Consideration of quality by design principles in the use of sterilizing grade filters for clarification and final sterile filtration in adeno-associated virus applications

Abstract

The development of gene therapy applications using recombinant adeno-associated viruses (AAV) as a gene delivery vector has gained significant momentum in recent years. Although there are numerous applications for potential therapies to treat unmet medical needs, the ability to implement robust AAV manufacturing processes continues to be a bottleneck to fully realizing the potential of AAV based therapeutics. This includes the requirement to understand the characteristics (quality attributes) that are critical to product quality and patient safety, and to define these in appropriate detail for regulatory submissions such as chemistry, manufacturing and controls (CMC) information. Sterilizing grade filtration plays an important role in AAV manufacturing, both for drug substance (DS) as well as final drug product (DP). However, to fulfill regulatory expectations for provision of CMC information, it is recommended that the principles of quality by design (QbD) are considered during the early product development stages of the AAV manufacturing process. Both prior knowledge and experimental data should be used to identify potential critical quality attributes (CQAs). Enhanced knowledge should result from increased experience, and ultimately the critical process parameters (CPPs) and critical material attributes (CMAs) that can impact the CQAs can then be defined. The objective is to define a manufacturing control strategy that includes appropriate control of CPPs and CMAs to assure the CQAs of the drug product. Here, the application of QbD principles for sterilizing grade filtration in both DS clarification and DP final fill steps of a typical AAV manufacturing process is described. Both experimental and data review approaches are included to help understand what a typical design space could look like, from which appropriate controls can be implemented. Ultimately, the expectations from regulatory agencies for assurance of product quality and patient safety are aligned with the requirement for a robust manufacturing control strategy to ensure consistent product quality is achieved.