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Proposed Draft Guidance
Reports of serious and life-threatening adverse events in clinical trials involving systemic administration of high doses (~1 x 1014 vector genomes per kilogram body weight or higher) of adeno-associated viral (AAV) vector-based human gene therapy products have been the subject of an FDA Cellular, Tissue, and Gene Therapies Advisory Committee Meeting. It is considered likely the reported adverse events may be linked to patient total AAV capsid exposure. One potential contributor to the immunotoxicity observed is the presence of empty AAV capsids in the final gene therapy product. Empty AAV capsids are considered a product impurity as they do not carry genomic material intended to provide a therapeutic effect. This guidance provides sponsors of AAV vector-based human gene therapy products with the recommendation to establish a maximum release criterion for empty AAV capsids to better control immunogenicity that may be due to empty capsid product impurity and provide for improved product safety in the context of systemic administration. This guidance applies to human gene therapy products and to combination products.
This guidance supplements the following final guidance: “Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (INDs); Guidance for Industry” dated January 2020 (CMC Guidance).
FDA’s guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidance documents describe the FDA’s current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in FDA’s guidance documents means that something is suggested or recommended, but not required.
Recent preclinical and clinical experiences with some systemically administered AAV vector-based human gene therapy products highlight the need for additional specific guidance on process-related impurities and product-related impurities. In prior guidance on Chemistry, Manufacturing, and Control (CMC) Information for Human Gene Therapy Investigational New Drug Applications (Ref 1) FDA outlined broad recommendations for reporting manufacturing process and control information on drug substance molecular structure (section 3.2.S.1.2), and impurities (section 3.2.S.3.2) resulting from both the manufacturing process and the product. Table 1 below summarizes a list of product-related and process-related impurities described in CMC Information for Human Gene Therapy Investigational New Drug Applications (Ref 1) as well as representative examples of additional identified impurities that merit consideration. Here, we wish to expand on the assessment of empty capsid content in AAV products as this may relate to overall vector safety, particularly at higher vector doses administered systemically.
 Cellular, Tissue, and Gene Therapies Advisory Committee (CTGTAC) Meeting #70: Toxicity Risks of Adeno-associated Virus (AAV) Vectors for Gene Therapy, September 2-3, 2021; Available at https://www.fda.gov/media/151599/download
 Combination products are comprised of any combination of a drug and a device; a device and a biological product; a biological product and a drug; or a drug, a device, and a biological product; see 21 CFR 3.2(e) for the complete definition of combination product. Combination products are assigned to a lead center for review; see 21 CFR 3.4.