Issue link: https://www.e-digitaleditions.com/i/1222740
8 Pharmaceutical Technology REGULATORY SOURCEBOOK MARCH 2020 P h a r mTe c h . c o m tial CQAs may be revised as your knowledge of the product increases," notes the guidance (6). The final guidance also spells out, explicitly, the need for quality control testing and control func- tions and manufacturing departments to be sepa- rated, which, some experts have pointed out, may be for the benefit of academic laboratories that have never manufactured before and are only familiar with lab research practices (7). The guidance also provides more detailed information on drug sub- stance vs. drug product, a distinction that is much more obvious in traditional biopharmaceuticals than in gene and cell therapies. For Module 2 of the IND, which focuses on qual- ity information, the guidance explains CQAs and how to identify, measure, and test for them in gene therapy, for both drug substance and drug product. It also suggests that they be established as early as possible and notes their importance to analytical studies required to show product comparability (5). It also emphasizes the importance of evaluating product characteristics during early clinical devel- opment to ensure ability to assess process controls, manufacturing consistency, and stability, noting the importance of having these systems in place for expedited development programs. This portion of the guidance also explains how vectors should be defined, whether as drug product or drug substance, asking developers to select an option and explain their definition (8). Manufacturing and control information The final CMC guidance document goes into a lot of detail on how to present data in Module 3, which cov- ers the manufacturing process and control informa- tion, and offers examples from current gene therapies, including viral-based, microbial-based and ex-vivo ge- netically modified types (8). It also includes a detailed section on cell banking systems for starting materials and their importance. In this section of the IND, developers will need to provide information on drug substance and product, facilities and equipment and information on adventi- tious agent safety. Hacker noted the following as key CMC requirements in the final guidance (2): • Definition of batch-scale and quantification of drug substance (such as vector genomes), and harvesting or intermediate pooling and stor- age conditions to be established for each pool • Preference for non-animal derived reagents and some explanation of current thinking on qualification of different cell banking systems • Written standard operating procedures for all stages of manufacturing development • Use of comparability studies to determine the impact of manufacturing changes on product safety • Analytical procedure validation, in particular, the use of qualifying assays to determine the initial clinical dose. • Verification of the compatibility of drug prod- uct with the diluent used to reconstitute or de- liver the therapy • Use of in-process sterility tests for releasing drug product for ex-vivo genetically modified cells • Use of assays to determine safety and dose, and for product release • Use of sterility, endotoxin, and identity testing on containers of final product • Specification of facility information, including manufacturing flow diagrams and some de- tails showing facility design • Assessing the potential risk, and avoiding con- Gene and Cell Therapies