Comparability Amid Change

When manufacturing changes bring challenges, standard reference materials can save the day.

Adeno-associated viruses (AAVs), a vehicle for delivering DNA into cells and tissues, are fast emerging as a leading tool for treating genetic diseases. The transfer of a product from early development to clinical grade manufacturing often entails changes in the manufacturing process of therapeutic AAV products, including switching suppliers of raw materials, tweaking the formulation of a product, or upgrading to a larger manufacturing facility. 

Throughout each manufacturing change, AAV producers must supply customers with a product that meets the comparability requirements of regulatory agencies such as the United States Food and Drug Administration (FDA), which considers two biological products comparable if testing reveals that a manufacturing change has not affected the product’s safety, identity, purity, or potency.

But ensuring comparability amid change is no easy feat. An effective way for AAV producers to best meet comparability requirements in the future is to develop a comparability assessment strategy during the early stages of development. This assessment should identify anticipated manufacturing changes that could occur down the line and which quality attributes those changes are likely to impact.

This shows that it is fundamental for AAV producers to collect extensive enough data along the way so that, in case a manufacturing change is implemented in the future, the process of demonstrating two products’ comparability can go as smoothly as possible.

Despite these techniques, which are helpful in mitigating risks, the field of AAVs still faces a fundamental challenge in demonstrating comparability: the lack of commercially available standard material. Having access to standard material – serotype-specific reference material with reliable information about viral genome titers, capsid titers, and other conclusive parameters like purity, endotoxin levels, and aggregation state – enables AAV producers to accurately characterize their gene therapy product and ensure consistent safety, identity, purity, and potency.

To further complicate matters, it is essential that standard reference material be available for each of AAV serotype – AAV vectors binding differing cell receptors that enable them to enter cells in different types of tissues. Currently, commercially available reference material exists for only two AAV serotypes, AAV2 and AAV8, and while this is a step in the right direction, the amounts of even this material is limited. This leaves AAV producers in the position of needing to manufacture their own standard material, which is not feasible for many companies.

Because PROGEN, however, is fortunate enough to have the capacity to produce standard material, we have tackled this challenge head-on. We are grateful to have the opportunity to produce a variety of reference material for AAV gene therapy products, with the goal of doing our part to ease the process for other players in the field of bringing new gene therapies to market. 

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