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Navigating the FDA Draft Guidance Document “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products”

Post thumbnail Navigating the FDA Draft Guidance Document “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products”

In the ever-evolving landscape of pharmaceuticals/biopharmaceuticals, manufacturing changes play a pivotal role in ensuring the quality and effectiveness of medicinal products. This becomes even more critical when dealing with the complexities of cell and gene therapy (CGT) products. In this blog post, we explore the key considerations from the FDA Draft Guidance for Industry “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products issued in July 2023 for managing manufacturing changes, with a focus on CGT products, shedding light on the intricacies of tissue-engineered medical products (TEMPs). The draft guidance is the result of acknowledging the industry’s need for direction on how to address comparability for CGT products, and it is open for comments until November 13th 2023. The Agency is currently gathering feedback from Industry stakeholders prior to issuing a final guidance document. 

Key considerations of the draft guidance

The Importance of Risk Management 

Manufacturing changes demand a systematic approach to quality risk management, especially for CGT products. These therapies are intricate, and understanding their risks is paramount. Defining acceptable ranges for critical quality attributes (CQAs) and aligning product development with the clinical stage can help avoid unexpected delays. 

Ensuring Stability and Compatibility 

For CGT products, demonstrating stability and compatibility after manufacturing changes is critical since these therapies are sensitive to storage and handling conditions. Changes in the container closure system, formulation, product concentration or shipping conditions could affect the product stability and/or compatibility with the delivery device. For example, a change in the formulation could lead to an increase of the formulation’s viscosity, impacting the flow properties of the product and making it more challenging to inject with the delivery device, affecting precision of delivery and potentially increasing the risk of clogging or damaging the device.

For changes implemented during late stages or post-licensure, real-time stability data should be generated with the post change product to ensure that the manufacturing change did not impact shelf-life.  

Regulatory Requirements 

Navigating the regulatory landscape is crucial when reporting manufacturing changes for Investigational New Drugs (INDs) and licensed products. Clear and comprehensive information, including a well-structured cover letter and a summary of changes, is essential. The submission process varies depending on the stage of the product and the nature of the change requiring thorough data evaluation by the FDA. 

The Comparability Assessment Process 

Demonstrating that manufacturing changes do not affect product quality is the core of comparability assessments. In addition, the FDA draft guidance states that if a manufacturing change significantly increases potency, the post-change product might be considered a different product and thus not comparable to the pre-change product. Seeking FDA guidance for substantial changes and designing rigorous comparability studies is advised. The comparability study report should include a detailed rationale, timeline, study design, and comprehensive insights into manufacturing and clinical experience. 

Tissue-Engineered Medical Products (TEMPs) 

TEMPs are a unique challenge due to their incorporation of living cells and scaffolds, simulating the in vivo cellular environment. Understanding product quality, cell-scaffold interactions, and sensitivity to manufacturing changes is an ongoing process. Comprehensive risk assessments, considering scaffold and cell characteristics, are crucial. Moreover, effective communication with the FDA during later product lifecycle stages is also vital. 

As the world of CGT and TEMPs advances at an unprecedented pace, the management of manufacturing changes is more critical than ever. The new FDA draft guidance represents the Agency’s current thinking on how to appropriately address comparability, and thus their recommendations should be followed as Sponsors implement manufacturing changes during product development.


Published on: November 01, 2023


blog post by

Victoria Quiroga, M.Sc. thumbnail
Victoria Quiroga, M.Sc.
Associate Director, CMC
As Associate Director in Chemistry, Manufacturing and Control (CMC), Victoria is responsible for the preparation, writing and reviewing of a wide variety of regulatory documents. These comprise the Quality module of IMDP, IND, MAA, BLA and briefing documents for meetings with Regulatory Agencies (pre-IND, pre-BLA, Scientific Advice, ITF, INTERACT) as well as technical documents including comparability, analytical method validation, stability, shipping validation protocols and reports.