Pharma groups call for changes to FDA’s potency assurance guidance

Several pharmaceutical industry groups and companies have criticized the US Food and Drug Administration’s (FDA) recent guidance on potency assurance strategies for cell and gene therapies (CGTs) products as being overly broad and not specific enough in addressing potency testing for these products.

The Biotechnology Innovation Organization (BIO) and other groups objected to the broad sweep of the guidance and complained that it was not tailored to potency testing for CGTs.

FDA issued the draft guidance in December; when finalized, the guidance is meant to replace a 2011 final guidance on potency tests for CGT products. (RELATED: FDA CGT draft guidance focuses on potency assurance strategy, Regulatory Focus 2 January 2024).

Building on 2011 guidance

BIO said that the guidance needed to be more “modality specific” to cell and gene therapy products and recommended the document “include a few specific points” from the 2011 guidance on developing assays for specific classes of CGT products.

The group noted that “the draft guidance describes strategies and considerations for potency assurance, while the 2011 guidance outlines potency test strategies” and that “many topics” in the earlier guidance are unaddressed in the 2023 draft guidance.

For example, the guidance should include Table 1 from the 2011 guidance acknowledging the challenges to potency assay for CGT products. BIO said that “examples in the table can be especially valuable to less experienced developers on the points to consider.”

The guidance should also include information on the use of surrogates to measure biological activity and the agency’s expectation on correlation analysis to support this approach. It should also include information on the use of alternative approaches or an assay matrix, when a single assay cannot provide adequate measure of potency, as well as include a section on considerations for assay design.

BIO wrote that “since the 2023 guidance will supersede the 2011 guidance after it became final, BIO encourages the Agency to include a few specific points from the 2011 guidance (see Appendix 1) in the 2023 draft guidance, and to issue additional guidance documents that provide further advice about selection and development of potency assays for specific classes of CGT products.”

Asymmetrex, a biotechnology company, expressed similar concerns that the guidance lacked clarity on potency testing for CGT products.

“This draft guidance has many excellent concepts for industry guidance for therapeutic products in general, including gene vectors, but it is greatly deficient for crucial considerations for actual cell therapy products, which are either primary human tissue cell preparations or cultured human tissue cell preparations, which are characteristically and invariably cell-heterogeneous,” the company wrote.

It added that the guidance is missing “crucial” information on potency testing and that “the specific-dosage of the critical cell subtype for a therapeutic effect is, a priori, crucial for the potency of a cell therapy product. Yet, the cell and gene therapy industry currently operates without determination of this essential information for ensuring potency.”

Asymmetric also recommended the guidance address new potency testing technologies. “An updated guidance for cell therapy potency assurance is deficient if it does not include these new advances and their importance for better progress in cell and gene therapy development. The current draft makes no mention of delineating critical cell subtypes (CCSs) and quantifying them for potency evaluation and potency assurance.”

Incorporating ICH Q9 and Q10

In its comments, BIO said more clarity is also needed with respect to how sponsors should incorporate the International Council on Harmonization’s (ICH) Q9 on quality risk management and ICH Q10 pharmaceutical quality system concepts in their potency testing programs.

The group wrote that “to improve the clarity of the guidance, we request that the Agency provide explicit expectations on the application of these concepts during the development of a potency strategy for CGT products. The absence of such clarity may pose challenges for stakeholders attempting to implement the 2023 guidance in an effective manner.”

ISPE and BioPhorum want clarity on certain terms

The International Society for Pharmaceutical Engineering (ISPE) recommended that FDA define certain terms in the guidance such as strength, potency assay, and bioassay.”

ISPE writes that the defined terms are used interchangeably, which adds to the confusion. The group urged FDA to “please consider including a glossary including comprehensive definitions. It is crucial for the understanding of the nuances in the guidance to clearly distinguish the terms (and their interchangeability), such as e.g. bioassay, potency, strength, and assay.”

BioPhorum, an industry group, expressed a similar view, writing that “a glossary or table that defines the important terms used within this document would be beneficial to help the reader understand, follow and avoid misinterpretations based on different levels of experience.” BioPhorum said it brought together 35 subject matter experts from 24 member companies to discuss the guidance.

Container closure testing

In other areas, Regeneron complained that a provision in the guidance which recommends that manufacturers test containers, closure and product-contact contact equipment for potential adverse effects on product potency is underly burdensome.

“The specific testing of the impact on potency by product contact equipment is not required as per current FDA IND guidance on gene therapy. Rather, this impact is evaluated as part of PPQ [process performance qualification] and commercialization activities,” wrote Regeneron. “If the evaluation of product contact equipment is an additional expectation for CGT INDs, and does not allow for phase appropriate strategies, then this may be difficult to meet for early phase drug substance (DS) and formulated drug product (FDP) due to limited production capacity and small batch sizes.”

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Pharma groups call for changes to FDA’s potency assurance guidance

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