How to learn about biologics CMC: advice on technical issues, regulatory strategy, and more

Chemistry, manufacturing and controls (CMC) are an integral step in creating an effective biological product — and a crucial element of an effective biologics regulatory submission.

CMC activities ensure that a biologic or biosimilar product remains safe and consistent from drug discovery through technical development and production, and ultimately through regulatory approval and commercialization. But various factors — new guidances for industry, biologic product categories, advances in published research — all add to the difficulty of learning about CMC for pharmaceuticals, let alone mastering it.

RAPS spoke with Patricia Cash and Joe Quinn, presenters at Biologics CMC: Regulatory Challenges and Trends, a workshop on 10-11 October 2024, to get their takes on common problems in biologics CMC, pitfalls that often affect CMC experts trying to better navigate regulatory affairs, and more.

What are some common technical issues that arise in biologic product development, registration, and lifecycle management?

Patricia: One of the biggest differences between biologics and small molecule drugs is the size and complexity of the biologic. This means that the biologic can never be fully characterized (the complexity requires that there may be variants or forms that we do not see analytically). Therefore, we have to be much more diligent about the regulation of biologics, as we need to confirm that any changes in the process have not adversely affected the product. We also must include extensive analytical testing throughout the process, not just at the end.

Joe: There is complexity to dealing with biologics, including molecular, cellular, and viral product types as well as other sophisticated biologically based constructs. There is also an inherent level of uncertainty in terms of elucidating structural/functional characteristics as described above, establishment of a suitable body of scientific knowledge and supporting data to successfully develop a biologic product is a long-term process accompanied by ever-present technical challenges.

As examples, the enhanced focus on the manufacturing process definition and well-characterized control strategies that are required entail considerable development efforts of an iterative nature throughout a product’s lifecycle. Some common technical challenges include manufacturing process variability, consistency of biologically sourced materials, and linking operational parameters to various aspects of product quality in operations that employ complex biological systems.

What’s one common challenge that CMC experts run into when diving deeper into the regulatory implications for their products?

Patricia: One of the challenges is that biologics are generally grown, not synthesized. As nature is growing the biologic, we can direct that growth, control what we feed the cells, etc., but nature is doing the production work, and that means there is an aspect that we cannot control. Since we cannot directly control every aspect of production, we need to implement tight ranges and analytical tests to monitor production, thereby ensuring a consistent product.

Joe: One general challenge that accompanies biologics development and regulatory is that with limited exceptions, there is nothing resembling a “one size fits all approach” to rely on. Interpreting and applying relevant regulation and guidance, understanding current expectations based on evolving best practices and technical advances, and working collaboratively with regulatory agencies are examples of important foundational elements that support the development and ongoing management of appropriate regulatory strategies.

How did you end up learning about — and then improving your knowledge of — CMC for biologics?

Patricia: As Joe and I like to borrow from the Farmers Insurance commercial, “We know a thing or two because we’ve seen a thing or two.” The best way to gain knowledge of CMC is through experience, but a great way to gain experience is by hearing about and heeding the experience of others. One of the things that I love about teaching the RAPS workshops is that our “students” are usually very experienced and willing to share those experiences with the class. The interactive nature of the class allows me to learn something new every time.

Joe: Agree fully with Pat’s comments, particularly the shared experiences in the RAPS workshops. Working effectively in the field of biologics requires continuous learning – technology is evolving very rapidly. For example, the emergence of new biologic product categories in recent years such as CAR-T therapies, viral vector gene therapies, and mRNA vaccines, just to name a few.

The regulatory landscape is evolving rapidly to address the needs of these new technical frontiers as well as to continuously align with evolving best practices associated with more established biologic categories such as monoclonal antibodies, recombinant proteins, etc.

Maintaining competence in our complex regulatory field is challenging. Dedication to ongoing study of guidances, keeping up with relevant publications, review of regulatory precedents such as approved product technical information, and digesting materials from advisory committee meetings are just some examples of important knowledge-improving practices. Participating in virtual or in-person workshops is highly valuable. RAPS provides some great resources and tools in addition to workshops, for example collaboration with members of the regulatory community via Regulatory Exchange, Regulatory Focus articles, chapter events, etc.

What motivated you to host an online workshop about this topic? And then host it again, and again, and again?

Patricia: When I first was asked to teach a RAPS workshop, I thought I would give it a shot because I really do love teaching. I keep coming back to teach because of the caliber of participants in the RAPS workshops. When you have a class with directors and VPs of regulatory from multiple sizes and types of companies, as well as regulators from different countries, it is impossible to walk away from the class without learning something. I keep teaching because I am continuing to learn from others in the class.

Joe: For me, serving as an instructor for biologics CMC RAPS workshops, both in-person and online, was initially a logical extension to the teaching that I had been doing (and continue to enjoy) in the Temple University Regulatory Affairs/Quality Assurance graduate program.

Additionally, leading workshops was an opportunity to increase my involvement in RAPS initiatives. Although similar in some respects to teaching university courses, I find that the immersive experience of a RAPS workshop is quite stimulating — each time out, I look forward to collaborating with and learning from other professionals over the course of two full days, always meeting interesting people and establishing great network contacts in the process.

What do participants get out of attending Biologics CMC: Regulatory Challenges and Trends?

Patricia: Participants who attend will get an overview of the CMC process, with a focus on why and how it is more complicated for biologics than small molecules. We review each of the CMC sections, emphasizing what is required to develop a drug and file for approval, based on the section. The class is packed with practical examples, which stimulates discussion of pragmatic ways to conquer some of the CMC-related problems that we all face. 

Joe: Pat and I endeavor to provide a solid scientific and technical understanding of biologics CMC with an organized and practical connection to the regulatory process. For example, we cover not only what technical information and data, in what form, is required to successfully develop content in specific sections of regulatory submissions. We also strive to reinforce why these expectations exist.

Biologics CMC: Regulatory Challenges and Trends takes place on 10-11 October 2024.