CMC Sections of Regulatory Filings and CMC Regulatory Compliance during Investigational and Postapproval Stages

Introduction ... 200 Pharmaceutical Quality ... 200Drug Substance ... 201 Manufacture ... 202 Characterization (Structure Elucidation)... 204 Control of Drug Substance (Specifications) ... 205 Reference Standards or Materials ... 206 Container Closure System ... 206 Stability ... 207 Drug Product ... 207Description and Composition of the Drug Product ... 207 Pharmaceutical Development ... 207 Components of the Drug Product ... 208 Drug Product Development ... 208Manufacture (Manufacturer(s)/Method of Manufacture) ...210 Control of Excipients (Specifications) ...211 Control of Drug Product (Specifications) ...211 Justification of Specification(s) ...214 Reference Standards or Materials ...214 Container Closure System ...214 Stability ... 215The chemistry, manufacturing, and controls (CMC) section of a regulatory filing [investigational new drug (IND), IND amendments, IND annual reports, new drug application (NDA) or biologics license application (BLA), postapproval CMC supplements, and NDA annual reports] contains detailed information pertaining to the characteristics, manufacturing, and quality aspects of the drug substance and drug product. Under the International Conference on Harmonization (ICH) Common Technical Document (CTD) format,1 the CMC section is referred to as the quality section and the structure is outlined in the ICH CTD guidance.2 This chapter first discusses the details of the quality section of a CTD, followed by how CMC changes are managed during the IND development phases and postapproval stages. As this book addresses the Food and Drug Administration (FDA) regulatory affairs, the focus of the discussions is primarily based on the US FDA expectations and requirements. Other health authority requirements such as those found in Europe, Canada, Japan, or China could vary significantly from this chapter with respect to CMC, and the reader is encouraged to seek other reference materials as appropriate.