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HPLC for Pharmaceutical Scientists 2007 (Part 14)

In the drug discovery area, a compound with desired therapeutic properties is identified, and its structure may be modified by synthetic alterations to enhance potency and specificity or to decrease toxicity and undesired side effects. The lead drug candidate is then transitioned into the drug development area. Only small amounts of drug (typically less than a gram) are required to support the required studies in the Drug Discovery area. However larger amounts are required to support the studies conducted in the Drug Development area. The amount required in the preclinical stage typically ranges from 20 to 2000 g | 14 ROLE OF HPLC IN PROCESS DEVELOPMENT Richard Thompson and Rosario LoBrutto 14.1 RESPONSIBILITIES OF THE ANALYTICAL CHEMIST DURING PROCESS DEVELOPMENT In the drug discovery area a compound with desired therapeutic properties is identified and its structure may be modified by synthetic alterations to enhance potency and specificity or to decrease toxicity and undesired side effects. The lead drug candidate is then transitioned into the drug development area. Only small amounts of drug typically less than a gram are required to support the required studies in the Drug Discovery area. However larger amounts are required to support the studies conducted in the Drug Development area. The amount required in the preclinical stage typically ranges from 20 to 2000 g. This material is required to support studies including subchronic toxicity genotoxicity ancillary pharmacology early animal pharmacokinetics PK salt form selection and formulation development. As the drug candidate progresses through the various clinical stages the drug requirements typically range from 1kg to 200 kg. This material supports the various clinical studies as well as chronic toxicity carcinogenicity development and reproductive toxicity and formulation development. Finally tons of drug may be required upon successful approval and commercialization Figure 14-1 . The synthetic pathway to the drug substance is likely to evolve during the various stages of development. It is highly unlikely that the synthetic process HPLC for Pharmaceutical Scientists Edited by Yuri Kazakevich and Rosario LoBrutto Copyright 2007 by John Wiley Sons Inc. 641 642 ROLE OF HPLC IN PROCESS DEVELOPMENT Prep Lab Pilot Plant 1 kg to 200 kg Lab Prep Lab 20 g to 2000 g Sub-chronic Toxicity Genotoxicity Ancillary Pharmacology Early PK in Animals Formulation Development IND Clinical Manufacturing 100 kg to tons Chronic Toxicity Phase I II III DART Carcinogenicity Formulation Development NDA Demonstration Validation Technology .