Impurity Designation in Pharmaceutical Sciences

R.A. Hajare, L.R. Gandhi, A.V.Chandewar

Abstract: Before finished pharmaceutical dosage forms are produced, the identity, purity and quality of raw material must be established with use of suitable test method. Raw material testing ensures that the raw material used in pharmaceutical products is suitable for their intended use. US Pharmacopoeia – National Formulary (USP- NF), European Pharmacopoeia and Japanese Pharmacopoeia provide standard test method for the most common and widely used materials. To perform basic monographic testing, laboratories must be equip with wide variety of instruments. Impurities in pharmaceuticals are unwanted chemicals that are remaining with the active pharmaceutical ingredients (APIs) or developed during formulation, or upon aging of both API and formulated APIs to medicine. The presence of these unwanted chemicals even in small amount may influence the efficacy and safety of the pharmaceutical product. The different pharmacopoeias, such as the British Pharmacopoeia (BP), the United State Pharmacopoeia (USP) and European Pharmacopoeia (EP) are slowly incorporating limits to allowable level of impurity in the APIs or formulations. Impurities, which are commonly present in pharmaceutical, can prove to be toxic to human life or can enhance the degradation of active ingredient. Hence detailed profile of such impurities needs to be prepared.
The synthesis of an active pharmaceutical ingredient (API) normally consists of several synthetic steps. Process-related impurities can be formed at any step and could ultimately appear in the final drug substance, particularly in the scale-up drug candidates1. Impurities must be controlled because of their potential toxicity. Impurity control is a continuing concern of regulatory agencies and the pharmaceutical industry. The international conference on harmonization (ICH) was formed in the 1990s to coordinate the technical requirement for the registration of pharmaceuticals in the european union, japan, and the united states2. The presence of impurities even in small amount may influence the efficacy and safety of pharmaceutical. Moreover, safety regulations require insight into the structure and amount of impurities in pharmaceutical before they can be applied to human. Identity and content of impurities are requested for submission of registration / notification dossiers to the regulatory authorities. Today, modern pharmaceutical analysis entails much more than the analysis of active pharmaceutical ingredients or the formulated product. There are many reasons for this change such as1: Our ability to better understand physicochemical properties of pharmaceutical compound through the use of advanced instrumental method. 2 : There is a need for quality assurance of pharmaceutical product throughout their shelf life3. This requires that we study interaction of the drug substance with the excipients in the presence of residual solvents, as well as other potential degradation reaction that may occur in the formulated product over a period of time under various stress conditions. Impurities in a pharmaceutical compound or NCE (new chemical entity) originate mainly during the synthesis process from raw material, solvent, intermediates, and by- product4. The raw materials are generally manufactured to much lower purity requirements than a drug substance. Hence, it is easy to understand why they would contain a number of components that, in turn, could affect the purity of the drug substance. Similarly, solvents used in the synthesis are likely to contain a number of impurities that may range from trace level to significant amounts that can react with various chemicals used in the synthesis to produce other impurities5, 6. ICH has issued the guideline "Impurities in new drug substances," recommending that, for a maximum daily dose of less than or equal to 2 g per day, any impurity at the 0.10% level (or 1 mg per day intake, whichever is lower) must be identified. The food and drug administration (FDA) has adopted the ICH guidelines, and has published the guidelines.



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