The number of cell and gene therapies coming into the market each year is increasing steadily. An article published by McKinsey and Company in 2022 expected as many as 21 cell therapy and 31 gene therapy launches in 2024 itself. The growing focus on cell and gene therapies (CGT) presents a unique set of challenges to be addressed in the manufacturing sphere. These challenges include, but are not limited to, the need to ensure the safety and quality of Animal & Human Derived Materials used in the manufacturing of these products.
Regulatory agencies are proactively working towards publishing guidance documents to help provide CGT manufacturers with the support they need in ensuring the safety & quality of human & animal-origin materials. For example, in April 2024, the FDA released a draft guidance document for manufacturers and sponsors of CGT products that should be followed to meet FDA standards set for human and animal derived materials. The document also provides recommendations for Chemistry, Control and Manufacturing (CMC) information to be submitted in an Investigational New Drug (IND) application regarding the same topic.
What are some general recommendations provided by the FDA for Animal & Human Derived Materials?
The US FDA guidance document delineates some of the key considerations related to critical parameters to ensure safety of human and animal material i.e., adventitious agents, risk management process, and material acceptance testing.
Adventitious agents: The process to remove or inactivate adventitious agents needs to be demonstrated well in the regulatory submission. If this process cannot be demonstrated, a possible way to mitigate contamination is to carefully source the human or animal derived product. Until the material is tested for its safety, it needs to be quarantined until the completion of the testing.
Risk management process: Risk management process includes a thorough risk assessment of possible adventitious agents that can be introduced by the human or animal derived product being used in the manufacturing process. Any possible risks, such as those associated with material sourcing, should be detailed in the risk assessment, including ways to mitigate those risks. The FDA recommends the risk assessment to be included in CTD section 3.2.A.2 of the regulatory submission.
Material acceptance testing: The identity of all materials being used during manufacturing needs to be examined using specific tests (if provided) according to 21 CFR 211.84(d)(1). The FDA recommends identity testing to be carried out even during Phase I clinical trials to minimize risk. Materials should be evaluated for consistency by assessing performance. FDA licensed tests should be used only to test for communicable diseases and disease agents.
What are considerations for materials derived from humans?
Materials derived from human blood and blood components: To collect, process store and distribute human blood samples, requirements in the 21 CFR part 606 must be followed. Blood and blood components can only be collected following donor eligibility and donation testing requirements detailed in 21 CFR parts 630, 640 and 610.40. The FDA recommends to source blood and blood components from FDA registered establishments only. Recommendations to test for safety by the FDA differ based on type of blood component. The same information should be detailed in the regulatory submissions by the sponsor.
Considerations for human derived materials are as follows:
- For human platelet lysate (HPL), a commonly used human-derived material, the following should be documented—whether expired or non-expired platelets were used, storage and procedures used to produce HPL. Donor platelets should be acquired through FDA-registered establishments only.
- The entire manufacturing process for human serum used in manufacturing should be documents properly.
- For human serum albumin (HSA) used in the manufacturing process as an excipient needs to be licensed in the United States. HSA not used as an excipient should also be US licensed or US Pharmacopeia (USP) grade. Any exceptions to these conditions should be properly justified.
- Human derived proteins used in culture media should be properly documented, and information about conformance to donor testing requirements should be included according to 21 CFR 610.
Human derived feeder and bystander cells: The FDA recommends that feeder and bystander cells and cell particles should be obtained from only those donors that meet the eligibility criteria stated in 21 CFR part 1271, subpart C. Cell banks should be tested for absence of adventitious agents and ensure sterility. If feeder and bystander cell bank testing is limited, the manufacturers will need to show that the banks are free of adventitious agents.
What are considerations for materials derived from animals?
The FDA recommends manufacturers to carry out testing of all animal-derived materials consistent with 9 CFR 113.47 and 9 CFR 113.53.
- All feeder cells and feeder cell derived products should be tested to ensure they are free of any adventitious agents. Tests should include in vitro, in vivo and retrovirus testing.
- Use of bovine and ovine derivatives should be properly documented. Safety of bovine and ovine derived materials should be ensured by followed procedure detailed in 9 CFR 113.47 9 CFR 113.53, Cell Therapy CMC Guidance (link), and Gene Therapy CMC Guidance (link). Additionally, documentation should be provided to show that the materials are free from adventitious agents.
- Safety of porcine derived materials should be ensured by followed procedure detailed in 9 CFR 113.47 9 CFR 113.53. Documentation needs to be provided to show that the materials have been tested for porcine circovirus 1 and 2 and porcine parvovirus. Reagents such are trypsin that are porcine derived and commonly used should be replaced with porcine free alternatives.
- Materials derived from insects must be tested for rhabdovirus, mycoplasma, and spiroplasma. Documentation should also be provided to show materials are free from adventitious agents.
What are considerations for recombinant materials and Tissue Engineered Medical Products (TEMPs)?
The US FDA also provides recommendations on other critical components such as recombinant materials and Tissue Engineered Medical Products (TEMPs).
- All recombinant materials should be purified and tested for adventitious agents. Details for a specific, commonly-used recombinant material, monoclonal antibodies, are included in the following document: “Guidance for Industry: Monoclonal antibodies Used as Reagents in Drug Manufacturing”, published in March 2001.
- TEMPs follow the same set of recommendations as stated for human and animal derived materials above. They should be tested for adventitious agents and be documented properly, including all procedures and sourcing. In the case that TEMPs require devices to function, recommendations are in the document “Medical Devices Containing Materials Derived from Animal Sources (Except for In Vitro Diagnostic Devices); Guidance for Industry and Food and Drug Administration Staff”, published in March 2019.
Conclusion
The CGT landscape is consistently evolving highlighting the need for stringent regulatory frameworks to ensure the safety and quality of human and animal-derived materials used in Cell and Gene Therapy Products manufacturing. Given the expected rise in the number of CGT therapies, regulatory agencies (like the US FDA) is proactively working towards release comprehensive guidance to those who need it. CGT manufacturers can better navigate the complex and evolving regulatory environment by adhering to the recommendations- and contribute to the safe and successful delivery of CGTs to global markets.
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