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The gene therapy space has yet to achieve the level of standardization that typifies established modalities, such as monoclonal antibodies. There exists a tremendous amount of diversity among these products, which demands a complex and individualized Chemistry, Manufacturing, and Controls (CMC) strategy for each product brought to market.

Researchers continue to work on defining the true critical quality attributes (CQAs) for these drug products, as well as the process parameters and testing methods best positioned to measure and monitor those attributes. As the industry continues to develop the knowledge to advance gene therapy using viral vectors, manufacturers with existing experience will prove invaluable to biopharmaceutical companies.

Prioritizing Analytics Early for Late-Stage Success

One immediate challenge when delivering a complex CMC strategy relates to product testing: to minimize the time and resources needed to support an analytical workflow, operators must prioritize identifying more accurate testing methods that require lower product volumes. Core to developing an adequate testing paradigm is understanding both a molecule and an assay—a final analytical panel must be capable of interrogating all products’ CQAs in a way that is both fit-for-purpose and phase-appropriate.

Not every analytical method is created equal; there can be multiple technologies that allow interrogation or assessment of a particular CQA, but it is up to the assay developer to assess whether a particular technology is the right fit for the process stage as well as the overall stage of program development. Additionally, the cost of implementing a particular technology plays an important role in deciding if or when to invest.

Companies may overlook testing methods that are not immediately necessary for regulatory purposes, such as a functional potency assay. For example, the FDA typically does not require that a functional potency assay be in place when entering Phase 1. While three months may be sufficient to stand up other assays, potency methods often take as long as a year to fully develop, which can have a significant impact on timelines and stall regulatory filings.

Innovating Platform Approaches

The matrix of any sample impacts the overall performance indicators of an analytical method: the selectivity, specificity, accuracy, precision, linearity, range, limit of detection (LOD), limit of quantification (LOQ), and robustness. A matrix is profoundly defined by the manufacturing strategy. Modular manufacturing platform processes and analytics can help standardize inputs to a matrix.

The power of platformed processes to simplify and accelerate development cannot be understated—without them, a development and manufacturing partner may need to develop dozens of assays independently before it can move on to clinical manufacturing. Compare this to just three or four product-dependent assays, and the potential time and cost savings become clear.

Platform approaches have been pioneered to standardize gene therapy, but the siloed nature of the field has limited these endeavors. There are at least 10 naturally occurring AAV serotypes being used, many of which are being modified to change their tropism or target cell type. This poses challenges for both platform manufacturing and analytical paradigms.

As manufacturing partners like Resilience continue to innovate on product-specific analytical methods, modular platform approaches will enable greater standardization. Resilience has developed many off-the-shelf platform-related assays, with product-specific assays measuring genome titer, potency, and dosage forming the primary focus of its assay development. For assays such as those measuring host cell protein, host cell DNA, subvisible and submicron particulates, endotoxins, and process-related impurities, Resilience utilizes its preexisting assays to perform confirmation for a client’s product, expediting assay qualification.

As gene therapy capacity continues to come online across the industry, organizations will need to become more discerning about technology investments and data strategies that differentiate partners.


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To learn about how the Resilience Gene Therapy platform can give your innovation its best destiny, connect with Resilience today. resilience.com.

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