Key Questions to Consider When Licensing Cell & Gene Therapy Products

Manufacturers often ask if there is a checklist for CMC readiness before entering pivotal or Phase III study or if they plan to ask the agency for one of many expediated designations. Since the agency does not have a guidance or points to consider document in this area, a helpful list of questions to considered can be found below. Keep in mind this list includes most but not all the points which should be considered by manufacturers of cell and gene therapy products.

• Have you performed a careful review of your manufacturing process to ensure that you are entering Phase III trials with a product which is optimal?
• Have you introduced major manufacturing changes that may require conducting comparability studies and if so what is your plan to conduct such comparability studies?
• What is the status of your analytical method development. Have you qualified or preferably validated your assays prior to initiation of your pivotal trial?
• Do you have appropriate potency assays in place for the final drug product?
• Do you have knowledge of Critical Quality Attributes (CQA), Critical Process Parameter (CPP), and Key Process Parameters (KPP)?
• Have you determined shelf life of the final drug product by conducting stability assays using assays which are appropriate and qualified/validated?
• Do you have a well-defined plan to collect materials, reserve samples, for in-process and the final drug product?
• What is your plan of action to conduct process validation to demonstrate that the final drug product can be successfully manufactured consistently?
• Have you defined Standard Operating Procedures (SOP) and protocols, instructions for use outlining any additional manufacturing, processing, formulation or thaw/dilution of the final drug product at clinical sites?
• Do you plan to gain a better understanding of the requirements for conducting leachable and extractable studies for materials which are in direct conduct with your product?
• What is your plan for manufacturing of the final drug product? Do you anticipate needing to make a change to your existing facility? Do you plan for automation, scale-out or scale-up post approval or prior to initiation of Phase III study?
• Have you made a final determination if the current release specifications are adequate for ensuring safety and potency of your final drug product?
• Have you conducted shipping validation for source materials and the final drug product under worst case scenarios or conditions of transport?
• Have you reviewed the quality of ancillary materials, reliability and sustainability of your supply chain and do you have a plan to review your quality agreements and SOPPs which are in place for material qualification, vendor qualification? Have you developed an identity test for your critical ancillary materials?
• Have you finalized your choice of the final container and have a plan how to affix the label on the final drug product?
• What is your plan for testing of the source material, in process materials or the final drug product? Do you plan to outsource your testing, or will it be conducted in house? 
• Do you need to develop any in house standards (physical or performance standards) for your assays? Do you know what standards are needed for your product development and release testing?
• Have you had an EOP2 meeting with the agency to assess your CMC readiness?

CMC readiness remains to be the major hurdle when conducting cell and gene therapy trials. As a result, insufficient readiness could potentially lead to unnecessary delay and may further complicate and  convolute interpretation of very costly clinical trial studies. For this reason, we recommend that our clients conduct a comprehensive and detailed CMC readiness exercise prior to the initiation of their pivotal or licensing trials.