INTERNATIONAL PHARMACEUTICAL QUALITY IPQ Inside the Global Regulatory Dialogue IPQPUBS.COM VOL. 8, NO. 5
MONTHLY UPDATE - AUGUST/SEPTEMBER 2016
UNITED STATES
● Review/Inspection Control Strategy Communications Key to Advancing Biotech p. 4 Regulation, FDA Biotech Official Stresses
● More Clarity Sought in FDA’s Inactive Ingredient Database Regarding Drug Delivery Devices p. 13
EUROPE
● Protein Sequence Variants, Process Development and Spec Setting Are Generating Queries p. 20 from EU Biopharmaceutical CMC Assessors
● Procedures, Eligibilities and Goals of EMA’s Accelerated Access Efforts Are Taking More p. 32 Concrete Shape
INTERNATIONAL
● Goal of FDA/EU Mutual Inspection Reliance is Nearing Realization p. 36
UPDATES IN BRIEF p. 47 U.S. CMC: ● GDUFA II Agreement ● ANDA Impurity Refusals ● Capsule Supplier Changes ● Co-Crystal Classification ● ANDA Impurity Refusals
U.S. GMP: ● Insanitary Compounding ● NIH Clinical Manufacturing ● Establishment Registration ● Generics Facility ID'ing ● USP on Analytical Lifecycles
EUROPE CMC: ● EMA Streamlining ● EMA Adaptive Pathways Workshop ● EDQM on ICH Q3D
EUROPE GMP: ● EMA WFI Q&A ● EC on Plastics
INTERNATIONAL CMC: ● Antimicrobial Resistance Roadmap ● WHO on Variations ● Canada on ICH Q3D
INTERNATIONAL GMP: ● China on Drug Manufacturing ● India Manufacturing Self-Assessment
FDA WARNING LETTERS, EMA NON-COMPLIANCE REPORTS, AND FDA RECALLS POSTED IN AUGUST/SEPTEMBER p. 51 MONTHLY UPDATE - AUGUST / SEPTEMBER 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.
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Editor-in-Chief Editorial Staff–Europe Bill Paulson Nuala Calnan [email protected] [email protected] 202-841-5027 +353 87 9786968
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NOTE ON THE ISSUE: Two of the stories in our August/September issue build on the dis- cussions that took place at the opening plenary session of the 2016 CASSS European CMC Strategy Forum. The session followed the traditional forum model of bringing together a panel of regulators from different agencies around the world to highlight and compare ideas with the forum participants on the key issues they are facing and their recent initiatives to address them.
Irish regulator Sean Barry led off the session with a review of recent developments in Europe. Bill Paulson, Editor-in-Chief Our story highlights, in particular, his insights on the CMC questions that European assessors are having in reviewing biotherapeutic marketing applications. Barry also covered: ● EMA’s priority medicines (PRIME) and adaptive pathways approaches and how they relate to each other ● the CMC challenges presented by these accelerated approaches and how they can be dealt with by industry and regulators, and ● the implica- tions of EMA’s recently published guideline on process validation for biotech-derived active substances.
Complimenting Barry’s European update is a story honing down on how the procedures, eligibilities and goals of EMA’s accelerated access approaches have been taking more concrete shape, informed by its growing implementation experience. A wave of releases on EMA’s PRIME and Adaptive Pathway efforts has been forthcoming since March that provide insight into their progress and interrelationships.
Barry was followed to the podium at the Paris forum by FDA Office of Biotechology Products’ Sarah Kennett, who pro- vided the FDA vantage point. Like Barry, Kennett provided updates on the progress being made and the CMC challenges involved in accelerating the development and review of new therapies that warrant the extra regulator resources involved. She also followed the Irish regulator's lead in probing the issues that are being seen in reviewing biotech product applica- tions – emphasizing the need for strong regulator/industry communication in shifting to a more flexible and continuous improvement-friendly lifecycle regulatory paradigm.
Also in focus in this issue is an aspect of drug/device combination product regulation that is getting more attention – the expectations for the excipients/materials involved in their formulation. The story focuses on the dialogue that took place at a session of the 2016 IPEC-Americas/ExcipientFest Conference on the regulatory issues encountered in formulating prod- ucts like transdermal patches, metered dose inhalers and implants, and how FDA’s inactive ingredient database (IID) can be restructured to make it a more relevant and useful resource for both industry and regulators.
And in this issue we also pick up the thread of the impact of globalization and the rapid growth in foreign manufacturing facilities on quality regulatory processes, and the need for international coordination in addressing the challenges involved. Included in the 2012 FDASIA legislation in the U.S. was a mandate and some additional tools for FDA to pursue partner- ships with other countries that would extend the agency’s ability to reach into the more high-risk elements of its inventory. With 40-50% of FDA’s overseas inspections being performed in Europe, where a healthy regulatory oversight process al- ready exists, the EU became a prime candidate.
Our story builds on an engaging presentation by Associate Commissioner Dara Corrigan in which she shared her expe- rience as head of FDA’s European office in Brussels tasked with driving forward a mutual inspection reliance agreement between FDA and the EU. Corrigan explains how – with strong support coming from the new FDA Commissioner, Robert Califf, for questioning and moving beyond the status quo – the vision of a unified inspectorate across the US and EU is now taking shape.
The plethora of warning letters posted by FDA during August and September that are reviewed in this issue also sheds light on these global enforcement challenges. Also clear in assessing the recent warning letters is how much energy FDA is putting into its effort to oversee pharmacy compounding in the U.S., and why this is a very real priority.
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AUGUST / SEPTEMBER 2016 3 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 UNITED STATES Review/Inspection Control Strategy Communications Key to Advancing Biotech Regulation, FDA Biotech Official Stresses Advancing biotech product and process knowledge has She charted the progress the biotech industry has made in created the foundation for regulatory changes, but close developing an array of new products as well as in advancing communication and coordination between manufacturers the processes and technologies. This “back and forth” and the and regulatory agencies will be necessary to realize those knowledge and experience gained “has led us to some of the changes while ensuring and advancing product quality, changing landscape that we are seeing now and the potential FDA Center for Drug Evaluation and Research (CDER) for changes in how we are managing product lifecycles and Office of Biotechnology Products (OBP) Review Chief Sarah for some of the control strategy changes.” Kennett emphasized at the 2016 CASSS CMC Strategy Forum Europe. While FDA may not be ready “to do a 180 in how we are thinking about lifecycle management and Kennett took the opportunity in her presentation at the control strategies,” the OBP official said, “we have been not only having discussions about some of opening international regulator panel session to offer these advances, but actually approving a lot of the a nuanced view of the regulatory opportunities, on the proposals that are being sent to us.” one side, and the challenges that have to be addressed in realizing them, on the other. The agency has approved modifications in control strategies for legacy products, and is also “kind of changing our “I think we are in a time period now where we really have expectations for what we want coming in at the time of the a potential to see a lot of change,” she affirmed – “thanks initial BLA filing or a prior approval supplement.” Kennett in part to a lot of the advancements that have been made stressed that “this is a change in the expectation of how the by industry over the last few years. At the same time, I control strategy would be run or what the proposals are for think that we have to have some good communications and the strategy – not changes in our expectations that these coordination between manufacturers and the regulatory strategies would really assure product quality.” agencies to get some of these changes implemented.” FDA has been involved in “a lot of discussions regarding the This central theme of Kennett’s talk reverberated use of multi-attribute methodologies, using CPV [continued also through the presentations at the opening process verification], using predictive modeling, and other plenary session by Ireland Health Products advanced ideas around control strategies.” Regulatory Authority (HPRA) Pharmaceutical Assessor Sean Barry (IPQ September 28, 2016), Shortfalls Seen in Justifications and Japan Pharmaceuticals and Medical Devices Agency (PMDA) Office of Cellular and Tissue-based After highlighting the potential for the new approaches Products Principal Reviewer Yasuhiro Kishioka. to control strategies and lifecycle management, the OBP Review Chief provided examples illustrating where biopharmaceutical applicants are falling short in what they The three presenters addressed a similar range of front- are submitting to support what is being proposed – an area burner CMC issues for biotech products, including problems where reviewers “are running into a lot of problems right in recent applications, their respective agency’s accelerated now.” development programs, and the shifting approaches and expectations for lifecycle management. Both examples involved a de-emphasis on specifications in favor of in-process controls and quality system management. Biotech Advances Support Regulatory Changes The examples highlight the problem for the reviewer Kennett began her remarks by commenting on the when the application does not contain enough importance of the CMC forums in helping “both regulators information to be sure that the sponsor’s process has and industry keep pace with each other and understand the claimed capacity and reliability, or there is an what is going on.” [Kennett’s presentation is provided in indication in what is submitted that it actually may full below.] not meet those claims. WWW.IPQPUBS.COM
AUGUST / SEPTEMBER 2016 4 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 The first example illustrated the quandary reviewers The examples she provided at the Paris forum underscore can face where the applicant’s justification may not be the stresses involved for both regulators and manufacturers sufficient, but the reviewer can see, based on other data in the complex world of biotechnology in shifting to a more and information submitted, that the risk is low. Kennett flexible and continuous improvement-friendly lifecycle explained the problem that then arises in not being sure regulatory paradigm. that the inadequate scientific justification won’t come back to bear when the sponsor “is doing investigations into The OBP official explained that comparability/ deviations or when they are looking at change controls, and change protocols are one of the tools that come into they are doing all that under their own quality system.” play in making this shift. She noted that the new The Application is Not the Control Strategy edition of the draft comparability protocol guidance that the agency issued in April 2016 now explicitly Along with the meetings like the Paris forum, Kennett encompasses biological products. noted that the development of ICH Q12 is providing the opportunity for the discussion between industry and FDA, she pointed out, has been approving protocols for regulators on how lifecycles should be managed. manufacturing of new working cell banks, new reference materials, resin and membrane reuse, and reprocessing. She pointed out that the guideline is “supposed to promote innovation and continual improvement, but it is also The agency is also now seeing more protocols for “major supposed to be strengthening quality assurance,” and comparability” in introducing new manufacturing sites, stressed the need to “make sure that these two are going reflective of “the advances and knowledge that we have hand in hand.” Q12 is also “supposed to be promoting that makes this type of protocol more viable.” She provided scientific and risk based foundations for the changes” – an an instructive list of the issues that FDA has been seeing objective “that is really important to us right now as we are with change protocols, particularly those involving new trying to make changes and make everything work better manufacturing sites. and be a little more consistent across the board.” Biosimilars and Breakthroughs on CDER’s Kennett pointed to FDA’s contribution of a draft guidance on established conditions (ECs). Sufficient detail is needed Biotech Agenda in the application, she advised, to provide the confidence that process performance and the quality of the approved In her brief update on biosimilars and breakthrough products, product is assured. Kennett noted that as of the May forum, two biosimilars had been approved – Sandoz’ filgrastim and Celltrion/Pfizer’s OPB is “seeing some issues about control strategies infliximab – and that there are a number of products in line being complete,” Kennett said. She offered an “to potentially be approved soon.” At the time, there were intriguing example involving a drug substance unit five companies that had publicly announced the submission operation that typically takes less than an hour, of a total of eight applications for biosimilar products for six which was found on inspection to have been run 16 reference products. hours without being flagged and investigated as a deviation. As of the beginning of March, 58 programs were in FDA’s Biosimilar Product Development (BPD) program, and The example illustrated clearly the changing dynamic CDER had received meeting requests to discuss biosimilar between the application and the quality system. In this case, development for 18 reference products. the firm used the pared down specification commitment in the application as a justification for not doing extra work on In reviewing the breakthrough product approvals, the quality systems end, since the commitment was met. The problem was that the specification reduction reflected the Kennett found it “really interesting” that half of assumption of process consistency, which was not the case. those in 2015 were biotechnology products.
“What we are really looking for,” Kennett commented, “are Overall 10 of 45 novel drugs during the year had the established conditions – the control strategies, testing, breakthrough status and five were biotech: Alexion’s asfotase the quality system to all work together to form a really alfa and sebelipase alfa, Janssen’s daratumumab, Bristol- complete control strategy that provides a product that is of Myers Squibb’s elotuzumab, and Boeringer Ingelheim’s consistently high and appropriate quality.” idarucizumab.
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AUGUST / SEPTEMBER 2016 5 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 Navigating the Shifting Regulatory Sands authorities that are here. That includes that the drugs are safe, they are effective, they deliver the performance In her “closing thoughts,” Kennett circled back to that was described in the label, they perform consistently, underscoring the balancing act that FDA – and OBP in and they are really high quality drug products. We really particular – faces in navigating the shifting regulatory sands. want the patients and care givers to be able to make those assumptions. So we are going to be carefully considering all The agency “really wants to be able to approve new of those aspects when we evaluate the life cycle management products,…get new good therapies to patients, and plans and control strategies, and the changes to the plans and approve…updates to legacy products – to update control strategies.” manufacturing processes, update the entire control strategy.” In recognition of the focus of the Paris forum, the agency, she stressed, “looks forward to all of the discussions regarding However, “we also know that patients and care givers, the new strategies for lifecycle management and change health care providers, have certain assumptions about drugs reporting and the development of new products with that are approved by FDA and by many of the regulatory challenging CMC aspects.”
Biotech Product Regulatory Update from CDER Office of Biotechnology’s Sarah Kennett
At the opening “regulatory updates” plenary session of the 2016 CASSS CMC Strategy Forum Europe, CDER Office of Biotechnology (OBP) Division of Biotechnology Review and Research 1 Review Chief Sarah Kennett provided the FDA update. In her talk, Kennett reviewed: ● the advancement of the biopharmaceutical industry in understanding their products and processes ● examples of the CMC problems that OBP is seeing in applications ● the impact of Q12 and established conditions ● the use of comparability protocols, and ● developments in biosimilar and breakthrough products.
I would like to thank the organizing committee for inviting me here again. I was here a couple years ago. I certainly have not been here all ten years, but the year I was at this meeting, I thought it was really informative. And I think the discussions at all of the CMC forums are really important to help both regulators and industry to keep pace with each other and understand what is going on and help each other learn different things.
I think we are in a time period now where we really have a potential to see a lot of change. This is thanks in part to a lot of the advancements that have been made by industry over the last few years. At the same time, I think that we have to have some good communications and coordination between manufacturers and the regulatory agencies to get some of these changes implemented….
Advancement of the Biopharmaceutical Industry
As I was thinking about what is currently happening in the world of biotechnology products, I realize I really should not be surprised with all of the advancement. Because just using some of the monoclonal antibody products as a model, it is really easy to see that we have come a long way in the 30 years since OKT was approved back in 1986….
[This slide] shows what I wanted to get across, and that is the increase not only in the numbers of products, but the increase in knowledge that has gone hand-in-hand with the increase in products – increases and advancements in knowledge and understanding not just about the products themselves, but also about the processes that are used to manufacture the products and all of the advances in the technologies that are used for manufacturing and for doing testing of these products.
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AUGUST / SEPTEMBER 2016 6 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
One thing has supported the other, and, in the reverse fashion, advances have really supported the development of antibodies. We get more antibodies being developed, and they drive more advances, and it is a back and forth process and has been for a while. That has lead us to some of the changing landscape that we are seeing now and the potential for changes in how we are managing product lifecycles and for some of the control strategy changes.
I am certainly not going to stand here and say that FDA is ready to do a 180 in how we are thinking about lifecycle management and control strategies. But I think we really have been not only having discussions about some of these advances, but actually approving a lot of the proposals that are being sent to us.
We have had modifications in control strategies for legacy products, and we are also kind of changing our expectations for what we want coming in at the time of the initial BLA filing or a prior approval supplement. This is a change in the expectation of how the control strategy would be run or what the proposals are for the strategy – not changes in our expectations that these strategies would really assure product quality.
We have also been involved in a lot of discussions regarding the use of multi-attribute methodologies, using CPV [continued process verification], using predictive modeling, and other advanced ideas around control strategies.
Problems OBP is Seeing in Applications
One of the points I think that I really need to get across during this talk is that the data and other information that is submitted needs to fully support the proposed control strategies. This is where we are running into a lot of problems right now, and I want to spend some time talking about a couple of examples. I used ‘specifications’ for a few examples because they are kind of easier to think about and present.
First Example
In the first example, the manufacturer has provided justifications for not having reduced and non-reduced SDS testing for an antibody, which has really been a typical standard that we would see on almost every single specification for this type of product.
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AUGUST / SEPTEMBER 2016 7 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Some of their justifications are: ● fragments are well controlled by the process ● the levels are historically low ● there have been minimal or not practically significant changes over shelf life under the recommended conditions, and ● they also say that they will be monitoring these as in-process controls. So I have a number of questions or potential issues with some of the justifications.
‘It is well controlled by the manufacturing process:’ Well how variable was the actual manufacturing process that was used to manufacture clinical and development materials, and how variable will the process be allowed to be post licensure?
Of course, as was presented, we are not only looking at the real full scale data to support a control strategy and the process aspects of the control strategy. We will also be looking at a lot of developmental data, small scale data, DOE studies, that support your process. In this case, there were minimal development data provided. The data were provided only for production bioreactor, specific hold around the time of harvest, and a low pH viral inactivation step. And there was impact on fragments identified in every single one of those steps.
There was also no data looking specifically at clearance of any of the types of fragments that would be picked up by these assays. There were no data provided for holds, and the holds were only evaluated using one of the assays. There might be some good scientific reasons for this – for not having the data or doing those particular studies – but none of that was discussed in the application.
Around the historical levels being consistently low: Here we are talking about past versus future – what is the purpose for looking at the drug substance and drug product and testing them at release and on stability in the first place?
‘No practically significant changes observed during shelf life:’ What does practically significant actually mean? Again, we run into the issue of past versus future – historical data versus what is going to happen when manufacturing is performed post licensure.
We also have a sponsor saying that they will monitor these as in-process controls at some pool during the purification process. Here we need to think about action limits versus specification acceptance criteria or rejection limits for in-process controls and what is really appropriate to be used, and at which step in the process does it actually make sense to be doing the in-process testing? Are you going to generate additional variants at some time after that test? Then maybe that is not the appropriate part. Are you going to do a lot of clearance after that step, and do you really have a high level of clearance validated? Well then maybe that is the appropriate step anyway.
This particular sponsor also indicated that they were going to be doing the second test also as an in-process control, but I could not find any mention of that test in the description of the manufacturing process and process controls, or in the control of critical steps in intermediate sections. So I kind of wonder what is really going on, and I also wonder if the FDA draft established conditions guidance that will be talked about more later would say having that control is actually a commitment even though it is not in S.2.2. or S.2.4? And could that lead to a potential inspectional observation?
So that is just what the sponsor had provided as justifications. As I am looking through the submission, I also noticed that there was a significant amount of data provided about forced degradation studies. I am wondering if the sponsor could actually include that as part of their justification for the proposed specifications?
If you are looking at data for lots of different types of forced degradation, lots of different types of conditions, and this is the greatest amount of degradation that was seen, with that support – not looking at those particular variants as part of release and stability specifications – what are agencies supposed to do in a situation like this?
In my hypothetical, I have me as a reviewer saying ‘I do not agree that what the sponsor submitted is actually sufficient to justify their proposal. However, I found some data in the submission that would allow me myself to justify the proposal.’ This puts us in a little bit of a quandary, and this is not a unique situation. We have been dealing with similar situations for a long
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AUGUST / SEPTEMBER 2016 8 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 time, where the agency’s justification and the manufacturer’s justifications might not be quite the same. A lot of time we have approved things, and we do that on a risk basis and after an evaluation – to try to say, ‘well, do we think it will actually make a difference in the future?’
When a sponsor comes up with a specification acceptance criterion using one method, and we have come up with basically the same number using a different method, then we have generally been okay saying that number is fine, because we don’t think there is going to be a huge impact in the future because of our differences in how we got to that number.
However, in this case, I think we are also going to be expecting a manufacturer to use some of their justification and the scientific thinking behind that justification as part of, for example, when they are doing investigations into deviations or when they are looking at change controls, and they are doing all that under their own quality system.
What if we want their quality system to also be thinking about our reasons for saying that it is okay? Now we are in a little bit of a predicament, and I think we have less assurance that saying okay automatically would be a low level of risk – we would think of it as a low level of risk. I would invite any kind of suggestions for what would be best practice for managing this type of situation.
Second Example
Another example involving specifications: We have a justification for not including a reduced SDS assay as part of release specifications. The sponsor says, ‘well we don’t need it because low molecular weight species will be controlled by our SEC testing.’
But then I go and look at the SEC method, and I determine that the SEC method acceptance criteria includes only one specific low molecular weight species – not any of the other specifics that have been identified and would be controlled by that reduced SDS assay. I also can’t tell whether detection of new peaks would lead to an SDS assay failure. So I am really not sure that that SEC assay could replace the reduced SDS assay.
In the case of an SEC assay that is proposed to be performed in-process only, not on release or on stability, the sponsor’s justification was that testing in-process, a step that was in mid-purification, would ensure that aggregate levels are controlled by the process, because the step effectively removes aggregate.
I had a number of questions about this. Some are the same as previous questions, but one that was really important to me was that aggregate clearly impacts the potency of this product as evaluated using one of their potency assays. However, the potency assay that is actually on the current specification is really not very good at detecting aggregate. It is not sensitive to aggregate.
So the way that I am thinking, just having this amount of information, is that you can’t take the aggregate assay off, because you are not going to see any of the impact on potency. Just because one assay is not sensitive does not mean that it is not important in vivo. We don’t really know looking at the in-vitro assays which is really important in vivo.
Some of the other questions and issues I have with this justification are similar to the first example regarding lack of data to support the step at which in-process testing is performed – for example, again, no hold data and no data to demonstrate anything about aggregate formation or removal of aggregates. I am really not sure about not including it on stability for some of the same reasons – when are aggregates really going to form?
Q12 and Established Conditions
One of the opportunities that we have for discussing some of the changes like this and other changes that sponsors are proposing are meetings such as this. But another opportunity right now for discussions of how lifecycle should be managed
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AUGUST / SEPTEMBER 2016 9 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 are the talks that are happening around the development of ICH Q12. Q12 is going to be discussed a lot more later, so I do not want to go deep into Q12, but I just wanted to make a couple of notes.
One is that the guideline is supposed to promote innovation and continual improvement, but it is also supposed to be strengthening quality assurance. I think we need to make sure that those two are going hand in hand and that we are not forgetting about quality.
The other thing is that the Q12 is supposed to be promoting scientific and risk based foundations for the changes. I think getting into the science and making sure things are risk based is really important to us right now as we are trying to make changes and make everything work better and be a little more consistent across the board.
In advance of ICH Q12, FDA has published a draft guidance for industry on established conditions. Again, this is going to be talked about more later. I just want to point out that this is a draft guidance, and I have heard that there have been a significant number of comments submitted to the draft. I also want to point out that there is supposed to be sufficient detail in the application regarding the proposed established conditions, and they should be assuring process performance and the quality of the approved product.
The guidance goes into what established conditions are and what they are not and where they are commonly located in the CTD. But it also says that no matter where they are located, relevant information would still be considered an established condition – hence my earlier question about whether something that is not in 2.2 or a 2.4 would still be an established condition and impact some of the inspectional findings.
Recent Example of Incomplete Control Strategy
Established conditions are supposed to be one aspect of a control strategy. We expect that all of the different aspects of the control strategy really make a complete strategy. We are seeing some issues about control strategies being complete, and I have tried to illustrate some of those with this example:
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AUGUST / SEPTEMBER 2016 10 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
On an inspection in the not too distant past, the reviewers identified a drug substance unit operation that typically takes less than an hour. In this case it ran for about sixteen hours. The sponsor did not consider that a deviation or event or whatever you want to call it, because a time limit for that stuff is not included in the description of the manufacturing process. So they say: ‘It is not an established condition. It is not a regulatory commitment. Therefore, it is not a deviation.’ But this step is intended to run in a continuous manner. We also do not want to put requirements and limits on every single step or part of a step in a process. But I wonder why in a situation where the process ran so differently than the historical process, there was no thought about calling it a deviation or an event.
This particular sponsor had the opportunity to really evaluate this delay as part of a different deviation, because they did call the event that caused the delay a deviation. Overall product quality could have been evaluated as part of that investigation but was not.
Some of the other responses that this sponsor gave to the investigators was that ‘well we know that the quality is okay because the drug substance met spec.’ Sometimes that is probably true, but in this case the proposed specifications are actually extremely limited with respect to purity. This is not an uncommon occurrence anymore. We are getting more and more proposals with fewer and fewer assays as part of specifications. A lot of manufacturers are trying to use the control of the process to support the limited specifications.
But then what should happen when the process then does not run correctly? Do you think about all of the things you did not put on the specification? Should you think about all of the things that were not on the specification?
The sponsor, manufacturer, also gave responses about a separate hold time that is included in the process, and it happens right after the end of the step that normally takes less than an hour. That hold time is also significantly shorter than the sixteen hours that was sort of a hold in the middle of the process. They said that that hold time is really short because that was the micro hold time and that was the data that they happened to have it full scale.
That is fine. But then they also made the point that the small scale data they have show significantly longer acceptable times. They might be able to use those data to support their big long 16-hour delay. But the pool hold happens under conditions that are really different than the conditions under which the material is being held during that 16-hour time. So there needs to be some additional information provided to support using the real hold validation data to say that there was no impact to product quality during the 16-hour delay time.
It really seems like there is one argument that says,’ okay, so we are not going to have specifications because the process is okay. Then the process isn’t okay, but they don’t have to look at anything because things met specifications. What we are really looking for are the established conditions, the control strategies, testing/no testing, the quality system to all work together to form a really complete control strategy that provides a product that is of consistently high and appropriate quality.
Comparability Protocols
One of the things that we can also use to manage changes post-approval, manage some of these specification changes and all of the other changes that sponsors want to make, are comparability protocols or change protocols.
FDA has issued a new draft guidance, or really an updated draft guidance, to industry regarding the comparability protocols. This time biologics are included in the guidance. Last time the guidance did not include biological products specifically.
This is a newer guidance, a new edition. However, comparability protocols have been used for a long time. We have been approving them for quite a few years. We have approved them for some manufacturing sites, but we also approve what are really similar protocols for manufacturing of new working cell banks, new reference materials, resin and membrane reuse, and reprocessing.
We looked at quite a few of these, and now we are looking at more and more protocols for major comparability on the introduction of new manufacturing sites. I think we might be getting more and more of them because of the advances in knowledge that we have that makes this type of protocol more viable.
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AUGUST / SEPTEMBER 2016 11 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Some of the issues that we have seen with these change protocols, specifically the ones for new manufacturing sites, are: ● a lack of data to support the acceptance criteria ● acceptance criteria for comparability that are the same as the release criteria ● very few descriptions of the mechanism for evaluating stability with respect to comparability ● requests for downgrade of submissions that are just not going to be able to be downgraded, because there are requirements in addition to comparability, such as inspections, that will need to be done, and that will mean for the US that you need to submit a PAS, [and] ● protocols for changes that would include some additional requirements, but don’t address those requirements at all. That might be something like validation. So if you want to add another manufacturing site, you need to look at the comparability of the product, but you are also going have to do validation of the process at the new manufacturing site.
It could be possible to actually include a validation protocol as part of this whole entire comparability or change protocol, but sponsors are not doing that very much. It is indicated in the draft guidance that this is the type of protocol that might not be something you would want to submit as a comparability protocol. However, there are some manufacturing site changes that are likely to not require an inspection – some of the drug product manufacturing site changes probably more than drug substance. I think this really is a viable protocol for that type of change.
Biosimilar and Breakthrough Products
So quickly as part of the updates part of the talk, I think all of this advanced knowledge has really been driving biosimilar products and also what the US calls ‘breakthrough’ products.
For biosimilar products, the US update is that we finally do have some approved biosimilar products. So we have the filgrastim and infliximab, and there are a number of products that are in line to potentially be approved sometime soon.
With the breakthrough products: As has been indicated, these products really need this advanced knowledge and the new technologies, because the CMC development needs to be expedited at the same pace as the clinical development. For us, breakthrough designation really does not change the general CMC requirements and expectations. We can talk about tweaking things, we can talk about leaving a little bit post approval, but there a number of things that are just expected to be provided up front.
One of the figures I noticed that was really interesting to me was that half of the breakthrough products that the US approved in 2015 were biotechnology products, not small molecule drugs.
Closing Thoughts
Just a few closing thoughts: We really want to be able to approve new products. We want to get new good therapies to patients. And we really want to be able to approve updates to legacy products – to update manufacturing processes, update the entire control strategy.
But we also know that patients and care givers, health care providers, have certain assumptions about drugs that are approved by FDA and by many of the regulatory authorities that are here. That includes that the drugs are safe, they are effective, they deliver the performance that was described in the label, they perform consistently, and they are really high quality drug products. We really want the patients and care givers to be able to make those assumptions. So we are going to be carefully considering all of those aspects when we evaluate the life cycle management plans and control strategies, and the changes to the plans and control strategies.
FDA looks forward to all of the discussions regarding the new strategies for lifecycle management and change reporting and the development of new products with challenging CMC aspects.
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AUGUST / SEPTEMBER 2016 12 5-6 December 2016 Tokyo Marriott Hotel Tokyo, Japan
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January 23, 2017 January 24-26, 2017 Methods on the Move: Addressing Method Transfer 21st Symposium on the Interface of Challenges for the Biopharmaceutical Industry Regulatory and Analytical Sciences - and - for Biotechnology Health Products Production Cell Line Development and Control of Product Consistency during Cell Cultivation – Myths, Risks and Best Practices
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ABSTRACT SUBMISSION DEADLINE SYMPOSIUM CO-CHAIRS: November 30, 2016 for poster presentations Anissa Cheung, CBER, FDA Michele Dougherty, CDER, FDA Joseph Kutza, MedImmune, A member of the AstraZeneca Group
For program updates, on-line registration, abstract submission, information on exhibiting and/or sponsoring, please scan the QR code or visit www.casss.org. MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 More Clarity Sought in FDA’s Inactive Ingredient Database Regarding Drug Delivery Devices FDA and the excipient industry are giving more thought to much of each of the ingredients is used in the layers.” The how the inactive ingredient database (IID) can be improved question is, “do you need those amounts as a maximum to better support the development of emerging dosage potency in the IID, or would it be most useful to say this forms, including drug delivery devices such as transdermal ingredient is used in the backing of the patch?” patches, metered dose inhalers, nasal sprays, and implants. Colorcon Global Regulatory Affairs Director David A session was held at the 2016 IPEC-Americas/ Schoneker suggested that if the quantities in the backing are ExcipientFest Conference, held in late April in “something that is going to be assessed at the time of filing Baltimore, Maryland, to explore the regulatory where it could, potentially, if you are exceeding at some issues encountered in formulating emerging dosage level, create a refuse-to-receive (RTR) letter, then it does need forms and how the IID can be restructured to make to be in the IID.” On the other hand, if it is “not something it a more useful resource for both industry and where that maximum matters – that I put whatever I want in regulators. the backing as long as it is justified in my application – then it is probably not needed in the IID.” At the session, FDA Office of Pharmaceutical Quality (OPQ) IID Working Group leader Susan Zuk provided an For sponsors, Schoneker maintained, knowing the update on her office’s ongoing effort to make the IID as expectations at the time of filing “is a critical piece.” Zuk useful as possible to industry. She concluded with a review acknowledged the “need clarity on that.” of some of the challenges for emerging dosage forms, in particular. [See IPQ July 31, 2016, for a broad review of the As a segue into Raghuram’s remarks and the issues involved in improving the IID.] discussion period that followed, Zuk acknowledged that CDER also “does not actually know the best way Lubrizol Life Sciences Global Regulatory Affairs Manager to represent the amounts of ingredients in the IID” Meera Raghuram, who chairs IPEC-Americas Regulatory for other emerging dosage forms, such as metered Affairs Committee, followed with an industry view of the dose inhalers and intra-uterine devices. need for more regulatory guidance and further clarity in the IID regarding excipients in drug delivery devices. For metered dose inhalers, “I can tell you that in applications we get everything from percentage per actuation to weight Raghuram maintained that careful consideration is needed per weight. So what would be most useful to industry?” she as to how excipients are evaluated, what data is captured, querried. and how the precedence of use is established. More transparency is essential, she stressed, to improve the utility For nasal sprays, Zuk continued, “a dose is usually a spritz of the data in the IID for excipients with a long history of in each nostril. So what would be the best way to represent use in medical devices such as discs, rods and patches. the amount of ingredients in this type of product in the IID? And for a more complicated device – for example, an inter- CDER Weighs in on Transdermal Patches uterine device where the ingredients in the device dilute over time – what is the best way to represent the amounts of Zuk began her discussion of the emerging dosage form ingredients in these types of products in the IID if we were to challenges by focusing on transdermal patches, which are state the maximum daily intake, for example?’ listed in the IID with the maximum potency as milligrams per patch. She acknowledged that FDA struggles with the FDA/Industry Cooperation Needed composition statements for these products since they are submitted in different formats in drug applications. In her presentation, Raghuram recommended that IPEC as an organization should seize the opportunity to collaborate “Clearly, the amount of excipient in the layers to touch the with FDA on the IID issues that are surfacing with these skin – the amount of ingredients in the layers that deliver novel dosage forms, with the goal of assuring as much the drug – is important,” she said. “But probably not so transparency as possible. [Raghuram’s complete remarks at important is the amount of the ingredient in the backing.” the conference are included below.]
In the composition statement that is provided in the Drug delivery systems and implantable devices, she noted, application, she clarified, “we would like to know how represent a revolutionary opportunity in dosage form design
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AUGUST / SEPTEMBER 2016 13 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 for the future for several reasons: ● their ability to deploy a along with tactifiers and detactifiers, which may have lower level of API, with less adverse effects ● the growth extractable and leachable concerns as well as functionality in device use in chronic diseases, and ● the opportunity issues in assuring that the appropriate release of the patch they present to address expiring patents using the 505(b)(2) from the liner. pathway. Colorcon’s Schoneker followed by commenting that a lot Raghuram provided commercial examples of implants of time has been spent over the years on what information including devices for prostate cancer, uterine fibroids, is needed to improve the database. However, one of the and hormone therapy for contraception. Other common important session takeaways, he suggested, is the need for examples listed in the IID include intravaginal rings, establishing “clear guidelines on how the database is used subcutaneous implants and bladder implants. High tech both by different kinds of reviewers in different situations” devices, such as microchips, are being evaluated as an and by industry. implant in the bone to deliver a targeted dose over an extended period of time at a more precise amount than an Zuk responded that the FDA is in the process of writing injectable drug product. an IID guidance, with involvement of the Office of Generic Drugs filing review, chemistry, and toxicology staff, which The excipient-related issues that must be evaluated for “we are hoping…can bring clarity to all of these things.” emerging drug delivery systems, she noted, include: ● Zuk noted that as project lead, she has tasked people with biocompatibility ● leachables and extractables ● stability of explaining “FDA's viewpoint on what comes into us and the API ● interactions ● drug adherence to the implant, and how do we use this information.” ● low temperature processing. Industry consultant Irwin Silverstein queried if “we Critical issues that FDA needs to address in the IID for are trying to force a square peg into a round hole. polymers used in drug delivery systems, for example, Would it make sense to have a separate database of include: ● the meaning of precedence of use ● the these combination products where we can stipulate FDA procedure for utilizing the IID listings, and ● the fields that we would ordinarily not need for standard interpretation of the IID records. dosage forms?”
Raghuram concluded her remarks by stressing the Zuk took Silverstein’s point. “I look at the polymers that opportunity for industry to work up front with CDER make up the device and I wonder, do we want to talk about on how the IID should interface with the excipient the maximum potency? It doesn't seem really appropriate. issues related to the review of drug delivery systems. This is the system that we have now, but I think we need to look more carefully at how we want to represent these “This is still in its infancy, so we do not have to be in the dosage forms, because I think a lot of the information seems position in which we have thousands of records, which we inappropriate.” have to go back and clean up if we do it right now. And I think we have got many people with lots of experience that As an example, Raghuram highlighted the issue of addressing can collaborate and contribute to this.” the formulation of an implantable without connection to the API with which it is compatible – “especially if it is controlled How excipients are evaluated for these emerging dosage release,” Ulman added. forms “needs to be a transparent process, so that everyone has a clear understanding,” Raghuram maintained. In turn, Zuk pointed out in response that this is true with any “establishing clear guidelines and clarity will really go a excipient in the database. The IID “is just a list. It does not long way in helping people move forward in these new mean that the amount of excipient is appropriate for your emerging areas.” product. It is just a starting point and it is really not an evaluation. The evaluation has to be done by the applicant.” Planned FDA IID Guidance Could Bring More Clarity Including MDIs and Collapsing Dosage Forms Draw Comment Dow Corning Health Global Regulatory Compliance Manager Kathy Ulman led off the discussion that followed The conversation turned to two other concerns Zuk had the remarks by Zuk and Raghuram by commenting on addressed in her talk: ● the inclusion of the maximum daily the formulation complexity of transdermal patches. She intake (MDI) as part of the identification of excipients in the noted that along with the adhesive, the backing layer and IID, and ● the collapsing in the number of dosage forms the release liner that Zuk had mentioned, there are often delineated in the IID listings. [Editor’s Note: For a more enhancers used to help advance the delivery of the drug, in-depth review of these issues as part of Zuk’s IID update
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AUGUST / SEPTEMBER 2016 14 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 presentation and subsequent discussions at the GPhA/FDA will probably do, she said, is base the maximum amount May generic drug CMC conference, see IPQ July 31, 2016.] on what the agency has seen in the newer applications – an approach, she acknowledged, that is not going to be perfect. The OPQ official had noted in her talk that while the IID currently lists the maximum amount of an Schoneker asked Zuk to comment further on the inactive ingredient per route/dosage form, listing consideration the agency is giving to collapsing the the amount of each excipient on an MDI basis was dosage form categories in the IID and taking a more a goal. An audience member asked if industry could route-of-administration approach. “I think it would expect the top 20 high-volume excipients to be simplify how a lot of people use the IID,” Schoneker included in the first phase of the MDI listing. maintained. “All they really need to know is that maximum for a particular route and not the dosage Zuk responded that the agency can identify which form amount.” excipients are used most frequently and prioritize them for MDI inclusion. However, she noted, the older applications Zuk responded that “what we would like to have, when we feeding the 13,000 IID listings did not have an MDI, and restructure the IID, is a collapsible list, so that you can see the going back and calculating them would be a lot of work highest level per route of administration, which is really the with unclear value. safety issue and not the administration. If you want to know all the different dosage forms and the different granularity Since at least half of the entries in the IID come from then you can see that. Right now we do not have that, but applications that were approved after 2000, what her office that is something we would like to have.”
LUBRIZOL’S MEERA RAGHURAM ON EVOLVING THE IID FOR DRUG DELIVERY DEVICES
The concluding session of the 2016 IPEC-Americas/ExcipientFest Conference explored the challenges facing FDA in addressing excipient usage and IID listings for emerging dosage forms. Following OPQ IID Working
Group leader Susan Zuk to the podium, Lubrizol Life Sciences Global Regulatory Affairs Manager Meera
Raghuram, who chairs IPEC-Americas’ Regulatory Affairs Committee, focused on the issues for drug delivery devices such as transdermal patches, metered dose inhalers, nasal sprays, and implants.
We all heard Susan’s excellent presentation on the agency’s efforts with the IID. I am going to take you on a ride into the future and look at a different slice of the IID. I am going to talk about novel dosage forms, and my focus today will be drug delivery devices and implantables.
You may ask, ‘why should we care?’ I am here to convince both the regulators and the industry of why this is the future. I think this is where IPEC as an organization and the regulators should be working in a collaborative way. As Susan said, the intent of this presentation is to stimulate discussion.
The Drivers
Why are drug delivery systems and implantables important? I am telling you that this is almost a revolutionary opportunity in dosage forms moving forward. They offer targeted therapies for targeted systems. ● One of the advantages is that you can have a lower level of API in an implantable that is targeted and with less adverse effects. ● They are also increasingly being used in chronic applications as chemotherapy release agents, depression, and ADHD. ● Patient compliance: You may have younger patients or you may have older folks where remembering to take a few tablets or other dosage forms everyday can be a challenge.
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AUGUST / SEPTEMBER 2016 15 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
● And also one of the most important things is that, as patents are expiring for blockbuster drugs, folks are looking for new ways to repurpose them. Many of us are familiar with the 505(b)(2) pathway. That is where some of these drugs that may have been used in OSD [oral solid dosage] applications are going into implantables. And excipients play a major role in this area.
So these are some examples: implants for prostate cancer, uterine fibroids, and then you have hormone therapy for contraception.
You know this article is very recent and maybe a lot of people have read it. [The article appeared in the Journal of Science Translational Medicine.] Microchips were implanted into the bone to deliver targeted dosage. And what they found is that they can do delivered doses over an extended period of time and it was more precise then injectables. This is where the technology is going, and we need to take the IID along with us here.
Design and Formulation
So I am going to briefly discuss this, because this is relevant to the IID and what is captured there. In looking at implantable systems, drug delivery devices, usually you have to make two types: ● One is a matrix form where the API is impregnated into the polymer. Usually it is a hot melt extrusion process or it is dissolution and solvent casting. Basically you have a polymer matrix with the API in it, and you implant it, and it releases the drug over some time period. ● The reservoir system is really a drug core, a hollow core, and then you have an outer release membrane that controls the release.
And these systems are already captured in the IID. That is why I think it was important for us to look at it.
So where are excipients used in drug delivery devices? Well, they are already there in intravaginal rings, in subcutaneous implants, bladder implants – the list is really, really long.
And then polymer materials: Now this is not an exhaustive list. There may be others. These have been used in medical devices for a long time. And these are now becoming excipients…. These bring up new regulatory issues related to excipients.
Flexible Delivery System Design
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AUGUST / SEPTEMBER 2016 16 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Now, let us briefly review why drug delivery systems are important for us.
When you look at combination products, how do you determine if it is a device or drug? It is fairly simple – I am not going to go into all the complexities – but really the primary mode of action. What the agency looks at, is the device part responsible for the primary mode of action or is it the drug? So briefly if you have a drug that has a therapeutic effect, it is going to be reviewed by CDER and either it will be an NDA or ANDA pathway. But if it is the device function that is primary, it goes to the device side.
So I am going to focus here. We had a lot of discussions on GMPs and what is a drug: any component of a drug is a drug.
Implantables
And so when you are looking at these implantables you have the API, but what is the rest? The rest is inactive ingredient and excipients. So your hollow tube that you are implanting is an excipient.
Now when you look at excipients and drug delivery systems, there are slightly different things you look at: ● Implantables have to be biocompatible. ● You look at leachables and extractables. ● Will it impact the stability of the API? How will it interact? ● Will the drug adhere to your tube or implant? ● The ability to do controlled release of the API. ● And can you process it at relatively low temperature. So the IID is critical for polymers in drug delivery systems. One of the things that we have to look at is, what does precedence of use mean for drug delivery systems? How is the agency going to review this? And what does it mean when you look at records in the IID? I don’t know how many people have looked at these records, but they are currently in the Inactive Ingredient Database.
So the route is implantation. The dosage form is a rod. Where is it implanted? How big is the rod? Is that important? What is the chemistry of the rod? Then what unit do you give this rod? And if somebody is formulating this drug delivery system do they say: ‘Okay, this rod was used. It is in the IID. So maybe I can use the rod with the same dimensions and it is going to be okay with the Agency.’ We do not know, right?
And so there are many intrauterine devices. By their very nature, you are saying ‘a device.’ Why is a device in the IID? Because it is being viewed as a drug. The agency is reviewing it as a drug.
So there are many interesting examples, and I would urge folks here to go and take a look: subcutaneous implants, topical disk. There was an implantation wafer. I don’t know if it is really a thin wafer-like implant – interesting. Topical disc/dressing, transdermal. Susan you gave me a real good segue. And I am going to come up with some questions on transdermals. And of course you have vaginal implants and there may be others. Drug Delivery Records Currently in IID
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AUGUST / SEPTEMBER 2016 17 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Transdermals
So Susan really talked about the transdermals. But I want to bring up some additional questions.
You have the backing layer. You have the adhesive reservoir, which has the API. I would say this layer, which has the API, could be the excipient. Because the release layer and the backing layer never really come in contact with the skin. They really don’t have a function other than being the release layer and the backing layer.
When we look at records in the IID, you see this polyester. I think this record probably belongs to the middle layer, the reservoir, or adhesive that has the API. But one thing we don’t know is what does this represent? Is it the release layer? Is it the backing layer? Or is it the adhesive film?
And then you see some of the other records here. What is probably happening here is that some of these are excipients that are part of the drug that is in your transdermal system.
So if you think about it, you are looking at two different excipients in a drug delivery system. One is the excipient that came with the drug, but the other is the excipient that is causing the drug release in a drug delivery system.
Transdermal Records in IID
So here are a couple of questions – I think you may have answered a couple of them, Susan: What is captured in the IID? The backing and release layer really do not contact the skin, right? But [Dow’s Kathy Ulman] brought up a good point: ‘Is it relevant to the reviewers?’ We need to know.
We have learned that FDA is working on a guidance document on the IID. And some of these questions would be nice to be answered, because if there is a disconnect between what the reviewers are looking at and what is in the IID, that is a concern for us.
Again, should there be differentiation between the excipient in the drug product and your delivery system or an implant that is acting as the excipient? I think Susan you answered this question, right? [Are the listed amounts relative to units per patch or the API?] It is per patch. Implants
Here are a few more examples, and then we will open it up to questions. So look at some of these records here. This is a tubing. There is no potency. I am not sure why. But then, there is another copolymer here that has a potency value. Again, as I mentioned before, how do you interpret that?
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AUGUST / SEPTEMBER 2016 18 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
When you look at the route – implantation, a rod – it is not telling us whether it was a bladder, heart, or kidney implant, or if it was just a simple subcutaneous implant.
So those things need to be clarified. This is another interesting one. This is an EVA [ethylene vinyl acetate] copolymer that is used in a vaginal insert. Look at the high amount. So I think it is most likely the weight of the vaginal ring itself that has been captured here.
Example of Records for Implants Currently in the FDA IID
As you look at others, here the hydrogel polymer: I am thinking this was the excipient in the drug formulation. But this is just not clear in the IID.
And this goes back to our bigger question, right? As CDER is reviewing the drug delivery systems, how are they looking at the excipients? How are they reviewing it? What are the rules going forward for precedence of use, and also safety of these excipients? That is really important to review.
The Path Forward
So here is my summary. I think this is a great opportunity for organizations like IPEC and for the regulators to collaborate. This is still in its infancy. So we don’t have to be in a position where we have thousands of records, which we have to go back and figure out and clean up if we do it right from now. I think we have got many people with lots of experience that can collaborate and contribute to this.
Again, polymeric materials, which are now excipients – rods and disks and implants – they have a long precedence of use in devices. They are not necessarily new. That again goes back to the review policy that the agency has.
We really need to look at how the excipients are evaluated and captured. I think there needs to be a transparent process, so that everybody has the same understanding.
Establishing of clear guidelines and clarity will really go a long way in helping people move forward in these new emerging areas.
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AUGUST / SEPTEMBER 2016 19 Will you play on our Team? IPEC-Americas is part of a global federation that brings together manufacturers, distributors and users of pharmaceutical Excipients to set-the-bar on quality standards. We strive to achieve harmonization of pharmacopeial monographs and cGMP-regulatory guidelines for world-class qualification of Excipient suppliers.
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IPEC-Americas is the industry association that develops, implements, and promotes global use of appropriate quality, safety, and functionality standards for pharmaceutical excipients and excipient delivery systems. MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
EUROPE Protein Sequence Variants, Process Development and Spec Setting Are Generating Queries from EU Biopharmaceutical CMC Assessors Protein sequence variants have been generating more controlling the process and setting the specifications “can questions among European CMC regulators in reviewing become quite messy.” monoclonal and recombinant product dossiers – joining process development/validation and specification setting Cautioning that reviewers are seeing “more and more” of the as areas where they are often not finding what they need to variant problem and that it is also surfacing during scientific complete the review. advices, the HPRA assessor suggested to the conference attendees that it is “something to think about earlier in An informal survey of 20 recent biotech product CMC development rather than later.” reviews by Ireland Health Products Regulatory Authority (HPRA) Pharmaceutical Assessor Sean Barry supported his During the panel discussion that followed the own experience that the amino acid sequence variants has regulator presentations, Barry was asked by Lilly’s become a recurrent focus of questioning. Michael De Felippis to elaborate on the variant issue and “whether or not there will be requirements for Barry reported on the findings of his survey as part data in the dossier in the future?” of an “update from the EU,” which he provided at the opening regulatory plenary session of the 2016 Barry reiterated that the reason it is getting more attention CASSS CMC Strategy Forum Europe, held in Paris is presumably “based on the fact that mass spec has become in May. much better at picking out sequence variants.” As alluded to in his presentation, he said, “I am sure if we took products Also providing updates on their respective agency activity on the market for many years and ran the more modern mass in the biopharmaceutical CMC arena were Center for Drug spec on them we could pick out sequence variants that have Evaluation and Research (CDER) Office of Biotechnology been there.” Products (OBP) Review Chief Sarah Kennett and Japan The situation is not like a normal impurity, “and it is quite Pharmaceuticals and Medical Devices Agency (PMDA) tricky when you get to MAA and then you realize that there Office of Cellular and Tissue-based Products Principal are a sequence variant or variants, or multiple sites where Reviewer Yasuhiro Kishioka. amino acids are changing, and it is actually a pool of different The three presenters addressed a similar range of front- monoclonal antibodies.” The question then becomes “what burner CMC issues for biotech products, including has the patient been exposed to – what percentage of certain problems in recent biotech product applications, their ones and combinations of sites? And how do you build a respective agency’s accelerated development and review control strategy around it?” programs, and the shifting approaches and expectations for The advice from regulators “would normally be if lifecycle management. you could remove it, that is best…. But if not, it needs Regulator Advice is to Address Variants Early a really careful control strategy. The best way is to look at it early in development and try and make “No doubt there are products on the market that have sure there is not any sequence variance, and then sequence variations that were not picked up at the time if there is, you have to really reengage early with because mass spec technology has come along so much,” the regulators to try and figure out what is the best Barry said in his presentation. Nevertheless, the issue is approach to deal with it.” now “quite common” and has been causing difficulties during recent marketing authorization application (MAA) If the issue continues to surface as an observation in reviews. applications, it may have to be addressed more formerly in guidance, Barry said. However, he noted, “there are plenty In terms of remedies, he suggested that “there are good of papers out there now, and I am sure that most companies error tolerance searches now for mass spec data where are aware that it is a problem, even at the clone stage, that you can pick out low-level sequence variants early on in you get many sequence variants, and there are all sorts of development rather than reaching the problem in late weird monoclonal ways it can happen.” The objective should stage development” – when dealing with the issues around be “just really to minimize it.” WWW.IPQPUBS.COM
AUGUST / SEPTEMBER 2016 20 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 Process Development/Validation also Prompts How specifications are clinically qualified is Queries something that seems to be getting more focus, he said, adding that a justification is expected Along with protein sequence variants, Barry reviewed the when specifications are outside the clinical batch issues that “keep popping up” in centralized biotherapeutic range. MHRA does incline toward allowing wider dossiers submitted to EMA regarding process development/ specifications in clinical trials, which broadens the validation and specification setting. range of what then is clinically qualified in future Common questions in the process development section specification setting. (S.2.6) of the application, he noted, relate to the control strategy, designation of criticality and risk-ranking A low number of clinical batches and the role of prior approaches. knowledge in this context, such as in the biosimilar case, presents issues that need to be teased out, Barry noted. For These S.2.6 questions involve inadequate/unclear biosimilars, leveraging ranges in the reference product, explanation of: ● how the criticality of critical process which is clinically qualified by definition, can be a way to parameters (CPPs) and non-CPPs were decided ● why handle the problem, he advised. the cut off in a risk ranking approach was chosen ● how small scale studies underpinning the control strategy are Widening specs due to assay variability also can raise representative of the full scale process, and ● how the range issues when the connections are not clear. While reviewers of each proven acceptable range (PAR) is justified. Barry are “much more comfortable and used to seeing statistical advised firms to avoid using non-ICH terminology where approaches to setting specs,” the chosen statistical approach possible as it makes the communication process more does need to be adequately justified, the HPRA assessor difficult. cautioned.
During the panel discussion, Barry was asked to Changing specifications post-approval is also “becoming comment further on the issues around the control more common now possibly than it was,” Barry said, and strategy and risk management, and how tests can be there are “more variations now to remove specification tests” leveraged in making the assessments. and put the control in process or remove the specs entirely. Among examples are potency and purity assays with data For example, when risks across different products are being modeled from process knowledge. These changes may be considered, a forum participant said, sometimes the basic more possible as manufacturing experience increases post- physical/chemical properties of the proteins “can already approval, he pointed out, allowing predictive models to be indicate the risk level within our process.” Properties used and “good correlation” to be made “between analytical like hydrophobicity, “can indicate the risk we have in the surrogate tests and the one that you want to change or downstream processing during purification, and even the remove.” fill/finish process.” Barry depicts this “regulatory relief” as a quid pro quo for Barry agreed with her that this kind of physical/chemical investing in and gathering greater knowledge of the process. property of the protein can be considered when assessing risk, along with biobliographic and other prior knowledge. In his review, Barry found that major objections The challenge is “just explaining it – why you think that were cited for about 15% of monoclonal dossiers because of that physical/chemical property the risk is a and 30% of recombinants. The average number of certain way. It may be obvious, and maybe it is not so questions overall was 60 for monoclonals and 80 for obvious. So it is just really a matter of trying to explain your recombinants in the cohort. risk assessment and why things are considered a certain risk or not. As I kind of mentioned before, sometimes it can seem He commented that the onus is on regulators to explain more a little bit random if it is not well-described.” clearly to industry what they want when the same issues The Balancing Act of Specification Setting continually resurface. It is also about industry explaining more clearly to regulators why conclusions were drawn. Setting specifications, the reviewing official summarized in his presentation, involves a balancing act – with clinical “A lot of times,” the Irish regulator commented, the solution qualification on the one side of the see-saw, and historical is “just to tell a story. It is just an explanation and does not batch data, manufacturing consistency, statistical analysis even rely on a lot of extra data. It is just an understanding and prior knowledge on the other. and the dialogue so we are both on the same page.” WWW.IPQPUBS.COM
AUGUST / SEPTEMBER 2016 21 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 PRIME and Process Validation Also on EU Forum Hones in on Accelerated Pathways and Biotech Agenda CMC Impact
Along with the recent trends in CMC questions from EU The accelerated development and review initiatives in the regulators, Barry’s presentation at the regulator plenary US, Europe and Japan, and their implications for the quality management and regulation of biotech products across their session encompassed: ● EMA’s priority medicines (PRIME) lifecycles, were in the forefront of the discussions throughout and adaptive pathways approaches and how they relate this year’s CMC Strategy Forum Europe. to each other (see IPQ Sept. 9, 2016) ● the CMC challenges presented by these accelerated development approaches and Central to the discussions that took place at the Paris how they can be dealt with by industry and regulators, and meeting were the adaptations to the traditional approaches ● the implications of EMA’s recently published guideline to development and manufacturing and their regulation that need to be made to allow CMC to keep pace when early on process validation for biotechnology-derived active access timelines are in play. substances. [Barry’s presentation is provided in full below.] The discussions started at the traditional In going through the CMC considerations for “satellite session” sponsored by the European the PRIME scheme, he acknowledged that they Biopharmaceutical Enterprises (EBE) during the represented his “own opinion, as we have not gone morning before the forum itself began (IPQ May through applications yet – it is still in the very early 28, 2016) and continued at the plenary international stage.” regulator panel that led off the forum.
Using the regular EU scientific advice procedures, the Joining Barry, FDA’s Kennett and PMDA’s Kishioka on the panel during the probing discussions that followed their HPRA official pointed out, PRIME offers an opportunity presentations were CBER Division of Viral Products Deputy for the applicants: ● to discuss plans for process validation, Director Robin Levis, Health Canada Center for Evaluation scale up, and stability “quite early on” ● to get “continuous of Radiopharmaceuticals and Biotherapeutics Regulatory feedback on pharm development and process validation Scientist Anthony Ridgway, and EMA Quality of Medicines activities,” which is important since “there may not be very Principal Scientist Pascal Venneugues. many batches to work with,” and ● generally “to engage Breakout sessions were then held over the course of the forum with regulators on areas which are challenging” both for the to hone in on: ● leveraging continuous process verification applicants and regulators. to facilitate the faster patient access ● the Q12 dialogue on established conditions ● the evolution of post-approval “Because we have this longer lead-in time with scientific change protocols in biopharmaceutical lifecycle management advice,” Barry advised, sponsors and assessors can “come ● the regulatory and scientific challenges of combination to an understanding of how best to deal with…these product development, and ● innovative approaches, tools difficult questions before filing, so hopefully all these issues and techniques to streamline the manufacturing and control are ironed out.” development process.
EUROPE BIOTECH CMC REGULATORY UPDATE FROM HPRA’S SEAN BARRY
At the opening “regulatory updates” session of the CASSS CMC Strategy Forum Europe 2016, HPRA Pharmaceutical Assessor Sean Barry provided the European update. Barry’s talk focused on ● EMA’s new PRIME scheme ● the Adaptive Pathways program ● CMC challenges presented by these accelerated development approaches ● the implications of EMA’s recently published guideline on process validation for biotechnology-derived active substances, and ● recent trends in CMC questions from EU regulators.
This is quite a broad title for a talk – “Regulatory Updates in the EU” – so I will touch on a few different topics.
A quick outline: ● I will discuss briefly the recently launched PRIME scheme ● a bit on adaptive pathways and what the CMC challenges are for those ● and possibly you saw those a little bit with the new process validation guideline – but (Netherland Medicines Evaluation Board biological product assessor) Martijn van der Plas will discuss that in a bit more detail in a later talk as well. ● I will switch focus in the last bit of the talk and talk about recent trends and what we are seeing in terms of dossiers and quality questions in the EU.
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PRIME
The PRIME scheme: I am sure many of you are aware of it, but just to give you a bit of background. It launched just in March of this year, 2016. The idea really is to provide enhanced interaction and early scientific breakthrough support. And I want to highlight that they are enhanced and early – which are the real drivers of the PRIME scheme.
The idea between regulators and industry is to optimize development plans, which will hopefully speed up the evaluation process. How this is done is that a rapporteur is assigned early during development. The idea is to provide continuous support throughout the development cycle and to help build knowledge. Practically, this would start with a kick-off meeting with multidisciplinary participation with EU, which would discuss the proposed development program.
There would be an enhanced scientific advice, and importantly is that key development milestone. In the traditional way, you come for your scientific advice, you go away and you take the scientific advice on board, and you may or may not come back. With the PRIME scheme, the idea is that there are milestones along the way. So you apply for scientific advice, and you come back to us with the outcome of what you have implemented, and then you go on from there. So there is enhanced interaction. Hopefully, this leads to the optimization of the benefit/risk data and will enable accelerated risk assessment.
You have some visualization in three different areas: ● to reinforce scientific and regulatory advice and to [support] the early interaction with multidisciplinary expertise. One of the key areas here is parallel scientific advice with HTA bodies. We know as regulators a lot of time, at least with clinical data, what we want for a clinical trial to show efficacy is not always the same as what an HTA body wants to show for real world use in terms of what payers want. Also, the applicants would be advised on milestones as you go along. So it is a very close interaction.
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● In the middle there we have optimized development. So we focus on efficient development with robust data generation – to understand early what the regulators would like to see in the MAA, so you know by the time you get there that the data you have is the data that the regulators want. ● At the end, the whole idea behind it then is that hopefully that will enable accelerated assessment. Because of the knowledge that the rapporteur and the agency has throughout the development lifecycle, by the time it comes to MAA, there is a better knowledge of the process or the product – the process is being guided along the way, so hopefully, the applications will be more streamlined and easy.
In terms of when you can apply to be part of the PRIME scheme: SMEs and academia can apply a little earlier — basically at the proof of principle stage, with some very early first-in-man studies. And for every other sponsor, it will be proof of concept stage, so you would have some early trials done. As I said, the CHMP rapporteur is appointed quite early during the lifecycle of the PRIME scheme.
Who can apply? It is applicable to medicines in indications with an unmet medical need and where there is a therapeutic innovation. Once you make an application to PRIME, the scientific advice working party discusses that application, and within 30 days will decide if the medicine and the development plan is eligible.
What would you need to apply for it? Basically data to support the claim that the product has the potential to bring a major therapeutic advantage to patients.
Importantly, the outcome of whether or not medicines are successful will be published, but not the name of the medicine – just the number of recommendations adopted will be published each month, so you can see how many medicines are being taken on board by the PRIME scheme.
If the medicine is unsuccessful in getting into the PRIME scheme, it is no reflection on the development scheme. By all means, you can come back later on during development and still apply for accelerated assessment prior to filing.
So the general outline of the PRIME scheme: We are hoping that through this enhanced interaction that really it will streamline the entire process and make the assessment a much easier process for everyone involved.
What are the benefits? ● You have better informed development plans ● regular checkpoints, which you do not really have at the moment ● more streamlined type of scientific advice ● hopefully leading to the improved quality of marketing authorization applications, and finally ● a shortened timeframe for review.
In terms of the CMC considerations: This is really my own opinion as we have not gone through the applications yet. It is still in the very early stage. ● [Using the] regular scientific advice procedures, it is an opportunity for the applicants to discuss plans for process validation, scale up, stability quite early on. ● It is an opportunity to get continuous feedback on pharm development and process validation activities, because, of course, if there is an accelerated assessment, there may not be very many batches to work with. This we know is going to be a problem for certain aspects, but because we have this engagement all along the way, it is an opportunity to discuss this very early on. ● Really it is an opportunity to engage with regulators on areas which are challenging – challenging for the applicants and also challenging for the regulators. Because we have this longer lead-in time with scientific advice, we can really deal with these difficult questions and come to an understanding of how best to deal with them before filing, so hopefully all these issues are ironed out.
That is just a quick overview of PRIME and what might the possible CMC considerations be. And no doubt we will be hearing more about it as the process goes on and as more products are taken up by PRIME.
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AUGUST / SEPTEMBER 2016 24 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Adaptive Pathways
Switching focus slightly, we have heard a lot already about the adaptive pathways. As you know, it is about treatments in high medical need areas where collection of data via traditional routes is difficult and where large clinical trials would unnecessarily expose patients who might not benefit from the medicine.
You can look at it as being based on three principles: ● There is iterative development, which is important. You can get an expansion of the target population. So you can initially get approval in a small patient population and then it expands later on – or possibly through progressive reduction of uncertainty, where you maybe get conditional approval using surrogate markers and then this is validated clinically post approval. ● The progressive gathering of evidence through real life data: That is probably something we don’t have much of at the moment – how the real life data, how the medicine behaves in the population and the clinic, how does that feedback into the regulatory process? It is there now, but it has not really been formalized. This is quite an important piece of the jigsaw – data post-approval. ● Finally, then, there is early involvement of patients and health-technology assessment bodies involved in the discussion of the medicine’s development. Because part of the idea of the adaptive pathway is to help real-world use of the medicine, and part of that does involve payers and HTA bodies.
Hopefully this will lead to the optimization in the use of regulatory tools and, importantly, flexibility. The evidence gathered should address not only our issues but also [those of] the HTA bodies. You may have seen some studies on this, particularly in clinical trials, where what a regulator wants and what an HTA body wants are quite different. But actually when you get parallel scientific advice, you can come together and decide on a trial that suits everybody needs. So actually we reduce costs quite a lot, because one trial design will suit everybody.
It is important that there no real change to the principles of benefit versus risk, because that is how we are still thinking. It is just that I guess as regulators we are changing the balance of where the uncertainty lies. We have a bit more uncertainty now pre-approval and hopefully that will start to be reduced post-approval. So for regulators, there is a change in mindset, and something I guess that we will have to become more familiar with.
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AUGUST / SEPTEMBER 2016 25 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
You have probably seen this figure quite a few times. You have the two options on the top where you get a widening of an indication, where you get the first approval in the subpopulation, and then with the real world data, you get a second approval and a more widened indication.
At the bottom, as I spoke about, the reduction of regulatory uncertainty, where you get approval in a patient population based maybe on early surrogate markers and then that is later on validated in real world patient data. That is generally how we view the adaptive pathway.
The adaptive pathway obviously makes perfect sense clinically, but it leaves us with a lot of challenges, particularly from the CMC point of view. We hear a lot about this. It is a recurring theme in how we deal with this as industry and regulators.
● One of the things is that there may be very few batches manufactured. If it is for a small patient indication or there are only very trials done, there may only be very few batches that are manufactured or available. ● How is process validation going to look? Concurrent process validation? Post-approval validation? ● How to set specifications based on few batches? That is a real challenge. There is no easy answer, But, again, hopefully you can use, as we have heard about earlier, some prior knowledge can help in that area. ● How will stability studies look? They may be ongoing, and we probably need to identify stability indicating assays quite early on in development. ● There might be less time involved in scale up and optimizing the manufacturing process. That might have to be done later. ● And ideally, maybe the analytical methods would need to be validated early in development.
So there are quite a few challenges there. What are some of the solutions we have? ● I guess one of the solutions as regulators is that we are going to have to shift some or our emphasis to post approval and be quite comfortable with that – that we won’t have the amount of data that we currently have pre-approval. Some of that will shift to post-approval. ● A lot of this can be captured in the post-approval change management protocol, which we already have. ● There will need to be a well thought out plan in the MAA – how the post-approval data is going to look, so we as regulators will approve the plan for how the information is going to come in and what we want to see post approval.
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AUGUST / SEPTEMBER 2016 26 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
● There will be greater emphasis on lifecycle validation rather than just pre-approval validation. ● Again, greater reliance on prior/platform knowledge. ● Maybe more leveraging of data from early development lots. Comparability issues come in here. ● And maybe there is also room for ICH Q12 approaches to product lifecycle.
So there are some of the solutions, not all of them. And what are some of the questions? ● Where does the balance lie with the limited data that you are going to have versus regulators acceptance of risk? This is always an issue for regulators – benefit versus risk. Now you have less data to work with, the risk is still there, where does the balance lie? This may involve a change in mindset for us. ● Can specifications and control strategy be reassessed post-approval and how will that look with the site and the post-approval change management protocol? What tests are going to be done? What studies will be carried out? But then when that data is brought back up, what specifications will change? ● How will the control strategy change? Those are issues that we have to deal with and that it still an open question. ● Is there flexibility to adjust the control strategy and the specifications once the validation is complete? ● How will we deal with post approval extension of shelf life? ● Leading on to my next slide, how will the process validation guideline that was just recently published help in terms of post-approval process validation? I would argue that in that guideline, it is already being thought of that this type of validation is going to become more common.
Process Validation Guideline and Accelerated Development
This is a nice figure prepared by [Danish Health and Medicines Authority reviewer Nanna Kruse]. I am not going to go into a discussion of the entire process validation guideline. Just a little of how it might affect the adaptive pathway – just go through quickly how we view process validation now.
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AUGUST / SEPTEMBER 2016 27 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
At the top you have the entire process validation broken down in the left into characterization which is your development and your small scale studies and evaluation. In the middle, which would be the area of our sort of traditional process validation, now broken down into traditional verification, continuous process verification, and concurrent verification. Then on the right hand side we have ongoing process verification, which is also called continued, but we get confused between ‘continuous’ and ‘continued,’ so we call it ‘ongoing.'
As I said, [Martijn van der Plas] will probably address this a little bit more later on: How will the process validation guideline help with the adaptive pathway – in any situation, maybe accelerate approval with a few batches and limited data?
Already written into the guideline, we know we are going to accept prior knowledge probably more and more than we used to, and how can we use it as supportive information? And [in] justification of operating ranges, use continuous process validation with inline tools and so on? Use of PAT and multivariate statistical process control…is something we will have to become more familiar with. And these really are enablers of continuous process verification.
A lot of it is based on the level of process understanding and our understanding of your understanding, which is difficult to grasp. Is there a role for concurrent validation? Possibly, but really it is in exceptional circumstances, maybe, where there is a very strong benefit/risk ratio. In that case, it may be acceptable not to have a complete validation program before routine production. But again, it is probably in exceptional circumstances.
Products under accelerated programs can leverage ongoing process verification, which would be done to some extent anyway. There is the opportunity to provide a protocol that indicates how the process knowledge, the control strategy and the characterization – how these will all be used to assess the product quality throughout the lifecycle as part of ongoing process verification.
For this, protocols will need to include tests and acceptance criteria that will be used to further demonstrate that the process remains in a validated state. This is moving to not having all the process validation data before final approval, but having a protocol, so that we as regulators and industry agree how that is going to look post approval.
Recent Trends in CMC Questions from EU Regulators
That is looking forward, I guess, in terms of PRIME and adaptive pathways. To change the flavor a bit, what is the situation now? I thought, this is how I feel for the poor industry when they get our list of questions. They are just bombarded with lots of questions that you may think are completely unnecessary, and too many.
I thought I would just have a look [at] what are the trends in what we are asking, what we are looking for, and what are the common areas of questions where there may be confusion between the regulators and industry?
This is not official data, this is just me having a quick look – looking at some of the dossiers we got last year. This is based on around twenty dossiers. I just, for convenience, broke them down into monoclonals and recombinants. I did not really include advanced therapies or vaccines or anything like that.
We see, for monoclonals, about 15% of the dossiers with major objections. For recombinant proteins it is maybe 30%, but it is based on small numbers. So I would say that major objections are the exception rather than rule. At least in these, there is no real particular area that major objections are focused on. New manufacturing process description, potency assays, process development, comparability.
On the right there you can see the number of other concerns, other questions. For monoclonals it averaged around 60 or so, and for recombinants slightly more, around 80. In general, recombinants seem to have a few more questions, although that might be just based on small numbers. I don’t know if this is a true reflection.This is just data from last year.
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AUGUST / SEPTEMBER 2016 28 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Looking at those questions, where are the areas that would get most questions? If you just look at the top, on the drug substance – this is just an average number of questions: process development, process validation, specifications. For the drug product, I stuck in there adventitious agents – also stability, specifications. I am not going to go through all of this. That would take quite a longer talk.
Three of the most consistent areas for questions: So what sort of questions are we constantly asking them? I guess there is a miscommunication of what we want to see as regulators in the dossier. It would be process development [S.2.6], process validation [S.2.5], and setting specifications [S.4.1, S.4.5, .5.1,P P.5.6].
Common Process Development Questions
If we look at the process development questions, what are the common questions we are asking? Three of the greatest relate to the control strategy, designation of criticality and the risk ranking approaches: ● How was criticality of CPPs/non-CPPs decided? What is your understanding of why a process parameter is critical versus non-critical? Sometimes it is difficult for us to figure out why things are registered as critical versus non-critical. ● When using a risk ranking approach, a lot of times it is difficult to understand why a certain cutoff was chosen – so a standard risk ranking of superiority versus occurrence or so on. If you multiply them, there is a number, and above that threshold it will be critical. Sometimes this threshold can seem arbitrary. So sometimes it just needs a little bit of explanation as to why that threshold was chosen. ● Something we see a lot of – I have seen this in the dossiers: There is going to be tons of small scale studies. But really the data to show that the small scale studies which underpin the control strategy are representative of the full scale is quite important. ● Another area is to make it clear how the range of each PAR is justified. In the dossier, there are a whole lot of PARS. For some, it is very easy to see in the small scale studies that, yes, okay, maybe the edges were challenged, or so on. That is how the power is justified. But for a lot of them, it can be maybe sometimes a little difficult to see how the PAR is justified. ● Some dossiers use a lot of non-ICH terminology, which can get a little bit confusing if there is quite a complicated control strategy. So ICH terminology helps us simple regulators to understand what is going on.
Common Questions Around Setting Specifications
So that is process validation and so on. In terms of setting specifications, this is my idea of how we deal with setting specifications. Some people might disagree. On the one side, we have clinical qualification. On the other we have historical batch data, manufacturing consistency, statistical analysis, and I guess I really should put prior knowledge in here as well. It could be another circle we could include in here. ● We are constantly asking how specifications are clinically qualified. It seems to me – I don’t know about others who have maybe been at BWP [Biological Working Party] longer – but maybe it is something we are focusing on more now than in the past: How are specifications clinically qualified? ● When the specifications are higher or lower, outside the range of any batch that was used in the clinical study, a justification needs to be provided – really just to say what batches were used in the trial, this level of whatever the specification is was used in patients, it is safe, it is fine. That is clinically qualified. If not, if it is wider, there needs to be some justification. ● This was spoken about briefly earlier on. [Sweden Medical Products Agency’s Mats Welin] was asked a question on it. If there is a choice of batches available during the clinical trial, could you consider which batches should be used in a trial with an eye to how to set future specifications? As we have said, the clinical colleagues may not agree with this. I can only speak for Ireland. When we approve clinical trials, we are much more amenable to approving wider specifications than we would at MAA, because we see the connection I guess. With a clinical trial if you [are told] you need narrow specifications, it is then unfair to come back at MAA and say ‘why didn’t you clinically justify them?’ if you
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AUGUST / SEPTEMBER 2016 29 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
don’t allow wider specifications during the trial. I think from the quality assessor’s point of view, in the clinical trials, if a certain wide specification is allowed in the trial, there is the opportunity to hopefully clinically qualify your future specifications. ● How are you going to clinical qualify specifications when there is a low number of batches? That is difficult. Specifications need to be changed post approval. Is there room there for prior knowledge? This all has to be teased out. ● This is my only comment on biosimilars. It is a similar kind of idea: how do you clinically qualify specifications in biosimilars? Again, you may have a low number of batches. You may have just one confirmed trial. You may have no batch numbers. One of the ways there is to leverage the reference range of your reference product, because whatever data you have gotten from your reference range is clinically qualified by definition, because the originator is on the marker. ● What I have noticed a lot actually is you set a specification and widen it due to assay variability. This assay variability is sort of a catch-all as in, ‘These are the specifications. Well maybe we will add on 10 or 15% percent because the assay is variable.’ Really that would need to be linked to the actual variability seen during analytical validation. Because sometimes what you would see is maybe widening the specifications by 20% because of analytical variation. But then when you go in to look at the data for the assay, it might have a low CV of 2 or 3%. So there is maybe not that connection a lot of times. ● We are much more comfortable and used to seeing statistical approaches to setting specifications – so more comfortable than we used to be. But again, it just needs to be properly justified as to why the chosen statistical approach is the right one for your data set to justify the proposed ranges. That will link, of course, with the statistical range that you set for specifications and how that links in with the clinical qualification. So it is a mixture of things really.
We spoke earlier about how many things including specifications may need to be changed post-approval. How are we comfortable with changing specifications post-approval? I think it is becoming more common now possibly then it was. I may be wrong about that. But there are more variations now to remove specification tests – remove them to IPCs or to where the most appropriate area in the manufacturing process is to test – maybe not in the end, but if the data shows whatever step is the best place in the process to test. We are happy to have that specification moved in a variation to an in-process control, or even to remove specifications entirely, if the data supports it. I have seen quite strong data to support that.
For example, things we have seen: replacement of potency assays, purity assays, with data modeled from process knowledge. This may be difficult to do pre-approval. It is really post-approval when there are a lot of batches and you can get good correlation between analytical surrogate tests and the one that you want to change or remove. Predictive models have been used to good effect for this approach.
For me, that is the sort of quid pro quo for investing in and gathering greater knowledge of the process. You gain some ‘regulatory relief’ by having a greater knowledge of the process – that you can remove specifications because you know your process. It can be tested somewhere else and it will do the same job essentially. I think we are somewhat more open to discussion on this than in the past. That is just a personal opinion.
Protein Sequence Variants
One final kind of thing. This is a little bit left field, but it is something that I have kind of noticed, if we are thinking of trends. Maybe it is just me, but what I have seen quite a lot of, so it is kind of fresh in my mind, is protein sequence variations.
That can be caused by a lot of different things: point mutations, misincorporations, DNA rearrangements – all the different reasons for amino acid sequence variants.
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AUGUST / SEPTEMBER 2016 30 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
It is quite common, and no doubt there are products on the market that have sequence variations that were not picked up at the time because mass spec technology has come along so much now. Be that as it may, it can lead to difficulties at MAA. We have seen this with some products now.
Really, what remedies are there if there are these sequence variants in your product? It may be difficult to solely rely on changes to the mass or charge to pick it up later on in development. There are good error tolerance searches now for mass spec data where you can pick out low- level sequence variants early on in development rather than reaching the problem in late stage development.
Some mass-spec methods can miss sequence variations if there are sort of very small or large tryptic peptides. So you might do some deep sequencing or transcriptome sequencing of the cell line if it was a DNA or RNA problem.
Because the problem is, if sequence variants do persist into commercial manufacture, how they are going to be controlled? How can the specifications be clinically qualified? It can become quite messy actually if these sequence variants are found late in development. Trying to figure out what was done in trials, how you are going to control the process, setting the specifications – it is really quite difficult. It is just something to bear in mind that we are seeing more and more of, so something to think about earlier in development rather than later, I guess.
Conclusions
They are just some of the topics that I think are to the fore in the last year really. In conclusion, new pathways are now being developed to facilitate faster patient access to medicines. This is really where we are trying to go for the right medicines in areas of unmet medical need that will get the medicines to patients as fast as possible.
Through things like PRIME there will be closer interaction and dialogue throughout the development – not just random scientific advises and then an MAA, but it is that products are steered throughout development. And hopefully this will lead to faster review times.
There are more options for staged approval. Rather than just having an MAA or conditional MAA, now we have adaptive type of MAAs.
The new PV guideline outlines possible alternative process validation schemes. It is a very good guideline. We are now very much removed from just having traditional process validation. We are much more ready to accept, and comfortable with, new paradigms for process validation.
In some areas of the dossier there still remain common areas of questioning. As a regulator in meetings like this, if we see questions that are common in dossiers and are quite frequent, then I guess the onus is on us to explain to industry what we want, or if they keep popping up, what is it we are looking for, so you guys are not rained down with loads questions that you are cursing us with – and forums like this where we can discuss what we need.
A lot of times, as Nanna [Kruse] said, it is just to tell a story. It is just an explanation and does not even rely on a lot of extra data. It is just an understanding and the dialogue so we are both on the same page.
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AUGUST / SEPTEMBER 2016 31 The Parenteral Drug Association presents the...
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From April 6-7, expand your knowledge with education courses that will complement what you learned at the Meeting. Learn more and register at pda.org/2017AnnualCourses. MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 Procedures, Eligibilities and Goals of EMA’s Accelerated Access Efforts Are Taking More Concrete Shape The procedures, eligibilities and goals of EMA’s accelerated As such, PRIME aligns closely with FDA’s access approaches for new medicines that fill unmet breakthrough therapy approach, which also targets medical needs, including “Priority Medicines” (PRIME) extra agency hands-on support when early clinical and “Adaptive Pathways” (AP), have been taking more results indicate that the medicine may fill an concrete shape, informed by the European agency’s important gap in the therapeutic arsenal. growing implementation experience. PRIME does include an additional provision for support of Since March 2016, there has been a wave of EMA small and medium-sized enterprises (SMEs) and applicants releases on the different facets of its effort to from academia to apply at a still earlier stage of development when they have “compelling non-clinical data in a relevant give enhanced support for the development and model” providing “early evidence of promising activity,” approval of qualifying new medicines. The releases and first in man studies indicate adequate exposure and provide insight into the interrelationships between tolerability. SMEs and academia “can particularly benefit the components of the effort, and where the agency from earlier scientific and regulatory support,” EMA and industry are in implementing them. notes “since they often lack experience with the regulatory framework.” Setting loose the document flow was the meeting of EMA’s Committee for Medicinal Products for Human Use Based on a late 2015 draft and public comment, the March (CHMP) in late February. At the meeting, CHMP cleared 2016 document defining the scheme for “enhanced early the launch of PRIME, along with a final document defining dialogue to facilitate accelerated assessment of PRIority the “scheme” and a guidance for applicants on seeking MEdicines (PRIME)” lays out the background, objectives, access. [Links to all the documents referenced in the story eligibility criteria and procedure, support features, are provided below.] development monitoring, and EMA interaction with health technology assessment (HTA) bodies. Included are annexes Also cleared by CHMP were revised guidelines on EMA’s on justifying the eligibility to PRIME and the procedure for accelerated assessment and on conditional marketing reviewing requests. authorization processes, which are mechanisms that the EU has legislated to foster early patient access to promising new In the release on the PRIME launch, EMA’s Executive medicines. The revised guidelines factor in the experience Director Guido Rasi explained that the goal “is to foster EMA has had in implementing the two processes. better planning of medicine development to help companies generate the high quality data we need to assess quality, Accelerated assessment status shrinks the time limit on the safety and efficacy of medicines. Patients with no or review opinion on marketing authorization applications insufficient treatments could then benefit from scientific (MAAs) from 210 to 150 days. Conditional authorization progress and cutting edge medicines as soon as possible.” is intended for products where the benefit-risk balance is The guidance for industry covers much of the same such that immediate availability outweighs the limitations ground as the scheme’s explanatory document – of less comprehensive data than normally required, and putting the information in the form of a Q&A on carries post-authorization obligations to fill in the gaps. what is expected from applicants.
PRIME Aligns with FDA’s Breakthrough Along with a description of PRIME’s intent, eligibility criteria Therapy Initiative and application timing, the industry guidance addresses: ● how to apply ● how the requests are reviewed ● the support The PRIME scheme builds on the existing regulatory mechanisms that kick in when eligibility is granted ● what framework, including the scientific advice and accelerated happens when products are not granted eligibility or loose it assessment procedures, to provide proactive and during the development process ● how PRIME differs from strengthened regulatory support through the development adaptive pathways (see box below), and ● the availability of and approval process. Eligibility rests on having compelling other tools supporting early access to medicines including preliminary data indicating the potential for the product conditional marketing authorization, accelerated assessment to address an unmet medical need and bring a significant and compassionate use, irrespective of their eligibility to the therapeutic advantage to patients. PRIME scheme. WWW.IPQPUBS.COM
AUGUST / SEPTEMBER 2016 32 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 The last section of the guidance links to a comparative Of the nine requests reviewed at CHMP’s July 2016 overview of the various support mechanisms that EMA is meeting, two were granted and seven were denied. offering for early patient access. The early support descriptor Both of those approved were advanced therapy notes that the approaches are not mutually exclusive, oncology treatments. and that PRIME participation could include accelerated assessment, compassionate use and conditional marketing One of the two advanced therapies that were accepted by authorization. The guidance explains that the PRIME and CHMP at its late-July meeting was Adaptimmune’s “NY- adaptive pathways approaches may also be combined if the ESO-2401.” The sarcoma therapy is being developed in respective criteria are met. partnership with GSK and has received FDA’s “breakthrough therapy” status. CHPA Clears Two Oncology ATMPs for PRIME at July Meeting The other is DNATrix’ “DNX-2401” for treating recurrent glioblastoma. The treatment has received a fast-track but not The outcome of the CHMP reviews of PRIME eligibility breakthrough designation in the US, and has been awarded requests are being made public. After each CHMP meeting an orphan designation in both the US and Europe. at which PRIME requests are reviewed, information on those approved is listed, including: ● the name of the active Another advanced therapy that has been accepted into substance, INN, common name, chemical name or company the PRIME scheme is Novartis’ Car-T oncology therapy code ● the type of product (chemical, biological or advanced “CTL019,” which also has been designated as a breakthrough therapy) ● the therapeutic indication ● the type of data in the US. supporting the request, and ● the type of applicant (SMEs, applicants from the academic sector, or other). Cumulatively, of the PRIME eligibility requests received as of June 1, the CHMP has approved eight and denied 27. Two A similar list is also provided of those whose eligibility were found “out of scope” of the scheme or with a format has been denied. It includes more abbreviated information and content inadequate to support their review. Of the eight on the therapeutic indication and does not include the approved, four were for oncology therapies. The acceptances substance naming information. have been equally split between SMEs and large pharma.
EMA ON PRIME VERSUS ADAPTIVE PATHWAYS
At the session on knowledge management at the ISPE/FDA/PQRI Quality Manufacturing Conference in June, Pfizer Right First Time Program Office Senior Manager Mariah Deguara-Pagan explored the relationship between KM, QRM and the control strategy and the program Pfizer now has in place to strengthen it.
PRIME aims to provide early and enhanced scientific and regulatory support to promising new medicines that fulfil the criteria for accelerated assessment, while adaptive pathways is for treatments in high medical need areas where collection of data via traditional routes is difficult and where large clinical trials would unnecessarily expose patients who are unlikely to benefit from the medicine. It relies on the targeted development of a medicine in a restricted patient population as an initial step and the progressive gathering of evidence through real-life data prospectively planned, as a supplement to clinical trials data and with the view to expand the patient population in which the medicine can be used.
As part of PRIME, EMA will provide advice to medicines developers on the possible authorisation routes for their medicine as well as on the overall development plan; as part of these discussions, the adaptive pathways approach can be envisaged if the medicine fulfils the criteria (e.g. potential for a gradual extension of the target population and possibility to collect and use real-world data). In such case, the medicine will continue to benefit from PRIME support.
However, the adaptive pathways approach to medicine development may not be appropriate for all medicines that are eligible for PRIME. Vice-versa, a medicine eligible to adaptive pathways may not be eligible to PRIME if it does not fulfill the eligibility criteria.
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AUGUST / SEPTEMBER 2016 33 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
EMA Reports on Adaptive Pathways Pilot stakeholders and delineates how real world evidence will Results be collected to refine the benefit/risk profile, the therapeutic value and the price of a medicine. EMA’s defining and crafting of the PRIME scheme was heavily influenced by its experience in development and During the pilot EMA received 62 applications. implementing the adaptive pathways pilot program. The Eighteen proposals were selected for in-depth, face- pilot was launched in March 2014 to explore the viability of to-face meetings with the participation of other the AP approach and refine the process. stakeholders.
By the end of the pilot, six of these applications had At the end of July 2016, EMA released a comprehensive progressed to receive formal parallel advice by EMA and 23-page report on its adaptive pathways pilot. HTA bodies and one to benefit from simple scientific advice. The pilot received applications covering a wide range of The report begins with a summary of the pilot, including the therapeutic areas, with oncology accounting for a third of the figures, learnings, issues identified for further consideration total initial submissions. and next steps. These are reviewed in more depth in individual sections that follow – one of which addresses the The report explains that the majority of the proposals CMC issues (see box next page). received did not fulfil the eligibility criteria for the pilot, and that the applicants were advised to pursue traditional EMA stresses that adaptive pathways is not a new route of development routes. Reasons for non-acceptance in the pilot approval for medicines, but “makes use of existing approval included: ● development programs that did not afford scope tools, in particular conditional marketing authorization, for expansion and iteration ● proposals for areas without which has been in operation in the EU since 2006.” Also unmet need, and ● late stage development programs, where brought to bear are the strengthened post-marketing tools no changes to the plan could be effected. introduced by the 2012 pharmacovigilance legislation, including post-authorization studies and patient registries. Of the proposals accepted in the pilot, the report indicates, “some did not progress beyond the initial discussions The key to the adaptive pathways approach, the report because the subsequent scientific advice on more detailed notes, is a prospective, iterative development plan that protocols cast doubt on the feasibility and methodological includes the involvement of HTAs and other downstream robustness of the development plan.”
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AUGUST / SEPTEMBER 2016 34 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
CMC ISSUES IN THE ADAPTIVE PATHWAY CONTEXT
The following is the discussion of CMC issues in EMA’s final report on its adaptive pathways pilot program.
EMA recognizes that CMC evolves continuously, both pre- and post-authorisation. At the time of approval, however, regulators require a product of good quality based on a robust manufacturing process according to legal requirements, so that the product can be reliably supplied to the patient. In the context of the lifecycle approach, certain validation and/ or upscaling/change activities may be agreed to be conducted post-marketing with the use of appropriate regulatory tools available (e.g., post approval change management protocols).
The acceleration of development time presents challenges in delivering a product of appropriate quality for the conduct of clinical studies and reliable supply to the patient. The product used for the clinical trial needs to be representative of the product that will be submitted for approval. The impact of any manufacturing changes must be proactively explored. This is particularly true for advanced therapy medicinal products (ATMPs), where initial development costs are high, and logistics complex.
Applicants for two ATMPs which entered the pilot had dedicated discussions with the Biologicals working party (BWP) and experts from EMA’s Committee for Advanced Therapies (CAT) to discuss expectations and impact on the conduct of clinical studies of changes and delays in the manufacturing process and quality specifications. This initial informal discussion of the options was then followed by a more detailed scientific advice procedure on quality.
Adaptive pathways is a lifecycle approach that seeks to explore flexibilities within the regulatory framework, and involve the relevant expertise from all committees. If companies foresee an impact of manufacturing on the clinical trials, they are invited to discuss specific CMC aspects and how they impact on the development timelines.
Particularly in the case of ATMPs, where initial development costs are substantial, it is important to agree a strategy that ensures that initial clinical data are not invalidated by subsequent manufacturing changes.
Report Followed by Guidance to Potential bring multiple stakeholders together in support of medicine Applicants development in therapeutic areas where evidence generation is challenging, such as infectious diseases, Alzheimer’s The report was followed a few days later with a “guidance for disease, degenerative diseases, and rare cancers. companies considering the adaptive pathways approach.” Adaptive pathways “is still a developing concept which The guidance reframes some of the content of the longer will be refined as more medicines are considered for this report – using the learnings from the pilot to advise approach,” the release points out. EMA is organizing a candidates on what the content of an adaptive pathways workshop to be held on December 8, 2016, to gather views proposal should look like and on the various phases of and proposals from its stakeholders on the approach. the application process. It notes that EMA is continuing to accept proposals fulfilling the adaptive pathways criteria. Links to EMA Documents: ● PRIME The guidance explains that the design of a development Release on Launch plan fulfilling the adaptive criteria “has a greater degree Description of complexity, as it may encompass several indications, Guidance for Applicants different subpopulations, and the design of protocols for Eligibility Request Outcomes through July data acquisition in the pre and post authorization phases.” ● Adaptive Pathways Report on Pilot Participating companies, in turn, will have the opportunity Guidance for Applicants for additional meetings “to informally discuss the possible Press Release options and preliminary ideas before investing resources in ● Links to Other EMA Releases the detailed drafting of the protocols that will be the subject of the advice.” Accelerated Assessment Conditional Marketing Authorization Support Mechanisms for Early Access An early August EMA press release accompanying the Biotech Process Validation report and guidance stresses that adaptive pathways can WWW.IPQPUBS.COM
AUGUST / SEPTEMBER 2016 35 European Directorate for the Quality Serving public health in Europe sinceof 1964 Medicines & HealthCare E uropean D irectorate for the Q uality of M edicines & HealthCare PREMS 051116 – PRDD-16-10 ENG
Serving public The EDQM is edqm.eu health in Europe a leading organisation since 1964 that protects public health
European Directorate Direction européenne for the Quality de la qualité of Medicines du médicament & HealthCare & soins de santé Europe‘s Active Pharmaceutical leading APIC a sector group of Ingredients Committee API Conference
Authority Speakers: Hélène Bruguera EDQM, France Brendan Cuddy EMA, United Kingdom Graeme McKilligan 19th APIC/CEFIC European Conference on MHRA, United Kingdom Jean-Louis Robert Chairman of the EMA QWG, United Kingdom
active Industry Speakers:: Richard M. Bonner United Kingdom Tom Buggy pharmaceutical DSM Corporate Operational Audit, The Netherlands Graham Cook ingredients Pfizer, United Kingdom Marieke van Dalen Aspen Oss B.V., The Netherlands Barcelona, Spain Ralf Gengenbach Gempex, Germany 23 - 25 November 2016 Roisin Hickey Hovione, Ireland George Hartong van Lokven Aspen Oss B.V., The Netherlands GMP Conference Graca Mata Hovione, Portugal 23 - 24 November 2016 Rudy Peeters Janssen Pharmaceutica, Belgium Colin Rienewerf Regulatory Affairs Conference Piramal, United Kingdom Anthony Storey 24 - 25 November 2016 Pfizer, United Kingdom Francois Vandeweyer Janssen Pharmaceutica, Belgium Hilde Vanneste Janssen Pharmaceutica, Belgium Lore Vignoli Roquette Freres, France Victoria Waddington Macfarlan Smith Limited A Johnson Matthey Company, United Kingdom Organisation / Contact Helen Xue CONCEPT HEIDELBERG Intertek Chemicals P.O. Box 10 17 64 You will find more details at & Pharmaceuticals China D-69007 Heidelberg, Germany Phone +49 (0) 62 21/84 44-0 www.api-conference.org Fax +49 (0) 62 21/84 44 34 [email protected] MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
INTERNATIONAL Goal of FDA/EU Mutual Inspection Reliance is Nearing Realization
FDA and the EU have made significant progress down the FDASIA, Globalization Refuel MRA Effort long and winding road of formalizing an agreement to rely on each other’s drug GMP inspections. In the wake of FDASIA’s passage, Corrigan’s assignment to Europe at the beginning of 2013 included the mission to move An intensive mutual evaluation process has been underway the ball forward with the EU, as the US’ first such mutual over the past two years – including direct observance of reliance agreement to be put in place. In her presentation, each other’s inspection processes – that is providing the Corrigan provided a wealth of insights into what she learned and the ongoing efforts to bring an agreement to fruition. foundation and confidence needed to move to the sign-off stage. A key component has been a mutual auditing process to confirm the capabilities to meet each other’s In a keynote presentation that commenced the ISPE/ requirements. FDA/PQRI Quality Manufacturing Conference in Bethesda, Maryland in June, FDA Associate The assessment of the US inspection system by Europe was Commissioner for Global Regulatory Policy Dara relatively straightforward. It involved a visit to three FDA Corrigan provided an informed review of the district offices, the main campus and a drug laboratory – heightened motivation and concerted effort it has using the same 78-item criteria list used internally within the taken to pave the way for an inspection reliance EU for its assessment of member state agencies. agreement between the US and EU. FDA’s problem was much more complicated, with 28 Corrigan returned to FDA headquarters in the later part different countries to evaluate. It was agreed that FDA of 2015 after a two-plus year assignment as the second would observe the EU’s internal auditing process directly. In late 2014, a team from FDA that included Corrigan director of FDA’s European Office in Brussels, Belgium. observed the audit by the UK and Norway of Sweden and Finding a way to move forward on an inspection MRA additional audits have followed. The plan calls for FDA to was a first-order priority during her tenure in Brussels, as have observed audits of about half of the member states in an important component in FDA’s risk-based strategy to the EU by the end of 2016, with the remainder to follow in address its global regulatory challenges. 2017.
The Associate Commissioner began her engaging remarks Corrigan’s insights into FDA’s evaluation process and how with a review of the impact of globalization and the rapid it impacted the agency’s thinking are noteworthy. Among growth in the number of foreign manufacturing facilities questions to be answered were: ● the ability of the various that FDA and European regulators now have to deal with. inspectorates in the member states to manage their inventory [Corrigan’s keynote presentation at the ISPE/FDA/PQRI with adequate frequency and in a risk-based manner ● Conference is included in full below.] whether inspectors have the right qualifications and meet the US conflict of interest constraints ● whether inspection Congress, she noted, passed the FDA Safety and Innovation reports convey what needs to be conveyed ● how to reconcile Act (FDASIA) in 2012, which included a mandate to actively the GMP certificate-based system in Europe with that in the US, and ● the ability to share unredacted inspection reports. seek out regulatory partners in other countries that have inspectorates capable of conducting inspections meeting Corrigan explained that FDA has been working on a tool that FDA’s standards, in the effort to extend FDA’s ability to can not only be used for assessing European member states reach into the more high-risk elements of its inventory. but for other countries in the world as well. Provisions to make that easier to accomplish were included in the legislation (IPQ Monthly Update, October 2012). “The real goal,” she explained, is having a unified inspectorate across FDA and the EU that would be With 40-50% of FDA’s overseas inspections being performed “work sharing. It would not be duplicating work. We in Europe, where a healthy regulatory oversight process can look at risk and have better data and minimize already exists, the EU became a prime candidate. public health risks globally.”
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AUGUST / SEPTEMBER 2016 36 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 FDA Commissioner Robert Califf, who took the helm in Ongoing Program Alignment at FDA is a Wrinkle early 2016, is driving agency management to question the status quo and find ways to further “engage our global Ultragenyx Quality and Compliance Executive Director partners,” Corrigan stressed. The recognition is that “there Mark Tucker, a former FDA field investigator and compliance is a need for change and a need for action. And I can tell you officer, turned the conversation around to what issues the with confidence that” over the next year “change is going EU may be identifying with FDA inspections and how those to happen.” would be handled.
What Happens if Differences are Found? “I think that both sides are very cognizant of the need to not compare an inspectorate to the ideal state,” Corrigan responded. What is needed is “a decision model that has Following her presentation, the Associate Commissioner been carefully thought through, and we can explain why we was asked about the differences FDA is finding in the said yes or no.” inspection capabilities and practices between the different member states, and how differing inspection capabilities The ongoing program alignment effort at FDA (IPQ would be dealt with. Dec. 27, 2014) does create some additional questions for Europe, she noted: “How do you evaluate The statute calls for a country’s inspectorate to be something that is evolving?” found “capable” of conducting inspections, and does not indicate that “there has to be an exact match “They went to see three districts, and now we are telling up,” she responded. them” the way the districts are structured “is going to change.” There is “active dialogue” to come to the needed “What you want is an inspectorate that can produce an understanding of how the FDA process will work in inspection report that highlights deficiencies – that we can the future. [Editor’s Note: An update on FDA’s program use in making our own decisions. So ‘capable’ is a common alignment initiative will be provided in an upcoming IPQ sense type of determination. It does not mean, for example, story.] that we have to have to rate them ‘highly capable’ or Europe and Japan Also Expanding Information ‘minimally capable.’ We have to find them ‘capable.’” Sharing
“There is variability among the member states,” – for Efforts are also being made to expand the sharing of example, in the way they are funded. Corrigan continued. inspection information between Europe and Japan.
She cited the inspectorate in Greece, which FDA joined EU In September, the Japanese health ministry (MHLW) and the in reviewing “at the height of the financial crisis.” However, European Directorate for the Quality of Medicines (EDQM) since the Greek inspectorate was “almost entirely funded agreed on the details of how the sharing of information will by industry fees,” it was found to be functional. Noting that be enhanced concerning the outcome of GMP inspections FDA also relies on industry funding, Corrigan explained of manufacturing sites of active pharmaceutical ingredients that the agency’s focus is assuring that inspectors are (APIs), while respecting the confidentiality of information adequately resourced and have enough people to handle that is not in the public domain. the workload. A 5-year “memorandum of cooperation” was While industry funding would not be a barrier in also signed which defines concrete measures for recognition, what would be is a situation where strengthening collaboration between the European and Japanese Pharmacopoeias (Ph. Eur. and JP, countries do not have a conflict of interest rule respectively). preventing inspectors from holding stock in pharmaceutical companies and were not willing/ The EDQM release explains that “these include the option able to change, she explained. of organizing bilateral meetings, workshops and internships between the Ph. Eur., the JP and various Japanese regulatory In general, the assessment process is not intended to “say bodies in either region/country, in order to share experiences no” to a candidate country, but to define what “needs to be and information on the development of monographs and fixed before we can say yes,” Corrigan pointed out. “It is methods of testing. To this end, the EDQM and MHLW likely that in some countries we are going to have to have also agreed to set up an ad hoc Technical Working Group a dialogue about some issues, before we would have full involving staff members of the EDQM and Japanese recognition.” regulatory bodies as well as relevant experts.” WWW.IPQPUBS.COM
AUGUST / SEPTEMBER 2016 37 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
FDA’s DARA CORRIGAN ON US/EU MUTUAL RELIANCE ON INSPECTIONS
As the opening keynote speaker at the June ISPE/FDA/PQRI conference, FDA Associate Commissioner for Global Regulatory Policy Dara Corrigan provided an insightful review of her experience in helping the agency move down the pathway with the EU toward mutual reliance on drug GMP inspections. She explained: ● the impact of globalization ● the transition from thought to action ● her experience as director of FDA’s European office in Brussels ● the movement from self-pride to sharing best practices ● the growing dialogue on mutual reliance ● the mutual assessment process ● the sharing of unredacted inspection reports, and ● the changing FDA perspective on achieving a unified inspectorate.
I am very happy to be here this morning, among such a distinguished group of people who work on issues that we care about every day at FDA….
When I first read the program I noted that, and I quote: ‘Today you will hear from global regulators who will provide you with invaluable insights as your company attempts to navigate the increasingly complex nature of regulatory compliance and quality expectations.’ It is quite the broad admonition to the speakers. But I accept the challenge of the keynote, and I am going to talk to you today about an initiative that you may know a bit about, but probably not in the depth that I am going to talk to you about it.
I can tell you the last two plus years of my career have been the most satisfying since I began working in 1990. The reason why it has been the best two years is because of the progress that we are likely to make in the next six months at FDA. Because I know many of you have heard all the statistics before that ground the work that we are doing, I will try to move very quickly past the statistics to tell you what we have been doing that is different from anything that we have done before – to put it in context, which I know everyone is going to talk about, which is the context of globalization.
Just three weeks ago, President Obama spoke at Rutgers University about world trends. In particular, he noted that we live in an age of global supply chains and cargo ships that crisscross oceans and online commerce that can render borders obsolete. I know ISPE acknowledges this world view. If you look at your last month, your organization was in Singapore, Sao Paulo, and Stockholm.
The Impact of Globalization
For FDA over the last two decades, globalization has informed the work that we do, and we acknowledge this new world view. It has changed the way that we operate and the way that we look at challenges.
Perhaps most importantly, we are closely focused on the ever-increasing volume and complexity of FDA regulated products coming to America’s shores. I do help lead an office that sounds quite lofty – the Office of Global Regulatory Operations and Policy. Within that office there is the inspectorate, import personnel, thirteen laboratories, and the office of criminal investigations. There are also our four offices worldwide – in Europe in Brussels, Belgium, in China, India, and Latin America.
You know about changing drug supply chains. When we started working on our initiative, which I will talk about later, we looked at a lot of data. I would put the data up here except I don’t think it would be helpful to look at it piece after piece after piece ─ that can come in another session.
But to imagine, if you looked at trends in the world, I will pick one data point: drug facilities worldwide. If you put a graph up there and you looked at the US, India and China – if you looked at a manufacturing facility that represented all manufacturing facilities in the United States in the last five years, 2011 to 2015 – you would see that the growth in facilities in the US is about 30%. And you would see the growth in India and China. The percentage increase in India was 55%, and the percentage increase in China was 63%.
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You can look at the data in a lot of ways. You can pick small data points and you can look at large data points. But what the statistics clearly show is that we need to look at the way we do things and do them differently. It is not like we haven’t been trying to do that. Congress passed a law in 2012, which most of you know as FDASIA [the FDA Safety and Innovation Act], that gave us additional tools to help us do this.
From Thought to Action
So the question is what are we doing versus thinking? And what I am going to talk about is the way that we have been trying to identify other regulatory partners that can we can rely upon, and advance beyond conversations and joint-work.
I am not discounting that. I have been at FDA long enough to know that the rigor of the scientific dialogue is the foundation of all of the work that we do. And I know that when you are dealing with other countries and other languages and other cultures, conversation is very important. And doing these together is very important. But what can we do that is beyond that? And what does the public expect, and Congress expect, from the FDA?
They expect, I think, what Congress described in section 712 of the law – which is that the US actively seek out regulatory partners in other countries that have inspectorates that are capable of conducting inspections that meet our requirements. It is what I have been working on for the past two-and-a-half years – both when I was in Brussels, Belgium, and now that I have returned to the US.
We have been working with the European Union to see if we can reach a mutual reliance agreement by the end of this year. And even though I am going to be talking about pharmaceutical manufacturing specifically, you can easily see how this work is a small step in a larger group of issues. Of course it is not a small step really, because we have never done it. We have never implemented a mutual reliance agreement with another country, ever, at FDA. So taking that small step to do it with countries in the European Union is significant.
But what is more significant is being able to look at another regulator, and not say, ‘is that regulator the same as us’ but ‘are they capable of doing the same work that we do, so that we can pool resources and really look at risk as it exists around the world, and perhaps target risk very differently?’
When you are looking at regulators in another country, it isn’t confined only to drugs. What you will be looking at in that country is the foundation of their civil servant laws, and you will be looking at other things that inform the way we think about other FDA-regulated products.
So I want to explain to you in different ways how this started so that you will see the progression, and then you will be able to see what we did differently in 2014 and what we have done to date that will make it successful.
The View from Abroad
A little more than three years ago, in January 2013, I moved to Brussels, Belgium to be the second director of the Europe office for FDA. When the office opened in 2009, there was one person in Brussels, there was one at the European Food Safety Authority in Parma, Italy, and one at the European Medicines Agency in London.
In Brussels, FDA is one of the many agencies that are part of the embassy community like in most countries. Of course, the State Department runs the embassy, but the US Department of Commerce and the US Department of Agriculture are the big players at the embassy.
Brussels is unique because it has three embassies in one city. It has the embassy to Belgium, the embassy of the EU, and the embassy to NATO. So there is an enormous diplomatic community, even though they serve different functions.
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As a part of the embassy community, FDA works within the economic section of the State Department and closely with the Department of Commerce and Agriculture. As somebody who has been immersed in the US FDA world, to go sit in on another country and to see how another country functions is one thing, but to sit within an economic section of an embassy that is focused on diplomacy and American business was a very enlightening and very helpful experience on the regulatory side. It is hard to put all of that together. I never would have put it together for myself had I not gone. I certainly studied it before going, but it is a very different thing to study and write than to actually live there yourself and watch it in person.
I thought I would give you two concrete examples of my experience that would actually make this come to life.
I move to Brussels, Belgium, in the middle of winter in 2013. One of the first things I was invited to do was to watch a hearing before the European Parliament. And at that time the European Parliament was debating the medical device legislation in the EU and how they were going to revise it. In 2016, this is still going on, but hopefully it will be concluded soon. [Editor’s Note: The text was agreed upon in June, and as of the end of September, was being finalized.]
When I arrived there, I sat in the audience to hear the hearing. About a half an hour in, somebody started talking about an FDA official, and quoting them at the hearing. This was a European speaker and it was not flattering. And then they were quoting another FDA person, and it was not flattering either. And there was a lot of discussion about the need to keep innovation for medical devices in Europe. There was even a slogan at the time called: “Keep the Five.” And the five was allegedly how many years ahead in the market for medical devices the EU was. That is how ahead they were.
Another example was that I was invited to a meeting where a newly minted Director General for the European Commission started talking about an issue that was germinating at FDA and also in the EU. The person basically said: ‘If the FDA is going down that path, then we just need to think about going down another one…’ It wasn’t a sense of denigrating the FDA. It was more just a pride in the EU system. And FDA is always out there and just because FDA is out there, does not mean we need to be out there. There is that sense of tremendous pride that I felt all the time when I was in the EU, about the EU system – and certainly if you were at the country level, the countries by themselves.
But now I am back at FDA [in the US], and in some ways it is not that different sometimes. You hear: ‘Nobody does it better than FDA,’ when you are at FDA, and you hear, ‘How could anybody do it better?’ I don’t think that it comes from an arrogance, I think it comes from a pride in the way that we have done things and the fact that people really care about the work that they are doing. And then there is the big ‘but’ of course – but that does not help us accomplish things together.
From Amour-Propre to Sharing Best Practices
I think there is a lot to be proud of on both sides. The challenge is to figure out how we can actually walk down the path together, rather than talking at each other from both sides of the path. I think we have a lot to learn, and they have a lot to learn from us, about best practices. [Editor's note: The text was agreed upon, and as of the end of September, was being finalized.]
The other thing that informed my thinking as we started thinking about this initiative was learning about other pieces of the EU system. I learned about how lobbying works in the EU, which is very different from here. They don’t have campaign contributions, which completely changes the way the lobby works in the EU. I learned about the trade concerns of American business – something that you are somewhat isolated from sometimes at the FDA and was very useful here.
I tried as a lawyer to really master the EU legal system, which is not an easy task, and about the complex relationship between the EU government and the countries within the EU.
In many ways you want to think that Belgium is a bit like Washington. It is where the central government sits. You can think of it as very transient. And that is true – they do have some similarities in that regard.
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But the way of life in Brussels, Belgium is very different from Washington. The way that the governments are structured and the way that they look at innovation and regulation is different. It does not mean it is better or worse. It would be simplifying the process too much to say, ‘Oh, the bureaucratic people in Washington and Brussels just can’t figure this out.’ It is not that. I mean, it really is grounded in a history of culture and tradition and pride that you have to work through to ensure that the incredible scientific dialogue that has been going on matures into something else.
I do think that sometimes industry seizes upon this – seizes upon the fact that there are these different sensibilities, cultures and pride, and everything else – to say that regulators should be criticized. And I am not going to say what you think, which is that we don’t deserve the criticism. I think, actually, that it is not only the business community that should be innovative. I think that you should expect the regulators to be innovative as well.
One of the questions I get a lot is: ‘If this initiative that you have is successful, won’t the public be worried? You are going to be doing things differently.’ And I would say to people, ‘the world has changed dramatically in 20 years. And if we keep the status quo, people should be worried.’ The status quo is a decision, and I will come back to this at the end. You are deciding that everyday you should be doing things exactly the same way. And I don’t think we are an agency that wants to do that, or an agency that should be doing that.
Why is this possible? How is it that we can be innovative? And I want to tell you how we got here. It didn’t come out of the blue. People have been thinking about this for 20 years.
About three years ago, the trade talks began between the EU and the US. Never in a million years would I have thought that I would have been sitting at the table for the trade negotiations between the EU and FDA. But that is how things work out sometimes. It is fortuitous.
There was a spark that came in the initial part of the trade negotiations, where somebody brought up the fact that in 1998, the US and the EU signed a mutual recognition agreement to recognize each other’s GMP surveillance inspections. As I said, this had been talked about for a long time, but this spark happened. It shouldn’t matter where good ideas come from. What it did was it sort of sparked people to start talking about this again and whether or not we could go back to 1998 and see whether we could do something now.
If you could imagine a bar graph with the inspections that the US does in the EU, and you looked at it over the last five years, what you would see is the bars would be going up gradually and then they would dip last year, but not by much. FDA does 43% of its foreign drug inspections in the EU. And that number has remained the same, slightly up, a little bit down recently, since 1998.
So the agreement that was signed in 1998 was not implemented. And you might be saying to yourself, ‘so why 20 years? Why is it going to happen now?’
I think it is important to remember that FDA has changed a lot since 1998. We have foreign offices. We have 15 years of collaboration or more with the EU on a day-to-day basis. We do more foreign inspections than we ever have and our risk models have evolved. We now have FDASIA to help us work globally in an easier way. And there are many, many examples.
Mutual Reliance Conversation Heats Up
What we did in May of 2014 was we got together with the EU to structure our collaboration to evaluate whether or not we could rely on each other’s inspectional information. Strengthening that reliance would give us a more practical means to oversee the large number of drug manufacturing sites around the world. It would also avoid…inspecting the same facilities on a routine basis, which I know is an issue industry has raised repeatedly over that last 20 years. We have had a lot of support to move this forward, from leadership in the FDA to the EU, from industry, and from others, and we knew that we had to try and figure out a way to move this forward and get it done.
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How do you get a big bureaucracy like the FDA to move? I have been there for five years and for half of that time, I haven’t been on the White Oak campus. As you will remember, I said in the beginning that I am a lawyer. So how do lawyers do these things?
When I graduated from law school, what I wanted to do was to be in court. Why? Because I loved the discipline of it. I loved getting all of your facts together, analyzing them, and realizing there were different outcomes ─ otherwise, you wouldn’t be in court. You make your presentation and a judge or a jury makes the decision – so not necessarily how it works in a regulatory facility.
What I found is that it is similar but different with scientists or engineers. There is this gathering of facts, and there is this tremendous desire at FDA to have consensus, so that public health risk is minimized. And there is a very strong and good fear that something will be missed -- that you can’t monitor everything. And so sometimes data collection goes on for a very, very long time.
I appreciate both parts, I mean I am a data geek as much as the rest of them. But the question is, how do you tap enough data, and when can you move? And I think that is what we have been trying to do on both sides of the Atlantic. It is to say, how do you thread a needle carefully enough where you can reach decisions in the most efficient way and have a robust evidence base? It is what everybody does, but it is not easy to actually do.
When we started in 2014, people had talked about this but they had not really looked at it in a very long time. So we knew we needed data, and there was a lot of it. We just did not know exactly where it was in the EU and what we could tap into. And obviously the marketplace had changed too.
The Assessment Process
So, what were we going to look at? And how were we actually going to get people to focus? How were we going to assess 28 different countries?
Just to be very clear, it is not that this easy for the EU to do this, but we are one inspectorate at the FDA, under one set of rules. If you are an investigator in Arizona, or New York or California you have the same conflict of interest rules that apply to you. It is not the same in the EU. You have 28 countries. Each one has its own inspectorate, and there is variability between the member states. There is variability in operational ways and in other ways within the EU.
And to complicate it, there is always the really difficult exception like Germany. After WWII, the German constitution was structured such that Germany does not have a centralized inspectorate, it has a decentralized inspectorate of over 16 inspectorates, like a mini EU within Germany.
So this is not an open the book, check a few boxes and move along assessment. It is very complicated in the EU. But complicated does not mean impossible. We have a saying among the team that is working on this: ‘There will be a lot of hills, but we are going to get over them.’
We started out by looking at virtually every document we had in house related to the 1998 effort. But we decided also to really try to look at things we maybe had not looked at before. We learned about a system they have in the EU that we had been unaware of at the FDA. It is an audit system, where two member states go to another member state and audit their inspectorate. It is a way of checking not only that the member state is doing what it is supposed to be doing, but also to do a check on: what is the inventory? How are they covering the inventory? If they have any laboratories within the inspectorate, are they accredited? How are they operating? They look at all of their enforcement actions.
We learned about this. We learned that member states would be audited and held to a 78-item checklist – that auditors would actually go on inspections with the inspectors of the audited member state. And then a report would be written that would describe any deficiencies within that member state’s assessment.
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The great thing was that the EU in 2014 said to FDA that we could observe these audits. So three of us went in September of that year to Sweden when Sweden was being audited by the UK and Norway. We went and we sat in a room with the auditors from the UK and Norway, while the Swedish inspectorate sat there – not all of them at one time – and answered each of the 78 criteria. And then we went on a separate inspection with the Swedish inspectors.
Can you imagine being a company where you are there, there are two Swedish inspectors, one auditor from Norway and then an observer from the FDA. They were quite calm. I don’t know if that was a Swedish trait. But it was quite something to see the company operating with four people – some auditing, some observing and some actually conducting an inspection. It was very, very useful.
And over the last year, we have had the opportunity to go observe audits in Sweden, Greece, Croatia, Germany, Italy, the Czech Republic, Hungary and the UK. We had never done this before.
There have been some issues in the past with the frequency and funding of the audits. There is no question the EU is committed to this program, and has plans for audits in the next five years. In 2016, six additional audits will be done in the EU and the FDA will observe six more audits. We will have observed half of the member states in the EU by the end of this year.
I have been able to personally observe three: the Czech Republic, Germany and Sweden. I do believe it is a testament to the EU that they did not simply select four Western European countries that FDA was more familiar with. To let us go in and see the audit of Germany, which is incredibly complex, and Croatia, the newest member of the EU, was good strategy in a way. And if you really want something to work, you really open the door and let people see things. I mean if you hide things until the last minute and people don’t trust you, it is not going to work. I know that the EU was doing this in an effort to show us the landscape, as it were.
So we went. We sent people from all different parts of the agency at FDA. We wanted to make sure that the right people were going and that FDA would have the views of a lot of different people – people from ORA [Office of Regulatory Affairs], CBER [Center for Biologics Evaluation and Research], CDER [Center for Drug Evaluation and Research], and the Office of Policy. We had engineers go, and scientists, and the token lawyer go, and it was very useful.
We had a meeting after all of the audits last year, where we sat in a room with the individuals who went, to talk about exactly what happened in each one of those audits and what our impressions were of the inspectors, of the auditors, of the audit protocol. As you recall, we have never done this before. There were a lot of people who thought this was kind of a joke: Like there is a list. What do they do? Do they just go in and check the box? They don’t just go in and check the box.
It is the oddest thing to see two countries really taking apart another country’s inspectorate. But you can see why. In the EU, they do not have mutual recognitions. They have to accept product from every other country in the EU. If you are in Britain, you don’t get to say, ‘I am not so sure about ‘X’ country.’ It comes in…. This is how [the EU] economy works – by having this flow of commerce. But they want checks and they want to know what is happening.
If you saw the audits, it reminded me of a very good attorney doing a cross-examination, where they would be reading a response to a question, and then they would see something and they would say, ‘Do you have documents to support that?’ Then we would take a break, and we would look at the documents. They would find a reference to another document and they would ask for that document. We would look at more documents. They would ask for other people from the inspectorate to come in. And they would pull out enforcement actions. They would ask questions about the enforcement actions. They would go over the inventory. They would go over the products in the inventory. They would go over the ethics statements for each inspector.
There were inspectorates that do checks at the end of every year to compare each inspector to the next inspector. It was actually sort of amazing to see everything that certain inspectors did. It is a best-practices opportunity.
We came back [to the US] and we realized – and it really brought home – that FDA cannot be the inspectorate, and has never been the inspectorate, for the world. But it is important that we rely on others, and we use our resources to target the greatest risk.
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We have, and we have had, a lot of questions. What do you want to know before you sign a mutual recognition agreement? You want the inspectorate to be able to manage its inventory. You want them to know what is in their inventory. And you want to see how often they are inspecting it, and whether they are doing it in a risk-based way. You want to make sure that the inspector who goes in has the right qualifications to be in a facility. Are they objective? Do they have the right ethical standards? Can they identify problems when they need to? Can we look at their inspection reports? Can we pick up an inspection report from Croatia, have it translated, and know what it means? Were there problems in the facility? And how do we reconcile a system that is GMP certificate based versus our own system?
Again, lots of hills, lots of questions. And we wanted to make sure at the very beginning that all of these auditors could go in there, really look robustly, and get to the bottom of the 78 criteria – that deficiencies would be documented, that there would be corrective action plans, and that there would be a feedback loop.
Now everybody knows that is the basics. That is the bottom of a really well-functioning system. It is not that it doesn’t have deficiencies, but it is how you fix them. And it is exactly the same thing we have been doing when we go in and we observe these audits.
Not surprisingly, the EU has been doing this with us, as well. The EU came and conducted an audit of the FDA in September of 2015. They visited three district offices of FDA, the main campus, and a drug laboratory as a part of its assessment. They used the 78 criteria that they use for their own member states when they went to our district offices and main campus. And we believe that that audit is proceeding in exactly the way we hoped that it would.
The Sharing of Unredacted Inspection Reports
Another piece of what we are doing that hasn’t been done before, but is critical to the success of this endeavor, is figuring out a way to share unredacted inspection reports with the EU.
Interestingly, when I have spoken to people both here and in the EU, many people do not know that the EU has been giving us unredacted inspection reports for years. So there was an imbalance there. We have had the inability to share trade secret information with our colleagues. We have shared commercial confidential information, but not trade secret information.
But the law changed in 2012 to allow us to do this under certain circumstances, when the commissioner certifies that the country is capable of keeping the information confidential and has the legal authority to do that. But we have not done it. So it is hard to imagine a mutual recognition agreement where you could not share unredacted inspection reports. It sounds like a small thing, but it is really not.
We wanted to know if it actually was a small thing. So we had experts at FDA line up redacted inspection reports with unredacted inspection reports that we had generated – to look at the information that was redacted, and to determine whether or not that information could have an impact on public health. And the conclusion was even beyond what we thought, which was that it could have an impact on another country’s ability to evaluate the state of a facility, which could have an impact on public health. But also, the experts were concerned that without this information, the other country would not be able to identify trends that could actually affect the way that FDA looks at its public health obligation and public health. We knew that this was a public health issue. It was not simply an issue of giving each other information. And we knew that we had to change this, and the law gave us a real opportunity to do this.
So we did what we usually do at FDA, we gathered all the information we had on the countries to see whether or not they had the legal authority to do this, and whether they could keep our information confidential, and what the history was of our relationship with the countries.
As part of that research – and I think this is the key to not only FDA succeeding globally, but FDA succeeding in general – we looked beyond FDA and HHS to see what other agencies are doing within the US.
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We found out – and it wasn’t surprising, it is just that we hadn’t looked – that the Justice Department, the Treasury Department, and the Securities and Exchange Commission, already share confidential information, classified information, and criminally sensitive information with every member state in the EU, and certain EU authorities. So it is hard to imagine if the Justice Department has already found every member state, and all of the institutions that they deal with in the EU, are capable of keeping this information confidential for a decade or more, that FDA could not reach that same conclusion.
We believe we are on the right path for that to happen, and again, for the first time in FDA history, that we will be able to share unredacted inspection reports with our foreign counterparts who we trust, which will ultimately benefit not only them but benefit the FDA.
The Changing FDA Perspective
As I said earlier, I think it is different to study something versus living there. You need to see the country and understand it and verify your facts, and if you cannot do that, then you have try to simulate it in some way. Because taking this group of 10 people and observing these audits, you see the really aggressive approach to document review and questioning. You also get to know inspectors from around the world.
This experience has changed FDA and changed our thinking. I can assure you that we have lots and lots of documents catalogued – that we have asked lots of questions. We have verified, and we are very cognizant of the need to minimize risk and maximize benefits in any agreement that we sign.
But we want this to lead to concrete results. If in three years you come back and the inspections are still 40-50% in Europe, this will not be successful.
But I think that this on the ground collaboration is unprecedented, and it is the first real assessment of variability among the member states. You can’t talk about it in the abstract. It is too hard to say that two inspectorates, on paper, are equivalent. I think observing was critical and seeing the robustness of those internal audits.
In addition, the conflict of interest rules have changed in the EU. Back in 1998, it was not really possible, even though an agreement was signed, because the first country we looked at, the UK, allowed their inspectors to hold stockin pharmaceutical companies. And that was a barrier versus a hill.
There wasn’t any way that expert analysis on the FDA team would have led to a successful result there. But the laws changed in 2005. And we have found that doing an analysis and comparison of the EU’s structure to FDA’s conflict of interest structure does preserve the objectivity of the inspectorates.
But, again the complexity of the EU is that the member states can vary from the overall EU directives and legislation. So we are doing [the analysis] because we have to. We do need to go member state by member state to ensure that their conflict of interest laws are robust enough for us to know that the objectivity of the inspectorate is sufficient for us to rely on them.
Finally I would say, we do need to look at inspection reports. We want to make sure we have looked at everything we need to per member state. We are in the process of putting together a tool that will be used in the EU for every country.
But it is beyond the EU. We want something that is not EU centric. We want something that the FDA could use for any country in the world. And we will.
The Goal of a Unified Inspectorate
So what is the hope? The hope is to have an outcome. The hope is to make decisions. The real goal is a virtual inspectorate, a unified inspectorate, containing investigators and inspectors from the FDA and from across the EU.
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There are different legal frameworks in the US and in the EU, but this virtual inspectorate would basically be work sharing. They wouldn’t duplicate work. They would look at risk, they would have better data, and they would minimize public health risks globally.
Our new commissioner, Dr. Califf, talks about this in a much more grandiose way. Because he is working on the cutting edge on many, many issues like clinical trial data, clinical trials in general, as well as other issues that he cares about passionately. This is but a very small piece of what he hopes to accomplish while he is here.
But it is the same mantra: It is harnessing data, moving away from duplicative work, and taking bold action. He sees inaction as a decision, and he expects us to justify the status quo. So if we come in and say, ‘we can’t do X,’ he wants to know why we cannot do X. And that is the best possible Commissioner you could hope for – somebody who is going to be that rigorous in their thinking, and demand that of the people who work for him. He understands, just like FDA understands, that we must engage our global partners.
In going back to the Rutger's address three weeks ago, President Obama noted that engagement means using all of our levers of our national powers and rallying the world to take on our shared challenges. To engage globally in different ways has been discussed for a long time. But there is a need for change and a need for action, and I can tell you with confidence that this year that change is going to happen.
12th Annual International Symposium on Pharmaceutical Reference Standards Co-sponsored by: EDQM, Council of Europe and USP November 3, 2016 - November 4, 2016
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AUGUST / SEPTEMBER 2016 46 Nanomedicines: Technical and Regulatory Perspectives Workshop March 20-22, 2017 | USP Meetings Center | Rockville, Maryland, USA
Presented in partnership with: Who Should Participate?
• Analytical chemists • QA/QC analysts • R&D scientists, managers • Manufacturing scientists, managers • Regulatory affairs specialists • Contract research organizations • Contract manufacturing organizations About This Workshop Nanomedicines are drug products that are formulated Confirmed Speakers using colloidal systems, generally known as liposomes, nanospheres, microspheres, etc. This workshop is a forum for the discussion of the new • Ecevit Bilgili, NJ Institute of Technology challenges presented by this type of products • Susanne Bremer-Hoffman, European including nomenclature, regulatory requirements, Commission analytical techniques and procedures for the • Daan Crommelin, Utrecht University characterization and control of the critical quality • Martin Fritts, NCI attributes of these colloidal systems. • Alexis Guillot, PHAST GmbH • Anthony Hickey, RTI International Why Attend? • Mario Hubert, Bristol-Myers Squibb • Fred Klaessig, Pennsylvania Bio Nano Systems • Better understand the nomenclature of this type • Andrew Latham, Merck Research Laboratories of drug products. • Tao Lu Lowe, University of Tennessee • Gain insight on the regulatory requirement for • Margareth Marques, USP formulations containing colloidal systems. • Scott McNeil, National Cancer Institute/NIH • Discuss possible critical quality attributes for Ajit Narang, Genentech, Inc. nanomedicines and the analytical techniques to • Don Parsons, BIND Therapeutics monitor and control them. • Christie Sayes, Baylor University • Areas of Discussion Donald Tomalia, NanoSynthons, LLC • Katherine Tyner, U.S. FDA • Sylvia Wagner, Fraunhofer-Institut • Nomenclature, Definitions, Regulatory • Jingtao Zhang, Merck Expectations (FDA, EMA, ASTM, ISO) • Ye Zhang, U.S. FDA • Drug Release • Analytical techniques for the characterization of colloidal systems For Additional Information • Challenges in the formulation, manufacturing and • Visit www.usp.org/nanomed-workshop stability of drug products containing colloidal • systems E-mail [email protected] • Call +1-301-816-8130 3rd Synthetic Therapeutic Peptides Workshop – Regulations, Standards, and Quality November 14–15, 2016 • USP Meetings Center, Rockville, Maryland, USA Who Should Attend?
§ Analytical chemists and biologists
§ QA/QC analysts
§ R&D scientists, managers
§ Manufacturing scientists, managers
Peptides represent one of the fastest growing segments in the biopharmaceutical § Regulatory affairs specialists market. Being able to manufacture peptides with consistent high quality is an § Contract research organizations important priority for manufacturers of this drug class. As the global manufacturing § Contract manufacturing organizations landscape continues to transform, public standards for the quality of peptides will play a growing role in the supply chain integrity of these drugs.
After a successful program in 2015 focused on raw material control strategy, Workshop Steering Committee the types of impurities and appropriateness of impurities methods, peptides in vaccines, conjugated peptides, and regulatory considerations, USP is bringing its § Donna Christner, Ph.D. Synthetic Therapeutic Peptides Workshop back again in 2016 for a more in-depth § Michael De Felippis, Ph.D. program that will examine manufacturing considerations, impurities, specifications, novel peptide therapeutics, and regulatory considerations. § Gary Erickson, Ph.D.
§ Cory Evans, Ph.D. Why Attend? § Elena Gubina, Ph.D. § Better understand USP’s standards for peptide products § Gerhard Haas, Ph.D. § Discuss control strategies for raw materials and impurities § Maura Kibbey, Ph.D. § Learn regulatory expectations for peptides, conjugated peptides, and peptide vaccines § Marion King, Ph.D.
§ Achieve common regulatory understanding between USP, industry, and FDA § Michael Pennington, Ph.D.
§ Provide feedback about proposed changes/new information on peptide § Ved Srivastava, Ph.D. monograph(s) and chapter(s) § Michael Verlander, D.Phil. § Explore compendial science topics in order to inform the development of specific monograph(s)/chapter(s)
REGISTRATION AND ADDITIONAL INFORMATION: Group, academia, and other discounts available. Visit www.usp.org/2016Peptides, email: [email protected], or call: +1-301-816-8130.
GAMS408F _ 2015-04 www.usp.org MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 Updates in Brief
UNITED STATES
CMC/REVIEW
Industry/FDA Agreement on GDUFA II
Negotiations between FDA and the generics industry for the first reauthorization of the Generic Drug User Fee Amendments of 2012 have concluded. According to an announcement from the Generic Pharmaceutical Association (GPhA) at the end of August, GDUFA II will include ● GDUFA backlog ANDA provisions ● priority and standard review ● enhanced communication and transparency ● complex product meetings ● enhancements to the inactive ingredient database (IID) ● resource management and planning and performance reporting, and ● small business relief. GDUFA II will apply to FDA FY 2018-2022.
ANDA Refusals for Impurity Justifications
CDER has released a guidance for industry highlighting deficiencies in impurity information that may cause the agency to refuse to receive (RTR) an ANDA for a new strength of the drug product. The guidance explains that FDA may RTR an ANDA for not justifying specified identified and unidentified impurities that are above ID thresholds, and proposing limits for unspecified im- purities above ID thresholds.
Updated Policy on Capsule Supplier Changes
In a two-page document released by the Office of Pharmaceutical Quality, FDA clarifies the reporting category for a postapproval change in the supplier of a hard gelatin capsule shell. The policy explains that when an applicant changes the supplier of a hard gelatin capsule shell, with no change in capsule composition or appearance, the information should be submitted in an annual report. However, changes in size, color or dye, or a change from gelatin to non-gelatin alternative, should be categorized as a prior approval supplement (PAS).
Pharmaceutical Co-Crystal Classification
FDA issued revised guidance for NDA and ANDA applicants on the appropriate regulatory classification of pharmaceutical co-crystal solid-state forms. The guidance also provides information about the data to submit for supporting the appropriate classification of a co-crystal ─ and the regulatory implications of the classification. The recommendations apply to materials not previously evaluated and determined to be pharmaceutical co-crystals. The recommendations do not apply to materials previous- ly designated as salts, complexes, or other non-co-crystalline forms. Criteria is provided, based on pKa values (acid-dissociation constants), to differentiate a salt from a co-crystal. When applicants believe the classification is not predicated on these relative pKa values, FDA advises using spectroscopic tools and other orthogonal approaches to provide evidence.
Generics Office on New Strengths
CDER’s Office of Generic Drugs (OGD) releasedguidance intended to assist applicants preparing to submit original abbreviated new drug applications (ANDAs) and prior approval supplements (PASs) to ANDAs for which the applicant is seeking approval of a new strength of the drug product. The guidance highlights deficiencies in relation to information about impurity limits that may cause a refuse-to-receive (RTR) decision, indicating an ANDA is not sufficiently complete to permit a substantive review. The document finalizes the 2014 draft and provides background with a list of typical deficiencies leading to an RTR.
GMP/INSPECTION
FDA Guidance on Insanitary Conditions at Compounding Facilities
FDA released new draft guidance addressing insanitary conditions at 503A and 503B drug compounding facilities. The guidance includes numerous examples of conditions considered insanitary for both sterile and non-sterile facilities and procedures to “assist compounding facilities in identifying insanitary conditions so that they can implement appropriate corrective actions.” Though 503A compounders are not required to register with FDA, and are primarily overseen by States, the document includes parameters for working more closely with State regulatory agencies. [For more on FDA’s guidance and enforcement activity in compounding see IPQ’s Monthly Update for March/April 2014 and search “pharmacy compounding” at IPQpubs.com.] WWW.IPQPUBS.COM
AUGUST / SEPTEMBER 2016 47 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 NIH Drug Manufacturing Cessation and Move
After multiple cGMP violations were identified in a Form 483 last year (IPQ June 30, In Brief), NIH's Pharmaceutical Develop- ment Section in Bethesda, Maryland, has permanently halted drug manufacturing operations for clinical trials. In July, FDA con- firmed NIH plans for an interim Intravenous Admixture Unit (IVAU), which will include robust cleaning and disinfection SOPs. The agency acknowledge the indication from NIH that it would be moving its manufacturing operations into an interim IVAU by October 31, 2016 and are designing and building a new facility “that will meet or exceed all relevant regulatory requirements.”
Revised Regs for Drug/Establishment Registration
FDA has issued a final rule amending its regulations governing how and when manufacturers of finished drugs and APIs, in- cluding repackers/relabelers, must register their establishments with FDA and list the drugs they manufacture. The “significant” amendments reorganize, modify and clarify the current regulations with the aim at “modernizing these regulations and improv- ing efficiency and reliability for FDA and drug manufacturers” as well as bringing them into alignment with the pharmaceutical legislation issued since the original regulations were put in place and changes to the regs were proposed in 2006. The 200-page final rule includes an in-depth review of the comments on the proposed rule and how they were dealt with, as well as a detailed chart describing the changes from the proposed rule, some involving the National Drug Code (NDC) system.
Generic Drug Facility Self-Identification
A new FDA guidance for industry describes how to comply with the annual self-identification and user fee requirements con- tained in the Generic Drug User Fee Amendments of 2012 (GDUFA). The guidance addresses: ● which types of generic facilities, sites, and organizations are required to self-identify ● what information is requested ● the technical standards for electronically submission ● the penalty for failing to self-identify, and ● who is required to pay user fees.
USP on Analytical Lifecycles
In June, USP published for comment a new General Chapter <1220> on “The Analytical Procedure Lifecycle.” Comments were due by the end of July. The chapter incorporates the QbD lifecycle concepts in ICH Q8-11 and the current process validation guidelines. Following in the Sept.-Oct. 2016 Pharmacopeial Forum (PF) was a new USP General Chapter <1210> on “Statistical Tools for Procedure Validation.” Comments are due by the end of November. Proposals for the two new chapters had been issued by USP in the Sept.-Oct 2014 PF. Also in the Sept.-Oct. 2016 PF were “Stimuli Articles” on the analytical control strategy, and the analytical target profile across the analytical lifecycle. ICH has on its agenda the creation of an Expert Working Group (EWG) to focus on the analytical procedure lifecycle issues in the later part of 2017. USP and ECA will be cosponsoring a meeting on the lifecycle approach to analytical procedures in Prague in November. [For an in-depth review of the discussion of the an- alytical procedure lifecycle issues and their relationship to ICH Q12 at a formative USP/AAPS/IQ workshop held in late 2014, see IPQ Dec. 26, 2014.]
EUROPE
CMC/REVIEW
EMA Streamlining Management Structure
Building on the 2013/2014 reorganization, the European Medicines Agency (EMA) has announced organizational adjustments and strategic amendments of its corporate management structure that will result in a streamlined architecture with improved administrative support. “We want to do more with the resources we have by designing the Agency’s structures and processes around the lifespan of medicines,” said EMA’s Executive Director Guido Rasi. Effective September 1, 2016, the main changes include: • reduction of the number of divisions dealing with human medicines from four to three • creation of a new function dedicated to strengthening the collaboration between EMA and the national competent authorities, and • streamlining the division dealing with administration and corporate management. “Interactions between stakeholders and the Agency will not be affected by these changes,” EMA states.
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AUGUST / SEPTEMBER 2016 48 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 EMA Workshop on Adaptive Pathways
EMA has announced a meeting on December 8, 2016 to hear what drug developers and other groups have to say about its adap- tive pathways program. The workshop agenda will an opportunity to discuss the lessons of the two-year pilot program and figure out the future of the staged approach to drug approvals. [For more on the adaptive pathways program and how it compares to EMA’s Priority Medicines (PRIME) approach for accelerating product development and review, see stories on pp. 20-32.]
EDQM on ICH Q3D and CEP Procedure
EDQM released guidance on how to implement ICH Q3D in the procedure for the “Certification of Suitability to the monographs of the European Pharmacopoeia” (CEP). Addressed are pharmaceutical substances introduced in medicinal products within the scope of ICH Q3D. EDQM encourages applicants to provide a Risk Management Summary (RMS) for elemental impurities that may be present in the manufacturing process of the final substance and to include all potential sources of contamination ─ includ- ing elemental impurities intentionally introduced into the process, contributions from raw materials (such as water), equipment, and packaging. All elemental impurities mentioned in ICH Q3D should be considered. The document also provides an example of a RMS in the form of a table containing the 24 elements covered by the council. [For more on ICH Q3D implementation, search “ICH Q3D” at IPQpubs.com.]
GMP/INSPECTION
EMA Q&A on Non-Distillation Methods for WFI Production
EMA has issued a draft Q&A on the production of water for injection (WFI) by non-distillation methods. The comment period ends November 4, 2016. The Q&A addresses the European Pharmacopeia decision to revise its WFI monograph to take into ac- count current manufacturing practices. The purpose of the Q&A is “to provide clarification and guidance in relation to the use of reverse osmosis in the manufacture of Water for Injection (Part I) and also to provide more detailed guidance on the control of Biofilms (Part II).”
Europe on BPA Limit for Plastics
The European Commission published a draft regulation that lowers the specific migration limit (SML) for BPA from plastic food-contact materials in line with the EFSA opinion published in January 2015. Taking into account uncertainties surrounding potential health effects of BPA on the mammary gland, reproductive, metabolic, neurobehavioral and immune systems, the overall uncertainty factor was increased and applied to establish a new Tolerable Daily Intake (TDI). On the basis of a new “tem- porary” tolerable daily intake (t-TDI), the allocation factor, and the exposure assumption, the SML is limiting from 0.6mg to 0.05 mg of BPA per kg of food (mg/kg). The Authority designated the TDI as temporary pending the outcome of a long-term toxicity study on BPA in rodents, currently being undertaken by FDA and the National Toxicology Program. USP has also been focusing on its plastic packaging standards, indicating in a revision to its <661> that packaging materials for oral solids and topicals are considered safe if they are compliant with food regulations (IPQ August 26, In Brief).
INTERNATIONAL
CMC/REVIEW
Major Pharma Roadmap to Combat Antimicrobial Resistance
The International Federation of Pharmaceutical Manufacturers & Associations (IFPMA) has announced the publication of a “com- prehensive roadmap” to combat antimicrobial resistance. It lays out what the 13 major pharmaceutical companies involved pledge to deliver by 2020 in line with the principles agreed to at the 2016 World Economic Forum in Davos, Switzerland. To over- come the “staggering threat AMR represents for our society, economies, and citizens,” the companies committed to: ● working to reduce the development of antimicrobial resistance ● improving access to high-quality antibiotics, vaccines, and diagnostics ● investing in R&D, and ● collaborating with governments and stakeholders to sustain those investments.
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AUGUST / SEPTEMBER 2016 49 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 WHO Guidance on Variations to Multisource Pharmaceuticals
As part of its technical report series, the WHO Expert Committee on specifications for pharmaceutical preparations has updated Annex 10, “WHO general guidance on variations to multisource pharmaceutical products.” Presenting change categories and reporting procedures, the revised annex explains that it is intended to serve as a guide for establishing national requirements for the regulation of post-approval changes. Reporting requirements are categorized into four “variations” differing in severity of risk. Other changes, however, “are so fundamental that they alter the terms of the accepted dossier and consequently cannot be considered as variations. In these cases submission of a new dossier should be considered, in line with applicable national requirements for applications for MA.”
Health Canada on ICH Q3D Implementation
Months after announcing the adoption of their ICH Q3D guidance document, “Guideline for Elemental Impurities,” Health Canada (HC) published on its website implementation dates for new and marketed products. The notice emphasizes that appli- cations for drug products received by Health Canada after December 31, 2016 should include the content requirements as per Q3D and include a risk assessment for elemental impurities, and how they are to be performed. In addition, HC states that “if the risk assessment indicates that previously manufactured and unexpired batches have levels of elemental impurities that could pose a potential risk to health, the appropriate Directorates in Health Canada should be notified,” and that corrective actions may include recall procedures. [For more on ICH Q3D implementation, search “ICH Q3D” at IPQpubs.com.]
GMP/INSPECTION
China FDA Stiffens Drug Manufacturing Expectations
Chinese authorities have organized a campaign to raise drug quality standards and hold firms accountable. In comprehensive efforts to overhaul drug quality and patient security in a rapidly intensifying market, a draft guideline was released to increase regulation of pharmaceutical production, including process management. Unannounced inspections will begin November 1, and drug manufacturers will need to report any revisions to their approved manufacturing processes, including studies demonstrat- ing these new processes will not adversely affect drug quality. Accordingly, producers in violation of the new protocols will face suspensions of production pending approval of the new processes. The action from China follows in the wake of multiple import bans on products from Chinese drugmakers by the U.S. and Europe, warning letters and non-compliance reports for violations of good manufacturing practices, and the discovery in March of a $90 million black-market scheme involving multiple vaccines, which led to hundreds of arrests.
India Calls for Drug Manufacturing Self-Assessment
In a letter to all drug manufacturers and pharmaceutical associations, the Drugs Controller General of India (DCGI) has requested that all manufacturers self-assess their units, assign themselves a quality rating, and submit a report to the appropriate licensing authority and to the office of DCGI. The quality rating is to be based on benchmarks taken from a detailed checklist provided by CDSCO, “to comply with the requirements of Good Manufacturing Practices (GMP) and Good Laboratory Practice (GLP).” The checklist contains an “elaborate toolkit” for verification of GMP/GLP and includes WHO GMP and PIC/S standards.
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AUGUST / SEPTEMBER 2016 50 PAREXEL® Consulting: Strategic C ompliance and Risk Management
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FDA DRUG GMP WARNING LETTERS
The following are the drug GMP warning letters posted by FDA during August and September cat- egorized 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 Diabetes Franklin, June 3, Finished • sterility assurance of containers • cleaning Corporation of Tennessee 2016 • hood studies America
Among sterile drug production deficiencies uncovered during an August 2015 inspection were not depyrogenating the container closures of injectable finished drug products and sterilized glass vials stored in an anteroom without an established hold time. Investigators also noted that multiuse solutions used to produce injectable drug products lacked a subsequent sterilization step, and that the integrity of container closures was not assured after puncturing. Furthermore, DCA was not using a sporicidal agent to disinfect the aseptic processing area, and failed to demonstrate through appropriate studies that the aseptic processing area was able to provide adequate protection of the ISO 5 area in which sterile products were processed.
The corrective actions outlined in DCA’s 483 response were inadequate, and some could not be evaluated due to a lack of supporting documentation, the letter states. The proposal to use dry heat for the sterilization and depyrogenation of glassware did not include parameters, such as temperature and duration, nor was there any corrective action regarding the depyrogenation of stoppers. In addition, the response did not indicate how the sterility of the finished product, after multiple punctures to the same container, would be ensured. Moreover, the firm stated it was making a change in cleaning policy to include the disinfection of the ISO 5 hood with a sporicidal agent but did not specify the required contact time. Nor was there sufficient documentation provided in the response confirming that dynamic smoke studies were performed for the ISO 5 hood.
Company Name Location Letter Date Product Type Areas Cited American Plano, Texas June 28, Compounded • unapproved drug • valid prescriptions • cleaning Specialty 2016 • gowning • training • hood studies Pharmacy
During a December 2014 inspection conducted after receipt of a complaint, FDA investigators reported an absence of valid pre- scriptions for individually-identified patients, and reported the production of domperidone, which is not approved in the U.S. for any indication.
In addition, the investigators observed serious deficiencies in practices for producing sterile drug products, including a technician with exposed facial skin performing aseptic processing of sterile drug product, a technician placing his head under the ISO 5 hood above the work surface while processing a sterile drug product, and reused mop covers to clean production areas.
Other CGMP violations noted at the facility included: • a lack of appropriate hood studies of the ISO 5 area • an inadequate sys- tem for monitoring environmental conditions in aseptic processing areas • failure to establish an adequate system for cleaning and disinfecting the room and equipment to produce aseptic conditions • failure to clean and, where indicated by the nature of the drug, sterilize and process containers and closures • failure to establish or follow an adequate written testing program de- signed to assess the stability characteristics of drug products • incomplete laboratory determination of satisfactory conformance to final specifications for each batch of drug product purporting to be sterile of pyrogen-free, and • failure to reject drug product not meeting established specifications.
FDA acknowledged ASP's action during the inspection to voluntarily recall hydroxocobalamin injection solution and the 483 re¬sponse indicating that it was voluntarily closing down its sterile lab clean room and “discontinuing preparation and mixing of all sterile drugs.”
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AUGUST / SEPTEMBER 2016 51 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Company Name Location Letter Date Product Type Areas Cited Health Southern July 8, 2016 Compounded • valid prescriptions • personnel monitoring Innovations Pines, North • aseptic processing • equipment • hood studies Carolina. • stability testing
Sterility deficiencies uncovered during a February 2015 inspection included not conducting personnel monitoring and not using a sporicidal agent as part of the disinfection program for the cleanroom and ISO 5 area. The facility also lacked magnehelic gauges to monitor pressure differentials between the ISO 7 cleanroom and the anteroom, and failed to demonstrate through appropriate studies that the hoods were able to provide adequate protection of the ISO 5 area.
FDA noted the firm was not receiving valid prescriptions of individually identified patients, failed to include a testing program designed to assess the stability characteristics of drug products, and failed to test each batch of drug product purporting to be sterile and pyrogen-free.
In its 483 response, Health Innovations said it had issued a voluntary recall of all sterile products within six-month expiry, initiated on February 12, 2015, following the order from North Carolina Board of Pharmacy to cease production of all compounded preparations.
Company Name Location Letter Date Product Type Areas Cited Kalman Health dba Peoria, July 22, Compounded • aseptic processing • HEPA filter disinfection Essential Wellness Illinois 2016 • cleaning • hood studies Pharma
During a July 2015 inspection, FDA investigators found inadequate disinfection of HEPA filters and laminar flow hood within an aseptic processing area prior to production. The disinfection program did not include a sporicidal agent, and non-sterile dis- infectants were used. Brown stains on the HEPA filter in the laminar airflow hood were observed. Furthermore, the firm failed to demonstrate through appropriate studies that the hood was able to provide adequate protection of the ISO 5 area.
The investigators collected environmental samples from multiple locations in the facility, including the aseptic processing area. Testing results of the samples identified microbial contamination, including spore-forming bacteria.
FDA acknowledged a commitment from the firm in its 483 response to cease production and distribution of sterile products until corrective actions had been taken, and to initiate a voluntary recall of all sterile products within expiry.
Company Name Location Letter Date Product Type Areas Cited American Peoria, July 22, Compounded • aseptic control • hood studies Pharmacy of Illinois Illinois 2016 dba Alwan's
During an inspection in September and October 2015, FDA observed serious deficiencies in practices for producing sterile drug products including: • non-sterile procedures for cleaning aseptic processing areas such as insufficient contact time for the spori- cidal agent, and • inappropriate studies that hoods were able to provide adequate protection for the ISO 5 areas.
The firm's 483 response did not include sufficient documentation, particularly regarding the smoke studies – neither a description of the conditions under which the smoke studies were conducted nor a video recording of such studies.
Company Name Location Letter Date Product Type Areas Cited Techni Med, Aurora, July 29, Compounded • valid prescriptions • unapproved drugs • cleaning Inc. dba The Illinois 2016 • aseptic processing • environmental monitoring Compounder • gowning • hood studies • spec testing
In their visit between May and July 2015, FDA inspectors noted an absence of valid prescriptions for individually-identified patients and that the firm had been producing domperidone drug products.
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AUGUST / SEPTEMBER 2016 52 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 Sterile drug production deficiencies observed included failure to: ● establish an adequate system for cleaning and disinfecting the room and equipment ● establish an adequate system for monitoring environmental conditions in aseptic processing areas, such as the sampling of personnel gloves involved in aseptic processing ● ensure that manufacturing personnel wear appropriate clothing ● demonstrate through appropriate studies that hoods were able to provide adequate protection to the ISO 5 areas ● filter the air supply through high efficiency particulate air filters under positive pressure for aseptic processing areas, and ● have appropriate lab determination of conformance to final specifications.
In its response, The Compounder said that it had ceased compounding and distributing products containing domperidone. The letter states that, although some corrective actions appeared adequate, the firm did not clarify how it will ensure processes are adequate to sterilize and depyrogenate items, nor did it include an evaluation of products previously produced under the observed inadequate conditions.
The firm had committed in its 483 response to complete certification with dynamic unidirectional airflow studies. However, the response did not address any interim actions to be put into place prior to the completed certification.
Company Name Location Letter Date Product Type Areas Cited Plainsboro Plainsboro, August 1, Compounded • misbranded drug Pharmacy New Jersey 2016
In July 2014, FDA investigators conducted an inspection after receipt of a MedWatch report associated with sustained release liothyronine (T3) capsules prepared by the firm. FDA analysis of a sample of the product received from the patient found that it contained approximately 2.3 mg of liothyronine per capsule, which far exceeds the label claim.
Company Name Location Letter Date Product Type Areas Cited Adamson Corona, August 2, Finished and • data integrity • spec testing Analytical Lab. California 2016 API
The CGMP violations found during an August 2015 inspection of the analytical lab included not exercising appropriate controls over computer or related systems. Specifically, the high performance liquid chromatography (HPLC) and gas chromatography data acquisition systems did not have sufficient controls to prevent deletion or alteration of raw data files. For example, either laboratory personnel use a shared password, or none at all, to access a computer systems. In addition, multiple instruments had no audit trail function to record information about each analytical test, such as: • type of injection • date and time • identity of analyst • reason for action taken (for example, modifying a record) – a repeat observation from a 2013 inspection.
FDA also found a lack of controls to ensure completeness and accuracy of laboratory procedures, analytical data, and test results. For example, secondary reference standards for oxymetazoline hydrochloride were not appropriately qualified as required by the firm’s standard operating procedure (SOP), and approved laboratory notebooks lacked data such as HPLC chromatograms and assay calculations.
For APIs, the findings included the failure to: ● ensure materials were appropriately tested and the results reported, and ● qualify the secondary reference standard for avobenzone API required by the firm’s SOP.
In its response, the firm stated that it had retrained the quality control unit personnel, and appropriately qualified secondary standards. However, not provided a risk assessment of the lots tested with the unqualified secondary reference standards, which called into question the accuracy of the analytical results provided to its API customers. FDA asked the firm to provide a plan describing how the quality control unit will verify that all the secondary reference standards have been appropriately qualified, and that the laboratory records include complete electronic raw data. The firm was asked to include a risk assessment regarding the practice of testing drugs with unqualified secondary reference standards.
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AUGUST / SEPTEMBER 2016 53 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Company Name Location Letter Date Product Type Areas Cited Wellness Center Chattanooga, August 5, Compounded • unapproved drug • misbranded drugs • aseptic Pharmacy, dba Tennessee 2016 processing • hoods studies Designer Drugs
In May 2015, FDA inspected the facility after receipt of a MedWatch report involving a patient who reportedly experienced an adverse event after being implanted with hormone replacement pellets produced by the firm.
The investigator noted an absence of valid prescriptions for individually-identified patients for all of the drug products being produced and that the firm produced domperidone drug products.
In addition, the investigator observed serious deficiencies in practices for producing sterile drug products, such as environmental sampling taken immediately after cleaning, which could potentially bias the results. Also, the firm: • did not use sterile wipes or have an adequate contact time for the sporicidal agent used to disinfect the aseptic processing area • used non-pharmaceutical grade nitrogen gas in the production of sterile drug products, and • failed to demonstrate through appropriate studies that the hood is able to provide adequate protection in the ISO 5 area.
While some of Designer Drugs’ response was deemed adequate, FDA questioned the firm's proposal to use non-sterile wipes. Also, the effectiveness of an agent at sporicidal disinfection was unsupported at the concentration and for the contact time indicated in the firm's policy, the letter states. Furthermore, the documentation provided in the response did not establish that smoke studies were performed under dynamic conditions during the latest certification.
Company Name Location Letter Date Product Type Areas Cited Noven Miami, August 5, Finished • spec testing • training Pharmaceuticals Florida 2016
The warning letter to Noven addresses an inspection in mid-2015 focused on two of the firm’s transdermal patch products, Minivelle (estrogen therapy) and Daytrana (ADHD therapy). Inspectors found that the complaint rate for Minivelle increased by 50% between its 2013 and 2014 reporting period, without the firm determining why.
From April 2014 to March 2015, 45% (1,734) of the firm’s complaints for Daytrana were for hard-to-remove liners stemming from adhesive transfer. However, the firm had not detected this problem during quality control testing or when samples were tested for stability monitoring. It was also noted that previous FDA inspections in 2010, 2009 and 2007 observed inadequate investigations.
The letter probes into the issues that were found during the inspection regarding Noven’s deviation/OOS handling program for the products. Noven “failed to maintain written records so that data therein could be used for evaluating, at least annually, the quality standards of each drug product to determine the need for changes in drug product specifications or manufacturing or control procedures." For example, the firm failed to analyze product and process data for commercial batches of Minivelle to identify adverse trends. FDA's review of the stability summary data for 15 lots of Minivelle produced in 2014 identified quality attributes inconsistent with the application specifications. Also cited were: ● the manufacturing of commercial batches using the raw material silicone with values other than those used in clinical batches, and ● findings from probe tack tests that the average adhesion of Minivelle commercial batches was much higher than the values specified in the new drug application.
The firm was judged to be invalidating OOS results without clear evidence of laboratory error. For example, an analyst prepared new standards, repeated the analyses, obtained passing results, and then invalidated the OOS results. However, the analyst did not thoroughly investigate whether the original standard was the root cause for the OOS and did not analyze the original standard against the new standard. It was possible that the OOS results were true failures, the letter points out, yet those drug product lots were released.
Test methods were also at issue. The investigators observed that methods for measuring were not scientifically sound. Qualitative test methods for Minivelle relied on an analyst's subjective visual interpretation. However, the results contradicted the investigator's observation of movement of adhesive past the edges or through the slit in a release liner. Also observed during the inspection was repeated handling of a test sample from a Minivelle that could result in unintentional
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AUGUST / SEPTEMBER 2016 54 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 adhesive removal affecting the accuracy of the test. The firm's written response stated that it would assess the testing methods and product specifications for Minivelle by September 2015 and implement new methods were needed, but continued to use inadequate methods for release testing, the letter pointed out.
The test method for Daytrana that is intended to detect adhesive transfer from the transdermal delivery system (TDDS) to the removable release liner was not validated, the warning letter notes, adding that “when this adhesive transfer occurs, the drug is removed from the TDDS and thus the product is rendered unusable."
The letter notes the earlier inspection findings of the Noven’s failure to "follow adequate written procedures describing the handling of all written and oral complaints." The firm conducted a retrospective review of complaint trends, FDA said, but did not identify sufficient corrective and preventive actions to improve the effectiveness of its complaint system and toprevent distribution of defective products.
As in other drug manufacturing warning letters, the agency requested Noven to contact CDER’s Drug Shortages Staff immediately if an action is likely to lead to a disruption in the supply of drugs produced at the facility.
Company Name Location Letter Date Product Type Areas Cited Sentara Chesapeake, August 8, Compounded • aseptic processing • HEPA filter condition Enterprises Virgina 2016 • hood studies • cleaning • gowning • training
In July 2015, FDA conducted an inspection of Sentara, in response to information received from the Virginia Department of Health regarding an investigation of two cases of leuconostoc bacteremia in two pediatric patients after receiving Total Parenteral Nutrition (TPN) products produced by the firm.
The investigators observed rust on HEPA filter grills as well as rusted vents of hoods used during aseptic production, and also observed an operator transferring materials into a hood without being disinfected. Furthermore, the firm failed to demonstrate through appropriate studies that aseptic processing areas were able to provide adequate protection of the ISO 5 areas. FDA collected environmental samples from multiple locations at the firm, including the aseptic processing areas, and the testing results of the samples identified microbial contamination in the aseptic processing areas, including spore-forming bacteria.
Sentara ceased compounding sterile drug products in September 2015 and recalled all sterile drug products within expiry. The firm then resumed sterile compounding operations two months later. Although several of the proposed corrective actions appeared adequate, the letter states, others were deficient. For example, the firm did not adequately investigate adverse environmental findings to identify the root cause of how contamination was introduced to the cleanroom. Also, the firm did not clarify what contact time of sporicidal agent will be required to be used to ensure adequate disinfection of the ISO 5 areas, nor if the multiple cycles of cleaning and disinfection performed by the firm would be included in the updated cleaning policy. It was also unclear whether the firm would be evaluating the ability of the operator to don gloves without contaminating them. In addition, the firm stated it had established department guidelines for fingertip testing. However, it did not provide the referenced guidelines in the response and therefore FDA could not fully assess the adequacy of the response.
The firm also did not provide adequate documentation for FDA review, such as a detailed description of the conditions at the time of the smoke studies or videos of the smoke studies, to show the studies were performed under dynamic conditions.
Company Name Location Letter Date Product Type Areas Cited Cape Apothecary Annapolis, August 12, Finished • unapproved drugs • valid prescriptions Maryland 2016 • misbranding • aseptic control and monitoring • gowning • training • hood studies • process validation • stability testing
From September 21, 2015, to October 7, 2015, FDA investigators conducted an inspection and noted the facility was not receiving valid prescriptions and was also producing domperidone products. In addition, investigators observed serious deficiencies in practices for producing sterile drug products. For example, the your firm did not use a sporicidal agent and used non-sterile sanitizers in the aseptic processing area, and operators were observed placing materials and components into the ISO 5 hood with their un-gloved hand. Furthermore, the firm failed to demonstrate through appropriate studies that the hood was able to provide adequate protection of the ISO 5 area in which sterile products are processed. WWW.IPQPUBS.COM
AUGUST / SEPTEMBER 2016 55 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 FDA investigators collected environmental samples of multiple locations in the facility, including the ISO 5 area. Testing results of these samples identified microbial contamination in multiple locations, including spore-forming bacteria within the ISO 5 hood.
A list of CGMP violations included failures to establish an adequate system: • for maintaining equipment used to control the aseptic conditions • for cleaning and disinfecting the room and equipment to produce aseptic conditions • for monitoring environmental conditions in aseptic processing areas • of procedures that are designed to prevent microbiological contamination of drug products • of testing designed to assess the stability characteristics, and satisfactory conformance to final specifications • to ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination
In the letter, FDA acknowledges the firms November 5, 2015 voluntarily recall of all sterile drug products within expiry, its discontinued sterile production, and a series of four written responses by the firm attempting to take corrective action. However, the firm had not demonstrated through environmental monitoring that the ISO 5 hood had been adequately cleanedand disinfected, and also lacked monitoring of the ISO 8 ante room. Additionally, gowning procedures did not specify the use of sterile gloves and when gloves will be donned in the gowning sequence. Furthermore, the glassware cleaning procedure did not provide sufficient detail on how endotoxins or pyrogens would be removed.
Company Name Location Letter Date Product Type Areas Cited Frontida Philadelphia, August 15, Compounded • API sterility assurance • data integrity BioPharm Pennsylvania, 2016 • stability testing
FDA inspected Frontida BioPharm, formerly known as Mutual Pharmaceutical Company, in June-July 2015. The letter provides three examples of how the firm "failed to establish an adequate quality control unit...to assure that no errors have occurred or, if errors have occurred, assure that they have been fully investigated:"
1) The quality unit knowingly released 27 lots of various strengths of clonidine tablets in March 2015, despite evidence that the API used in their manufacture was potentially contaminated. The supplier recalled this lot of API based on findings of inadequate controls to prevent cross contamination. Frontida was notified of this recall as early as July 2014, according to the letter, but had placed the lot on hold starting in July, hiring a contract testing laboratory to analyze retained samples of the clonidine API lot for cross contamination. However, the contract laboratory provided documentation that its test method was not validated to detect low levels of cross contamination, and explicitly stated that the test results “may not be used for batch release.” Despite this, the firm released the 27 lots of the clonidine HCl in March 2015 without testing the finished products using a method that was both validated and sufficiently sensitive to detect cross contamination. During the FDA inspection, the firm recalled all 27 lots.
2) The firm did not adequately investigate the stability failure of a felodipine 2.5 mg lot of tablets for an unknown impurity. The firm opened an investigation in February 2015. The records indicated that as of April 29, 2015, it was known that benzophenone had leached into the tablets from the ink and varnish on the primary container label, but the firm did not recall this lot until July 16, 2015, during the FDA inspection.
3) The quality unit failed to ensure that CGMP related records were accurate, contained appropriate documentation, and were consistent with the facility's SOPs. FDA found multiple discrepancies in quality unit-approved records, such as: • investigation reports containing data and documentation from unrelated investigations • records signed with only a first name • records missing dates, and • illegible entries in logbooks and lab notebooks.
During the inspection, there were numerous instances where the firm failed to provide FDA investigators with information regarding investigations, corrective actions, and preventive actions in a manner that would allow the investigators to fully understand and evaluate the firm’s internal processes and compliance with CGMP requirements. The quality VP repeatedly denied any knowledge of the clonidine HCl API supplier’s recall, the warning letter states, even though email evidence collected during the inspection suggested that this individual had been notified of the recall as early as July 2014. During the inspection, the firm removed the individual from his position. The firm committed to further correcting deficiencies.
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AUGUST / SEPTEMBER 2016 56 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Company Name Location Letter Date Product Type Areas Cited College Colorado August 15, Compounded • valid prescriptions • misbranded drugs Pharmacy Springs, CO 2016 • unlicensed biologics • aseptic process and validation • gowning • environmental monitoring • hood studies • spec testing
Following a 2013 inspection, FDA reinspected the College Pharmacy facility in May 2015 finding that it was not receiving the required prescriptions for drug products being produced, and observed serious deficiencies in practices for producing its sterile drug products.
During the 2015 inspection, investigators noted that non-sterile wipes were used to apply disinfectants to the ISO 5 work surfaces and that a portion of the lyophilization operations were not conducted under ISO 5 conditions. Also observed was a failure to demonstrate that hoods were adequate in protecting the ISO 5 areas.
FDA acknowledged that while improvements to the aseptic processing area were made after the 2013 inspections, objectionable conditions remained. In addition, FDA observed the use of unlicensed materials in manufacturing certain biological (allergenic) products.
Violations observed at the facility included the failure to: • validate the procedures used in aseptic and sterilization operations • establish an adequate system for monitoring environmental conditions in aseptic processing areas • establish an adequate system for cleaning and disinfecting the room and equipment to aseptic conditions • ensure that manufacturing personnel wear clothing appropriate to protect drug product from contamination, and • withhold components from use until the lot has been sampled, tested, examined and released by the quality control unit.
In the two responses dated July 2015, the firm was unable to provide sufficient supporting documentation for a full evaluation. For example, the firm did not clearly state whether it intended to use sterile wipes to clean and disinfect the ISO 5 work surfaces, nor did the firm provide sufficient information on when proposed corrections to the lyophilization operations could be completed and whether interim measures would be taken.
In addition, the responses lacked documentation showing smoke studies being performed under dynamic conditions, and did not address why the gowning practice did not conform to the firm's gowning procedure, nor when sterile coveralls and hoods would be implemented into the production process. Finally, copies demonstrating revisions to written procedures that would include establishing appropriate action limits were not provided, nor changes to monitoring frequencies applicable to aseptic processing.
Company Name Location Letter Date Product Type Areas Cited Brown's Englewood, August 17, Compounded • unapproved drugs • valid prescriptions • misbranding Compounding CO 2016 • hood studies • process validation • stability testing
FDA issued a 483 to Brown’s Compounding in August 2014 noting an absence of valid prescriptions and serious deficiencies in its sterile practices, including a lack appropriate hood studies. During the inspection, investigators also observed the firm com- pounding two drug products that appear on the withdrawn or removed list.
Subsequently, in December 2014, the firm registered the location as an outsourcing facility and was re-inspected in April 2015. Significant deficiencies were again observed including operators resting their gloved hands on the surfaces of the laminar airflow workbenches and not sanitizing their gloved hands after touching equipment outside of the aseptic production area.
Moreover, the firm failed: • to demonstrate through appropriate studies that hoods were able to provide adequate protection of the ISO 5 areas • to establish and follow appropriate written procedures that are designed to prevent microbiological contamina- tion, and that included validation of all aseptic and sterilization processes • to establish and follow an adequate written testing program designed to assess the stability characteristics of drug products, and • to submit a complete report to FDA upon initial registration as an outsourcing facility in December 2014 identifying all the drug products (sterile and non-sterile) that were com- pounded during the previous 6-month period. FDA also found that Brown was compounding unapproved and/or misbranded products.
The letter notes that in mid-2015, the firm ceased all compounding operations, surrendered its pharmacy license with the State of Colorado and deregistered as an outsourcing facility in mid-2015.
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AUGUST / SEPTEMBER 2016 57 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Company Name Location Letter Date Product Type Areas Cited Central San Diego, August 18, Compounded • unapproved drug • aseptic and sterilization Admixture, California 2016 process and validation • gowning • environmen- CAPS, (1) tal monitoring • stability and spec testing
Central Allentown, August 19, Compounded • unapproved drug • aseptic and sterilization Admixture, Pennsylvania 2016 process and validation • gowning • environmen- CAPS, (2) tal monitoring • stability and spec testing
Facilities in two locations were registered as outsourcing facilities by Central Admixture in 2014. Both were subsequently inspected by FDA and the subject of separate warning letters. The Allentown facility was inspected twice – in June 2014 and February 2015. The San Diego facility was inspected in August 2014.
Investigators observed serious deficiencies in practices for producing sterile drug products at both locations. At the San Diego facility, investigators also observed that drug product for distribution did not include appropriate lab determination of satisfactory conformance to the final specifications prior to release. (BUT LISTED ABOVE IN BOTH????) At both facilities, procedures designed to prevent microbiological contamination of drug products were not established, written, and followed.
The Central Admixture facilities were found not have an adequate system for: • conducting procedures designed to prevent microbiological contamination of drug products, including validation • cleaning and disinfecting the room and equipment to produce aseptic conditions • assuring that manufacturing personnel wear clothing appropriate to protect drug product from contamination • monitoring environmental conditions in aseptic processing areas, and • testing to assess the stability characteristics of drug product, and its satisfactory conformance to final specifications. Furthermore, the firm compounded drug products that "are intended for conditions that are not amenable to self-diagnosis and treatment and their labeling fails to bear adequate directions for their intended uses," causing them to be misbranded.
FDA acknowledged a produce recall in December 2014 and other corrective actions. And though labeling issues had been resolved, the investigations and corrective actions to multiple sterility failures that had occurred at the facilities were inadequate. As microbial contaminants in the aseptic processing areas were not routinely identified when total numbers of colony forming units were below action levels, no assurance that cleaning and disinfecting programs had sufficiently removed the identified sterility failure contaminant were provided.
Company Name Location Letter Date Product Type Areas Cited Jeffrey's Canonsburg, August 25, Compounded • unapproved drugs • valid prescriptions Pennsylvania 2016 • cleaning • aseptic processing • hood studies
A February 2016 inspection found that the firm was not receiving valid prescriptions for individually-identified patients for a portion of the drug products it was producing and that domperidone products were being produced.
Sterile practice deficiencies included: • not using a sporicidal agent as part of the disinfection program for the aseptic processing areas • dirt and grime on the plastic separation flaps between the anteroom and the ISO 6 cleanroom • presterilized stoppers remaining uncovered in the ISO 5 hood overnight • demonstrating through appropriate studies that the aseptic processing areas were able to provide adequate protection of the ISO 5 areas.
The warning letter notes that some of Jeffreys’ proposed corrective actions regarding the observed insanitary conditions could not be fully evaluated because the response did not include sufficient information or supporting documentation. For example, the firm’s response indicated that smoke studies would be completed within six months. However, the response did not include an adequate description of the conditions under which the study will be performed. Furthermore, the response did not include any interim controls or an assessment of potential product impact until the corrective action is implemented. In addition, the response stated the firm would incorporate bleach into daily cleaning procedures as a sporicidal agent but did not provide sufficient specifics regarding the concentration of the bleach intended for use or documentation supporting its effectiveness as a sporicidal agent. Moreover, no specific contact times were included.
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AUGUST / SEPTEMBER 2016 58 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Company Name Location Letter Date Product Type Areas Cited Central Illinois Peoria, IL September Compounded • cleaning • hood studies • training dba 2, 2016 Preckshot
Sterility practice deviations noted during an April/May 2015 inspection included failing to use a sporicidal agent in the compounding areas and failing to demonstrate through dynamic smoke studies that hoods were able to provide adequate protection of the ISO 5 area. The investigator also observed an operator passing gloved hands over open drug containers, closures, and components while producing sterile drug product.
Regarding the corrective actions Preckshot described in its response, the warning letter requests further documentation of dynamics smoke studies indicating what activities were simulated and the number of personnel present in the cleanroom during the study.
Company Name Location Letter Date Product Type Areas Cited Pacific Bellflower, September Compounded • valid prescriptions • aseptic processing Healthcare dba California 2, 2016 • cleaning • hood studies B&B Pharmacy
During an August 2015 inspection, investigators noted that the firm was not receiving valid prescriptions for individually-identi- fied patients and observed sterile practice deficiencies including: • a hood located on top of a laminated wood table • poor aseptic practices, such as an operator disinfecting his gloves with non-sterile isopropyl alcohol while performing aseptic operation, and another operator entering a ISO 5 work zone with exposed skin • instead of a sporicidal agent, using non-sterile disinfectants and wipes as part its disinfection program for the aseptic processing area • not demonstrating through appropriate studies that hoods were able to provide adequate protection of the ISO 5 areas.
FDA found that testing results of environmental samples of multiple locations in the facility, including the aseptic processing areas, had identified microbial contamination, including spore-forming bacteria. For example, investigators noted that one of the hoods in the aseptic production area was located on top of laminated wood where a corner of wood was exposed, and that sample results of that exposed wood identified spore-forming bacteria.
The letter notes that following the inspection, B&B decided to cease compounding sterile drug products and to voluntarily recall all compounded sterile drug products within expiry.
Company Name Location Letter Date Product Type Areas Cited Option Care Everett, September Compounded • HEPA filtration equipment condition Washington 7, 2016 • aseptic and sterilization processes • training • hood studies
A February 2016 inspection found that Option Care’s sterile practice deficiencies included use of a non-sterile process to clean the ISO 5 area. A technician was observed touching the inner liner of a waste receptacle and a metal cart and then performing aseptic operations in the ISO 5 hood without first disinfecting their gloves. The door separating the ISO 7 area from the ISO 8 anteroom was made of wooden materials, which the letter noted is difficult to clean and may harbor microbial contamination. Investigators also observed staining on the metal grates covering the HEPA filter of the ISO 5 hood, and the failure to demonstrate through appropriate studies that hoods were able to provide adequate protection of the ISO 5 areas.
Option Care indicated in its response to the inspection that it was relocating to a new facility on May 2016. However, FDA remained concerned, the letter said, regarding non-sterile disinfection processes and that the firm had not mitigated the risk associated with using such metal grates. In addition, some of the responses could not be fully evaluated by FDA because of insufficient supporting documentation. The firm had committed to performing smoke studies under dynamic conditions. However, it had not provided documentation for FDA review.
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AUGUST / SEPTEMBER 2016 59 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 INTERNATIONAL
Company Name Location Letter Date Product Type Areas Cited Xiamen Origin Fujian, China July 19, API • data integrity • aseptic and sterilization process Biotech 2016 and validation • cleaning • OOS testing • training
FDA inspected the API facility in January 2016 but received no response for corrective action. Xiamen Origin Biotech was placed on Import Alert in May 2016.
The inspection found that the firm had no written procedures for supplier qualification, relabeling operations, sampling, product release, document retention, or training. The firm was unable to provide the investigator with records for relabeling operations from before September 2014, and failed to transfer all quality or regulatory information received from the API manufacturer to their customers. For example, the firm repeatedly falsified and omitted information on the certificates of analysis (CoA) they issued to customers, and fabricated the name of an employee, using that name as the false signatory authority on the CoA sent to customers. The firm also omitted the name and address of the original API manufacturer and did not include a copy of the original batch certificate. Finally, the firm included an “expiration date” on the CoA that exceeded the manufacturer’s labeled expiration date.
The firm also made misleading or deceptive statements and delayed the investigator’s access to accurate and truthful information. During the inspection, an employee told the investigator there were no drugs on site. However, the investigator observed a room adjacent to the conference room being used as a warehouse for relabeled drugs. The same employee told the investigator that the firm stopped relabeling drugs in January, 2015. Yet, during the inspection, the investigator reviewed an exported drugs list that showed the firm had distributed drugs after January 2015 and into January 2016.
Observations also included a failure to keep the buildings used in the manufacture of API in a clean condition. During the inspection, the investigator recorded dirty warehousing spaces and observed a rodent in the room adjacent to the warehouse.
Company Name Location Letter Date Product Type Areas Cited Concept Tianjin, China July 26, 2016 API • OOS and stability • validation • cleaning • QA Products
During an August 2015 inspection, FDA found that Concept Products lacked: • appropriate testing for conformance to final specifications, including testing the stability characteristics of the drug, and proper sampling before release by a quality control unit • written procedures for production and process controls, including validation protocols and reports, and • written procedures for cleaning and maintenance of equipment.
In its response, the firm acknowledged the observations and did not commit to any corrective actions.
Company Name Location Letter Date Product Type Areas Cited Zhejiang Zhejiang, August 4, API • data integrity • spec testing Medicine China 2016
A June (YEAR???) inspection at Zheijang’s API facility revealed significant data integrity problems. These included the failure to: • have laboratory control records that include complete data derived from all tests conducted to ensure compliance with estab- lished specifications and standards • exercise sufficient controls over computerized systems to prevent unauthorized access or changes to data • provide adequate controls to prevent omission of data, and • to record activities at the time they are performed.
Laboratory personnel conducted unofficial testing without appropriate documentation, justification, and investigation. FDA found that analysts performed multiple gas chromatography (GC) analyses of samples for residual solvents and recorded these unofficial analyses into separate “R&D” folders before conducting the officially reported sample analyses. The original, unofficial analyses stored in separate R&D folders were not part of the official quality control records for the API, and the firm did not con- sider the results of these unofficial analyses in evaluating the quality of the API or in making batch release decisions for numerous batches of API.
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AUGUST / SEPTEMBER 2016 60 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 The GC system used to test for residual solvents was found to lack controls to prevent manipulation, data deletion, and unau- thorized access. For example, operators responsible for generating CGMP records had full administrator rights to access the computers containing temporary data prior to routine transfer of the data to a server. All analysts shared a common login ID and password. The use of universal administrator privileges and a single common login/password meant that actions could not be traced to specific individuals, and because the audit trail feature on the system’s software was not configured to create a file history for all activities executed by the user during analysis, the electronic data was exposed to manipulation and/or deletion without traceability.
It was also observed that different analysts predated or backdated results in the QC laboratory. Analysts were observed using predated laboratory worksheets to document system suitability testing for HPLC analyses for purity testing. The worksheets were dated five days before the tests that they purported to document were actually carried out. Investigators also observed an- alysts signing and dating microbiological testing laboratory worksheets five days before the test results would be available and backdating laboratory worksheets for impurities and content testing by four days.
The firm was asked to provide: • the results of a comprehensive investigation into the extent of the inaccuracies in data records and reporting • a current risk assessment of the potential effects of the observed failures on the quality of drugs with analyses of the risks to patients caused by the release of drugs and risks posed by ongoing operations, and • a management strategy for that includes the details of a global corrective action and preventive action plan. The firm was also directed to contact CDER’s Drug Shortages Staff if an action is likely to disrupt the supply of drugs.
Company Name Location Letter Date Product Type Areas Cited Huzhou Zhejiang, August 10, Finished • data integrity • cleaning • process control re- Aupower China 2016 cords • stability and spec testing
The September 2015 inspection by FDA of Huzhou Aupower’s drug manufacturing facility showed a basic lack of compliance with CGMP requirements. Found inadequate/missing were: • appropriate laboratory determination of satisfactory confor- mance for the drug product • a written testing program designed to assess stability characteristics • written procedures for production and process control • written procedures for cleaning and maintenance of equipment, and • batch production and control records with complete batch production and control information.
No response to the inspection had been received by FDA as of the time of the letter.
Company Name Location Letter Date Product Type Areas Cited Zhejiang Hisoar Zhejiang, August 11, API • data integrity • spec testing China 2016
Data integrity was a central concern emerging from FDA’s August 2015 inspection of Zhejian Hisoar’s API facility. Cited was the failure to • maintain complete data derived from all laboratory tests conducted • prevent unauthorized access or changes to data • provide adequate controls to prevent manipulation and omission of data, and • record activities at the time they are performed.
During the inspection, FDA reviewed electronic data from the HPLC system. An unknown impurity peak was present when the original three-month stability sample of a batch was run on October 9, 2014. This unknown peak was OOS and would have caused the sample to fail for unknown impurities, but it was not included in the official record for this stability test. Instead, an analyst ran a new sample to obtain a passing result on October 10, 2014, and only the passing result from the second sample was reported in the official record.
It was also observed that lab systems lacked access controls to prevent deletions or alterations to raw data. For example, FDA reviewed the electronic folder containing data files generated when the firm tested batches of an API for residual solvents by gas chromatography (GC). The investigator compared the file names in the folder with the metadata generated by the Chemstation software used to operate the GC system, and found two chromatograms had been deleted from the system. Because there were no controls restricting operators’ or supervisors’ abilities to alter or manipulate the data, an analyst had completed two runs and deleted the results, and then changed the subsequent file names in the folder where the reported data was stored to make it ap- pear that the deleted runs never occurred.
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AUGUST / SEPTEMBER 2016 61 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 The firm was found not to have worksheets for recording microbial test results and that the results were not contemporaneously documented. Other records that investigators requested during the inspection were not available for review. For example, during the inspection of the micro lab, investigators requested the completed microbial QC worksheet for an API batch. The lab staff led the investigators out of the lab to another room where the completed document was supposed to be located. After approximately 30 minutes outside of the laboratory without being provided the completed worksheet, FDA investigators reentered the microbi- ology lab and observed a microbiologist with a partially completed QC worksheet for the batch in question.
Noting that Zhejiang is using a consultant to audit operations and assist in meeting the agency's requirements, FDA requested: • a comprehensive investigation into the extent of the inaccuracies in data records and reporting • a current risk assessment of the potential effects of the observed failures on drug quality, and • a management strategy for the firm that includes details of a global corrective action and preventive action plan.
Company Name Location Letter Date Product Type Areas Cited Unimark Gujarat, India August 12, API • data integrity • spec testing • training • process Remedies & Ahmedabad, 2016 control • spec testing India
FDA inspections at Unimark’s Vapi and Bayla facilities in India, in mid-2015 cited inadequate documentation and investigation of OOS results and follow up corrective action.
At the Bavla facility, the firm routinely retested samples without documented justification and deleted analytical data. FDA found the firm did not adequately investigate failing or atypical results. For example, the firm obtained failing results in 2014, and did not initiate and document investigations for those failing results until July 2015. In addition, the conclusions of the investigations lacked supporting data. The firm’s response attributed all unauthorized retesting of API batches to the lack of adequate training of analysts.
At the Vapi facility, the firm was found to have concluded that the root cause of a failing impurity test related to manufacturing, even though records indicated that the same batch was manufactured at the same time as other batches that had passing results and were released. Similarly, for another batch, the firm attributed a failing test result to a step in manufacturing, even though the investigation lacked evidence to demonstrate this was the assignable cause for the failure. The firm's response to FDA’s findings acknowledged that its OOS investigations were deficient but did not provide an adequate CAPA nor demonstrate how the broad- er investigation procedure improvements will address similar root cause analysis deficiencies in the future.
The inspection found that the Vapi facility had modified the manufacturing process multiple times for an API. The quality unit did not approve these changes, nor were they documented through a change control review process. Furthermore, the firm did not place samples from any of the batches produced through modified processes in a stability monitoring program to assess the effects of these changes on the quality of the API throughout the expiry period.
Observations at the Bavla facility, not reported at Vapi, included: • lack of assurance that test procedures are appropriate to ensure that API conform to established standards of quality • lack of maintaining training records of employees involved in the manufacture of intermediates or API, and • failure to properly keep buildings and facilities used in the manufacture of API in a clean condition.
Employee CGMP training records were found to contain numerous discrepancies that raise doubts regarding their authenticity. For example, the inspection documented that 10 of 11 training records contained identical handwritten responses. The investi- gator also found incomplete training assessment forms for two employees. The forms indicated that the employees had not been evaluated as required in company procedures, yet the employees’ training files stated that they had been evaluated as “very good” for the skills in question.
Company Name Location Letter Date Product Type Areas Cited Xinxiang Tuoxin Henan, August 19, API • facilities and equipment condition China 2016
At the two facilities inspected in Xinxiang City, FDA observed a failure to properly maintain equipment, and properly maintain, repair, and keep clean buildings used in the manufacture of API where open equipment is used.
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AUGUST / SEPTEMBER 2016 62 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 For example, product contact surfaces of reactors contained product buildup, and chipped paint. Although the firm has preventive maintenance schedules, an investigator found that for those preventative maintenance activities the firm stated were conducted, there lacked records documenting their performance, and records the firm did have lacked sufficient detail.
The firm utilized open equipment for the manufacture of API. An investigator observed chipped paint on the ceiling directly above, which could have fallen into the open equipment and contaminated the API. An investigator also observed gaps around windows and doors, and holes in ceilings. The flying insects observed in clean rooms and on product transfer materials may have entered through these gaps and holes.
Facilities and equipment were reported "in such a state of disrepair as to be unsalvageable; small or minor repairs will not ade- quately correct the problems and prevent their recurrence." FDA requested written plans to renovate both facilities entirely, and submit photographic evidence of the completed renovations. A CGMP consultant was recommended. Failure to correct the devi- ations may also result in FDA continuing to refuse admission of articles manufactured in the facility, the letter stated.
Company Name Location Letter Date Product Type Areas Cited Lima & Pergher Minas August 25, Finished • QCU documentation • OOS testing • stability testing Gerais, 2016 Brazil
During a February/March 2016 inspection of Lima & Pergher’s finished pharmaceutical facility, investigators found that the firm had failed to establish adequate written responsibilities and procedures applicable to the quality control unit (QCU) and to pre- vent objectionable microorganisms in drug products not required to be sterile.
The responsibility of the QCU to review and approve all drug product production and control records, and of the unit to handle, review, process, and document change controls, out-of-specification test result investigations, and deviation investigations were not documented by the firm. Microbiological testing was also not performed on each lot of finished product. The firm approved and released for use one or more lots of components, drug product containers, or closures that did not meet the appropriate writ- ten specifications of identity, strength, quality, and purity and related tests and had no stability data to support expiry.
FDA placed Lima & Pergher on import alert in July 2016. Until the firm completely corrects all violations and FDA confirms compliance with CGMP, the letter states, the agency may withhold approval of any new applications or supplements listing the firm as a drug product manufacturer.
Company Name Location Letter Date Product Type Areas Cited Pan Drugs Vadodara, August 25, Finished • inspection delay • data integrity • QC • cleaning India 2016 • facilities and equipment condition • pests
Key concerns during an late 2015 inspection at Pan Drugs finished dosage manufacturing facility were data integrity, the lack of an adequately functioning QC unit, and the facility’s use of API manufactured at another Pan Drugs plant a few weeks after FDA had placed that facility on import alert for “egregious CGMP deviations” in May 2015. The firm used this API for the manufacture of product shipped to the U.S. market in October and November 2015.
Additionally, the quality unit approved certificates of analysis (COA) for API, as well as finished products, prior to conducting all quality control and release testing. The production manager falsified the documents by signing and dating the “Prepared By” and “Checked By” sections of the COA. Furthermore, the quality unit failed to identify data integrity issues in 11 batch production records reviewed by FDA. The production manager admitted that he falsified the signatures of other employees in the “Prepared By,” “Reviewed By,” “Approved By,” and “Authorized By” sections.
The firm also "failed to maintain buildings in a clean and sanitary condition." Investigators observed mold-like substances on the walls of the drug processing area, accumulations of powder throughout the facility, and gaps and holes in the walls around piping and air ducts. These gaps and holes were open to the surrounding environment and allowed pests to enter the facility. During the inspection, FDA observed a lizard exiting one of the holes, and evidence of other pest activity such as what appeared to be rodent droppings within three feet of bags purported to hold drug product.
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AUGUST / SEPTEMBER 2016 63 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 Investigators observed rust, dirt, and lubrication leaks on and around shared drug manufacturing equipment, and non-food- grade oil on and around it. The investigator was told that the firm had no cleaning procedure for the equipment or facility. The equipment was observed to be in poor operating condition.
The firm also "failed to exercise appropriate controls over computer or related systems to assure that only authorized personnel institute changes in master production and control records, or other records." The computer in the quality unit area did not have controls to restrict access and prevent unauthorized changes to data files and folders. All employees had access to the Annual Product Review (APR) spreadsheet, and the desktop computer containing the APR was not locked. The firm also attempted to delay the start of the inspection, and some records requested during the inspection were not provided.
FDA had placed the firm on import alert in December 2015 immediately following the inspection.
Company Name Location Letter Date Product Type Areas Cited Hebei Yuxing Hebei, September API • data integrity • aseptic and sterilization process and China 6, 2016 validation
An August 2015 inspection led FDA to have significant concerns about Heibei Yuxing’s lab records and recordkeeping practices. Missing were documentation of the time lab controls were performed, of departures from lab procedures, and of quality unit investigation and resolution of critical deviations. The following data integrity concerns were highlighted in the warning letter:
• Prior to conducting official analyses, the QC lab performed “experimental” analyses on product batches to assess whether the API met specifications, but failed to document these “experimental” tests in official laboratory records or to justify their exclusion. The investigator found the results of 2,404 HPLC injections in a folder titled “Experimental” on an instrument. The quality unit indicated that these “experimental” injections were being conducted in chromatographic units in the QC lab. Management provided different explanations in an attempt to justify the practice, including “fear” that the sample results would not pass.
• A review of the audit trails of several chromatographic systems documented that laboratory analysts had deleted raw chromatographic data on multiple occasions. The firm indicated that analysts may have been testing the system and may have deleted associated files. The firm also indicated that the deleted files may represent aborted analyses. However, FDA documented that some audit trail entries of deleted raw data files contained batch numbers for actual batch samples being tested.
• During the inspection, the firm provided an investigator a chromatogram for an assay analysis of a batch dated August 30, 2014, at 9:46:39 a.m. The firm later submitted to FDA a different chromatogram corresponding to the same analysis, instrument, date, time, and batch. The second chromatogram appears exactly the same as the one provided during the inspection, but it includes a different method file name, column type and serial number, and system temperature. Both versions of these documents could not represent the actual assay analysis conducted for the batch on August 30, 2014, at 9:46:39 a.m.
At the time of the inspection, Hebei Yuxing had documented 67 deviations in 2015 regarding microbiological contamination. FDA investigation found that microbiological contamination had been a persistent and unresolved problem at the firm since 2013.
FDA requested a comprehensive investigation into the extent of the inaccuracies in data records and reporting, a current risk assessment of the potential effects of the observed failures on the quality of drugs manufactured at the facility, and management strategy that includes details of a global corrective action and preventive action plan. The firm was also asked to contact CDER’s Drug Shortages Staff if an action is likely to lead to a disruption in the supply of drugs produced at the facility.
Company Name Location Letter Date Product Type Areas Cited Cheng Fong Taoyuan September API • facilities and equipment • aseptic and sterilization Chemical City, 15, 2016 process and validation • cleaning Taiwan
FDA inspected the manufacturing facility April 18 - 22, 2016 and reported significant deviations from CGMP for APIs. FDA re- viewed the firm's May 13, 2016 response in detail and acknowledge receipt of subsequent correspondences.
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AUGUST / SEPTEMBER 2016 64 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 Visiting the Cheng Fong API manufacturing facility in April 2016, FDA cited the firm’s “failure to have an adequate maintenance procedure to prevent contamination or carryover of a material that would alter the quality of the API." Observed were corrosion, pitting, dirt, and leaks, on and around drug manufacturing equipment. In response, the firm provided updated equipment line clearance and maintenance procedures, photos of cleaned or repaired equipment, and a list of batches potentially impacted by the poorly maintained equipment.
The inspection found that the firm had not adequately investigated customer complaints for black or foreign particles in finished drug product. For example, it received particulate complaints for a batch, but rather than evaluating reserve samples for that batch, a different batch was evaluated. The firm found that that batch contained foreign matter, but did not determine the identity of the foreign particulates in either batch, extend the investigations to other lots, nor implement adequate corrective actions. The investigator also observed filth, insects, wet layers of unidentified material on the floors, and foul odors in the cold rooms used to store raw materials and intermediates used in the manufacture of finished API. Firm officials noted that the rooms had never been cleaned.
FDA requested an updated and comprehensive investigation into customer complaints, a CAPA plan that includes identification of the foreign particles, an assessment of root cause, the impact on other potentially affected batches, and actions taken to prevent recurrence. Additionally, the firm was asked to provide an updated and comprehensive assessment of the state of maintenance of all equipment that can be used in the manufacture of APIs for US supply, and a comprehensive assessment of the adequacy of the maintenance program and cleaning procedures.
The firm was asked to contact CDER’s Drug Shortages Staff if an action is likely to disrupt the supply of drugs.
EMA GMP NON-COMPLIANCE REPORTS
The following are the drug GMP non-compliance reports posted by EMA during August and September listed by report date. The main areas of concern are listed 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 Jinan Jinda Shandong, July 29, 2016 API • raw data safety, control, OOS review China (nitrofurantoin) • training • change control • QA • process and cleaning validation
Jinan Jinda had its CEP for nitrofurantoin suspended and was issued a statement of non-compliance based on an inspection by the Italian Medicines Agency in June 2015. That inspection found an "unofficial and non-controlled storage area containing mainly raw materials and finished products...behind a panel with fixed screws to the wall," and six major deficiencies relating to breaches of data integrity, cleaning validation, and training. Although prohibition of supply was recommended based on the inspection, sales to EU customers continued.
When the Spanish Agency of Medicines and Medical Devices did a reinspection in June 2016, they found a total of 30 deficiencies, with two of them classified as critical and eight as major. The 2016 non-compliance report cites similar critical deficiencies regarding raw data safety, control and OOS review, and major deficiencies in training, change control, quality assessment, process and cleaning validations.
The 2016 report notes that a Prohibition of Supply action was taken and the nitrofurantoin CEP withdrawn (CEP 2011-240).
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AUGUST / SEPTEMBER 2016 65 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016
Company Name Location Report Date Product Type Areas Cited Alcor Guadalajara, Spain August 11, Syrup and oral • personnel • data integrity • product 2016 solution and raw materials identification • facilities, equipment, utilities and processes validation
An inspection by the Spanish Agency of Medicines and Medical Devices during June 2016, which focused on the manufacturing of oral solutions, reported 29 deficiencies, eight classified as major. The inspection found that the company did not have suitable facilities, personnel and materials resources to ensure proper compliance with GMP. The company had proposed a corrective plan in July, but during an August evaluation the inspectorate concluded that "there are many outstanding issues…. The proposed corrective actions were insufficient, diffuse and do not provide a description about the extent of the measures."
A lack of personnel at the facility remained unresolved to ensure the proper conduct required for EU GMP compliance, including the lack of a quality control laboratory suitable for performing chemical-physical, and microbiological testing, the non-compliance report indicates.
Other findings reported included "bad documentation practice, inadequate management of raw material suppliers and services providers, poor product and materials identification and deficient periodic control of the critical aspects of operations through qualification and validation processes in facilities, equipment, utilities and processes."
No specific quality defects were identified and a recall was considered unnecessary. The products are only marketed in Spain.
Company Name Location Report Date Product Type Areas Cited Artemis Hyderabad, August 12, API • QA oversight • Data integrity • Computer India 2016 (simvastatin) system validation • labelling and packaging
Based on a June 2016 inspection by the National Social Services Schleswig-Holstein in Germany, Artemis was cited for five major deficiencies across a total of 35 observations made by the inspection team.
Demonstrating a lack of QA oversight, the facility was using an Enterprise Resource Planning System (ERP) hosting GMP relevant data but outside the quality management system, the report states. "Repackaging operations were conducted without documentation and QA approval — the issuance of labels for raw materials and APIs was found inadequately controlled." Basic principles on data integrity, such as manual integration without justification and QA oversight, and the company's approach on the validation of computerized system were judged not in compliance with GMP requirements.
The inspection focused on the manufacture of simvastatin antioxidant butylated hydroxy toluene. The authority recommended prohibition of supply, but no recall, and the supplier not be approved in any new or ongoing applications.
Company Name Location Report Date Product Type Areas Cited Hospira Sriperumbudur, India August 19, Injectables • sterility • aseptic operations • 2016 environmental monitoring • autoclave load patterns • facility design
Concluding an inspection at the beginning of July 2016, the UK’s Medicines and Healthcare Products Regulatory Agency (MHRA) identified a critical deficiency regarding the sterility assurance of product manufactured at the Hospira facility. Other deficiencies noted included: • building classification and segregation by pressure differentials not based on a scientifically justified environmental monitoring program, and other procedures of critical risk not being monitored • sterility activities, such as autoclave load patterns that presented occluded surfaces and surfaces that were not free-draining, and • an SIP process with inappropriately sloped pipework requiring manual interventions not appropriately detailed.
The report summarized that aseptic processes had not been optimized to reduce the risk of microbial contamination and that simulation investigations had failed to identify root cause and appropriate actions were not taken. "All of the above issues were linked to a lack of scientific knowledge," the report concluded.
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FDA DRUG RECALLS
The following is a list of the drug product recalls included in FDA’s weekly Enforcement Reports issued during August. Included are the generic names of the products, the dosage form, the man- ufacturer, the number of lots involved, FDA’s classification, and the specific reason provided by FDA. The recalls are grouped by the general category of problem that caused them. The categories are: ● contamination/lack of sterility assurance ● dissolution ● GMP/GDP ● impurity ● labeling/ packaging ● NDA/monograph compliance ● particulate ● potency/content uniformity, and ● other spec nonconformance. Within the categories, the recalls are organized by class, with the most serious recalls (Class I) at the top.
Contamination / Lack of Sterility Assurance
Product Recaller Lots Class Reason
Ephedrine inj. Sandoz 17 II Lack of Assurance of Sterility: a recent FDA inspection at the manufacturing firm raised concerns that product sterility may be compromised. Acetylcyst Medicap 1 II Lack of Assurance of Sterility: Sterile products were not ophthamolic sol. produced in a controlled, sterile environment. Mupirocin cream GSK 13 II Penicillin cross contamination
Human Chorionic Talon All II Lack of Assurance of Sterility Gonadotropin Inj.
Ephedrine inj. Allergy Lab. 42 II Lack of Assurance of Sterility: An FDA inspection at the facility raised concerns that product sterility was potentially impacted.
Dissolution
Product Recaller Lots Class Reason
Glipizide tabs Actavis 5 II Failed Dissolution Specifications: Glipizide 2.5 mg ER Tablets exceeded dissolution specification rates for the 10 hour testing point.
Dextroamphetamine Actavis One II Failed Dissolution Specifications caps
Venlafaxine caps Zydus 34 II Failed Dissolution Specifications: out of specification dissolution results in retained samples
Venlafaxine caps Golden State 4 II Failed Dissolution Specifications: Out-of-specification results in retained sample.
Selegiline tabs Stason 4 III Out-of-specification result for dissolution of stability samples.
Bupropion tabs Amerisource One III Failed Dissolution Specifications: The out-of- specification result for dissolution was identified during 3 month stability testing.
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AUGUST / SEPTEMBER 2016 67 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 GMP/GDP
Product Recaller Lots Class Reason Amlodipine Besylate Mylan ~50 II CGMP Deviations: Pharmaceuticals were produced Tablets and distributed with active ingredients not manufactured according to Good Manufacturing Practices. Various Inj. (4) Teva All II CGMP Deviations Methylprednisolone Isomeric 2 II Lack of Processing Controls: the sterile injectable Acetate/Lidocaine products were sterilized too long leading to potential difficulty re-suspending particles. Betamethasone inj. Isomeric 13 II Lack of processing controls: Isomeric Pharmacy Solution, LLC is recalling Betamethasone Acetate / Betamethasone Sodium Phosphate 7 mg/mL INJ SUSP because of the potential of drug clumps in the vial of the sterile drug product and larger particle sizes. Amlodipine Besylate Lupin 13 III CGMP Deviations: finished products manufactured tabs using active pharmaceutical ingredients whose intermediates failed specifications. Lisinopril tab Lupin 4 III CGMP Deviations: finished products manufactured using active pharmaceutical ingredients whose intermediates failed specifications. Impurity
Product Recaller Lots Class Reason Acetasol otic sol.; Actavis 2 III Failed Impurities/Degradation Specifications: Out of Hydrocortisone otic specification (OOS) results for related compound G were sol. obtained at 12-month (at expiry) stability time-point for room temperature sample(s). Desoximetasone Gel Akorn One III Failed Impurities/Degradation Specifications: Product was out of specification for unknown impurity at the 9 month stability time point Mitoxantrone Inj. Teva One III Failed Impurities/Degradation Specifications: High out of specification results for Impurity D. Carvediol tabs Sun 15 III Failed Impurities/Degradation Specifications
Labeling / Packaging
Product Recaller Lots Class Reason Amphetamine tabs Amerisource 20 II Unit-dose mispackaging; blister cavities may contain more than one tablet /capsule.
Escitalopram tabs Lupin One III Labeling: Incorrect or Missing Lot and/or Expiration Date.
Plerixafor inj. Genzyme One III Labeling: Incorrect or Missing Lot and/or Exp. Date
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AUGUST / SEPTEMBER 2016 68 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 Labeling / Packaging (cont.) Product Recaller Lots Class Reason Mucinex caps Reckitt Benckiser One III Labeling: Label Error on Declared Strength; label on outer carton incorrectly states Diphenhydramine 25 mg instead of 12.5 mg. Also, quantity is incorrectly stated as 30 daytime and 30 nighttime
Amoxicillin oral West-Ward 2 III Labeling: Label Error on Declared Strength; bottles suspension missing colored coded panel where strength of the product is displayed.
Pantoprazole tabs. Aurobindo One II Presence of Foreign Tablets/Capsules: Firm received a market complaint stating the presence of one foreign tablet (Montelukast Sodium Chewable Tab 4mg) in the product bottle of Pantoprazole.
NDA/Monograph Requirements
Product Recaller Lots Class Reason Oxygen nasal Let's Talk One II Marketed Without An Approved NDA/ANDA: product is an wash (xylitol) Health unapproved drug due to nasal decongestant claims and not complying with the nasal decongestant final monograph.
Zinc acetate Spectrum One II Does not meet monograph: product exhibits lead levels in crystals excess of the USP monograph limits. Particulate
Product Recaller Lots Class Reason Oxacillin Inj. Sagent One II Presence of Particulate Matter; The firm received two product complaints for small, dark particulate matter identified in solution post reconstitution. Dobutamine Inj. Hospira One II Discoloration: Firm received complaints of product discoloration and particulates. Albuterol syrup Teva One II Presence of Foreign Substance: Presence of black particles described generically as cellulose- based bundles of brown fibrous material.
Potency / Content Uniformity
Procuct Recaller Lots Class Reason
Amoxicillin Oral Teva 1 II Superpotent drug: Out-of-specification test result for Suspension assay during stability testing. Beclomethasone Teva 1 III Failed Content Uniformity Specifications: Out-of- nasal spray specification test result for spray content uniformity.
Moisturizer cream Clinique All III Subpotent Drug: Two of the active sunscreen ingredients, broad spectrum octinoxate and octisalate, are below the specifications for SPF 15 assay.
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AUGUST / SEPTEMBER 2016 69 MONTHLY UPDATE - AUGUST / SEPTEMBER 2016 Other Spec Nonconformity
Product Recaller Lots Class Reason Divalproex tabs Teva 1 III Failed Tablet/Capsule Specifications
Urea Cream Stratus 7 III Crystallization: Complaints that cream appears to have crystallized
Urea Cream Exact-Rx 2 III Crystallization: Complaints received by the manufacturer of crystals forming in product
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