“Explore FDA guidelines for managing manufacturing changes in Cell and Gene Therapy products, ensuring comparability, and maintaining product quality. Learn about quality risk management, stability testing, and FDA communication during the BLA filing process.”
Due to their inherent complexity and complex manufacturing process, Human Cellular and Gene Therapy (CGT) products face unique challenges in development and manufacture. It is critical that interpretable clinical study data are available during the licensure process, showing consistency of product quality over the entire product lifecycle, including manufacturing changes. In the guideline “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products,” the FDA provides a number of considerations for managing manufacturing changes, along with recommendations to ensure comparability.
Significance of Quality risk management
Quality risk management is needed to manage manufacturing changes for CGT products. Conduct a risk assessment to identify, evaluate, analyze and mitigate the risks that may impact product quality due to changes made. By providing limits for Critical Quality Attributes (CQAs), setting operating ranges of the CPPs, as well as an evaluation of change risk and evaluation on potential impact before any actual manufacturing change occurs, these guidelines facilitate translation to a real-world process.
However, the risk of a manufacturing change should be assessed in consideration of factors like product and process knowledge, qualification/validation of methods and stages in clinical development. Final manufacturing alterations implemented shortly before BLA filing must be scrutinized to determine if the change negatively influences product quality. In that scenario, a full comparability study needs to be performed for sufficient assurance of the change’s safety and efficacy.
Stable and Compatible with Delivery Device
Modifications to the processess in which CGT products are created often impacts their stability, particularly if they are linked up with the container closure system or their formulation (or product concentration) or shipping conditions. Stability studies are needed to determine the influence of these changes on product delivery, device compatibility and quality. The acceptance criteria should be established in the stability testing plan based on assessment of stability-indicating quality attributes.
Long-term stability information, in real time, is critical as changes to manufacturing methods after licensure could impact stability. The time taken to generate these data can lead to a lag between product development and clinical development; hence synchrony of the pace of product development and stage of clinical development is key.
III. The Fourth Type: Nonclinical Studies and Clinical Studies
Manufacturing changes for investigational or licensed CGT products may require analytical and/or nonclinical comparability studies. If analytical studies do no achieve comparability, nonclinical studies can assist in the comparability data set. Where comparability cannot be established through analytical and nonclinical studies, further clinical investigation may be required to assess safety and effectiveness of the product post-change.
When analytical and nonclinical comparability studies do not suffice to assure the safety of a product, conversation with the FDA regarding plans for safety evaluation may be necessary for investigational products. If comparability cannot be established, the clinical development program for the product following a change may need to be adjusted.
IV. Conclusion
Effective management of the changes made in manufacturing is critical to ensuring continuity in product quality over the lifecycle of Human Cellular and Gene Therapy products. Using a systematic approach for quality risk management and conducting relevant stability, compatibility, and comparability studies is important to ensure that products are safe and effective. Close communication and collaboration with the FDA through this process may help reduce CGT product manufacturing change hurdles as well as bottlenecks in product licensure.
Reach out to BioBoston Consulting. Contact us or Visit website to find out more about how we can help your organization.
