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PDA Comments Address Risk Management Approach to Gene Therapy CMC

Earlier this year, the U.S. FDA released several, final guidances for cell and gene therapies, including Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs). In 2018, a PDA team of cell and gene therapy subject-matter-experts commented on the then draft version of the guidance.

The PDA Letter reached out to commenting team member Karen Walker, Senior Advisor, Cell and Gene Therapy Manufacturing, Genentech, and regular PDA volunteer, for her thoughts on the final guidance and how it compares to the PDA comments.

PDA Letter: What was it like to volunteer on the commenting team?

Walker: It was good. I have commented on other documents for PDA as well in the past and I think it is a good process. Generally, there is sufficient time given for people to dig into comments. There is a triage process within PDA going over the various comments, making sure that everyone’s point of view is considered but, at the same time, not overly commenting on areas where there might be similar points.

[Editor's Note: View the 2018 PDA comments on the PDA website.]

They try to avoid redundancy in commenting and make sure that the comments are relevant.

PDA Letter: Were any of the specific PDA comments addressed in the final guidance?

Walker: It looks like some were addressed and some were not addressed, which is okay. In general, the PDA commenting team’s main overarching general comments about focusing the guidance more specifically on what should be included in an IND and less on GMP principles. From what I see, the final document is more focused on what should be included in the IND, which is actually the title.

PDA Letter: Did the Committee compare the draft U.S. FDA guidance with regulations in Europe and other regions?

Walker: Yes, we did, and some of our comments were actually made in that light, trying to obtain more harmonization. I think that the final document does an okay job in harmonizing with all the different major regions, mostly Europe.

Risk management plays a key role in the guidance. Regarding cell and gene therapy manufacturing, what other PDA resources are available for CGT manufacturers to implement risk management in their processes?

Technical Report No. 81: Cell-Based Control Strategy is a really good document that a lot of people are already referencing and should continue to reference. It does talk about the risk assessment as it relates to your control strategy. It addresses the appropriateness of that strategy. It is focused on cellular therapies and it would be great if PDA could look at supplementing that technical report with guidance that would apply to other therapies that are considered advanced therapy medicinal products (ATMPs).

I think the other PDA documents around viral safety and setting up a traditional risk management strategy are good as well. The basics do apply.

[Editor's Note: In 2017, the PDA Letter filmed Karen Walker discussing the manufacturing behind the cell therapy Kymriah when she worked for Novartis.]

PDA Letter: Are there any next steps for the PDA commenting team?

Walker: I think, for this document, we are done. There are other commenting teams, of course, and they are assembled when there are guidances of specific interest coming out and people are recruited to comment on them. For example, we also recently commented on the PIC/S Annex 2A and B, which was issued for GMPs for ATMPs but also GMPs for biological products. That commenting is also finished.

PIC/S has revised Annex 2A and has sent it out again for comment the week of April 13, and the PDA team is currentlycommenting on the revision. I would say that it is a good process for industry to provide their voice to these emerging guidances.

PDA Letter: Do you expect to see more FDA guidances coming out that impact cell and gene therapies?

Walker: Well, they released a whole suite of them at the beginning of the year. I think there were seven issued in the January-February timeframe. There will likely be more coming out in 2020, provided they can keep to their timelines given this quarantine state that we are all in.

About the Expert

Karen WalkerKaren Walker is a Senior Advisor, Cell and Gene Therapy Manufacturing at Roche/Genentech, and is the Vice Chair of PDA’s Biopharmaceutical Advisory Board. She brings 30+ years’ experience in the biotech industry, holding positions in development, validation, regulatory affairs and quality, including the role of vice president and global head of technical development and manufacturing for Novartis’ Cell and Gene Therapy Unit at the time of the development and registration of Kymriah, Novartis’ CAR-T therapy.

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