Francesco Lanucara of PharmaLex, writing in the November 2023 edition of the DIA’s Global Forum magazine takes a look at how new guidance from the US FDA aims to tackle the myriad challenges of cell and gene therapy manufacturing comparability and complexity.
Development 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.
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.