An Overview Of FDA Draft Guidance On "Manufacturing Changes And Comparability For Human CGT Products"
By Raj Bandaru, Ph.D., Associate Director, Accenture Applied Life Science Solutions
The U.S. Food and Drug Administration (FDA) has issued a highly anticipated draft guidance to the industry that addresses “Manufacturing Changes and Comparability for Human Cellular and Gene Therapy Products.” Unlike previously issued guidance for CMC manufacturing changes and comparability assessment of investigational and approved biologic and biosimilar products, regulation of manufacturing changes to cell and gene therapies (CGT) and their comparability differs significantly due to extremely short lifecycle time for the development and a potential higher impact on patient safety and efficacy. For example, few major manufacturing changes for investigational or licensed CGT products are likely to have a significant effect on safety and efficacy which also changes risk established benefit assessment in patients. Therefore, manufacturing changes and comparability assessment for CGT products if not conducted as per the guidance may lead to new Investigational New Drug (IND) filings, and clinical hold of the IND applications for CGT products which not only pose significant delay to marketing authorization approval but also increases withdrawal or recall of licensed CGT products from the market.
Reporting Manufacturing Changes for Investigational CGT Products
In the draft guidance on manufacturing changes for human cell and gene therapy products that incorporate in vivo or ex-vivo manufacturing changes, FDA offers recommendations on the information to be submitted in an IND application and an accompanying analytical comparability assessment report. The recent draft guidance, issued in July 2023 by the Center for Biologics Evaluation and Research (CBER) division at FDA, provides a comprehensive information on CMC manufacturing changes requiring a new IND filing, and reporting manufacturing changes to an existing IND application as an amendment or in an annual report. In general, CMC changes, which fundamentally alter the design or nature of the investigational CGT product, may require initiation of a new IND filing with the FDA. Though this draft guidance did not categorize “major” and “minor” CMC changes explicitly unlike previous CMC manufacturing changes guidance issued by the Agency, it is sufficient to say those manufacturing changes which cannot be evaluated by analytical comparability assessment and effect on quality, non-clinical safety and efficacy would require a brand-new IND application filing with the FDA. Similarly, manufacturing changes which result in acceptable quality whose safety and efficacy can be tested by an analytical comparability assessment would be submitted as an amendment or in an annual report to the IND. Please note that failing to submit an amendment to the IND that the manufacturing change has an acceptable quality and safety may lead to clinical hold of the IND application. In addition, data on manufacturing changes and comparability assessment also needed for CGT products which do not allow for a conclusive determination that the manufacturing change has no adverse effect on product quality and its related safety and efficacy. In such cases where conclusive determination cannot be made, performing an additional toxicology study to evaluate whether the post-change product has an acceptable safety profile should be considered.
In general, an IND application for CGT products should also contain a phase appropriate detailed description of manufacturing process, testing plan, and analytical methods and procedures used for analytical comparability assessment. The draft guidance also provides information specific to manufacturing and testing data required for each type of manufacturing change during the investigation.
Reporting Manufacturing Changes for an Approved BLA of a CGT Product
Please note there is no change to reporting manufacturing changes to the approved BLA of a CGT product from previously issued guidance to biologic products such as antibody and protein drugs. Post-approval manufacturing changes to licensed CGT products which affect product quality, production process, quality controls, equipment, facilities, or labeling should be submitted either in a supplement or in an annual report with an accompanying risk assessment report. Previously, well-established procedures and regulatory framework for approved biologic drugs using a comparability protocol with a specific reporting category should also be considered for licensed CGT products.
Comparability Assessment and Report
Comparability between a pre-change and post-change CGT product should be assessed by the totality of evidence and the CMC data demonstrating that a change does not adversely affect product quality for the licensed or an investigational product. Though general principles of comparability assessment as described in ICH Q5E guidance on “Comparability of Biotechnological/ Biological Products Subject to Changes in their Manufacturing Process” is helpful, FDA has cautioned in the draft guidance that overall applicability of ICH Q5E guidance to CGT products is limited due to high complexity of manufacturing changes associated with CGT products. In addition to comparability protocols, comparability study reports should also be submitted to investigational and BLA applications to evaluate the totality of the comparability data, including historical manufacturing data, to determine if the pre- and post-change products are truly comparable. FDA also recommends submission of summary of findings from the comparability study, CMC data and analyses which support the conclusion in addition to assessing the limitation of the study.
Risk-Based Comparability Assessment
In general, FDA evaluates manufacturing changes to human CGT products using a risk-based approach weighing the benefits and risks of each product. The agency wrote in the issued draft guidance, “we recognize that risk assessment for changes to the manufacturing of CGT products may be more challenging than for other product types because the effects of manufacturing changes are often difficult to predict for these complex products. For example, manufacturing changes may unexpectedly alter product purity (increase process-related impurities, cellular impurities, aggregates, or particulates), reduce product stability, or change product potency.”
FDA also advocates in the draft guidance that risk assessment should also contain a statistical approach to comparability assessment. Please note that higher risk to critical quality attributes (CQA) typically warrant a more stringent statistical analysis than lower risk to CQA. Therefore, a side-by-side or graphical presentations (such as a dot plot) to allow visual comparison and representation, in lieu of statistical analysis, may be helpful for characterization of CQA for minimal manipulated CGT products being impacted by a manufacturing change.
Analytical Comparability
Prior to initiating a comparability study of an investigational or a licensed CGT product, FDA recommends submitting a detailed study protocol (comparability protocol) and requesting feedback from the FDA on the study design and statistical approach. The comparability protocol should also contain a prospectively written plan for assessing the effect of a proposed post-approval manufacturing change(s) on product quality and safety. Please note that these comparability protocols can be submitted with an original BLA at the time of filing or in a Prior Approval Supplement (PAS) to the licensed BLA as per previously issued guidance for biologics by the CBER division at FDA.
The extent of a comparability study should be driven by the conclusions from the risk assessment, which should inform selection of:
- a relevant set of quality attributes to measure the effect of the manufacturing change on product quality,
- appropriate test methods, and
- comparability acceptance criteria that are adequate to demonstrate a lack of adverse effect of the manufacturing change on product quality.
In addition to evaluation of the effect of the manufacturing changes on product quality, a comparability study should include measurement of quality attributes that are not routinely used for product release. FDA’s draft guidance also provides a high-level summary of selection of product lots, special considerations for CGT products derived from a variable cellular starting material, special consideration for vectors used for ex vivo cell modification, assessment of potency, comparability acceptance criteria and details of the analytical methods and procedures used for the comparability study.
The draft guidance also contains at the end a high-level summary of tissue-engineered medical products (TEMPs) which commonly incorporate viable cells and scaffolds, with cells either seeded onto the scaffold’s surface or embedded within the scaffold. For these reasons, manufacturing changes to TEMPs pose additional unique challenges which may impact the cells, the scaffold and/or the combined cell-scaffold product in ways that are not readily anticipated or detectable based on current measurement technologies.
In summary, the draft guidance of “Manufacturing Changes and Comparability for Human Cellular and Therapy Products,” may require careful interpretation, due to lack of general terminology for manufacturing changes such as PAS, CBE 30 and CBE 0, which mandates industry to continue to refer to all previously issued CMC guidance for CGT products and biologics especially that of recent genome editing and CAR-T product development guidance issued by the CBER at FDA.
Manufacturing-Changes-and-Comparability-for-Human-CGT-Products.pdf (fda.gov)
About the author:
Raj Bandaru is a Senior Regulatory Affairs consultant on the Quality and CMC in the Global Regulatory Affairs team at Accenture. Raj has an experience in the biopharmaceutical/ cell and gene therapy space, with a particular focus on manufacturing, CMC changes to CGT products and Healthy Authority strategy and communications for product development, and global regulatory submissions. Prior to joining Accenture, Raj worked for Enzon Pharmaceuticals, Inc., Girindus America, Valeant Pharmaceuticals International at Costa Mesa, CA and Viventia Bio Inc., in Canada. Raj is currently serving in the advisory role in Regulatory Affairs for a number of CGT and biopharma companies at Accenture.