The 278-page A-Mab case study, a thorough exploration of how Quality by Design principles and practices can be applied to a typical biologics molecule, is now available (click here). While the import of the document won’t be known for some time, it’s safe to say that it goes far beyond any other QbD case study that we have seen to date.
One of those seeing the project through was John C. Berridge, PhD, one of three facilitators to the CMC-Biotech Working Group consortium that developed A-Mab. Berridge, ISPE European Regulatory Affairs Advisor and PQLI Project Manager, answers our questions about how manufacturers can best digest A-Mab, and leverage it for their own operations.
PharmaQbD: Is it safe to say that this a milestone document for the biopharma industry, and if so, why?
J.C.B.: It certainly is. While there is a growing number of publications, even books, on QbD as applied to biotechnology, never before has such an extensive and integrated case study such as A-Mab been placed in the public domain. Until now, it has been difficult to discuss QbD and biotechnology in depth because of concerns over the proprietary nature of specific molecules. A-Mab at last provides the substrate that both Industry and Regulators can use to discuss how the principles of QbD can and might be applied to biotechnology. I use the word “might” because some elements discussed in the case study could be viewed as aspirational—things the industry wants to do in the future. By exemplifying these in the case study we have something concrete to debate and use in establishing future best practices.
PharmaQbD: Can you remind us how the A-Mab molecule (intended for non-Hodgkin’s Lymphoma) was selected for the case?
J.C.B.: We wanted to use as much real data as we could, and a monoclonal antibody provided that wealth of data together with extensive product and process experience. Additionally, a monoclonal represents a significant number of products in development.
PharmaQbD: The document is 278 pages. Will it be too daunting for manufacturers that don’t have resources and people fully dedicated to QbD projects?
J.C.B.: I understand that this is a real concern and we did discuss this between ourselves and with regulators as we developed the case study. To do everything indicated or implied in A-Mab could be a daunting prospect until you realize QbD is actually a systematic process and not a destination. I believe there is something for everyone here and I really hope that all sectors of the industry will be inspired by seeing that the application of QbD principles can be straightforward, and can be applied progressively, for example starting with just a single unit operation.
PharmaQbD: It will be hard for some manufacturers not to take this as a “prescriptive” document, simply because there have not been other examples that so thoroughly map out what a QbD approach to process development is. What’s the best way to approach it and benefit from it?
J.C.B.: A-Mab is not intended to create a standard. We deliberately chose not to construct a mock submission, or even present the case study in the CTD format. This was so that it is clear that A-Mab is not prescriptive document. What it does do is show a variety of approaches to applying QbD to biotechnology product realization. As an example, you will find 3 different tools described for assessing and ranking critical quality attributes.
My advice to your readers is that the maximum benefit comes in three ways. Firstly, by using A-Mab as a source of examples of the science and risk-based tools and techniques that support QbD.
Secondly, A-Mab is a true case study, a teaching tool that provides a systematic way of looking at the development of a monoclonal, using prior knowledge, using risk management, collecting relevant data and distilling it to information and understanding. As a result the reader can gain a greater insight into what was done and why, why particular decisions were made, and what might be important to think about in the future. For example, the chapter on regulatory implications doesn’t prescribe what you might need to do in a post approval world. It includes discussion on approaches or thought processes you might consider when moving around within a design space, or perhaps extending it, or if a new technology were to be introduced, and the associated risks.
Finally, as we found when developing the case study, enormous benefit comes from discussing and debating the case study. I would encourage you to join the workshops that are now being developed by ISPE, and CASSS, where we plan to engage both industry and regulators in debates on the scientific merits and applicability of the tools and processes described. Furthermore, within ISPE’s PQLI initiative, we hope to develop further the case study both in depth and breadth and this could provide opportunities for a far wider contribution to the biotech industry’s appreciation of the applicability and benefits of QbD, Please watch the ISPE website for updates.
PharmaQbD: The case study devotes a great deal of space to TPP, molecule design, and early-stage development. What’s the significance of this?
J.C.B.: QbD has to start with pre-defined objectives; one has to start with the end in mind. Product realization using QbD places a greater emphasis on the patient needs than perhaps was the case with more traditional approaches. Furthermore, one of the greatest challenges for biotech is complexity. Without an in-depth appraisal of the TPP and QTPP, it is not possible to identify the critical quality attributes (CQAs), to rank them according to criticality, and to understand the potential for their interactions. We’re talking about designing in quality, so it is important to ensure that the molecular design and development program will truly enable this.
PharmaQbD: The most substantial discussions of design space (which has often been a “starting point” for some QbD projects) come much later in the document. Again, what is the significance?
J.C.B.: Many people seem to think that QbD equates to design space(s). This simply isn’t the case. As I said earlier, QbD is a process, a journey. That process may enable you to propose one or more design spaces, or you may choose not to use the design space concept at all. A true, robust design space can only be constructed towards the end of a development program when the experimental data, coupled with a series of iterative risk assessments, support its establishment. In A-Mab, we felt that the process of acquiring the understanding of the relationships of the CPPs to the CQAs to support a robust control strategy should be our focus. There are design spaces proposed, of quite varying natures, and these in a way represent a milestone of that journey, providing as they do the support for change management and continual improvement.
PharmaQbD: What can small-molecule manufacturers and their QbD teams take away from A-Mab?
J.C.B.: Oh, so much, it’s hard to know where to start. Three major messages might be, firstly that there is no difference in the applicability of QbD principles between small and large molecules. For sure the molecules and their manufacturing processes differ, but they differ in the degree of complexity, not in any ways that would preclude the use of QbD. Secondly, QbD is here. If the principles can be applied successfully to complex molecules such as monoclonals, then they certainly can be applied to API’s made by chemical synthesis and their drug products. Finally, that by reading the case study and joining workshops and seminars on A-Mab, an even greater understanding can be gained of tools that are equally applicable to small molecules.
PharmaQbD: The release of the case study is not the end of the process. What are the next steps for A-Mab?
J.C.B.: The team that developed the case study did such an amazing job in its development that we now have a document that addresses so many of the concerns previously expressed by the biotech industry, and which may have been impeding implementation of QbD. Our goal, within ISPE’s PQLI initiative is to facilitate adoption implementation of the recent ICH guidelines with initial focus on QbD.
Our first steps are to create a greater understanding of why the case study was developed and presented in the way it is, and how it can help dispel these concerns. We’ll be doing that in presentations at our upcoming meetings, and through webinars, etc. During 2010 we are planning more extensive workshops where we will be inviting CMC-BWG authors and regulatory representatives to join in more detailed discussions on the aspects of the case study that are generating the greatest interest.
Simultaneously, within our PQLI biotechnology team and with our PQLI community of practice, we are looking at how to extend the utility of the case study by considering some of the areas that are not fully addressed within the current case study, and perhaps by showing how the tools can be applied to other therapeutic proteins. The dates and times of all these activities will be published on our website.
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