FDA issues draft guidance on reporting manufacturing changes for gene therapies

The US Food and Drug Administration’s (FDA) Center for Biologics Evaluation and Research (CBER) on Friday issued a guidance to assist sponsors of cell and gene therapies (CGTs) in determining whether certain types of manufacturing changes to their products would necessitate the filing of a new investigational new drug application (IND) or biologics license application (BLA).

The guidance also addresses the information that should be included in comparability studies demonstrating that manufacturing changes do not adversely affect the quality of the post-change products.

Current FDA guidance addresses comparability studies and managing manufacturing changes for biological products, but not cell and gene therapy products. Excluded from the scope of the guidance are vaccines for infectious disease indications, bacteriophage products, live biotherapeutic products, fecal microbiota for transplantation (FMT) products and allergenic products.

FDA states that “to facilitate manufacturing changes during rapid clinical development, CGT product manufacturers should ensure that the pace of product development is aligned with the stage of clinical development. For example, if you initiate clinical studies using product generated by a manufacturing process designed with a potential for scalability, this will help decrease the likelihood of delays later in clinical development when the manufacturing process is scaled up.”

This advice aligns with FDA officials’ comments at an earlier meeting to avoid instituting manufacturing changes later during pivotal studies to prevent problems later on, such as products being out-of-specification (OOS). (RELATED: FDA officials offer CMC advice for gene therapies at OTP town hall, Regulatory Focus 25 April 2023)

Due to the complexity of these products, managing such manufacturing changes is challenging. Such changes may be introduced to improve product quality, expand product supply or improve manufacturing efficiency, FDA said.

FDA states that “some changes can fundamentally alter the design or nature of the product, resulting in a new product. Initiation of clinical studies with the new investigational product generally requires the submission of a separate IND (21 CFR 312.20).”

Some examples of changes that may require a new IND include:

Changes in the cellular starting material of a cellular product such as going to allogeneic sourcing versus an autologous donor; or shifting from adipose-derived cells to umbilical cord-derived cells;
Changes in the types of cells used, such as going from a mixture of CD4+ and CD8+ T cells instead of relying solely on CD4+ T cells;
Modifying a viral vector capsid or envelope that changes the tropism or serotype of a viral vector used for in vivo gene therapy;
Changing the sequence of a transgene or adding a transgene such as modifying the intracellular signaling domain of a chimeric antigen receptor.

Comparability studies

Sponsors must submit comparability studies to FDA showing that the changes do not compromise the quality of the post-change products. These study reports should be submitted in the Common Technical document (CTD) sections 3.2.S.2.6 or 3.2.P.2.3 of the biologics license application (BLA) or IND.

The comparability study report “should evaluate the totality of the comparability data, including historical manufacturing data, to determine if the pre- and post-change products are comparable.”

When submitting a comparability study report to an IND or BLA, manufacturers should submit a cover letter outlining the contents of the submission, describing the proposed change, providing a rationale for the proposed change, and a timeline for implementing the change.

The agency advises sponsors to consult the International Council for Harmonisation (ICH) Q9 guideline to determine whether the manufacturing change impacts product quality.

“The process of evaluating the risk of a manufacturing change for a CGT product is similar to risk evaluation for other types of drugs, and the same tools can generally be applied,” said FDA.

FDA recommends that sponsors discuss any significant manufacturing changes with CBER, especially if such manufacturing changes are implemented during later stages of the product lifecycle.

The deadline for commenting is 12 September.

Draft guidance

FDA issues draft guidance on reporting manufacturing changes for gene therapies

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