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Food & Drug Administration (FDA) guidance is just now addressing the challenges of manufacturing cell and gene therapy (CGT) products with a proposed draft guidance, Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products.

The draft guidance outlines a lifecycle approach to managing and reporting manufacturing changes, as well as robust comparability studies to determine the effects of such changes (including transferring manufacturing to new facilities) on product quality. The comment period ends September 12, 2023.

“Managing changes to manufacturing processes has been a common roadblock for many CGT companies to navigate, particularly given that manufacturing challenges have been pervasive in this industry,” Stacy Cline Amin, leader of the FDA, healthcare regulatory and compliance practice at Morrison Foerster, tells GEN. “CGT companies have been frustrated with written-response-only meetings and the lack of informal opportunities to consult with the agency. This guidance should reduce some of the uncertainties CGT sponsors face and help facilitate more meaningful discussions between FDA and industry on some of these nuanced quality issues.”

Stringent risk management procedures

Stringent risk management procedures throughout the product life cycle, following recommendations of the International Council for Harmonization, feature strongly in the proposed guidance. The FDA draft guidance calls for:

  • Conducting risk assessments and identifying ranges for critical quality attributes and critical process parameters before making any changes. Also consider product and process knowledge, method qualification and validation, and the stage of clinical development, particularly when changes are contemplated just before submitting a Biologics License Application (BLA). “We recommend that any extensive manufacturing changes be introduced prior to initiating clinical studies… in support of a BLA,” the draft guidance says.
  • Conducting clinical studies with the same process that will be used for commercial manufacturing to streamline scale-up.
  • Annual data evaluations, even when no changes have occurred, to identify any needed alterations in product specifications or in manufacturing or control procedures.

Because CGT products are particularly sensitive to storage and handling conditions, the draft guidance calls for assessing drug product stability after any changes to the container closure system, formulation, product concentration or shipping conditions. Importantly, the draft guidance recommends basing shelf-life determinations on real-time stability data under long-term storage conditions. Manufacturers also should ensure that manufacturing changes have not affected compatibility with delivery systems.

Although analytical assessments, nonclinical studies or pharmacokinetic/pharmacodynamic assessments may be adequate for investigational products or for licensed products, FDA consultation is recommended when they cannot establish comparability. Additional clinical investigations or adding safeguards and evaluations to ongoing trials may be recommended. Sometimes, the FDA may advise filing an investigational new drug application (IND) for a post-change, licensed, product.

The draft guidance also advises notifying the FDA of manufacturing changes to investigational drugs through a Biologics License Application supplement or annual report.

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