FDA is announcing the availability of a draft document entitled “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products; Draft Guidance for Industry.” The management of manufacturing changes presents many challenges for human CGT products due to the complexity of these products. The draft guidance provides sponsors of INDs and applicants who intend to submit or currently hold BLAs for CGT products, with recommendations on product comparability and the management of manufacturing changes for investigational and licensed CGT products, considering the unique challenges that apply to these products.

While existing guidances provide general principles and recommendations regarding comparability studies and management of manufacturing changes for biological products, they generally do not address specific CGT product challenges. The purpose of this draft guidance is to provide FDA’s current thinking on: (1) management and reporting of manufacturing changes for CGT products based on a life-cycle approach and (2) comparability studies to assess the effect of manufacturing changes on CGT product quality.

The guidance covers numerous topics, including risk-based approaches for evaluating manufacturing changes and the preparation of analytical comparability studies.

Specifically, the guidance recommends conducting analytical comparability studies to provide scientific evidence of the impact that manufacturing changes may have on the safety, potency, and purity of human cellular and gene therapy products.

These analytical comparability studies should be designed based on the extent of the manufacturing change and the risk it poses to product quality.

The document provides information on the analysis, design, data analysis, and reporting of analytical comparability studies. The guidance suggests conducting a thorough analysis of the manufacturing process to identify potential changes that may impact product quality. It recommends categorizing manufacturing changes into three levels based on their risk to product quality: minor, moderate, or major. This analysis helps to determine the extent and complexity of the comparability studies needed.

The document outlines the importance of appropriate statistical analysis of the data obtained from analytical comparability studies. Key statistical methods for comparing critical quality attributes between reference and test products are described, including equivalence testing, non-inferiority testing, and assessment of effect size. The guidance also provides specific recommendations on interpreting the results and establishing acceptance criteria for comparability.

Finally, the guidance highlights the importance of timely communication with the FDA during the evaluation of manufacturing changes. The agency recommends that manufacturers utilize the Chemistry, Manufacturing, and Control (CMC) pre-submission program to discuss manufacturing changes before submitting IND or BLA applications.

In summary, the FDA’s draft guidance document provides detailed recommendations for manufacturers of human cellular and gene therapy products on how to manage and evaluate manufacturing changes effectively to ensure product quality and safety. The guidance emphasizes the importance of conducting analytical comparability studies and communicating with the FDA during the evaluation process.

SourceU.S. Food and Drug Administration

Comments on the draft guidance must be submitted either electronically or written by


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