The control of API impurities – A critical issue to the pharmaceutical industry

In the present era, there is a tremendous upsurge for impurity profiling of pharmaceutical products. Presence of impurities in trace quantity in drug substance or drug product is inevitable. Therefore, their level should be controlled and monitored. They can reinforce or diminish the pharmacological efficacy of the Active Pharmaceutical Ingredient (API). Sometimes, the effect produced by impurities can be teratogenic, mutagenic or carcinogenic. This can jeopardize the human health by affecting quality, safety and efficacy (QSE) of the product. Therefore, there is an ever-increasing interest in controlling and monitoring impurities present in API / pharmaceutical products. Hence, API impurity profiling (identification, isolation and characterization) is required. Their limits and threshold values should comply with the limits set and specified
by official bodies and legislation (Pharmacopoeias and International Conference on Harmonization (ICH) guidelines). This is very important when company files Investigational New Drug Application (IND) or Abbreviated New Drug Application (ANDA). However, monitoring and controlling of impurity is different for different people. Therefore, there must be unified system to ensure that every one speaks the same language when addressing “Issues related to impurities”
ICH has published guidelines for validation of methods for analysis of impurities in new drug substances, new drug products, residual solvents and microbiological impurities for registration of pharmaceuticals for human use. ICH defines impurities as “substances in the API that are not the API itself”. For pharmaceutical products, impurities are defined as “substances in the product that are not the API itself or the excipients used to manufacture it” i.e. impurities are unwanted chemicals that remain within the formulation or API in small amounts which can influence QSE, thereby causing serious health hazards. According to ICH guidelines on impurities in new drug substances and new drug products, identification of impurities below the 0.1% level is not necessary unless the potential impurities expected to be unusually potent or toxic. In all cases, impurities should be qualified. If data related to qualification of the proposed specification level of an impurity is not available then studies were required to obtain such data. According to ICH, the maximum daily dose qualification threshold is as follows: <2g/ day 0. 1% or 1 mg/ day intake and >2g/ day 0.05%
As impurity profile received a critical attention from regulatory authorities, different Pharmacopoeias such as British Pharmacopoeia (BP), United States of Pharmacopoeia (USP), European Pharmacopoeia (EP) and Indian Pharmacopoeia (IP) are slowly incorporating limits to allowable levels of impurities present in new drug substances or APIs and formulations. Moreover, a number of articles have stated guidelines and designed approach for isolation and identification of process related impurities and degradation products using Mass spectroscopy (MS), Nuclear Magnetic Resonance (NMR), High Performance Liquid Chromatography (HPLC), FT-Ion Cyclotron Resonance MS (FT-ICR-MS) and Tandem MS for pharmaceutical substances. Impurity profiling is a major concern in drug developing and processing.
Identification of impurities is very important task during the synthesis of drug substances and manufacture of dosage forms. It can provide crucial data regarding the toxicity, safety, various limits of detection and limits of quantitation of several organic and inorganic impurities, usually accompany with APIs and finished products. ICH has outlined guidelines with regard to impurities but much more need to be required. There is strong requirement to have unified specifications/standards with regard to impurities.