In this podcast, we talked with Parth Trivedi, Business Development Manager, Pall Corporation, about the importance of implementing a Quality by Design strategy for AAV product manufacturing and specific key steps for successful assessment. We began by talking about the importance of Quality by Design (QbD) in AAV product manufacture and how this pertains to the regulatory landscape. Parth explained that there have been several recent regulatory approvals of gene therapy products, but in 2020 there were also regulatory setbacks. These setbacks mostly involved lack of sufficient data in the chemistry, manufacturing, and controls documentation or CMC. This led Pall to create a framework for QbD assessment and implementation for AAV based products. Parth pointed out that for over a decade the FDA has advocated for a QbD approach in pharmaceutical manufacturing and there is good documentation and regulatory guidance around this approach. QbD is heavily based on prior knowledge and detailed understanding of both the product and the process variables. Most of the industry’s experience in QbD has been in traditional drugs and now we need to learn and apply these principles to gene therapy products. Implementing Quality by Design I then asked Parth if he could talk a bit more about what companies should consider before implementing a QbD approach. He said that QbD relies on prior knowledge and detailed understanding of the product and the process, so prior to implementation, it is important to collect and generate information data, analyze it and interpret any process changes that have an impact on the product. Thus, it is important to understand the quality target product profile (QTPP) and define it, focusing on specifications around the safety, purity, and efficacy of the drug product. A Framework for QbD Assessment for AAV Products I then asked Parth if he could discuss a recent white paper that Pall released, “Quality by Design (QbD) for Adeno-Associated Virus (AAV) - A Framework for a QbD Assessment for AAV Products Within the Chemistry Manufacturing and Controls (CMC) Documentation.” I asked him to walk listeners through the four steps that the Pall team identified in creating a risk- and science-based QbD assessment. Identification of CQAs based on QTPP and Risk Assessment Parth explained that in this step it is important to focus on the empirical view, starting with a deep understanding of product knowledge and process knowledge. The product knowledge is where you should focus on the QTPP and the critical quality attributes (CQAs) and the risk associated with it. He went on to say that how we identify CQAs depends on the drug substance or drug product’s physical, chemical, biological, and related characteristics, which will eventually impact the quality, purity, activity, efficacy, and safety of the drug. Another important consideration is impurity profiling, there are three categories an impurity can be profiled into - product related impurities, process related impurities and adventitious agents. There are variations in the impurities, especially with upstream vs. the downstream. Specifically focusing on the AVV process on the upstream side, there are different processes that create different impurities, for instance - transfection process vs infection, adherent vs suspension, and mammalian cell vs. insect cell culture types. These parameters and the method of manufacturing will have its own impact on the process related impurities and product related impurities. From there, it is important to know what the target product profile is and what the quality attributes are. Examples of common quality attributes are non-infectious AAVs, empty capsids, aggregated AAVs, and encapsulated host cell DNA. The next step is to ask which of these are critical attributes and this can be determined using a risk assessment ...