Industry calls for revisions in FDA’s CGT manufacturing change guidance

Pharmaceutical industry and regenerative therapy groups want the US Food and Drug Administration (FDA) to take a more nuanced approach in guidance on reporting manufacturing changes for cell and gene therapy (CGT) products. They called on the agency to better differentiate between the types of CGT products, their stages of development and the level of risk these changes pose.

The comments were submitted in response to FDA’s draft guidance on manufacturing changes for cell and gene therapy products (RELATED: FDA issues draft guidance on reporting manufacturing changes for gene therapies, Regulatory Focus 17 July 2023).

The guidance, which was issued by FDA’s Center for Biologics Evaluation and Research (CBER) in July 2023, aims to assist sponsors of CGTs in determining whether certain types of manufacturing changes would necessitate the filing of a new investigational new drug application (IND) or biologics license application (BLA). The guidance also outlines the necessary information to include in comparability studies demonstrating that manufacturing changes do not adversely affect the quality of the post-change products.

The deadline to provide public comments was originally set for 12 September but was extended to 13 November. FDA received 37 comments on the guidance from a mix of cell and gene therapy companies and industry groups.

‘Limited differentiation’ provided between product types

REGENXBIO, a company that manufactures gene therapies, commented to FDA that the draft guidance “provides limited differentiation between the different classes of Cell and Gene Therapy (CGT) products in terms of assumptions made and guidance provided.”

“There are, however, significant differences in the level of product understanding and characterization between CGT product classes,” REGENXBIO wrote. The group added that viral vectors are “less complex and better characterized than cell therapy products, so many of the statements that the draft guidance makes regarding a lack of product understanding are not accurate for viral vectors.”

BIO concurred in its comments and noted that a final guidance “needs to recognize differences in CGT product modalities and the Phases of Development.” For example, in vivo gene therapies, such as nucleic acid-based or viral vector-based products are different than ex-vivo cell-based gene therapies, and manufacturing changes need to be handled differently.

BIO also suggested that FDA provide examples for each modality. The group said that applying a “broad approach” could create confusion about how the guidance applies to different CGT modalities.

The Alliance for Regenerative Medicines (ARM) also voiced concerns about the lack of differentiation on product classes, specifically calling out differences in viral vector manufacturing and development.

The International Society for Stem Cell Research (ISSCR) urged FDA to highlight specific manufacturing and comparability considerations for each type, including gene-modified cell therapy, viral vector/gene-edited hematopoietic stem cells and induced pluripotent stem cells derived. “We recommend adding a dedicated section towards the end to address these differences,” the group wrote.

Addressing stages of development

Several commenters requested that FDA better differentiate between manufacturing changes at various stages of development.

“The expectations and recommendations for licensed products and products in early- and late-stage development are all presented together. It is not feasible to apply the same rigor for comparability assessments at all of these stages due to, for example, limited manufacturing experience and product characterization in the early stages of development,” BIO wrote.

Additionally, BIO noted that “as the product moves towards late stages of development, the comparability exercise becomes more comprehensive.”

ARM commented that the draft guidance “does not describe a phase appropriate approach to performing comparability studies” while BioPhorum wrote that the guidance “does not fully address the different phases (approaches for early-stage vs late-stage development, and from there towards commercial).” BioPhorum asked for additional support and guidance from the agency.

Tailoring approach to risk levels

Industry groups said the guidance should better accommodate the level of risk that manufacturing changes pose to products.

“While the Draft Guidance seeks to cover a diverse product mix, the Agency should give further consideration to the fact that the type and phase of change made carries a different level of risk across product types,” ARM commented.

For instance, a manufacturing site change for a platform adeno-associated virus (AAV) as part of a phase 3 study is potentially less risky than a similar change made for a novel cell therapy, ARM wrote. The group called on FDA to provide “product-type risk discussions” for each section of the guidance or a standalone section that delves into risk-based expectations across product types.

Clarification needed on extensive manufacturing changes

In other areas, Bayer requested that FDA clarify what constitutes an “extensive” manufacturing change that would necessitate the filing of a new BLA submission.

The guidance advises manufacturers to “carefully assess risks to product quality if extensive manufacturing changes are introduced shortly before BLA submission.” The case of extensive changes, a comprehensive comparability study is needed to demonstrate the change does not adversely affect product quality.

Bayer asked the agency to provide examples of what it considers to be “extensive” manufacturing changes.

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Industry calls for revisions in FDA’s CGT manufacturing change guidance

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