Cell and Gene Therapy Manufacturing: Achieving Consistency and Reducing Variability

Cell and gene therapies are novel therapeutic modalities which enables difficult to treat disease states. Patient (or donor) cells, protein or DNA are isolated and modified to generate a precision therapy before the material is readministered to the patient. Whilst each approach works differently, they both have the potential to treat, prevent, or potentially cure complex diseases and rare disorders. Cell and gene therapies first gained regulatory approval in 2017 by the US Food and Drug Administration (FDA). Several more therapies have since been developed, and there are now 18 approved to treat a variety of diseases. 

Technology Networks recently had the pleasure of speaking with experts at Bio-Techne to learn more about the cell and gene therapy manufacturing process.

Q: How has the cell and gene therapy sector developed over the last decade?

A: In the last ten years, cell and gene therapies have experienced considerable growth. With the emergence of commercial CAR T-cell therapies, significant milestones were attained in the field that have propelled the area even further. The advancement of natural killer (NK) cell therapeutics in regard to solid-state tumors, and the growing traction which induced Pluripotent Stem Cell (iPSC) therapies have gained, are evidence of the significant opportunities associated with cell and gene therapies. Proper scale-up and manufacturing development need to continue to advance, to support the technology. This includes the need for availability of high-quality raw materials embedded in cell therapy processes.

Q: How do you ensure the raw materials you use in your manufacturing are appropriate to make products that can be used for ex vivo manufacturing?

A: Raw materials are sourced from qualified suppliers in accordance with a formal supplier qualification and monitoring process. Risk assessments for critical raw materials used in the manufacturing process of GMP products are conducted periodically. Identification and traceability are maintained for all raw materials, incoming materials must conform to an acceptance specification and incoming inspection is conducted prior to entering the material into inventory. Identity confirmation is required for critical raw materials prior to acceptance. Appropriate documents are maintained for raw materials: Certificate of Analysis; Certificate of Origin (if applicable); transmissible spongiform encephalopathy/ bovine spongiform encephalopathy (TSE/BSE) statements (if applicable); and an Animal-Free statement (if applicable). Animal-derived materials are sourced from countries considered to be of negligible or controlled risk for BSE.

Q: What advice would you give to cell therapy developers when sourcing their raw materials?

A: Materials used by cell therapy developers should be sourced from reliable suppliers, using GMP-grade or pharmacopeial grade if possible. Bio-Techne GMP products are manufactured and tested according to applicable standards in Unites States Pharmacopeia (USP) Section <1043> Ancillary Materials for Cell, Gene, and Tissue-Engineered Products, and European Pharmacopeia (Ph. Eur.) General Chapter 5.2.12 Raw Materials of Biological Origin for the Production of Cell-based and Gene Therapy Medicinal Products.

A supplier should have a certified quality management system (QMS), such as ISO 9001:2015 or ISO 13485:2016. An ISO certified supplier has been independently audited and certified to have demonstrated the ability to consistently provide products and services that meet customer and regulatory requirements. Suppliers of critical raw materials should be evaluated, qualified and monitored on an ongoing basis to verify their ability to consistently provide necessary materials. A Certificate of Analysis, Certificate of Origin and other related documents should be received from the supplier and maintained with development and manufacturing records.

During product development, developers should have discussions with suppliers regarding expectations of a quality agreement and a supply agreement to assess the ability of suppliers to meet future needs as required during product scale-up and clinical use of the product. If a supplier cannot support these anticipated needs, significant time and resources may be needed to successfully qualify the product for human use.

Secondary suppliers should be identified early. Raw materials may look identical on a Certificate of Analysis but could behave differently in the developer’s biological system. It should never be assumed that one can easily switch between suppliers for a given raw material. Validation studies are required to show equivalency between raw materials from different suppliers. 

Q: How do you ensure a smooth transition from research use only (RUO) to good manufacturing practice (GMP)? 

A: For some materials, RUO-grade product is functionally the same as GMP-grade product with the exception of more rigorous quality testing and robust documentation, such as quality assurance personnel performing final review and approval of batch documentation, and formal validation conducted for GMP products. For GMP-grade product, a minimum of three consecutive lots are manufactured, tested and released in accordance with approved standard operating procedures and must meet predetermined acceptance criteria.

One should consider that for a product that was developed much earlier, meaning the RUO product was developed during the early period of cell and gene therapy development, there may have been modifications in the manufacturing process and/or final product testing which are applicable to the GMP product. In this case, it is advisable that the GMP-grade product is used for any ex vivo clinical studies.

Q: Cell and gene therapy manufacturers need to bridge batches. How can you ensure lot-to-lot consistency and reduce variability?

A: GMP-grade products are released after successful manufacturing of three consecutive batches and passed with stringent specifications, providing evidence that the product can be made in a reproducible way and establishing reasonable acceptance specifications which can be used to assess future batches.

Results of batch release analysis for each bulk lot of GMP-grade product is compared against the stringent specifications of the master lots. This ensures lot-to-lot consistency and reduces variability in product performance. 

Interview responses were provided by:

• Qi Cheng, Senior Director, Product Support/Improvement, Bio-Techne
• Diane Wotta, Senior Director - Global Quality Assurance, Regulatory Affairs & Safety, Bio-Techne
• Deana Khobdeh, Senior Manager, Regulatory Affairs, Bio-Techne
• Rachel Somsen, Senior Manager, Quality Assurance and Regulatory Affairs, Bio-Techne
• Helen Zhang, Scientist/Manager, Quality Control, Antibody Applications, Bio-Techne