really have to be aware of is, with the US market being about four billion new units a year, sending serialization data around, however it is decided to do that, is going to be [challenging]. It is not big data, it is huge data.
To test some of these things in a very small scale probably does not stress it enough. So getting partners together around a very specific business scenarios – maybe not the whole 2023 model, maybe a part of it, or a certain kind of a linchpin sort of technology involved in developing that model, is really the key here. But doing it in the big scale – not just a couple of hundred cases or something like that – and doing it over a period of months to see exactly where the stress points are and where the problems are.
Because we are still sending a transaction statement in 2023, if there are errors in terms of what is reported, there will be an awful lot of error correction that could really bog down the flow of product in your supply chain. So I think that is a very important thing to keep in mind as we do any of these pilots.
GUTMANN: Yeah, I think that, from a piloting standpoint, as Brian mentioned, piloting has really been going on for some time in the industry. In the early days of piloting, it was primarily, get your serial number on the product, get the product shipped to a customer, and then ship them the serial numbers and kind of see what happens.
The pilots I think that we are going to see in the future are going to be much more specific around, like Brian said, volume. But I also think there are going to be a lot of different scenarios that get tested, because there is what you call kind of the ‘happy path’ of the product. But then there is also the reality of day-to-day. Things happen to it. There are damages, there are returns, there are chargebacks that happen. There are a lot of things that happen to our serialized product. And exactly how is putting a serial number on that product going to affect those processes?
So, I think the pilots that we are going to see – and I think we are going to see a lot of them: Again, it is going to be the vehicle that helps us define what 2023 looks like, and it is also going to be that vehicle that your companies have to interact with their trading partners at a level that has not been seen, I think, in a long time. There is going to be a lot of end-to-end connectivity – what I opened up with. And that, to me, is where the value in serialization is for the manufacturer.
There is compliance, but I also think there is going to be some value once we get in, do these pilots, and understand how the serial numbers are going to change the process….
Summary of Key Points
MARSHALL: I will offer a few parting thoughts and try to recap this for everybody. I think maybe there are three key things really coming out of this:
● One is there has been a lot of work done by industry already, but there is also a lot more work to come.
This thing continues to build as we talk about it. We got through 2015, starting to build towards 2017…. How do you leverage all of that into a 2023 system? I think there is a lot of work yet to be done, but also as Mark mentioned, a lot has been done.
● Second point – Mark, you said it well – which was to get involved.
There is a great opportunity here to get involved and shape how this works both domestically and internationally. It really is amazing to see how interconnected the supply chain is – how necessary it is to get involved and to work with your customers and your trading partners in that way.
● And then, the third point would just be to start thinking about how you build a strategy that accounts for all of these things – that stays nimble and flexible enough to account for the fact that new technologies are going to come along.
You do not know what 2023 looks like. But we have requirements, and you need to manage your capital investments that you need to make on a shorter timeframe as well. So how do you start to think and build that strategy, as well?
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JANUARY 2016 80 PDA Education – Where Excellence Begins
The Parenteral Drug Association Education Department presents the... 2016 Annual Meeting Course Series March 17-18, 2016 | San Antonio, TX JW Marriott San Antonio Hill Country Resort and Spa
EXTEND YOUR KNOWLEDGE!
At the 2016 Annual Meeting Course Series, you’ll have the opportunity to learn more about manual aseptic processes, risk based environmental monitoring, quality metrics, process validation and verification and more
Recommended Practices for Manual Aseptic Sterile Pharmaceutical Dosage Forms | March 17-18 Processes l March 17 This introductory course will address clean room design; Receive practical insights into the technological challenges environmental monitoring and control; sterilization associated with designing, operating and evaluating manual principles; dosage form development, packaging and stability aseptic processing. requirements; QA/QC for parenterals, and much more.
Establishment of a Risk Based Environmental Clean Room Design, Contamination Control Monitoring Program l March 17 and Environmental Monitoring for Controlled Learn about the establishment of new environmental Environments l March 18 monitoring programs as well as reassessment of Case studies and practice failure investigations will be used current programs to bring them into compliance with to demonstrate common errors to avoid as well as best industry standards. practices to implement.
Quality Metrics: Performance Indicators l March 17-18 Process Simulation Testing for Aseptically A recognized industry expert will present his perspective on Filled Products l March 18 selecting the appropriate quality metrics, determining how This course will address all the various elements required in the best to collect the data and how to use the data to improve design and execution of a media fill and the use of risk-based the quality system. decision making will be considered.
To register and to learn more, visit pda.org/2016AnnualCourses
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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 •
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• • NOVARTIS • MYODERM • MYLAN • KGaA MERCK • . CO & MERCK • MERZ • LIGAND • TECHNOLOGIES LIFE • LIFECONEX • LABOCHIM • JOHNSON & JOHNSON • HOVIONE • HOSPIRA • NOVOZYMES BIOPHARMA HIKAL MONTHLY UPDATE - JANUARY 2016
Updates in Brief
UNITED STATES
CMC/REVIEW
CDER 2016 Guidance Agenda
CDER has published its 2016 guidance agenda, containing a list of 102 guidance documents in 15 categories that it plans to publish in FY 2016. Included on the list are a dozen guidances related to generic drugs, 16 in the pharmaceutical CMC category, three covering CGMP manufacturing standards, and six dealing with the implementation of the Drug Supply Chain Security Act (DSCSA).
Vet Drug Guidance
FDA has released for comment a draft guidance on “Modified Release Veterinary Parenteral Dosage Forms: Development, Evaluation, and Establishment of Specifications.” The draft provides recommendations for what CMC and pharmacokinetic information is required for the approval of the products. Included are recommendations regarding: ● development of an in vitro drug release test method ● components of a drug release method ● the role of an in vivo/in vitro correlation (IVIVC) or an in vivo/ in vitro relationship (IVIVR) in a product application ● methods for establishing IVIVC/R for a parenteral product ● establishing clinically relevant in vitro drug release specifications ● methods for using in vitro product specifications for setting expiry and for supporting batch release, and ● filing information for in vitro drug release methods and data as well as material for the Pharmaceutical Development Report, and the CMC technical section for modified-release parenteral dosage forms. Comments are due by March 19.
Bioequivalence Guidances
FDA has announced the availability of product-specific draft guidances for the design of bioequivalence (BE) studies to support abbreviated new drug applications (ANDAs) for 31 active pharmaceutical ingredients (APIs) and revisions of existing guidances for 11 APIs. The guidances contain the agency’s current thinking and expectations on how to develop generic drug products that are therapeutically equivalent to specific reference-listed drugs. Comments are due by March 28, 2016.
USP Protein Standards
USP is currently developing a suite of physical and written standards for therapeutic proteins to help manufacturers in their development and analysis. USP General Chapter <129> on “Analytical Procedures of Recombinant Therapeutic Monoclonal Antibodies,” which will become official on May 1, 2016, focuses on common quality attributes for MAbs and subtypes (e.g., IgG1 and IgG2). Proposed General Chapter <212> on “Oligosaccharide Analysis” will include validated analytical procedures and associated reference standards for system suitability assessment that are commonly used to analyze oligosaccharides in recombinant glycosylated biological products. Proposed General Chapter <507> on “Protein Determination Procedures” will contain multiple validated methods for the measurement of total protein – providing users with options depending on their sample matrix and measurement purpose.
USP Packaging Components
USP has released for comment in the January/February edition of Pharmacopeial Forum a revised version of its general chapter <670> on “Auxiliary Packaging Components.” The primary change from the previous version is the addition of a section on desiccants and their test methods – specifically, bentonite, anhydrous calcium chloride, calcium oxide, molecular sieves, and silica gel. Desiccants are used to remove moisture from air in containers in order to protect drug products, particularly solid oral dosage forms. USP also proposes cross referencing <197> on “Spectrophotometric Identification Tests” to allow the techniques to be used as alternative methods for pharmaceutical coil testing. Pharmaceutical coil is used as a filling material in multiple-unit containers for solid oral dosage forms to prevent breakage of tablets or capsules during shipment. The revised chapter is available on the USP website after logging in. Comments are due by March 31, 2016.
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JANUARY 2016 81 MONTHLY UPDATE - JANUARY 2016 USP Plastic Packaging Q&A
In late January, USP published a Question and Answer document on standards for plastic packaging systems for drug products. Questions addressed include: ● What types of “plastic packaging systems” are used in the pharmaceutical industry? ● What are the key quality considerations for manufacturers of plastic packaging systems for drug products? ● What are extractables and leachables?, and ● What USP standards are available to support work with plastic packaging systems, as well as extractables and leachables?
GMP/INSPECTION
Compounder Consent Decree
In early January, a consent decree of permanent injunction was filed at FDA’s request by the U.S. Department of Justice against Dallas, Texas-based Downing Labs, formerly known as NuVision Pharmacy. According to the complaint filed with the consent decree, Downing Labs manufactured and distributed purportedly sterile drug products that were adulterated because the drugs were made under insanitary conditions and in violation of GMPs. In July 2013 and September 2014, based on findings from FDA inspections ending in April 2013 and July 2014 respectively, FDA formally requested that Downing Labs recall all of its unexpired sterile products on the market, and warned health care providers and consumers against their use. Downing Labs refused the recall requests. In June 2015, Downing Labs registered as an outsourcing facility. Most recently, as a result of serious deficiencies identified by FDA during an inspection ending in October 2015, the company conducted a nationwide recall of its purportedly sterile drug products due to a lack of sterility assurance, and it ceased sterile operations. The deficiencies included microbial contamination of injectable drug products, inadequate cleaning and sanitization of sterile processing areas, and inadequate sterile practices. FDA investigators also determined that the firm had distributed drug products that failed sterility testing.
Tainted Supplements Seized
FDA announced in early January that U.S. Marshals, at the agency’s request, seized nearly 90,000 bottles of dietary supplements labeled as containing kratom. The product, manufactured for and held by Dordoniz Natural Products located in South Beloit, Illinois, is marketed under the brand name RelaKzpro and worth more than $400,000. In the press release, FDA Associate Commissioner for Regulatory Affairs Melinda Plaisier said, “We have identified kratom as a botanical substance that could pose a risk to public health and have the potential for abuse. FDA will continue to exercise our full authority under law to take action on these new dietary ingredients, especially if they ignore the notification requirements, as part of our commitment to protecting the health of the American people.” Consumption of kratom can lead to a number of health impacts, including, among others, respiratory depression, vomiting, nervousness, weight loss and constipation. The biological substance was the subject of a February 2014 import alert that allows U.S. officials to detain imported dietary supplements and bulk dietary ingredients without physical examination that are, or contain, kratom.
ER Drug Shortages
A new study published in Academic Emergency Medicine shows that drug shortages in emergency rooms (ERs) across the U.S. increased by more than 400% between 2001 and 2014, the Washington Post is reporting. The study analyzed data from the University of Utah Drug Information Service, which uses information from the American Society of Health-System Pharmacists. Practicing ER physicians determined whether the drugs are used in ERs, and reported that of the nearly 1,800 drug shortages reported between 2001 and 2014, about 34% were used in emergency rooms. The study reports that while the number of shortages fell between 2002 and 2007, they have risen by 435% between 2008 and 2014. FDA, with the help of ISPE and PDA, have been actively involved in producing strategies to reduce and mitigate drug shortages (IPQ February 27, 2013). Regarding overall shortages, FDA reported to Congress in early 2014 that there was a clear reduction in new shortages during the first three quarters of 2013 (IPQ January 31, 2013).
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JANUARY 2016 82 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 - JANUARY 2016
EUROPE
CMC/REVIEW
New Active Substance Guide
EMA has released a reflection paper on “the chemical structure and properties criteria to be considered for the evaluation of new active substance (NAS) status of chemical substances.” The paper describes the chemical structure and properties criteria to be taken into account by the Committee for Medicinal Products for Human Use (CHMP) to qualify a chemical active substance as an NAS, as well as the required elements to be submitted by applicants to substantiate their claims. The bulk of the seven-page paper provides discussion of and guidance regarding how the committee will determine the NAS status of: ● isomers ● mixtures of isomers ● complexes ● derivatives ● esters and ethers ● salts, and ● solid state forms. Biological and biotechnological active substances and active substances to be included in radiopharmaceutical medicinal products are excluded from the scope of the paper. Other than minor modifications and clarifications, the paper is largely unchanged from a draft circulated for a 90-day comment period beginning in April 2015 (IPQ May 31, 2015).
EP Raman Spectroscopy Chapter
The European Pharmacopoeia Commission announced the publication of a revised general chapter on Raman spectroscopy in response to its increasing use in pharma applications and technological developments since the chapter was written in 2002. The chapter specifically addresses the use of Raman spectroscopy in process analytical technology (PAT) and hand-held applications. The revision also covers an update of the reference standards and reagents used for verification of the wavenumber scale. The revised chapter is published in EDQM Supplement 8.7 and enters into force on April 1, 2016. It can be accessed on the EDQM website after logging in.
INTERNATIONAL
CMC/REVIEW
WHO Setting up CoE in India
The World Health Organization (WHO) is interested in setting up a center of excellence (CoE) in regulatory science at the Food and Drug Control Administration (FDCA) office in Gujarat, India, Pharmabiz is reporting. This will be WHO’s first CoE in the Asia-Pacific region, and as such, represents a milestone for the state drug regulatory body. Reports indicate that the financial and technical support will be given by the WHO, while the state government will provide infrastructural support within the FDCA building.
Health Canada Biosimilar Guidance
Health Canada has released for comment a draft guidance on the regulatory requirements for registration of subsequent entry biologics (SEBs) – known in the US as biosimilars – that, when finalized, will replace its 2010 guidance. The draft guidance contains a new policy statement: “Once granted a Notice of Compliance (NOC), an SEB becomes a new drug with all of the associated regulatory requirements. However, the SEB designation is retained for the entire life span of the product. In addition, an SEB should not be used as a reference biologic drug for another SEB submission.” Also new in the draft is a definition of extrapolation and clarification on what aspects of the guideline are obligatory and which are “advised but not required.” The deadline for comments is February 15, 2016.
TGA Sunscreen Guidance
Australia’s Therapeutic Goods Administration (TGA) announced in late January a revision to its regulations covering sunscreens. The revision was written in consultation with Australia’s National Industrial Chemicals Notification and Assessment Scheme (NICNAS) and the pharmaceutical and cosmetics industries. A draft for public consultation was published in 2010, and the preparation of the final guideline “has taken into account the comments received as a result of the consultation and also the changes to the Australian and New Zealand Sunscreen Standard,” the announcement notes. Major changes include: ● adoption WWW.IPQPUBS.COM
JANUARY 2016 83 MONTHLY UPDATE - JANUARY 2016 of the ISO 24444:2010 in vivo test procedure for determining sun protection factor (SPF) ● increasing the maximum SPF that may be claimed on the label of a sunscreen product from SPF 30+ to SPF 50+ ● limiting of the permitted SPF claims to specific numbers ● adoption of the in vitro test procedure in ISO 24443:2012 for determining broad spectrum performance, and ● making “broad spectrum” performance mandatory for all primary sunscreens and for those secondary sunscreens classified as “therapeutic sunscreens” and regulated by TGA. In November 2015, FDA also revamped its regulations regarding sunscreens with the publication of four draft guidances as required by the Sunscreen Innovation Act (SIA) of 2014 covering ● 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 (IPQ “Monthly Update” Nov./ Dec. 2015 p. 76).
GMP/INSPECTION
India Track and Trace Implementation
The Directorate General of Foreign Trade (DGFT) of India announced that it has delayed the date by which manufacturers must comply with its system to track and trace drug exports. The guidelines were revised in May 2015, giving manufacturers fewer than five months to add barcodes to tertiary and secondary packaging and start uploading the data to a central portal. The Drug Authentication and Validation Application (DAVA). Bar code labeling at primary level is exempted until further notification. For the secondary level packaging, the government insists a (WORDING) one or two dimensional barcode, while tertiary level packaging requires a one dimensional barcode. The new deadline is March 31, 2016 for large companies, and March 31, 2017 for smaller companies. Smaller companies – termed small-scale industry, or SSI – had been vocal about their concerns with complying with the new requirements in the timeframes originally prescribed.
Indian Drug Inspectors Trained
Over a dozen drug inspectors in the Drugs Control Administration (DCA) of the Indian state of Telangana received training by U.S. FDA as part of special program conducted in Bengaluru, Hindu BusinessLine is reporting. Training was conducted in various aspects of good manufacturing practices in vaccines and bulk drugs, among others. The training was part of an initiative by DCA to align itself and industry with the “stringent regulatory regime” of the U.S. FDA, as Hyderabad has been the hub of drug exports to the US. Also reported is that the governments of Indian states Madhya Pradesh, Chhattisgarh, Maharashtra and West Bengal have shown interest in adopting some of these modernization schemes and some teams have already visited DCA headquarters.
CFDA Overseas Inspections
China’s FDA (CFDA) has announced the results of its recent overseas inspections of firms importing drugs into China, which includes warnings to firms in Austria, Japan, Italy and India. Austria’s EVER Neuro Pharma, Japan’s Jiuxin Pharmaceuticals, and Italy’s Bruschettini Laboratories were cited for GMP violations, with inspectors asserting that the actual production processes did not match the firms’ drug registrations. In addition, Jiuxin’s warning included observations related to its rework processes, process validation, and incomplete testing data, while Bruschettini received observations related to lab data integrity and potential cross- contamination. India’s Aurobindo “repeatedly” delayed inspections of its cefpodoxime facility, CFDA investigators asserted. Importation and registration status of some products from these firms will be impacted. The CFDA notice can be downloaded here (in Chinese).
WHO Drug Shortage Report
The World Health Organization (WHO) has released a five-page report on “addressing the global shortages of medicines, and the safety and accessibility of children’s medication.” The reasons for shortages, the report states, have been investigated in many studies and in several countries, and the leading possible causes include: ● difficulties in acquiring raw materials ● manufacturing problems ● barriers to competition ● business decisions ● the impact of new technologies ● expensive medicines, and ● fragmented markets. The report discusses approaches currently in place to help prevent shortages – including notification systems such as exist in the U.S. and EU – and suggests additional measures such as pricing interventions.
ISO 14644 Cleanroom Standard
ISO has announced the publication of a revision to its 14644-1 standard covering air testing procedures and methodologies for cleanrooms and associated controlled environments. The title has been revised to “Classification of air cleanliness by particle concentration” to be consistent with other parts of ISO 14644. The nine familiar ISO cleanliness classes have been retained with minor revisions. The announcement states that “the most significant change is the adoption of a more consistent statistical approach to the selection and the number of sampling locations and the evaluation of the data collected.” The standard is available for purchase here. WWW.IPQPUBS.COM
JANUARY 2016 84
PDA Bookstore New Release Aldrich, Cherris, Aldrich, Shabushnig
VISUAL INSPECTION AND Visual Inspection and Particulate Control PARTICULATE CONTROL BY: D. SCOTT ALDRICH, ROY T. CHERRIS AND JOHN G. SHABUSHNIG PDA MEMBER PRICE: $240 PDA NON-MEMBER PRICE: $299 ITEM NO. 17334
In this industry, due to stringent contamination controls for medical products, refining the process and product to yield high purity and stability is most important. PDA/DHI’s newest publication, Visual Inspection and Particulate Control, is a practical guide for the control of visible defects and contamination in pharmaceutical products. It is meant to familiarize and educate seasoned inspectors with the principles of microscopy, and seasoned microscopists with the elements of visual inspection, presenting readers with ways to find visible defects and what to do with them once found. The authors share personal experiences and lessons learned from decades associated with visual inspection and particle identification in the pharmaceutical industry, and provide references throughout to allow the reader to find the primary source of relevant information to allow further investigation and study. To fill the current industry knowledge gap, this book shares the authors’ professional knowledge and will help you experience the wonder of materials science as well as the gratification of finding the source of product rejects. Table of Contents: • Detection • Isolation, Characterization and Identification • Remediation and Prevention • Life-Cycle-Approach • Case Histories/Examples of Product Failure • Epilogue go.pda.org/visual
www.pda.org/bookstore | Tel: +1 (301) 656-5900 | Fax: +1 (301) 986-1361 MONTHLY UPDATE - JANUARY 2016
FDA DRUG GMP WARNING LETTERS
The following are the drug GMP warning letters posted by FDA during January 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 Spoonamore Louisville, December Compounded ● valid prescriptions for individually-identified Drugs Kentucky 18, 2015 patients ● EM ● cleaning and disinfection ● final testing ● stability program gowning ● validation of aseptic and sterilization processes
During a January 13 to February 3, 2015 inspection of Louisville, Kentucky-based Spoonamore Drug Company, the FDA investigator observed “serious deficiencies in [the firm’s] practices for producing sterile drug products, which put patients at risk.” Aseptic GMP practices found inadequate include not using a sporicidal agent as part of the disinfection program for the clean room and the ISO 5 area, a failure to monitor the pressure differential between the ISO 7 cleanroom and ISO 8 anteroom, and inadequate gowning and aseptic practices.
The CGMP issues, the letter maintains, causes Spoonamore’s products to be adulterated, and the production of final products that are not supported by an individual prescription causes those drugs to be misbranded. The letter notes that in its response to the Form FDA 483, Spoonamore stated that it is “in the process of closing the business.” However, at the time the letter was written, the agency had not received confirmation that that firm has ceased operations.
Company Name Location Letter Date Product Type Areas Cited Ionia Pharmacy Tustin, December Compounded ● valid prescriptions for individually-identified California 22, 2015 patients ● EM ● sterile practices ● gowning ● final testing ● stability program
A March 3-6, 2015 inspection of Tustin, California-based Ionia Pharmacy was conducted after FDA receipt of a MedWatch Report describing adverse events associated with drug products prepared by the firm. CGMP violations observed included inadequate EM, no monitoring of pressure differentials between the ISO 5 hood and the ISO 7 cleanroom, the use of non-sterile wipes to disinfect the ISO 5 area, and items introduced to the ISO 5 hood from the ISO 7 area that were not always disinfected appropriately.
The investigators also observed: ● operators with facial skin and eyes exposed while working in the ISO 5 and ISO 7 areas ● a lack of appropriate laboratory determination of satisfactory conformance to final specifications for the drug products prior to release, and ● a failure to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products and to use results of such stability testing to determine appropriate storage conditions and expiration dates.
The CGMP issues, the letter maintains, causes Ionia’s products to be adulterated, and the production of final products that are not supported by an individual prescription causes those drugs to be misbranded.
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JANUARY 2016 85 MONTHLY UPDATE - JANUARY 2016
INTERNATIONAL
Company Name Location Letter Date Product Type Areas Cited Zhejiang Hisun Taihou City, December API ● data integrity ● lab instrument audit trails ● Pharma China 31, 2015 microbiological testing ● access to information
A March 2-7, 2015 inspection of API manufacturer Zhejiang Hisun Pharma, in Taizhou City, Zhejiang Province, China, revealed numerous data integrity issues. FDA maintains in the letter that the firm disabled lab instrument audit trails, deleted non- conforming analytical data, and retested lab samples without justification. According to the letter, when asked about the disabled audit trails, an analyst stated that “another employee, who was no longer with the company, had disabled the audit trails.” The firm could not explain why the audit trail was disabled or why the original data was deleted, nor could it demonstrate whether the original results were within specification.
Investigators also asked for the firm’s raw analytical data of the lots associated with several complaints, but the raw data was unavailable as it had been deleted. Regarding microbial testing, investigators observed culture media plates that were dried out and cracked, which compromised microbial growth promotion and accurate enumeration, and noted customer complaints that microbial results were out-of-specification (OOS) when they tested the API upon receipt.
Also at issue during the inspection were potential attempts to delay or limit the inspection. For example, the letter states that “during the inspection, an analyst removed a USB thumb drive from a computer controlling an HPLC. When asked to provide the drive, the analyst instead exited the room with the thumb drive. After approximately 15 minutes, management provided our investigator with what they asserted was the USB thumb drive in question. It is impossible to know whether management provided the same USB thumb drive that the analyst had removed.”
Company Name Location Letter Date Product Type Areas Cited Ipca Labs Mumbai, January 29, Compounded ● data integrity ● computer systems ● deviation India 2016 investigations ● lab controls ● microbial testing
In 2014, FDA performed inspections at three Ipca Labs facilities in India – the Ratlam API facility (July 14-18), the Pithampur tablet facility (October 13-17), and the Piparia Silvassa tablet facility (December 1-19) – and issued one letter covering all three sites. Data manipulation and data integrity issues were observed at all three locations.
At the Ratlam API facility, investigators found that lab computer systems permitted inappropriate manipulation of integration parameters, and allowed backdating and deletion of original injections. Investigators documented a conversation with an analyst who reported that “if we find a failure, we set back the date/time setting and re-integrate to achieve passing results.” The analyst explained that deleting, overwriting, changing integration parameters, and altering computer date and time settings were done for raw materials, in-process testing, and finished API drugs. Overwriting and deleting lab injections were also noted at the Pithampur tablet facility, while the use of trial injections and not reporting all data generated was noted that the Piparia Silvassa plant.
Also of concern at the API facility was a failure to adequately investigate and resolve critical deviations, failure to follow and document laboratory controls at the time of performance, and failure to document and explain any departures from laboratory procedures. At the Piparia Silvassa tablet manufacturing site, issues were noted with microbial testing – for example, testing for Staphylococcus aureus using a medium that is intended to inhibit its growth.
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JANUARY 2016 86 PAREXEL® Consulting: Strategic C ompliance and Risk Management
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© 2014 PAREXEL International Corporation. All rights reserved. MONTHLY UPDATE - JANUARY 2016 EMA GMP NON-COMPLIANCE REPORTS
The following are the drug GMP non-compliance reports posted by EMA during January, listed by report date. The main areas of concerns are listed along with the agency performing the inspection and links to the compliance reports themselves. Included is a review of the report’s salient features.
Company Name Location Report Date Product Type Areas Cited Shaoxing Zhejiang, December API ● falsification of records ● maintenance and cleaning Pharmaceutical Co. China 28, 2015 of process equipment ● change control ● cleaning and storage of process hoses ● lab computer security and audit trails
A May 2015 French National Agency for Medicines and Health Products Safety inspection of API manufacturer Shaoxing Pharmaceutical Co. in Zhejiang, China, resulted in 18 deficiencies, including two critical and four major deficiencies. Both critical deficiencies were related to falsification of records. The first related to the firm purportedly purchasing thiamphenicol API from a non-GMP company (Zhejiang Runkang Pharmaceutical Co.), then repackaging, relabeling and selling of the purchased API as if manufactured in-house under GMP conditions. The second critical deficiency resulted from the firm releasing praziquantel API, manufactured as chemically pure (CP), USP grade, without a full traceability of the testing activities.
The four major deficiencies involved: ● maintenance and cleaning of process equipment ● a process change control that was found lacking ● hoses used for unloading of solvent that were not identified, had no cleaning status, and were stored on a dirty floor of an area not mentioned in the general layout of the site, and ● lab computer system problems, including the lack of a procedure or audit trail for chromatographic equipment allowing data changes or deletions to be tracked, and access to the computer data by all QC staff with administrator clearance levels.
The French agency recommended that “consideration of a recall of product should be given due to the critical findings observed. QRM principles, national supply situation, and clinical requirements should be taken into account when making this decision.” It also recommended withdrawal of the site’s GMP Certificate. The agency noted that the inspection was performed inthe framework of WHO prequalification of medicines program for the manufacture of praziquantel API.
Company Name Location Report Date Product Type Areas Cited Desarrollos Teruel, January 12, Oral solid and ● manufacturing ● packaging ● QC testing ● Farmacéuticos Bajo Spain 2016 liquid dosage import operations Aragón forms
The Spanish Agency of Medicines and Medical Devices March 2015 inspection of the Desarrollos Farmacéuticos Bajo Aragón oral solid dosage site in Teruel, Spain, noted deficiencies in the firm’s manufacturing, packaging, QC testing, and import operations. The agency noted that the firm “has not established a quality management system including adequate controls to ensure the accuracy and completeness of the critical records/data.” The firm’s Manufacturing Import Authorization (MIA) has been suspended.
Company Name Location Report Date Product Type Areas Cited S.C. Ircon Iaşi, January 18, Oral solid ● quality management system ● validation ● Romaina 2016 dosage documentation ● QC labs
A Romanian National Agency for Medicines and Medical Devices inspection in December 2015 of the Iaşi, Romania-based S.C. Ircon solid dosage site found 34 deficiencies, including four critical and ten major. Critical deficiencies were related to the quality management system, qualification/validation activities, manufacturing and material management documents, and quality control laboratories activity. The agency noted that three batches of product were recalled, and that the firm’s manufacturing authorization is only valid in Romania. No products are distributed outside the country.
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Company Name Location Report Date Product Type Areas Cited Agila Specialties Warszawa, January 19, Sterile ● design and qualification of HVAC system ● Poland 2016 products cleaning and maintenance of clean rooms ● batch release ● change control
The Main Pharmaceutical Inspectorate of Poland July 2015 inspection of sterile products manufacturer Agila Specialities in Warszawa, Poland, resulted in a non-compliance report that includes 29 major deficiencies that “pose a risk of microbial and particulate contamination and could not assure the sterility of the final product.” The report notes that in December, the firm’s HVAC system covering its vial and prefilled syringe lines was significantly modified, but was not qualified.
Issues inspectors found with the HVAC system included: ● inadequate pressure differentials between grade B and C clean areas ● a laminar air flow system that is not compliant with requirements given in Annex 1 ● inadequate dynamic particle testing, and ● technical condition of clean areas and equipment showing a lack of proper and regular maintenance, including crumbling insulation of pipes, peeling teflon on the ports of tanks and pumps, lack of labelling, and mixed clean and dirty equipment. The Polish agency reports that no manufacturing has been performed at the plant since October 2015, and that a re-inspection is planned after non-compliances have been corrected.
Agila was purchased by Mylan in late 2013. In August 2015, Mylan received a 14-page FDA warning letter covering three aseptic manufacturing sites in India, two of which were formerly Agila sites (IPQ July/August 2015, p. 54). The central concerns at all three plants involve practices, procedures, and behaviors that call into question the sterility of the products being produced.
Company Name Location Report Date Product Type Areas Cited Sas Jarmat Reventin- January 19, APIs and ● inadequate control over packaging operations ● Laboratories Vaugris, 2016 excipients cross-contamination risk ● pharmacopeial testing France ● batch production records
A French National Agency for Medicines and Health Products Safety November 2015 inspection of API re-packager Sas Jarmat Laboratories in Reventin-Vaugris, France, found the firm’s primary and secondary packaging and QC testing to benon- compliant with EU GMPs. The French agency emphasized in the report that the starting materials repacked by the site were only distributed to community pharmacies for pharmaceutical compounding activity. Inspectors found 21 deficiencies, including three critical and five major. The critical deficiencies were: ● “important risks of confusion” in the repacking operations ● risk of cross contamination by substances of high pharmacological activity or toxicity, and ● active substance and excipient batches not analyzed per the pharmacopeial specifications.
Major observations were in the areas of batch production records, cross-contamination risks in sampling operations, management of active substance suppliers, and transmission of information to pharmacies. The report noted that the inspection observations also apply to excipients, which are repacked and distributed under the same conditions as the active substances. The report further notes that the site recalled all batches on the market and ceased its activities related to starting materials on December 3, 2015.
Company Name Location Report Date Product Type Areas Cited Hubei Hongyuan Huanggang January 20, API ● EU GMPs not implemented ● QA ● Pharmaceutical Co. City, Hubei 2016 documentation ● supplier qualification ● data Province, integrity ● OOS handling ● quality control● 428 Yishui North China computer system validation ● change control. Road site
No. 8 Fengshan Road site
The Czech Republic State Institute for Drug Control inspected two sites on October 30, 2015 of the Hubei Hongyuan Pharmaceutical Co. – at 428 Yishui North Road and No. 8 Fengshan Road, respectively – in Huanggang City, Hubei Province, China, and produced separate inspection reports. Both sites produce APIs. [continued on next page]
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JANUARY 2016 88 MONTHLY UPDATE - JANUARY 2016 Yishui North Road site
The company’s facility at No. 428 Yishui North Road, the report notes, was subject to a spot check, because the site is mentioned as an intermediate manufacturing site in a CEP for metronidazole. The company “clearly stated in their introduction that the site does not follow EU GMP,” investigators noted.
The following observations were made and together categorized as critical: ● The manufacturing site and it’s equipment was “found in a devastated state,” with “huge layers of dust and product,” which indicated that “no cleaning was applied to either the facility or the equipment, leading to an extreme risk of cross-contamination.” ● The “extremely bad shape of the facility and the equipment showed that no maintenance was in place.” ● “Almost none of the products seen was labelled,” and no batch manufacturing documentation was noted.
Investigators concluded that EU GMP Part II had not been implemented at the facility. The Czech agency recommended the firm be removed from marketing authorizations and the CEP be suspended or voided.
Fengshan Road Site
Inspection of the No. 8 Fengshan Road site identified a total of 24 deficiencies. One of them was categorized as critical and related to the company’s quality assurance system for production of metronidazole. Ten deficiencies were categorized as major and were related to: ● QA ● documentation ● supplier qualification ● data integrity ● out-of-specification handling ● quality control● computer system validation, and ● change control.
The Czech agency recommended that if there are alternative suppliers and there is no risk of shortage, recall of medicinal product should be evaluated by the involved national competent authorities following assessment conducted in conjunction with marketing authorization holders. “Given the nature of non-compliances, assessment should include a complete retest of all imported batches of active substance.” It further recommended suspending or voiding the CEP, and that the facility should not be approved in any new/ongoing applications.
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JANUARY 2016 89 MONTHLY UPDATE - JANUARY 2016
FDA DRUG RECALLS
The following is a listing of the drug product recalls included in FDA’s weekly “Enforcement Re- ports” issued during January. Included are the generic names of the products, the dosage form, the manufacturer, the number of lots involved, FDA’s classification, and the specific reason pro- vided by FDA in the Enforcement Report. The recalls are grouped by the general category of prob- lem that caused them. The categories are: ● compliance with NDA/monograph requirements ● contamination/lack of sterility assurance ● dissolution ● GMP/GDP ● impurity ● labeling/pack- aging ● foreign product ● particulate ● potency/content uniformity, and ● other spec nonconfor- mance. Within the categories, the recalls are organized by class, with the most serious, Class I recalls at the top.
CONTAMINATION / LACK OF STERILITY ASSURANCE
Product Recaller Lots Class Reason Various Walgreens All lots II Lack of Assurance of Sterility compounded Infusion within products (33) Services expiry Domperidone API Freedom 26 II Penicillin Cross Contamination: Potential for products to Pharma be cross-contaminated with penicillin.
Sulfamethoxazole Mutual Pharma One II Presence of foreign substance. This recall has been and trimethoprim initiated due to the presence of a polyethylene piece on tabs the finished product.
Homeopathic Grato Holdings One II Microbial Contamination of Non Sterile Products; testing liquid revealed out of specification results for total aerobic microbiological count Baclofen inj. Amerita One II Lack of Assurance of Sterility Specialty Infusion Services Bromfenac Mayne Pharma 115 II Lack of Assurance of Sterility: Failed preservative ophthalmic sol. effectiveness testing.
IMPURITY
Product Recaller Lots Class Reason Epson salt PQ Corp. One III Failed Impurities/Degradation Specifications: Level of iron powder exceeds the limit set by the USP monograph for it.
Magnesium Avantor 2 III Failed Impurities/Degradation Specifications: Out of sulfate API Performance specifications results for impurities. Materials
Mixed salt Teva One II Failed Impurities/Degradation Specifications: High out amphetamine of specification test result for impurities during stability testing.
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JANUARY 2016 90 MONTHLY UPDATE - JANUARY 2016
LABELING / PACKAGING
Product Recaller Lots Class Reason Docusate National One III Labeling: Label mix-up. Docusate Sodium 100mg calcium softgels Vitamin Co. Softgels were mislabeled as Docusate Calcium 240mg.
PARTICULATE
Product Recaller Lots Class Reason Duloxetine Breckenridge One II Presence of Foreign Tablets/Capsules: One foreign delayed release Pharma capsule identified as omeprazole 10 mg was found in caps the bottle.
Bevacizumab Pine Pharma 26 II Presence of particulate matter: Presence of silicone oil inj. microdroplets in bevacizumab syringes for intravitreal use.
POTENCY / CONTENT UNIFORMITY
Product Recaller Lots Class Reason 5-methyltetra- Freedom One III Subpotent Drug hydrofolate Pharma calcium
Lindane lotion Morton Grove 2 III Super-Potent Drug: Out of Specification Assay test Pharma results were reported for stability samples.
OTHER SPEC NONCONFORMANCE
Product Recaller Lots Class Reason Baclofen powder Freedom 4 II Presence of foreign substance. pharma
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