Drug substances studies

Stress Testing (drug substance) — Studies undertaken to elucidate the intrinsic stability of the drug substance. 

Stress testing (drug substance) Studies undertaken to elucidate the intrinsic stability of the drug substance. Such testing is part of the development strategy and is normally carried out under more severe conditions than those used for accelerated testing. 

Considerable studies are required to establish the toxicological profile of the drug substance. These must assess its direct toxic effects, together with its potential as a reproductive toxin, mutagen, or carcinogen. 

In addition to the safety studies, extensive investigations must be undertaken to establish the quality of the drug substance and product(s) during the pre-clinical phase. These will usually commence with drug discovery, where the initial characterisation of... 

Data to demonstrate the stability characteristics of both the drug substance and the drug product must be collected. Studies using three different batches of both substance and product in their respective containers/packaging must be conducted. Real-time data should be collected under conditions of temperature and relative humidity in line with the recommended storage. Conditions in different world climatic zones must be taken into consideration for cases where normal environmental... 

Manufacturing process The descriptions of the manufacturing steps for the drug substance and product should include process flow diagrams and discussions of critical scale-up steps and process development history and process validation activities, together with assessment of the equivalence or differences in batches used for various studies. 

A guideline for evaluation of the photostability of new drug substances and dosage forms was published in 1997 [39]. Subsequently, a joint study was undertaken by the U.S. Food and Drug Administration (FDA) and Pharmaceutical Research and Manufacturers of America to evaluate the ICF1 guideline. A draft chapter for the United States Pharmacopeia, based on the guideline and the joint study, has been published in Pharmacopeial Forum [40]. 

There is another good reason not to aim too high in the physicochemical studies of the first sample of drug substance. In most cases the synthesis is only a first scheme in later scale-up it will be refined, and in general the first small samples contain some small amounts of impurities, which may influence the precision of the determined constants. But it is necessary... 

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