Life Science Leader Magazine Supplements

CMO 2017

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By S. Naganathan STRATEGY FOR EARLY-PHASE API DEVELOPMENT MATERIALS PLANNING Manufacturing LIFESCIENCELEADER.COM THE CMO LEADERSHIP AWARDS 2017 30 able world's supply of the drug! Thus, the debate over whether the chemical development group makes one batch of the drug substance for use in both the non- clinical toxicology studies and Phase 1 trials, or adopts the two-batch strategy by making a smaller batch for the toxicology studies followed by a batch manufac- tured under cGMP for Phase 1 trials. Obviously, each approach has its advantage and associated risk. The one-batch strategy is a linear process, and once manufactured, the materials can be engaged in the development activities without any risk or interrup- tion. However, all chemical development and manu- facturing have to be completed prior to the start of any dosing, human or animal, and could last about six to 12 months for a typical small molecule. Adding the cus- tomary six months it takes to obtain reports from IND- enabling toxicology studies, time for first-in-human dosing could be 12 to 18 months from nomination of a clinical candidate. Employing a two-batch strategy is likely to be con- siderably faster because several activities happen in parallel. First, a smaller batch of drug substance is prepared and used to initiate the toxicology studies, ost often, the delay in initiating human clinical trials is caused by the unavail- ability of suitable drug. Therefore, there is great pressure on the chemical devel- opment group to not be the limiting factor and ensure sufficient drug is available in a timely manner. As the drug development advances into later phases, drug supply is usually less of a constraint, because the physi- cochemical properties of the drug are better under- stood, and a reliable supply chain begins to take shape. There are multiple best practices for rapid filing of an investigational new drug (IND) application and ini- tiating clinical trials. But there are only a few trusted principles that ensure the chemical development group is not a barrier to the drug supply. "PERFECT IS THE ENEMY OF THE GOOD" When planning for the initial delivery of clinical trial material (both drug substance and drug product), the focus should be on the delivery of enough material to cover the Phase 1 trial and also initiate Phase 2 trials if needed. Along the way, material needs for formulations development may be fulfilled through judicious plan- ning of batch size and production schedule. If the clini- cal program is successful, there will be sufficient time and resources to develop an elegant and cost-effective commercial process. At this stage, a process that can be scaled to produce a consistent and predictable quality of the drug substance is entirely adequate. ONE BATCH VS. TWO BATCHES Initially, the drug substance requirements are gener- ally small and limited to conducting nonclinical toxi- cological studies, which enable the initiation of Phase 1 human trials. Drug substance needs for Phase 1 trials tend to be a few kilograms to a few tens of kilograms and usually consist of the entire quantity of the avail- M Strategy For Early-Phase API Development S R I R A M N A G A N A T H A N In our experience, the two-batch strategy has been employed successfully in over 20 programs.

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