Why You Need A Raw Material Control Strategy
By Diana M. Colleluori, Ph.D., MBA, and Vidhya Mathiyazhagan, MS
Biologics Consulting Group Inc.
The strategic development of a robust manufacturing process for cell and gene therapy products (CGTs) is difficult to navigate during the preclinical and clinical stages, from both a technical and a regulatory perspective. With the development of a solid manufacturing process comes the use of many raw materials to take your starting materials through to drug substances and drug products. As such, the FDA released the draft guidance for industry for Considerations for the Use of Human- and Animal-Derived Materials in the Manufacture of Cellular and Gene Therapy and Tissue-Engineered Medical Products in April 2024.
The draft guidance is structured to provide the drug development industry with insight into the regulatory expectations for the specific raw materials used to manufacture CGT products. In addition to human- and animal-derived materials, there are typically many other critical raw materials used during manufacturing. USP <1043> Ancillary Materials for Cell, Gene, and Tissue Engineered Products provides additional insights into the expectations surrounding other raw materials used during CGT manufacturing.
The control of raw materials is part of the overall potency assurance strategy for CGTs. Materials used in the manufacture of CGTs may impact a product’s potency, therefore thorough understanding of the raw materials used and implementation of adequate controls ensures the safety, quality, and identity of the product.
With respect to raw materials, this article intends to clarify the regulatory and technical requirements, identify common challenges, and propose considerations for assuring a successful manufacturing process that aligns with regulatory expectations.
Raw Materials In CGT Manufacturing
“Raw material” is an umbrella term that encompasses a range of materials used for the manufacture of drug substances and drug products. Subcategories of raw materials include excipients, ancillary raw materials, and starting materials. The regulatory, testing, and reporting requirements vary for each classification of raw material so it is important to understand the distinction between each.
Excipients are all the components of the final drug product, with the exception of the active ingredient(s). For example, a frozen cell therapy drug product may contain buffers, salts, stabilizers (e.g., albumin or sucrose), and a cell freezing medium. All these components of the final drug product presentation are considered to be excipients.
Ancillary raw materials, in contrast, include all raw materials that come in contact with the active ingredient(s) during the manufacturing process but are not intended to be present in the final formulated drug product. For example, cell culture medium and additives, such as antibiotics, serum products, cytokines, and antibodies that are used during upstream cellular manufacturing of the final drug product would be considered ancillary materials.
Starting materials are materials from which the active substance is manufactured or extracted. For example, autologous cell therapies utilize autologous donor cells that are used to produce the cellular drug product. In this case, the autologous donor cells are considered to be a starting material.
What Is A Raw Material Control Strategy And Why Do You Need One?
A raw material control strategy is a living document that should be refined throughout product development. It is expected that the raw material control strategy will evolve as additional manufacturing experience and clinical data are gathered. Raw materials used may naturally evolve as manufacturing sites or material availabilities change. Though it is expected to take a stage-wise approach to the control strategy, it is advantageous to start with the end goal in mind.
Regardless of the stage of development, all excipients present in the drug product must be of GMP grade. Ancillary materials, conversely, have greater flexibility in earlier stages of development and may leverage research grade or research use only (RUO) materials, with the expectation that they are transitioned to GMP grade in late stage and commercial manufacturing. However, it is recommended to use the highest-grade material available where possible, as RUO materials pose a higher risk to product safety, certainly in the eyes of regulatory authorities.
USP <1043> provides a four-tiered ranking system for minimizing the risk of ancillary materials used in CGTs based on the intended use of the material at preparation and cGMP practices in place. This risk assessment similarly will need to be updated throughout development if materials and grades change. The control strategies for ancillary raw materials and excipients are required to be documented and filed in the initial regulatory submission.
Risks can be mitigated by thoughtful sourcing, selection, and qualification of raw materials. Confidence in the material source can be gained by performing a raw material supplier audit, for example. Testing raw materials on receipt helps to confirm critical safety and quality attributes. Non-human- or non-animal-derived materials should be selected in order to mitigate the potential risk of BSE/TSE contamination. Finally, safety testing of any residual raw materials in the final drug product is an additional control to ensure manufacturing consistency and patient safety.
Common Challenges And Considerations
As discussed above, it is recommended to use the highest grade of raw materials available. This may not always be GMP grade, particularly in early development. It is a common challenge to source rare additives as GMP grade. The use of non-GMP grade raw materials in early development may be supported with risk mitigation activities as outlined in USP <1043>.
Redundant supply should be considered in order to mitigate the risks of supply shortages or other causes of unexpectedly unavailable material. Consider working closely with the suppliers for mutual support in the planning of the quantities of raw materials that you may need.
Performance testing of the raw materials may also be warranted, depending on the role that the raw material plays in the manufacturing process. For example, serums or cell growth additives may be assessed prior to use in GMP manufacturing to ensure their functionality. Consider a raw material qualification plan that includes use-testing of such materials prior to use.
Process development studies evaluating the presence of residual ancillary raw materials and their ability to be removed during the manufacturing process can help inform appropriate raw material, in-process, and drug substance specifications. Consider establishing residual assays early in development in order to assess the consistent removal of ancillary raw materials to acceptable levels.
Note that the FDA recommends engaging early in product development prior to IND submission when using human- and animal-derived materials in new drug products. For CGT products in preclinical development, consider presenting your raw material plans in a pre-IND meeting to gain approval of your strategy.
About The Authors:
Diana Colleluori, Ph.D., MBA, is a principal CMC consultant at Biologics Consulting Group Inc. She received her Ph.D. in biochemistry from Temple University School of Medicine and MBA from the University of the Sciences in Philadelphia. She has over 20 years of industry experience in CMC and quality control. Her experience includes technical and executive roles in biologics product development, from pre-IND to commercial stages. She has direct global experience developing numerous biological products, including monoclonal antibodies, vaccines, and cell and gene therapies.
Vidhya Mathiyazhagan, MS, is a CMC consultant at Biologics Consulting Group Inc. She received her MS in pharmaceutical sciences from the University of Florida and B.A. in chemistry from Boston University. She has over 12 years of experience in analytical development and quality control, managing projects from pre-IND to commercial stages.