Stakeholders ask for more clarity, risk-based approach in CGT, TEMP draft guidance

Industry stakeholders want the US Food and Drug Administration (FDA) to provide more clarity and to take a risk-based approach in a guidance on using human- and animal-derived materials to develop cellular and gene therapy (CGT) and tissue-engineered medical products (TEMP).

Several stakeholders commented on the draft guidance by 30 July, including the lobby group PhRMA, which asked FDA to include details about how sponsors can include additional data requested by the agency. In particular, the group noted that the guidance asks sponsors to evaluate the raw materials used in the manufacturing process of reagents, feeder cells, and excipients, which may not be available to them after they’ve been sourced from vendors. It asked FDA to clarify what sponsors should do if they lack information on the raw materials. (RELATED: FDA drafts two guidances on safety testing for cell and gene therapy products, Regulatory Focus, 30 April 2024)

The Alliance for Regenerative Medicine (ARM) also submitted comments on the draft guidance and said that sponsors may not always be able to provide additional information on materials used to make CGT and TEMP products. It recommended that the agency instead ask for relevant material specificities from the suppliers.

“Additionally, based on the stage of development and criticality of the material(s), sponsors may not be informed about all aspects of the chemistry and manufacturing controls (CMC) which suppliers of the material have in place; some of this information may also be considered proprietary by the supplier,” the group added. “It would be appreciated if the agency would consider reducing some of the reporting burden on sponsors by relying on master files provided by suppliers and/or prior knowledge of information about materials from vendors that may be accessible to the agency.”

PhRMA noted that the guidance asks CGT product developers to conduct early studies to define critical attributes for materials and to establish acceptance criteria for specified attributes of each material, which may not be feasible.

"Considering that there are a limited number of batches available for CGT products, setting acceptance criteria and critical material attributes early in clinical development could hinder the development process in the later stages since it may not represent the attribute’s acceptable range and does not take into account the evolving process capability," said the group. "Therefore, PhRMA recommends adding text to acknowledge that establishing acceptance criteria and the identification of critical material attributes may not be possible early in clinical development."

The draft guidance asks sponsors to conduct material identity testing during phase I studies, however, PhRMA noted that FDA's guidance on current good manufacturing practices (cGMP) states that identity testing is for investigational products only and not for phase I raw material. With that in mind, the group has asked for more flexibility in the guidance so that sponsors can rely on the manufacturer’s identity testing of materials or only require testing when there is concern about material misidentification.

In the same vein, the American Society of Gene & Cell Therapy (ASCGT) asked FDA to clarify for what stage of development the guidance is intended to address. It also said it would be helpful if the agency included more phase-appropriate benchmarks and expectations.

PhRMA went on to make additional recommendations, asking the FDA to take a more risk-based approach to its requirements regarding material supplies, supply, quality, testing of the raw materials and final products, and when using a biologics license application (BLA) and Human Serum Albumin (HSA) in developing their product.

Similarly, ARM asked FDA to take a more risk-based approach and asked for more detail in the guidance about how the agency wants sponsors to address risk.

“There is lack of clarity in the draft guidance on how risk assessments are used, both in defining the adequacy of materials in treatment and in research-use only cases, with focus on quality and safety,” said the group. “A specific example could be in handling an autologous product: sponsors seek additional detail on what criteria should be in place for manufacturing material from patients with a viral infection, when there is no opportunity for patient recovery unless a CGT treatment is given.”

Sartorius, which develops and manufactures cell culture and bioprocess technologies, commented that the draft guidance to be too specific in some places. The company said it would be useful if FDA clarified what would be considered higher or a lower risk for a material.

"Restricting the use of higher risk materials to be US licensed may prevent the global accessibility to the CGT or at minimal, putting an extensive burden on the developer and manufacturer," said Satorius. "This restriction in most cases cannot be risk/benefit justified.

"We would find it beneficial for this guideline to include recommendations on alternative sources for recombinant materials and other animal-component free alternatives," the company added. "Including explanations on the benefits of such materials over human or animal-derived materials, in mitigating risks for adventitious agents and lot to lot variability and geographic variations."

ASCGT also asked for certain words throughout the guidance to be clarified, such as the term raw material, reagent and grade. The group said that grade is not a standardized term, which could confuse sponsors about what kind of information they need to submit.

"For example, 'GMP-grade' may be used interchangeably to mean GMP-sourced, research-grade, or clinical-grade," said ASCGT.

The group also noted that outside of academic and small-scale manufacturing settings, stakeholders are increasingly moving away from human- and animal-derived materials and using chemically derived options instead. It asked FDA to update the guidance to include alternative pathways for developing CGT and TEMP products.

Guidance comments

Stakeholders ask for more clarity, risk-based approach in CGT, TEMP draft guidance

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