The Chemistry, Manufacturing, and Controls (CMC) information summary describes the manufacturing processes, controls, and analytical methods used for your investigational product and is intended to provide an end-to-end view of the entire workflow and quality control involved. This is an important part of the MIP that needs to be prepared with particularly great care to demonstrate without a doubt to the FDA that you will have an efficacious and most importantly, safe product to administer in humans.
You may find that the manufacturing details of your critical material suppliers (e.g., vector supplier) are proprietary and it may be challenging to provide that information in the Pre-IND. In this case, we suggest working with those suppliers to understand if a drug master file (DMF) is on file with the FDA (see IND Section - Drug Master File (DMF)) and only providing high-level descriptions for the Pre-IND.
Drug master files (DMF) provides the FDA with confidential, detailed information about the facilities, processes, or articles that you may have used in the manufacturing, processing, and storage of your products. For more information on the different types of DMFs and what to include in each, please refer to Drug Master File (DMF) Submission Resources | FDA.
At this point in your program’s development stage, you can include a high-level manufacturing plan up to to first-in-human / Phase 1/2 studies. Consider asking yourself the following questions:
Where is my organization sourcing all the different components of our drug product?
What is the current clinical trial plan in terms of regions? Is development conducted in one country? Or primarily in one and secondarily in another/other countries?
You can then plan how to structure and lay out the CMC summary.
You may want to start with an overview of manufacturing plans from your current stage of development until your first-in-human / Phase 1/2 studies (see below for an example).
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Plasmid Production and Purification | Upstream Processes | Downstream Processes | Fill and Finish |
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To best demonstrate your data and gain the confidence of the FDA in your process validation, consider categorizing data you include in your CMC summary into the broad sections below.
Drug substance and drug product: Vector production process
In this section, you can provide a summary description of your AAV vector gene therapy, including its physical and chemical properties, composition, and manufacturing process. This should include the method of production, purification, and characterization of the vector. As noted previously, some of this information may be proprietary to your vector supplier, however a summary description, or cross-reference to DMF or other documentation at most is expected for the Pre-IND.
Describe your drug product and list out the components. Include cloning and sequencing information on plasmids, sources for cells, e.g., bacteria cell banks for E. coli, American Type Culture Collection (ATCC) or other sources for HEK293 cells, including an analysis of possible contaminants from HEK293 cells.
Quality characterization of the vector, cells, and all components used in the process
The CMC information summary for the Pre-IND can provide information on the physicochemical properties of the AAV vector, such as its size, shape, and purity. The stability of the AAV vector is an essential factor that needs to be addressed as this demonstrates the long-term stability of the vector under various conditions, such as temperature, pH, and storage time. Overall, quality control measures that will be implemented to ensure the consistency and purity of the AAV vector should be described – this includes osmolality, sterility, in-process testing, release testing, and others. [6]
Pro tip:
If you are working with a commercial AAV, it is possible that the supplier has a Drug Master File (DMF) on file with the FDA, which describes the characteristics and production of the AAV vector. The supplier may be able to assist you in providing these details in the MIP and should they have a DMF, it may be possible to refer to it when you submit the Pre-IND meeting package and later, IND.