Pharmaceutical Technology - October 2020

PharmTech - Regulatory Sourcebook - October

Issue link: https://www.e-digitaleditions.com/i/1302985

Contents of this Issue

Navigation

Page 52 of 75

Pharmaceutical Technology Regulatory Sourcebook October 2020 53 The CMC guidance recommends that multiple product characteristics be evaluated prior to and during early clinical trials in order to identify a product's critical quality attributes (CQAs) and biological properties towards obtaining "relevant and meaningful " information about product potency (1). This approach conforms with that in earlier guidance on potency determination, which acknowledged that "no single test … can adequately measure those product attributes that predict clinical efficacy" and so recommends ap- plication of an assay matrix (3). The new guidance also builds upon an early clinical trial design guidance, which recognizes that cell and gene therapy (CGT) products have unique features relative to other drug products that make the CMC and preclinical data less pre- dictive of safety and potency observed in clinical trials (4): • Expectation of prolonged biological activity • Potential for immunogenicity. The "product-related" impurities to be measured are identified as "defective interfering"; "non-infec- tious"; "empty capsid particles"; and "recombinant virus contaminants" that are to be reported as ra- tios (e.g., full:empty or virus particles:infectious units). The brevity of the expected analyses for characterizing and quantitating these impuri- ties belies the complexity of these products, their manufacture, and the challenges of measuring these impurities with the accuracy and precision that have been possible for other drug products, including biotherapeutics. The presence of partially filled capsids, result- ing from encapsidation of fragmented genomes or non-transgene-related DNA contaminants, adds to this complexity. Analyses applied toward quantifying the viral particles for both genomes present and their ef- ficiency at delivering their genetic payload to cells are important because they are applied in early development to support clinical testing and guide early clinical trials. This review provides a lim- ited overview of product implications that arise from the associated product-related impurities found in AAV vector gene therapy products. It also reviews the range and relative performance of the technical applications used to characterize these impurities. Relevance to AAV vectors The features present in viral-vectored gene therapy products take advantage of the evolved effective- ness of viral agents at transducing cells and deliv- ering genes and genetic elements that can establish long-term expression of transgenes. However, be- cause the human immune system has evolved to identify and respond to viral agents, the vectors themselves, their recombinant nucleic acid con- tents, and the product-related impurities associ- ated with these vectors have the potential to im- pact both potency and safety. Observations from clinical trials of vectored gene therapy products demonstrate that the presence of defective or in- Analytical ultracentrifugation (AUC) is currently the preferred [analytical] method, but new and modified instrumentation capable of supporting this analysis has the potential to either augment or replace AUC.

Articles in this issue

Archives of this issue

view archives of Pharmaceutical Technology - October 2020 - PharmTech - Regulatory Sourcebook - October