Obtaining Approval of New Drug Applications and Abbreviated New Drug Applications from a Chemistry, Manufacturing, and Controls Perspective

INTRODUCTION Chemistry, Manufacturing, and Controls (CMC) is a relatively small section (approximately 15-20%) of a typical new drug application (NDA), but it often becomes a reason for delay in the approval of NDA/biologics licensing applications (BLAs). For abbreviated new drug applications (ANDAs), however, the CMC section is significant (around 80-90%). This section also becomes quite important in the postapproval life-cycle management of the products. It should be noted that the CMC section is made up of three distinctly different but overlapping disciplines/sciences: synthetic/fermentation chemistry, analytical chemistry, and formulation chemistry. Also, the CMC section continuously changes with clinical phases. Typically during clinical phase 1 trials, the CMC section is quite small and contains laboratory-scale manufacturing experience for the drug substance and the drug products with quite simple analytical methodologies. During clinical phase 2 trials, the CMC section evolves to pilot-scale manufacturing of the drug substance and the drug products, and the specifications and analytical methodologies become more sophisticated. End of phase 2 (EOP2) usually becomes a pivotal point in the drug development since at this point decisions and major commitments are made to as to whether to go forward with the phase 3 clinical development and marketing authorization application (NDA/BLA). EOP2 means for the CMC section a major shift in planning and execution. The drug substance and drug product manufacture typically need to be moved to commercial site at a commercial scale, and the specifications and the analytical methodologies need to be upgraded and finalized. So, one can see that the CMC section is a ‘‘moving target.’’ After the completion of clinical phase 3 studies, an NDA/BLA is submitted to the U.S. Food and Drug Administration (FDA) for review and approval. The CMC section of an NDA/BLA should contain all the relevant developmental information that bridges phase 1 through 3 leading up to the NDA/BLA submission.