Quality Attributes and Quality Assurance of the Manufacturing Raw Materials
Slowly but progressively more Advanced Therapy Medicinal Products (ATMP), including Cell Therapy Products, are reaching the market and a significant number are getting closer to a marketing authorization submission. One of the challenges in the development of Cell Therapy Products is the transfer from the pre-clinical to the clinical stage. As one of the key issues, the safety and quality of raw materials is critically evaluated by regulatory authorities.
Cytokines, growth factors, and cell culture media are commonly used in the processing of cells during the manufacture of ATMPs. They come in contact with the therapeutic products during manufacturing but are not intended to be part of the final cell product. Nevertheless quality, safety and efficacy of clinical cell products are largely influenced by these raw materials (RM, in the USA called ancillary materials). United States Pharmacopeia (USP) chapter <1043> states that „The quality of an ancillary material can affect the stability, safety, potency, and purity of a cell, gene, or tissue-engineered product“. This is why the cell manufacturers are obliged by their authorities not only to produce their ATMP in compliance with Good Manufacturing Practice (GMP), but also to qualify the critical raw materials and their vendors or manufacturers.
In recent years regulatory agencies recognized an increasing need for guidance for raw materials used for the production of ATMPs and started developing guidelines that outline general risk-mitigation strategies and qualification programs which can be used to select appropriate reagents. USP general chapter <1043> provides valuable tools for “Ancillary materials for cell, gene, and tissue-engineered products”, or European Pharmacopeia (EP) monograph 5.2.12 for “Raw materials for the production of cell-based and gene therapy medicinal products” (currently in preparation). Furthermore there is USP Chapter <92>, which outlines specific quality attributes for “Growth factors and cytokines used in cell therapy manufacturing”.
Despite arising guidance in this area, manufacturers of ATMP have to identify critical quality requirements to meet increasing quality and safety concerns. Therefore, the origin, composition, manufacturing process, quality control (QC) methods and release specifications of RM have to be shared by the suppliers of critical raw materials with cell therapy manufacturers and regulatory agencies. Since no certification by regulatory bodies of critical raw materials is foreseeable in the near future, the quality of raw materials has to be critically evaluated in the manufacturing process of cell therapy products. We propose three major quality standards for critical raw materials:
- RM must be safe. The origin and impurity profile of all raw materials used in the manufacture of RM must be assessed and procured from reliable manufacturers and suppliers. This implies clear definitions of “animal-free”, “xeno-free”, or “animal-derived component-free”. This implies not only the absence of animal- or human-derived materials in the RM, but also the exclusive use of safe and traceable materials throughout the RM manufacturing process. Recombinant products must be derived from and fully traceable to well-characterized Master Cell Banks as starting materials, following guidance of EP chapters 5.2.12 and 5.1.7.
- RM should be produced following applicable GMP guidelines to provide documented evidence of purity, potency, consistency, and stability. Since traceability is a key requirement, the quality assurance system must comprise major GMP procedures including change control, deviation and Out-Of-Specification procedures. Manufacturing and QC must be performed according to Standard Operating Procedures (SOPs) by qualified and trained personnel following validated and consistent processes, including manufacturing, cleaning and QC. The RM should be derived from well-characterized cell banks, product quality should be monitored at each manufacturing step by In-Process Controls (IPC). A clean room facility and qualified equipment should be available for manufacturing. Product quality should be tested by validated analytical methods, and product stability should be validated by stress, accelerated & real-time studies. Product release must be certified according to pre-defined specifications by an independent QC.
- RM must comply with regional regulatory requirements. The RM manufacturers must be prepared to provide technical and regulatory support, incl. on-demand customized documentation of their RM products for regional authorities. Moreover, the RM manufacturer should provide proactive information about major product changes.
As a consequence, the use of GMP grade and animal-derived component-free (ADCF) manufactured RM, derived from well-characterized cell banks, will significantly reduce qualification and validation efforts of ATMP manufacturers. All these factors help to ensure consistency, safety and purity of the final cell therapy products and contribute to the seamless transition from research to commercialization.
Bernd Leistler CellGenix GmbH
Director Development and Production
Phone: +49 761 88 88 9 – 0
Am Flughafen 16
79108 Freiburg, Germany