Discover FDA guidance on manufacturing changes for Cell and Gene Therapy products. Learn about quality risk management, stability testing, and the importance of clinical comparability studies for successful licensure.
The complex nature and the intricate manufacturing processes involved in Human Cellular and Gene Therapy (CGT) products create unique challenges for their development and manufacture. The continuous data collection longevity require uniform product quality at all times, even during manufacturing changeovers, to ensure clinical evaluation data is meaningful and of high informational value for licensure. The Food and Drug Administration (FDA) has published a set of responses to “Questions Regarding Manufacturing Changes and Comparability Claims for Human Gene Therapy Products” outlining best practices and recommendations for manufacturing changes in ways consistent with maintaining product quality.
Quality Risk Management Essentials
A systematic approach to quality risk management guides decisions in manufacturing changes for CGT products. A comprehensive risk assessment is required to review and investigate any risks posed on the quality of product due to manufacturing changes, and to discover, evaluate and minimize those risks. Surely it can be done, but only by establishing acceptable ranges for Critical Quality Attributes (CQAs) and defining operating ranges for Critical Process Parameters (CPPs), before the change is implemented to allow a matrix analysis of the risk and effect.
When determining the risk of a manufacturing change, it is preferable to consider things like product and process knowledge, qualification/validation of methods and how advanced it is in clinical development. Significant manufacturing changes to be introduced following completion of key clinical trials and prior to Biologics License Application (BLA) submission need to be reviewed critically to make sure that the change will not compromise product quality. It then should be followed by an exhaustive comparability study to ensure high level of confidence that the change is safe and effective.
Stability and Delivery Device Compatibility
Changes in the manufacturing process have the potential to adversely affect the stability of CGT products, including changes to container closure systems, formulation and drug product concentration, or shipping conditions. Stability or compatibility study with the delivery device must be conducted to evaluate the impact of change in product quality. For assayed impurities, the stability-testing plan should include suitable acceptance criteria based on the assessment of stability-indicating quality attributes.
To post-licensure manufacturing changes that may affect stability, real-time long-term stability data is a must. The time to the clinic for such data may slow product development and one should consider matching the phase of clinical development with timing of product development.
Nonclinical and Clinical Studies
Manufacturing changes for investigational or licensed CGT products may require analytical and nonclinical comparability studies. This is where nonclinical studies can help to highlight comparability when analytical studies are insufficient. If comparability cannot be established through analytical and nonclinical studies, then additional clinical investigations may be required to assess the safety and effectiveness of the post-change product.
If the pharmaceutical equivalence data and nonclinical comparability studies are not enough to establish safety, then a discussion with the FDA regarding a critical path to have a proper evaluation of the product may be required. This might result in the need for modifying the clinical development program of the post-change product if no comparability to pre-change product can be arrived.
Conclusion
The successful oversight of changes in manufacturing is essential to ensure consistency in product quality over the lifecycle of Human Cellular and Gene Therapy products. Adopting a systematic approach to ensure quality risk management, and the performance of relevant stability, compatibility and comparability studies is imperative for the safety and efficacy of products. Although manufacturing changes can be one of the challenges that need to be overcome in the licensure process for CGT products, close collaboration and communication with the FDA can help overcome this challenge & enable timely licensure.
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