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

Transcription

1 PhRMA REPS MARY OATES AND MOHEB NASR (RAPPORTEUR) ON ICH Q12 At the ISPE Quality Manufacturing Conference in early June, Pfizer Quality Global Operations, Environmental Health and Safety VP Mary Oates, who represents PhRMA on the ICH Q12 EWG, reviewed the development of the guideline, the issues it is tackling, and the objectives is it working to achieve. GlaxoSmithkline Global CMC Strategy VP Moheb Nasr, who is serving as the industry rapporteur for Q12, followed with an update at a PDA workshop, held in the early fall, on how the initiative had advanced in the intervening four months. [The first part of Nasr s remarks at the workshop, in which he covered similar ground to Oates, is not included]. Prior to joining GSK, Nasr was Director of the Office of New Drug Quality Assessment at CDER and participated in the development and implementation of the ICH Q8-11 guideline series. Both Oates and Nasr clarified that, although their remarks were informed by their participation on the EWG, they were speaking for themselves and not for the EWG, PhRMA or their companies. PFIZER'S OATES ON Q12 DEVELOPMENT AND ISSUES TO BE RESOLVED I am delighted to give you a very brief overview of ICH Q12. I will talk for a few minutes both about the vision of Q12 as well as its current status. I think that everyone who has any familiarity with Q12 is probably pretty enthusiastic about it, because we believe it has the potential to be quite impactful. It is taking on a very challenging topic. I will talk a little bit about those challenges as I go through the presentation. If we can address the challenges of change management, it will have a significant impact on all of us and by all of us I mean regulators, every element of the pharmaceutical industry, as well as patients. The exact title of ICH Q12 is Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management. Put a little bit more simply, what that means is: How can we optimize the change management process throughout the pharmaceutical product lifecycle? The vision is that Q12 will enable reliable supply of quality products to patients. How will it do that? It will do that by streamlining the change management process throughout the pharmaceutical lifecycle. So when we think about ideally how that would work and this is not a new concept, it is one that has been talked about for years ideally, a firm would be able, within the confines of their own quality system, to make manufacturing changes. That is really what we are talking about here today manufacturing changes to make manufacturing changes without prior regulatory approval. If we can accomplish that, and ensure that those changes are robust and that they meet all the

2 requirements, and that patients will actually benefit from those changes, that would be a significant accomplishment. The Problem So why did ICH agree that Q12 is an important document? Well, first let s talk about what the challenges are. These are incorporated in the problem statement identified for Q12. One of the problems for change management perhaps the most significant is a lack of a globally harmonized approach on these technical and regulatory considerations. So for a company like Pfizer we have approximately 20,000 SKUs that we sell in more than 140 markets around the world you can imagine that if we want to make a change to any of those manufacturing processes or products, it is quite an undertaking. I think five to eight years, as [moderator Steve Mahoney] said, is probably about right for a significant change. That has impact on patients, has impact on regulators, and it has impact on industry. Significantly, every time we want to make a change, we have to take a step back and say, is making a change worth the effort that has to be invested in order to make this change around the world in all the markets where it is affected? It is also quite difficult if you can make a change in a few markets, but not in all markets. It adds a lot of complexity. So this lack of global harmonization is really quite a challenge. And as the slide says down below, it does hinder innovation and continual improvement. Because really the choices that we have to make are to make the changes that are must haves, but not necessarily the changes that are nice to haves. And a lot of those around innovation and continual improvement really fall oftentimes into that nice-to-have category. Another reason that ICH decided that Q12 is important is because Q8, 9, 10, and 11, although incredible and important documents in and of themselves, when taken together had the promise of providing postapproval operational flexibility. Unfortunately that has not really been achieved. Perhaps one of the reason for that is that the main emphasis of ICH to date has really been on the early stages of the product lifecycle. And Q12 intends to address that by focusing on the later stages in other words, the post-approval stages of the product lifecycle. Background, Objectives, Scope, Issues to be Resolved, and EWG Makeup Background So just to give you a little bit of background on how Q12 came to be: There was a quality strategy workshop last year in Minneapolis, and Q12 in other words, change management was identified as the top priority. A concept paper and business plans were drafted, and

3 the ICH steering committee endorsed Q12 in September of last year. The EWG was formed, and in a little while, I will show you the members of the EWG. It is a very large and diverse group (see IPQ Dec. 18, 2015). As you can imagine, there is an awful lot of interest in this around the world. We held our first EWG face-to-face meeting in Lisbon in November. I am a member of the EWG. I am part of the PhRMA contingent to Q12. Our rapporteur is also from PhRMA, and that is Moheb Nasr. Since then we have done a tremendous amount of work. We have had multiple phone calls. And in fact, we have drafted original sections of Q12. We will be getting together this coming week in Japan for our second face-to-face meeting. Objectives As I have said, one of the things that we are trying to accomplish through Q12 is harmonization, at least across the ICH regions, of change management. Also, if we are going to accomplish this vision of having firms being able to make at least some changes without prior regulatory approval more than we can do today clearly regulators have to have confidence and trust in firms quality systems. That will be very important. We also believe we have an opportunity to optimize the division of labor between assessors and inspectors in regulatory agencies around the world. It will be very important from a Q12 perspective that the role of each function is clear. And obviously we want to support continual innovation and improvement for the benefit of patients around the world. Scope The proposed guideline will apply to all pharmaceutical products. Importantly, it does not just apply to new products - in other words, products that are currently in development - but it is intended to apply to products that have been approved and are currently on the market. Issues to be Resolved So just as [Q11 Q&A Rapporteur Tim Watson (Pfizer)] talked about [IPQ July 11, 2015], our concept paper identified issues that need to be resolved. There are three listed here: The first has to do with the regulatory dossier itself, and some of Tim s comments are quite relevant in terms of this as well. Really, a lot of times it depends on what you put into your dossier that determines how changes are made later on. This ties in to the definition of a regulatory commitment. Is everything in the dossier a regulatory commitment? Or are only certain elements a regulatory commitment? And can Q12 help to delineate that? If that is all we accomplish although that is not all that we hope to accomplish it should reduce some of the discussions that Tim was talking about earlier, because it will be very clear to firms as well as regulators what will need to be submitted for a regulatory change.

4 I talked about the importance of the pharmaceutical quality system. Specifically, Q10 talks about the entire pharmaceutical quality system, but specifically risk management, change management, and knowledge management are critical to a firm s ability to effectively and appropriately manage change and the risks that may be inherent in those changes. The third aspect that needs to be discussed and resolved is the use of post-approval change management plans and protocols. I am going to talk about this more in just a minute. This is a tool that is available, at least in the US and Europe to firms today. I believe that this is a highly underutilized tool. Q12 envisions enabling the use of this more effectively. Expert Working Group As I said, we do have quite a large expert working group, probably double the size of the one that Tim showed in his picture. Thirty or more folks are on the team, so we do have quite a diversity of experience and expertise. I will say, however, that the team dynamics to date have been outstanding and it is clear that everyone is committed to achieving the objectives. Everyone is very invested in doing that. The participating organizations are listed [in the box below]. EWG Progress and Possibilities This is our work plan. You can see where we are June We do plan to have our Step 2 document finalized by the middle of This, for an ICH guideline, is a very aggressive time frame. But we are all committed to meeting it. About the progress that we made at the face-to-face in Lisbon; Essentially that meeting was a brainstorming session an opportunity for everyone to share the thoughts that they have about the different important elements as well as foundation building, so we could identify the pieces that we thought were important so that we could separately and collectively work on them to make good and rapid progress. I want to spend just a few minutes on this slide.

5 At this point, I want to make the same disclaimer that Tim did earlier and say that everything I am going to say is reflective of my own opinions, my thoughts, having been working on Q12 for some number of months now. It is not reflective of any consensus of the Expert Working Group or of PhRMA. Post-Approval Change Management Plans When we think about Q12, what can Q12 accomplish? I think that Q12 can enable a couple of different pathways to change management. The first pathway can be done, at least in two of the ICH regions today, and that is the post-approval change management plan or protocol. Like I said, I think that industry does not benefit from that nearly as much as we could today. I think that what needs to be provided is clarity around how it can be used, probably from both a regulator perspective as well as an industry perspective. Essentially, if you are not familiar with it, basically it is a document that would be submitted to a regulatory body that defines future changes that you want to make. It would delineate the criteria that you are going to meet in order to make those changes. And that document would be approved in advance really before you start any of the work. Once the regulator approves the plan or protocol, you would go about doing the work to demonstrate the benefit and the value of the change. The change can be made. And then you would inform the regulator that you had met all the criteria you may or may not have to submit the data and without additional approval you can go ahead and implement the change. In order to do something like this, a firm really has to think about the future. They have to think and plan about where they want to go. So it does require a fair amount of investment. But once that work is done, implementation can be virtually immediate, so there is a lot of value in that. What Q12 can do here is to bring some clarity around how to do that more effectively. Relying on the PQS The second pathway that Q12 can enable, I think, is a bit more revolutionary than evolutionary. And I will use an example. Is it possible that a manufacturing site could be approved to implement the vast majority of their changes certainly, not every change, but the vast majority without prior approval? How could this be done even under the current regulatory constructs that are available to us? One potential pathway, just thinking out of the box, is that a post-approval change management plan could be used for something like this. So a manufacturing site that believes they have a very robust quality system, that they have all the elements that are necessary, could develop a post-approval change management plan where they list all the changes that they think they should be able to make within the confines of their pharmaceutical quality system. They would outline the robustness of their quality system, why they believe they are qualified to do this, and that could be submitted to a regulatory agency. Now clearly, under these circumstances, the bar is higher.

6 Certainly, an agency may want to come in and do a specific assessment of what is in this post-approval plan specifically to look at risk management, change management, and knowledge management to verify that the firm does have the proper systems in place to be able to accomplish this. Once the regulatory agencies assess that, they could grant approval under that post-approval change management plan for this manufacturing site to make those changes. Sort of a different concept, but it does fit in to some of the thinking that we are currently having on the ICH expert working group. I just wanted to leave that with you for you all to think about because it is something that we will be exploring again understanding that it does raise the bar. There would have to be some way for regulators to have that additional trust in the firm s capabilities. Also, in this sort of context there still has to be a lot of transparency with regulators in terms of the changes that are being made. One of the things we have talked about: Is it necessary, for example, to submit the changes as they are being made maybe even those that historically would not have been submitted so that the regulator has a full view of the current state of the manufacturing process, for example?... Desired Attributes I would like to conclude by sharing the desired attributes of Q12. We want this to be a clear, comprehensive, and self-contained document. We want to learn from the previous ICH experiences. Our desire is not to have an IWG later on, but to really enable everything to be in this single document. We do not know if that will be possible, but that is certainly our goal. We would like for this clearly to be a harmonized guideline that is useful globally in the future, at least initially useful in the ICH regions. It needs to be both forward looking and pragmatic, and both conceptual and practical. The EWG believes that if we come out of this exercise with something that is not practically implementable then we will not have succeeded in our objectives. Finally, the ultimate goal is to support innovation, continual improvement, and to assure reliable supply of quality product to patients. Q12 UPDATE BY RAPPORTEUR NASR AT END OF SEPTEMBER We had a meeting in Fukuoka a couple of months ago. We had a lot of activities and drafts. We were able to compile a version of the technical document. I can advise you that it has not been made public because it is not readable. But we have something that we can label as version one. And we got an agreement on how to progress moving forward with the guideline.

7 I am putting together the drafts we had from the work that was done this summer, and the outline [from Fukuoka] looked very different than this. The Vision Let s try to step back and see what we are trying to do. I think we have a vision. The vision that the group has is, what can ICH Q12 do in order to assure reliable supply of quality product to the patient? I think we all agree that, regardless of what we do the regulatory system, the technical information, the development, the business and all of that we all have an obligation that we should have high quality product available to patients. The development of drugs is not an academic exercise. We have heard from Dr. Woodcock and the FDA for years that they have a vision. Dr. Woodcock s vision that was presented in a workshop in October 2005 was that the industry should become, with regulatory help, more efficient, agile, and produce high quality products without extensive regulatory oversight. That was the FDA vision. And now we have our ICH Q12 vision. I think you can see the connection. The connection is, how can we assure quality products? How can we assure that good science and risk-management principles are used? How can we get there? In our view, if we achieve that desired state, most of the manufacturing changes should be managed under the company s pharmaceutical quality system. It is currently managed under the pharmaceutical system, but we are making the regulatory process part of the quality approach. So we delink that. So how can we continue to manage manufacturing changes under the pharmaceutical quality system? There is nothing new there. What is new is, without the need for regulatory approval prior to implementation or the do and tell. So in other words, if there is a need to make a manufacturing change, you make an assessment, based on science, based on product development knowledge, etc, and you have a plan, you start implementing the change, and you notify the regulator of the change. Progress in Fukuoka, June 2015 Established Conditions One of the key aspects is the regulatory commitment/established conditions. So at the time we were getting together to start the drafting, FDA issued the draft guidance, May this year, on established conditions. The draft guidance, in my personal view, has some good stuff. I disagreed with a couple of things. But it was good that the agency took the initiative to put something on paper about established conditions.

8 The team agreed a month later in June that rather than reinventing the wheel, we could use the FDA draft guidance as a starting point to work on the development of established conditions. The drafting team did a good job determining how we could do that. They came up with working conditions. And the process is moving forward. As a matter of fact, I can share with you that I am in the process of putting the different outputs into a single document now. I was working on it in the last couple of days and I continue to work on it. That section of the ICH Q12 guideline looks really good. So ICH Q12, I can assure you, will deliver on clarifying what established conditions are and how that will be translated into practical implementation. I would like to thank my ICH Q12 colleagues. I am not going to name names now, who is doing what, so you do not go after them if things do not go well. You can come after me. Frequent Manufacturing Changes We are also working on frequent manufacturing changes. I think we realize that there are frequent manufacturing changes, and ICH Q12 could provide guidance about the expectations with ICH Q12 and the tools and the enablers and all of that about how you can manage the frequent manufacturing changes differently. We know what we did before Q12. How can it be done after ICH Q12? We identified three types of changes analytical methods, manufacturing processes, and manufacturing sites and we are going to have some discussion on that in ICH Q12. Lifecycle Strategy Section There is a new section that we agreed to work on in Fukuoka and we continue to work on. It is not there yet. But here is where we are: Many of us think that there is value in having a section in the guideline about how to link product development to control strategy, and use that linkage between product development and control strategy to identify the established conditions. Why is that so important? Because having a discussion in ICH Q12 at a high level about established conditions is not going to be that valuable when it comes to implementation. In my view, and I think within ICH Q12 there is an agreement that the list of established conditions will depend on the level of development and the controls you have. If you have very empirical development and your control is only a list of testing that you do, the manufacturing process that you have and the list of testing that you have are your established conditions. If you are doing enhanced development quality by design development you understand the impact of attributes and parameters on the quality of the product. You have fewer critical parameters. And many of these critical parameters and attributes you are controlling within your robust control strategy. Therefore, you will have a much shorter list of established conditions.

9 So established conditions is not going to be one size fits all. It will depend on the level of development, the controls, and the quality system. And this will be a value of what Q12 can do, whereas Q8, 9, 10, and 11 did not do. That is why it is important to link the product to the established conditions. That section also could provide manufacturers with the opportunity to propose how to manage future manufacturing changes, rather than wait and submit and then you get back and forth discussions and so forth. You could also use that to develop and use comparability protocols and so forth. There is an agreement now within ICH that comparability protocols will be a part of ICH Q12. It will not be limited to only US and Europe our Japanese colleagues agreed to that. I am going to use that discussion to share with you the involvement of countries outside of ICH. We have been working really hard. Because from an industry perspective, even though we have challenges within ICH, the majority of the challenges come from outside the ICH regions. The question that I have that we can discuss: Would having that linkage and developing this product development lifecycle strategy be value added or not? Is it good to do it or not? How should we do that for a product? Can we use a similar approach for facilities? This is a schematic description of the product lifecycle based on ICH Q10 and some of the industry and regulatory activities that are currently happening. Issues Under Discussion My reason for coming to talk to you this afternoon is not only to accept the kind invitation, but also to seek your feedback. And I think you have an opportunity I am here, [FDA s Bob Iser], other EWG members are here to share with us your thoughts. This is more important to share now while we are

10 developing the guideline rather than after it is public and you provide your comments through the docket and so forth. I am summarizing on this slide some of the issues that are currently under discussion. I will try to explain why it is important to resolve these issues. [Story continues on the next page ] Level of Detail The first one is the level of detail of ICH Q12. We recently developed some high-level guidelines Q8, 9, 10, and 11. And I was part of that. I advocated for high-level principle guidelines, because when it comes to development, you lay the principles, and the development will depend on the product, business needs, and so forth. The question is, should we have the same level of detail in ICH Q12? Or should we describe more about best practices for example, for knowledge management and change management? Why is it important to have that discussion? It is because we need to provide regulators with the confidence that they need to trust our quality system and our change management process to manage the changes. So we need to have an agreement about what their expectations are and what they are going to do for all manufacturing changes regardless of the regulatory filing mechanism. Because right now the

11 regulators do not pay as much attention, even though they should, to what we are doing in our quality system. They do it during an inspection, but the assessors don t, because they see it in the file and they have an opportunity to review it and say yes or no. Now, we are not going to do that. We are going to do it ourselves. And we are going to share the data with them after the implementation. That is the vision. So how can we have that agreement? How can we gain their trust? And how can we assure that we do as well as we do now or improve upon what we do now across all the sites and across all the products? Product Development and Lifecycle Strategy The second point is the product development and lifecycle strategy that I mentioned a couple of slides ago. And again, what is it? It is a summary of product development, control strategy, proposed established conditions based on the above, product lifecycle management strategy, and proposed regulatory filing for future changes. Again, the question that I raised earlier, I will raise it one more time: What is the value of developing an additional section in Q12 and the inclusion of that section in the regulatory submission? It has to have a value, because we want to simplify. We do not want to make things more complex. If we agree there is value and some of us think there is considerable value how can we word that in the current CTD? Should it be in module two or module three? And how would that fit with the Japan application form, and so forth? Should we make that section mandatory or optional? My thinking is that there are some elements of that section that are currently mandatory the product development and the control strategy. And I will argue that every company will propose established conditions going forward. So there are some mandatory aspects as well. The only thing that could be optional is a company proposal of making future changes if you know that at the time of filing. Established vs. Non-established Conditions When it comes to established conditions, considerable progress has been made. But what about nonestablished conditions? What are we going to do with that? The company can propose established conditions for the product and the processes. What do you do with non-established conditions? Are they going to go away? Are they going to be left out? Are they going to be included in the file? How are you going to make that distinction? How can they be evaluated? What is the role of inspection, and so forth? So, you see from the above, that there is a linkage between development and established conditions and simplification of lifecycle management. Legacy and Bio Products How does that apply for legacy products? Many of these products were developed before the QbD age. How are we going to do that? What would be the opportunities? And how can Q12 facilitate the majority

12 of products we have on the market that were developed a long time ago? We need to have some discussion on that. And how can we assure their utility not only for chemical entities, but also for biopharmaceuticals and biological products? Conclusions In conclusion, as you hear in this meeting and other meetings as well, ICH Q12 is a priority for industry and regulators. It is a challenging topic, because we need to balance industry and regulatory expectations and needs. Saying that, I think it provides a unique opportunity to: enhance transparency and build trust facilitate product lifecycle management, including continual improvement if we adopt the do and tell strategy. I want to be very clear how that is going to take shape. I think Q12 tools could facilitate accelerated development, such as adaptive pathway and breakthrough therapy designations. Because with these new initiatives coming from the US and Europe, where less information will be available at the time of the filing, the lifecycle strategy becomes even more important. So if you think we have problems with products now where you are taking years and years to develop and get it through the review process, imagine if you have a very condensed time to get the product ready for review and approval to bring essential medicine to the patient. I think the lifecycle strategy and activities that you will be expected to do after launch will become more important. [address difficult regulatory issues such as regulatory commitments and improve compliance] harmonize technical and regulatory aspects within and outside ICH. We have considerable participation, not only within the expert working group, not only within ICH, but also outside ICH, from Asia, WHO, trade associations, and others. As I said earlier, I think today s discussion will be very helpful to me and others in the development of ICH Q12. I end my presentation usually by trying to frame where this discussion and other discussions are. I hope you can agree that we all have a shared vision of making sure that we have high quality pharmaceuticals available to the patients who need them. I believe that ICH Q12 is beneficial to the patient, the regulator, and the manufacturer, under the following understanding, if you wish: that manufacturers should be empowered and responsible for the

13 quality of marketed products and that has to be done with appropriate regulatory oversight to assure public health across the globe. Visit IPQPubs.com every day for IPQ s real-time tracking of the latest CMC and GMP developments from Inside the Global Regulatory Dialogue IPQPubs.com IPQ Publications LLC, 7920 Norfolk Avenue Suite 900, Bethesda, MD Phone: , Fax: Contact us at: customersvc@ipqpubs.com Contents Copyright 2016 IPQ Publications LLC. All rights reserved.