Drug substance, definition

In order to illustrate an example of process design for the manufacture of enantiopure drug substances on an industrial SMB system, consider manufacturing 10 ton/ year of an enantiopure drug. The racemic drug by definition is a 50 50 mixture of each enantiomer (products A and B). The goal is to process enantiopure drug substances in order to obtain 99 % purity for both the extract and the raffinate. 

Additionally, chronic drug use has been linked to neuropsychological problems that in turn make it harder to stop the cycle of abuse. Psychoactive drugs by definition affect the brain, and long-term or acute exposure to psychoactive substances can be toxic. Furthermore, we know that drug abuse can increase the risks of stroke, brain injury related to accidents, malnutrition, or liver damage, all of which can adversely affect brain function as well. 

For each dmg substance, the maximum acceptable levels of the various impurities are described in the drug substance monograph or the specification included in the submissions to the regulatory authorities. In this chapter, the ICH Q6A [4] and Q6B [5] definition of specification is used. A specification consists of three parts the test (e.g. moisture content, impurities), references to the analytical procedure (e.g. high-performance liquid chromatography [HPLC], gas chromatography [GC]), and the acceptance criterion (e.g. not more than 0.50%). 

FDA. 1970. Food and Drug Administration. Part 191-Hazardous substances definitions and procedural and interpretive regulations. Carbon tetrachloride findings of fact and conclusions and final order regarding classification as banned hazardous substance. Federal Register. 35 13198-13205. 

In a first approach, the definition of contamination in pharmaceutical products can be referred to in terms of related substances and process contaminants While related substances are structurally related to the drug substance, process contaminants are introduced during manufacturing or handling procedures. These two categories include all types of contaminants but do not define them. 

Release Mechanism The process by which the drug substance is released from the dosage form. Typically the definition contains the energy source or pictorially describes the way the drug is released. 

An important aspect of this definition is that the studies are part of the formal, definitive, storage program. In contrast, ICH, in Annex 1, Glossary and Information of the revised stability guideline (6) defined stress testing (drug substance) as ... 

The severe conditions that may be encountered during distribution can be covered by stress testing of definitive batches of drug substance. 

Assignment of a definite or probable cause should be simplified by the availability of analytical development reports prepared during various phases of drug substance or product development. If analytical development during drug development was carefully conducted and validated and was well documented, sufficient information should be available to expedite and facilitate the investigation. 

For analytical method validation during full development (after final synthesis has been set for drug substance and after final market formulation has been set for drug product) corresponding to the definitive control procedure for new drug application (NDA), a specific validation protocol has to be written. Before start of the experimental work, the protocols must be written... 

---