21/22 November 2023
Human cell and gene therapy (CGT) products are manufactured and controlled within the existing regulatory framework for biological products. They can be affected by factors such as limited knowledge of product quality attributes, lack of manufacturing experience, limited and variable starting materials, low amount of product, complex manufacturing processes and limited product shelf-life. These aspects can make managing manufacturing changes more difficult than for other biological products.
This complexity poses a major challenge. The FDA therefore published a draft guidance in August 2023 to provide recommendations to both Investigational New Drug Applicants (INDs) and Biologics License Applicants (BLAs) on how to compare products and manage manufacturing changes for investigational and licensed CGT products.
The purpose of this guidance is to set out FDA's current thinking on the following issues:
1) Management and reporting of manufacturing changes in CGT products on a life cycle basis.
2) Comparability studies to assess the impact of manufacturing changes on product quality.
Therefore, the new guidance addresses the following points in terms of content:
A manufacturer of CGT products may seek a manufacturing change for a variety of reasons, such as to improve product quality, expand product offerings or improve manufacturing efficiency. The risk that a manufacturing change will negatively impact product quality should be proactively assessed as part of the manufacturer's quality risk management processes. Product quality improvement is always desirable and encouraged. If the results of comparability studies indicate improved product quality suggesting a significant advantage in efficacy and/or safety, the products before and after the change may be different products and therefore not comparable.
A risk assessment should be carried out for all types of manufacturing changes, regardless of the stage of product development. If a risk assessment indicates that a manufacturing change could affect product quality, comparability studies should be carried out to assess the impact of the proposed manufacturing change. It may be difficult to fully characterise CGT products using analytical methods, and in some cases analytical studies alone may not be sufficient to draw a conclusion on comparability. In such cases, additional data from non-clinical studies may help to demonstrate comparability. Otherwise, additional clinical studies may be warranted.
The level of analytical evaluation required to adequately assess a manufacturing change in comparability studies generally increases with the stage of clinical development, and product development should be supported by knowledge of critical quality attributes (CQAs), accumulated manufacturing experience and a better understanding of the mechanism of action (MOA).
With the draft guidance, the FDA is supplementing the already published FDA guidance documents "Demonstration of Comparability of Human Biological Products, Including Therapeutic Biotechnology-derived Products" from April 1996 and "Q5E Comparability of Biotechnological/Biological Products Subject to Changes in Their Manufacturing Process" from June 2005. Other FDA guidance documents dealing with the management of manufacturing changes and risk management for biological products generally do not address the specific challenges of CGT products.
For the draft guidance document "Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products", the comment period has been extended until 13 November 2023.