New FDA Guidance Addresses Challenges with Cell and Gene Manufacturing Comparability and Complexity

Francesco Lanucara
PharmaLex

evelopment of cell and gene therapy (CGT) products is often challenged by the need to demonstrate product comparability following changes in the manufacturing process. Issues include limited process and product knowledge at different stages of product development compared to more conventional biotherapeutics, the complex mechanism of action, the limited and sometimes variable nature of the starting materials, and analytical methods which are often still in development during a comparability study.

Indeed, comparability is often discussed in dedicated meetings with the US FDA (see sidebar), and inadequacies in the assessment of comparability have resulted in major observations and/or objections in the evaluation of approved CGT products.

Recognizing the complexity, in July 2023 the FDA issued a new guidance, Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products, which is open for comments from industry until 13 November 2023.

The guidance includes advice for manufacturers of CGT products in three main areas: management of manufacturing; reporting manufacturing changes; and the design and assessment of comparability studies.

Early Meetings Sponsors Can Request with FDA

Pre-IND Meeting: This is usually the first meeting requested to discuss initial CGT product development plans, including proposed comparability approaches. Sponsors can get FDA feedback on comparability protocols and strategies.
Type B CMC Meeting: These meetings focus on chemistry, manufacturing, and controls (CMC) related topics. Sponsors can review comparability protocols and data to get input from FDA reviewers.

Emphasis on Risk Assessment

While the guidance recognizes the complexity of managing manufacturing changes for CGT products, it emphasizes the need for a thorough risk assessment of the potential for a manufacturing process change to adversely impact product quality and for comparability studies to be performed to evaluate the impact of the proposed changes, where required.

A risk assessment should enable the sponsor to systematically identify, assess, analyze, and mitigate potential risks from the proposed manufacturing changes. The agency advises limiting manufacturing changes to early clinical phases, since later extensive changes would inevitably result in higher risks. The guidance reiterates the importance of planning with the end in mind, ensuring that product development is aligned with the pace of clinical development.

When it comes to reporting, the guidance indicates that IND amendments and BLA supplements and/or annual reports are the tools available to the sponsor to notify the agency of planned manufacturing changes for investigational and licensed products, respectively. The guidance adds that without adequate demonstration of comparability, some manufacturing changes may result in a clinical hold.

With a licensed product, the guidance allows sponsors to include comparability protocols for post-approval changes in the original BLA submission. Post-approval, this protocol becomes an agreed-upon plan for the implementation of the changes described in the protocol, assuming successful completion of the comparability study against the predefined acceptance criteria.

The guidance is also clear on some types of CMC changes that fall outside the scope of comparability, as the post-change product would be considered a new product and therefore require a new IND submission. Such changes include, but are not limited to, changes from allogeneic to autologous starting cellular materials; changes in viral vector capsid or envelope; changes to the transgene sequence or addition of a transgene; and changes to the target gene of a gene-editing tool.

Defining Comparability Studies

During comparability design, the guidance indicates that the extent of comparability data required depends on the stage of clinical development as well as the risk associated with the changes. More rigorous studies are expected for changes introduced during a clinical study, before BLA submission and post-approval.

In defining their comparability studies, sponsors should follow the principles highlighted in ICH Q9 for the execution of a risk assessment, where the severity and probability of a change having an adverse effect on product quality, safety, and/or efficacy is evaluated for each change.

Special consideration is given in the guidance to lot selection for autologous cellular products, where the amount of cellular starting material is inevitably limited and variable. One alternative is the split approach, where the same pool of collected starting material is divided into two sublots and then used to manufacture the final drug product using both pre- and post-change process. Where the number of cells collected from the patient is not sufficient for this approach, alternatives proposed include pooling multiple collections from the same healthy donor or single collections from multiple healthy donors.

Analysis and Data Evaluation

Discussing the analytical methods used to demonstrate comparability, the guidance reiterates that accuracy and precision dictate the ability of the sponsor to interpret the results of the comparability study. Therefore, experience would indicate that release assays used in comparability should be qualified or validated depending on the stage of clinical development, while characterization assays should be fit for their intended use and precise enough to detect meaningful differences. The guidance also reiterates that limiting the comparability assessment to release and in-process control tests is generally not sufficient, and orthogonal methods should be considered, especially for highly critical attributes. A quantitative measurement of biological activity should be included in the assessment.

While advising sponsors to consult a statistician when it comes to statistical evaluation of the data, the guidance does note that different statistical methods can be used within the same study for different quality attributes.

Regarding the split donor approach, the guidance reminds the sponsor that the product data from each half are paired and not independent. The statistical test should, therefore, be suitable for the analysis of difference between paired data. Importantly, the guidance indicates that the absence of a statistically significant difference between pre- and post-change products does not necessarily demonstrate comparability and that a two-sample t-test is generally not appropriate. Rather, the sponsor should consider calculating an appropriate confidence interval, using, for example, the two one-sided t-test (TOST) procedure for comparison of mean values and one-sided, noninferiority testing for comparison of impurities and/or viability.

Sponsors should understand that not detecting a difference does not necessarily mean that comparability is demonstrated. The agency might believe that the study lacks adequate statistical power due to the number of lots included in the study and/or the precision of the analytical methods. Additionally, the sponsor might not demonstrate a sufficient understanding of the product quality attributes to convince the agency that the proposed changes won’t be detrimental to product quality, safety, and/or efficacy. As a result, additional nonclinical and/or clinical studies may be required before the post-change product can be introduced in the clinic or distributed commercially.

Begin with the End in Mind

These considerations reiterate the importance not only of planning with the end in mind, but also of using all available opportunities to discuss manufacturing changes and comparability studies with the FDA. This can be accomplished through IND amendments as well as dedicated agency meetings, depending on the stage of clinical development.

Once finalized, the FDA document will fill a gap in currently available regulatory guidance and is expected to be an invaluable tool for sponsors navigating the complex pathway of CGT product development.

The contents of this article are solely the opinion of the author and do not represent the opinions of Biopharma Excellence by PharmaLex GmbH or its parent, Cencora, Inc.

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