Whenever new acquaintances learn that I have worked in the Pharma industry for over 10 years, I am frequently hit with a barrage of comments and questions. Why are medicines so expensive? Do you have to throw away the medicines after the expiry date? Do they become dangerous? How are new medicines discovered? Why does it take so long for a newly discovered drug to be marketed as a medicine?

The answers to these questions are largely within the realm of Chemistry, Manufacturing, and Controls (CMC). CMC is a link which connects a drug’s clinical batches (those intended for investigational purposes only, with no requirement for validation of process or analytical methods) to its commercial batches (which are characterized by full validation). This ensures that the drug used in clinical studies is the same drug that is eventually marketed commercially and made available for consumers. It provides assurance that the drug sold to the public shares qualities which were shown to be safe and effective, promises that the quality of the drug consistently meets appropriate quality standards, and makes it clear that the drug prescribed and administered is the same as the one described on the label. CMC provides evidence that the manufacturing process of such drug is under control, which is vital to its quality and consistency. Ultimately, CMC ensures that patients will have access to consistently efficacious, safe, and high-quality pharmaceutical and biopharmaceutical drug products.

Chemistry, Manufacturing, and Controls (CMC) focuses on the rigorous analysis of the manufacturing process, quality control testing, specifications, and product stability of both the drug substance (DS) and drug product (DP). It also focuses 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.) which 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, ensuring 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 outlines key CMC Considerations, and describes the sponsor’s commitment to test and manufacture the product under investigation as stated. It should be noted that CMC information originally submitted for an early-phase study may be limited, and the effect of even the most minor manufacturing changes may not 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, which 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).

In addition to the information contained in Module 3, the Quality Overall Summary (QOS) in Module 2 of the CTD serves as a general introduction to the product under investigation and summarizes the 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. 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. Downplaying the importance of Module 2 QOS and CMC Module 3 is to proceed to submission at one’s own peril.

CMC is not a “one-size-fits-all” set of processes, nor is it a list of tests that must be performed on every product. If anything, it must be tailored to the specific platform and delivery system of the drug, whether injectable, controlled-release, inhalant, topical, solid dose, oral, etc. In addition, CMC applies to both the drug product (the manufacturing process; quality control release testing; specifications and product stability) and the facility in which a product is manufactured (design; qualification; operation; maintenance). The world of CMC brings together formulation researchers and developers, people who work in the manufacturing facility (“on the floor”), analytical and biological quality control lab personnel, stability coordinators, and, of course, CMC writers who are responsible for preparing the documentation required for submission to regulatory authorities around the world. Drug and health product submissions are submitted in a “common technical document” (CTD), and share a standard format for the technical documentation of clinical trial applications such as an investigational medicinal product dossier (IMPD) in Europe and the Food and Drug Administration’s (FDA’s) investigational new drug (IND) application in the US, as well as EU marketing authorization applications and FDA new drug applications (NDAs) or biologics license applications (BLAs). CMC Module 3 (Quality) is a module—and world!—unto itself.

References:

1. Guidance for Industry: M4Q: The CTD – Quality, August 2001. https://www.fda.gov/media/71581/download.
2. 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)
3. Guidance for Industry: Q8(R2) Pharmaceutical Development, November 2009, https://www.fda.gov/media/71535/download.
4. Guidance for Industry: Q11 Development and Manufacture of Drug Substances, November 2012. https://www.fda.gov/media/80909/download.
5. Guidance for Industry: Process Validation: General Principles and Practices, January 2011. https://www.fda.gov/media/71021/download.
6. Guidance for Industry: Q2B Validation of Analytical Procedures: Methodology, November 1996. https://www.fda.gov/media/71725/download.
7. Guidance for Industry: Container Closure Systems for Packaging Human Drugs and Biologics, May 1999. https://www.fda.gov/media/70788/download.
8. Guidance for Industry: Q1A(R2) Stability Testing of New Drug Substances and Products, November 2003. https://www.fda.gov/media/71707/download.
9. Guidance for Industry: Q1E Evaluation of Stability Data, June 2004. https://www.fda.gov/media/71722/download.