Understanding FDA's Draft Guidance On Human- And Animal-Derived Materials In The Manufacture Of Cell & Gene Therapy Products

By Blake Bergam and Sara Mills, Dark Horse Consulting Group

In April 2024, the U.S. FDA released the draft guidance for industry Considerations for the Use of Human- and Animal-Derived Materials in the Manufacture of Cellular and Gene Therapy and Tissue-Engineered Medical Products.¹ This guidance represents the FDA’s current thinking on the topic and is intended to supplement the following two guidances: Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs),² published in January 2020, and Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs),³ published in April 2008. The guidance discusses several key issues, including transmission of adventitious agents, material identity testing, and how to present a material qualification justification within a regulatory submission.

Qualification of human and animal derived materials is a crucial step in clinical program development but has previously been a nebulous subject to sponsors and material manufacturers alike. Materials ubiquitous in scientific literature or available for sale by well recognized vendors are assumed to be suitable for use in clinical manufacturing but this assumption is oftentimes misinformed. Inattention to material qualification programs for cell and gene therapy products can become a significant barrier to IND clearance.

Due to the non-prescriptive nature of guidances, this document may not offer a list of specific risk mitigations for your material of interest and intended use. It does, however, offer a well thought out methodology for risk assessment, qualification, and the subsequent cGMP control of materials. Also, for those of us who are raw materials subject matter devotees, it may replace the personal red string corkboard of interrelated FDA guidances, ICH guidelines glossary tables, 9 CFR subparts, and USP general chapters that currently aid in design of adventitious agent testing strategies.

Let’s take a highlight reel approach to evaluating this new draft guidance.

What’s Great About The Draft Guidance?

Indicative of a thoroughly considered guidance, the CMC methodology recommendations are straightforward and concise. This guidance states that INDs must list all materials used in manufacturing, including a description of the quality or grade, manufacturer, catalog number, source (e.g., human, animal), and stage at which the material is used in the manufacturing process. This information, along with Certificates of Analysis (COAs), Certificates of Origin (COOs), package inserts, and specifications, should be provided in sections 3.2.S.2.3 Control of Materials and 3.2.P.4 Control of Excipients. Risk assessments performed on human- or animal-derived materials should be included in section 3.2.A.2 Adventitious Agents Safety Evaluation. These risk assessments may detail viral clearance validation studies, manufacturing processes designed to inactivate potential infectious contaminants, or adventitious agent testing of donor or source material. Viral testing requirements are listed for common human derived materials (human platelet lysate, human serum, human serum albumin, etc.) and animal sources (bovine, ovine, porcine, and insect). This represents the largest list of specific FDA-proposed risk mitigation steps for raw materials.

The convenience of a single guidance listing the specific viral testing requirements cannot be overstated due to the ever-changing landscape of adventitious agents testing. For example, a media supplement manufacturer may use porcine trypsin as a secondary material in their process. This porcine trypsin is tested for the porcine specific viruses listed in 9 CFR 113.47: porcine adenovirus, porcine parvovirus, transmissible gastroenteritis virus, and porcine hemagglutinating encephalitis virus. The Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)³ states that any reagents produced using porcine products must also be free of porcine parvovirus. Luckily, this is already being tested for since it’s included in 9 CFR 113.47. In 2020, Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs)² was published and added porcine circovirus 1 and 2 and “other zoonotic viruses, as appropriate” as required tests. The requirement to test for porcine circovirus 1 and 2 is likely to be missed by any material manufacturers that have been offering their product since before 2020. The Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs)³ has not been revised since it was published in 2008 and does not mention porcine circovirus 1 and 2.

New guidances are published far more often than existing guidances are revised, which leads to conflicting requirements. Material manufacturers could not possibly keep track of all requirements within all guidances relevant to each customer’s use case of their products. This responsibility of material suitability falls on the sponsor, who previously had to have deep expertise or a well-polished crystal ball to foresee new viral testing requirements before they impacted clinical development. Moving forward, hopefully, the human- and animal-derived materials guidance will serve as a consolidated destination for any future, additional viral testing requirements.

What’s Shocking About The Draft Guidance?

The guidance explains that a sponsor’s risk management strategy should result in materials management cGMP controls such as supplier qualification, material quarantine, material specifications defining relevant acceptance criteria, material testing or inspection, and material release. One commonly debated element of materials management cGMP control is material identity testing. In section III.C., the draft guidance recommends that sponsors consider implementing identity testing as early as Phase 1 clinical investigations. This will come as a surprise to many early-phase sponsors, most of which do not perform any confirmatory testing of raw materials prior to disposition. Industry standard practice during early-phase clinical manufacturing is to rely on the material manufacturer’s identity testing and use their COA during material disposition.

In an FDA CBER OTP Town Hall regarding cell therapy CMC on June 8, 2023, Dr. Matthew Klinker (FDA CBER OTP Cell Therapy Branch 2 Chief) recommended that sponsors “start looking into reagent identity tests during pivotal studies.” He further stated, “reagent identity tests…are required at the stage of licensure.” The FDA’s Guidance for Industry cGMP for Phase 1 Investigational Drugs⁴ only specifically recommends confirmatory identity testing performed by the sponsor on each batch of the drug substance and not on raw materials. If the new draft guidance hopes to sway sponsors toward confirmatory identity testing of raw materials in Phase 1, it will be fighting an uphill battle.

What’s Missing In The Draft Guidance?

A subtle footnote on page 4 states “Please note that ‘serum-free’ medium and supplements may still contain human or animal components.” In addition to being easy to miss, this footnote only addresses the tip of the iceberg. The materials manufacturing industry has spawned material origin claims of “serum-free,” “protein-free,” and “xeno-free” as well as material quality claims of “tissue culture grade,” “clinical grade,” and “manufactured under ISO 13485” in an attempt to substantiate the suitability of their products for use in clinical manufacturing. The Alliance for Regenerative Medicine’s Project A-Cell has an entire table that attempts to define commonly used nomenclature from materials manufacturers. Without FDA definitions, these claims are unfortunately only marketing. The lack of standard terminology coupled with the unique and complex characteristics of human- and animal-derived materials have created a meandering path for sponsors to appropriately source and qualify materials for their intended use.

Sponsors are expected to read between the lines to determine that “xeno-free” means “contains human derived materials” and therefore must meet several requirements for donor eligibility, collection, processing, and/or testing explained throughout 21 CFR. A sponsor’s dream scenario for animal-derived materials is that the material manufacturer offers a cGMP quality version that includes a certificate of origin per lot. This COO lists each species used as sources of primary and secondary components, how they were sourced appropriately, and the necessary viral testing performed on each primary and secondary component. If applicable, a letter of authorization can be included in the sponsor’s submission upon which the FDA may view the material manufacturer’s master file. The master file should include all required information to support review by FDA, as well as results of any viral clearance validation studies performed during development. If any of these elements are missing it is possible for a sponsor to spend weeks tracking down required documentation for each material. If the only material quality available is for research use only (RUO) then the sponsor may be left beginning this journey with only a packing slip in hand and a vendor that refuses to communicate.

Difficulties wading through the sea of shoptalk and gathering necessary documentation are common industry sentiments not only for sponsors but for material manufacturers as well. In industry webinars, materials manufacturers plead that, previously, no guidances had been addressed to them so they were forced to bear the indirect burden of proof of suitability without the ability to engage the FDA prior to a sponsor’s regulatory submission. This has created a scenario where sponsors and material manufacturers can drive together toward material production and testing strategies that may fall short during regulatory review. An FDA guidance may not be the forum to expand on this topic; however, the draft currently does recommend using materials of the highest quality available and it acts as a North Star for sponsors and material manufacturers on their search for appropriate testing strategies of materials derived from common human and animal sources. It also concludes with the recommendation for sponsors to engage the FDA early in product development via an INTERACT or pre-IND meeting that includes questions specific to human- or animal-derived material safety and quality.

What To Do?

This bid by the FDA to assist in standardizing the methodology of raw material risk assessment and justification of material suitability within regulatory submissions should be applauded and supported by a reciprocal industry effort to participate.

For those invested or interested in human- and animal-derived material qualification, please submit comments to this draft guidance. The FDA is accepting comments until July 29, 2024, which may be submitted through https://www.regulations.gov.

References

1. Considerations for the Use of Human and Animal-Derived Materials in the Manufacture of Cellular and Gene Therapy and tissue-Engineered Medical Products. Center for Biologics Evaluation and Research. 2024.
2. Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Guidance for Industry. Center for Biologics Evaluation and Research. 2020.
3. Guidance for FDA Reviewers and Sponsors: Content and Review of Chemistry, Manufacturing, and Control (CMC) Information for Human Somatic Cell Therapy Investigational New Drug Applications (INDs). Center for Biologics Evaluation and Research. 2008.
4. Guidance for Industry: CGMP for Phase 1 Investigational Drugs. Center for Drug Evaluation and Research, Center for Biologics Evaluation and Research, Office of Regulatory Affairs. July 2008.

About The Authors:

Blake Bergam is a senior consultant at Dark Horse Consulting Group with nine years of experience in the field of cell and gene therapy (CGT). He began his CGT career in QA operations, starting up the first internal manufacturing facility at Juno Therapeutics. He then led process and technology development efforts at Juno, including development of a shortened CAR-T manufacturing process and a bespoke cell purification system. Since joining Dark Horse in 2021, Bergam has supported over 30 clients in the areas of CMC strategy, raw material qualification, GMP operations, and device development.

Sara Mills is a senior principal and head of the cell therapy CMC department at Dark Horse Consulting Group. She entered the cell & gene therapy industry over 14 years ago by way of UCSF, where she was in the neurosurgery department studying glioblastoma, epigenetics, and pluripotent stem cells. Mills joined Dark Horse Consulting Group in 2017 and enjoys leading a team of cell therapy and gene-modified cell therapy subject matter experts in supporting small, academic through large and late-stage programs developing CMC strategies. This work includes a minimum of 90 clients and over 100 unique products in nine different regulatory jurisdictions.