CMC Part 2.
The drug manufacturing program for a pharmaceutical product is designed to collect information to ensure that the drug used in clinical studies is the same drug that will be commercially available to consumers. Chemistry, Manufacturing, and Controls (CMC) focuses on the rigorous analysis of the manufacturing process, quality control release testing, specifications, and product stability of both the drug substance (DS) and drug product (DP), as well as on the facility in which a product is manufactured. The DS, or active pharmaceutical ingredient (API), is defined as any component that is intended to furnish pharmacological activity. The DP is defined as a finished dosage form (tablet, capsule, solution, etc.) that contains an active DS generally, but not necessarily, in association with inactive ingredients.
It is the job of CMC writers to turn the drug manufacturing data into a coherent narrative that conveys the current knowledge about the quality and safety of the product and ensures that the message and focus are consistent across documents.
Sponsors of investigational new DPs are required to describe the CMC information for both the DS and the DP. Products that are not intended to be distributed commercially, e.g., emergency use and treatment applications, are excluded from the “common technical document” (CTD) requirements. The CMC information submitted to health authorities describes the sponsor’s commitment to perform manufacturing and testing of the product under investigation as stated. It should be noted that CMC information submitted in the original submission for an early phase study may be limited, and the effect of (even minor) manufacturing changes on product safety and quality may not yet be fully understood. As product development proceeds, manufacturing changes may be necessary, and amendments to supplement the initial information submitted for the CMC processes should be submitted.
CMC data to be submitted to the regulatory authorities for approval are presented in Module 3 (Quality) of the CTD that shares a standard format for clinical trial. Module 3 provides tools for understanding the “big picture” as well as addressing specific manufacturing issues with the product. The regulatory requirements for Module 3 are set out in the FDA Guidance for Industry: M4Q: The CTD – Quality(1) and ICH M4Q Common Technical Document for the Registration of Pharmaceuticals for Human Use – Quality(2). There are additional FDA Guidelines for each section of Module 3 (3-9).
Module 3 must contain a description of the DS and DP, including physical, chemical, or biological characteristics, manufacturing controls, and testing information to ensure that they meet acceptable limits for identity, strength (potency), quality, and purity. A manufacturing process may include more than one DS, in which case separate DS sections for each active ingredient of the final product should be provided. Stability protocols, as well as a summary of the available stability data for the DS and DP, recommended storage conditions, and shelf life, if applicable, should be included in each DS and DP section.
In addition to the information contained in Module 3, the Quality Overall Summary (QOS) in Module 2 of the CTD is a general introduction to the product under investigation and summarizes quality-related data and information provided in Module 3 of the CTD. It includes an overview of the manufacturing process, controls to ensure product quality, and general information regarding the qualification of components and starting materials, including a description of its active ingredient(s), mode of action, and proposed clinical use. The summary should also include a description of potential critical quality attributes (CQAs) that are relevant to the safety and biological activity of the product as understood at the time of submission. These CQAs are physical, chemical, biological, or microbiological properties or characteristics that should be within an appropriate limit, range, or distribution to ensure the desired product quality. CQAs may change as knowledge of the product increases.
Since proper control of the finished DP is critical to investigational studies, the Module 2 summary should also include a description of how the product will be shipped to, received, and handled at the clinical site to ensure safety, product quality, and stability. Information on shipping and storage conditions, expiration date/time, and chain of custody from the manufacturer to the site of administration should also be included.
To downplay the importance of Module 2 QOS and CMC Module 3 is to proceed to submission at one’s own peril!
- Guidance for Industry: M4Q: The CTD – Quality, August 2001. https://www.fda.gov/media/71581/download.
- ICH M4Q Common Technical Document for the Registration of Pharmaceuticals for Human Use – Quality. ICH M4Q Common technical document for the registration of pharmaceuticals for human use – quality | European Medicines Agency (europa.eu)
- Guidance for Industry: Q8(R2) Pharmaceutical Development, November 2009, https://www.fda.gov/media/71535/download.
- Guidance for Industry: Q11 Development and Manufacture of Drug Substances, November 2012. https://www.fda.gov/media/80909/download.
- Guidance for Industry: Process Validation: General Principles and Practices, January 2011. https://www.fda.gov/media/71021/download.
- Guidance for Industry: Q2B Validation of Analytical Procedures: Methodology, November 1996. https://www.fda.gov/media/71725/download.
- Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, May 1999. https://www.fda.gov/media/70788/download.
- Guidance for Industry: Q1A(R2) Stability Testing of New Drug Substances and Products, November 2003. https://www.fda.gov/media/71707/download.
- Guidance for Industry: Q1E Evaluation of Stability Data, June 2004. https://www.fda.gov/media/71722/download.