Navigating FDA Guidelines for Cell and Gene Therapy: The Shift Toward Animal-Origin Free Components for Safer, More Efficient Manufacturing

With the rise of cell and gene therapy to treat diseases, there will inherently be novel methods for manufacturing therapeutic agents. In conjunction with these new manufacturing methods, the FDA must create new guidelines to ensure the utmost safety and quality in manufacturing. Earlier this year, the FDA provided an initial draft for the utilization of human- and animal-derived materials in cell and gene therapy manufacturing, titled, “Considerations for the Use of Human and Animal-Derived Materials in the Manufacture of Cellular and Gene Therapy and Tissue-Engineered Medical Products”. This draft provides critical information for the community of cell and gene therapy companies and researchers trying to bring these therapies to the clinic when choosing materials to source, grow, and cryopreserve cells for cell and gene therapies.   

The FDA highlights three critical challenges when utilizing human- and animal-derived materials in cell and gene therapy manufacturing, including, but not limited to safety, quality, and efficacy. One of the primary concerns is the risk of infectious disease transmission. Human- and animal-derived materials can introduce adventitious agents, such as viruses or pathogens, into cell therapy products, increasing the potential for transmitting infectious diseases. This presents a significant risk of compromising a multitude of cell culture batches, which could result in the obsolescence of extensive quantities of these cultures.  

Another significant challenge is the potential for product variability and quality issues. The inherent variability in human- and animal-derived materials can affect the reproducibility of the manufacturing process. For example, variations in serum batches when used in media for culturing cells can lead to differences in cell growth rates, culture conditions, and cell function, ultimately impacting the lot-to-lot consistency and quality of the final product. Ensuring consistent lot-to-lot production with quality-sourced raw materials is essential to maintaining regulatory timelines and therapeutic efficacy.  

To improve downstream quality and stay within regulatory compliance, material characterization and documentation will be needed. There are stringent regulatory requirements for documenting the safety and quality of human- and animal-derived materials used in manufacturing. This includes proper, detailed documentation of the Certificates of Analysis (COA) and Certificates of Origin (COO). Specifically, information on the testing of adventitious agents, detailed information on the source material, and robust material management procedures to verify the quality and safety of these materials. In addition to relying on supplier documentation, manufacturers may need to conduct additional in-house testing to ensure compliance with regulatory standards and maintain the integrity of the cell therapy products.  

The new draft of FDA guidelines also underscores the importance of adhering to Current Good Manufacturing Practice (cGMP) standards, especially for cell and gene therapies, including investigational therapies in the early phases of clinical trials. The recent increase in transitioning to Animal-Origin Free (AOF) components in the production of cell and gene therapy products is a response to several driving factors. These include the need to mitigate contamination risks, enhance product quality, and comply with stringent regulatory standards. 

 The push to use AOF components by the FDA is supported by a growing body of literature that discusses the benefits and challenges associated with their use. This literature provides insights into innovative strategies employed to maximize the advantages of AOF components in pharmaceutical and biotechnological production.. For instance, the article “Strategies for Sourcing Animal-Origin Free Cell Culture Media Components” by BioPharm, discusses the advantages of developing cell and gene therapy products under AOF conditions. It provides insights into the challenges and solutions associated with eliminating animal-origin materials to enhance the safety of active pharmaceutical ingredients (API) and reduce regulatory burdens. This research is instrumental in understanding the complexities of producing AOF reagents at scale while adhering to stringent safety and regulatory standards.  

 By eliminating the use of animal-derived materials, manufacturers can avoid the introduction of viruses, prions, and other infectious agents that could compromise the integrity of the final product. The FDA guidance underscores the importance of special considerations for specific animal-derived materials to mitigate contamination risks. For instance, bovine-derived materials such as bovine serum albumin must be devoid of bovine spongiform encephalopathy (BSE) and other adventitious agents. Similarly, porcine-derived materials, like trypsin, require testing for specific viruses such as porcine circovirus and porcine parvovirus. Insect-derived materials are also subject to testing for rhabdovirus, mycoplasma, and spiroplasma. Where feasible, the use of alternatives free from these specific animal-derived materials are advocated. The adoption of AOF components aligns with the industry’s commitment to safety and quality, as they significantly lower the risk of contamination from animal-derived pathogens.  

 Moreover, AOF components contribute to product consistency by reducing variability linked to animal sources and streamline regulatory compliance by minimizing the necessity for exhaustive risk assessments and validation. The inherent variability found in animal-derived materials can lead to fluctuations in the production process, affecting the uniformity of the end product. AOF components, being more standardized and controlled, ensure a more consistent product, which is essential for both consumer satisfaction and regulatory approval. A significant contribution to this field is the research paper “Effect Of Animal Origin Free (AOF) Peptone Supplementation In Batch And Fed Batch Modes On Productivity Of CHO Cells”. This study examines the effect of AOF peptones on the productivity of Chinese Hamster Ovary (CHO) cells, which are commonly used in the pharmaceutical industry to produce monoclonal antibodies (mAbs). The study suggests that peptones can provide rapid solutions for media and feed optimization to achieve high cell growth and titers. This highlights the importance of GMP in optimizing media for cell growth.  

In addition to enhancing safety and quality, the use of AOF components streamlines regulatory compliance. The rigorous risk assessment and validation studies required for products containing animal-derived materials are often complex and time-consuming. AOF components, however, simplify this process by reducing the need for such extensive evaluations. This not only accelerates the time-to-market for new products but also reduces the costs associated with compliance. In light of the lengthy process that can span 12 to 15 years for FDA approval of a therapy, the cost implications are significant. As the industry continues to evolve, the adoption of AOF components is likely to become a standard practice, further enhancing the safety, quality, and regulatory compliance of manufactured products and thus reducing overall cost.  

StemFit media can be used alongside iMatrix-511MG a GMP compatible and GMP adaptable resource that is a highly purified and refined product of human recombinant laminin-511 E8 fragment expressed by CHO-S cells. 

StemFit® For Differentiation (“StemFit® Diff”) is a chemically defined and human/animal component-free supplement for differentiation of human embryonic stem (ES) and induced pluripotent stem (iPS) cells to multiple lineages. It can be used with a variety of different induction factors or cytokines to support differentiation along ectoderm, mesoderm or endoderm lineages. Alongside StemFit® For Diff, StemFit Puroteins® is a range of animal-origin free recombinant cytokines and growth factors that play key roles in the differentiation of ES and iPS cells into liver, pancreas, kidney, heart, blood and immune cells. Available in GMP and non-GMP formats and PMDA approved for cell therapy products, StemFit Purotein® recombinant proteins enable a seamless transition from bench to clinical research. 

STEM-CELLBANKER® is a ready-to-use, chemically defined, animal-free stem cell cryopreservation solution manufactured under GMP conditions. It is optimized for embryonic stem (ES) and induced pluripotent stem (iPS) cell storage, as well as being a suitable solution for the cryopreservation of other fragile cell types. Containing only European or US Pharmacopoeia graded ingredients, STEM-CELLBANKER® is the optimal choice for storage of cells developed for cell therapy applications. It is also available as a DMSO free formulation. We lastly offer GMP-compliant Collagenase and Neutral Protease NB for isolation and passaging of a broad range of cells dedicated for tissue engineering and transplantation into humans. 

In essence, the use of human- and animal-derived materials in cell and gene therapy manufacturing presents several challenges, including the risk of infectious disease transmission, product variability, regulatory compliance, lot-to-lot consistency, and the enhanced need for thorough documentation and quality control. Managing these challenges when sourcing material during the initial research of  cell and gene therapy can decrease the regulatory approval timeline and increase the ultimate goal of providing the most efficacious treatment possible!  

Considerations for the Use of Human-and Animal-Derived Materials in the Manufacture of Cell and Gene Therapy and Tissue-Engineered Medical Products; Draft Guidance for Industry (fda.gov)  

Strategies for Sourcing Animal-Origin Free Cell Culture Media Components (biopharminternational.com) 

Effect Of Animal Origin Free (AOF) Peptone Supplementation In Batch And Fed Batch Modes On Productivity Of CHO Cells (bioprocessonline.com)