In the pharmaceutical industry, impurities may exist or develop in both API and formulation. The isolation, identification and quantification of these impurities are important for drug development and also for the regulatory requirement. The impurities present in APIs and finished products need impurity profiling to have control over quality.
ICH (International Council for Harmonization) formulated the guidelines and classified the impurities as organic impurities, inorganic impurities, and residual solvents. The impurities in New Drug substance refers to Q3A (R2), further guidelines address the impurities, chemistry, and listing of impurities in specifications its threshold, qualification, and identification.Q3B (R2) refers to Impurities in New drug products and it defines those impurities which might arise from drug substance as degradation product or from the interaction between excipient and drug substance or the primary packing materials (components). Q3C (R8) refers to the guidelines for residual solvents.
Pharmacopeias like British Pharmacopoeia (BP), Indian Pharmacopoeia (IP), and the United States Pharmacopoeia (USP) have also listed the allowable limits of impurities as present in the drug substance or drug products.
The Impurities in pharmaceuticals are organic or inorganic material or residual solvents other than the drug substances or ingredients that arise out of synthesis or unwanted chemicals that remain with the active pharmaceutical ingredients (APIs) or develop during formulation or upon aging of both API and formulation.
Pharmaceutical Impurities can be of three types; Impurities closely related to the product and coming from the chemical or from the biosynthetic route itself, Impurities formed due to spontaneous decomposition of the drug during the storage or on exposure to extreme conditions or the precursors which may be present in the final product as impurities.
According to ICH guidelines, impurities in the drug substance produced by chemical synthesis can broadly be classified into the following three categories:
Organic Impurities
Organic impurities are potential and most likely to arise during the synthesis process or maybe during the storage of drug substances. In synthesis, different chemical reactions are involved, and impurities associated with raw material may also contribute to the impurity profile of the drug substance.
The organic volatile impurities are residual solvents used in and produced during the synthesis of drug substances or in excipients used in the production of drug formulations. In addition, the Impurities from the intermediate or starting material may be present in the drug substance if they are not adequately removed during the multiple steps synthesis.
Sometimes the degradation of final products results in the formation of impurities during bulk drug manufacturing, and these degradation products may arise from storage, synthesis process, and formulation of the drug product.
Inorganic Impurities
Inorganic impurities are typically detected and quantified using pharmacopeial or other appropriate standards and may derive from excipients and manufacturing processes. These impurities are obtained in drug substances and products during manufacturing.
The most common inorganic impurity types are:
- Reagents, ligands, and catalysts
- Heavy metals or other residual metals
- Inorganic salts
- Filter aids, charcoal and other materials
Residual Solvents
The residual solvents in pharmaceuticals are volatile organic chemicals and potentially undesirable substances. They are present in traces amount and need to be removed. The presence of these unwanted chemicals, even in trace amounts, may influence the efficacy and safety of the pharmaceutical products, the presence of residual solvents may affect the properties of drug substances like crystalline, dissolution and, color, etc.
Analytical techniques like gas chromatography are used to identify the solvents present as residual solvents. Impurities above 0.1% should be identified and quantified by selective methods to reduce the number of impurities to an acceptable level.
The residual solvents as per the ICH guidelines are as:
Class 1: Solvents are to be avoided and not be employed in manufacturing drug substances due to their unacceptable toxicity, and usage must be restricted. Solvents such as Benzene have a 2 ppm limit, 1,2 Dichloroethane 5 ppm limit, 1,1 Dichloroethene 8 ppm limit,1,1,1 Trichloroethane 1500 ppm limit, and Carbon tetrachloride 4 ppm limit.
Class 2: Solvents should be limited in pharmaceutical products because of their inherent toxicity.
Class 3: Solvents have low toxicity potential and are considered less toxic and lower risk to human health. The residual solvents of 50 mg daily or less (corresponding to 5000 ppm or 0.5% under option I) would be acceptable without justification. Solvents adequate toxicological data is not available and the manufacturer should justify the levels for these solvents in pharmaceutical products.
The above ICH guidelines Class I, II, and III for residual solvents should be strictly followed, and details for solvents and their ppm limit refer tothe guidelines as mentioned in ICH Q3C (R8).
The quantitative determination of these impurities could be used as a method for the validation and quality control of drug substances. Regulatory authorities such as US FDA, TGA, CGMP, and MCA insist on impurity profiling drugs.
Impurities in new drug substances
(1) The chemical aspect includes classification and identification of impurities, report generation, impurities listing in specifications, and a short discussion of analytical procedures.
(2) The safety aspect includes specific guidance for quantifying impurities present, substantially at lower levels, in a drug substance used in clinical studies.
Impurities are found in APIs unless proper control is taken in each step involved throughout the multi-step synthesis, for example in Paracetamol bulk, there is a limit test for p-Aminophenol, which could be a starting material for one manufacturer or be an intermediate for the others as in fig 1, production of Paracetamol from intermediate, p-Aminophenol. The degradation of the end product can also form impurities while manufacturing bulk drugs.
The degradation of penicillin and cephalosporin are well-known examples of degradation products. The presence of a β-lactam ring and that of an a-amino in the C6 or C7 side chain plays a critical role in their degradation.
FAQs:
Pharmaceutical Impurities are the organic or inorganic material or residual solvents other than the drug substances or ingredients that arise out of synthesis or unwanted chemicals that remain with the active pharmaceutical ingredients (APIs) or develop during drug product formulation.
Organic impurities are process-related or drug-related pharmaceutical impurities. These impurities are potentially most likely to arise during the synthesis process or maybe during the storage of drug substances. In synthesis, different chemical reactions are involved, and impurities associated with raw material may also contribute to the impurity profile of the drug substance.
The residual solvents in pharmaceuticals are volatile organic chemicals and potentially undesirable substances. They are present in traces amount and need to be removed. These unwanted chemicals, even in trace amounts, may influence the efficacy and safety of pharmaceutical products.
Reference:
- https://database.ich.org/sites/default/files/ICH_Q3C-R8_Guideline_Step4_2021_0422_1. pdf
- https://www.researchgate.net/profile/Sv-Saibaba-2/publication/315728030_PHARMACEUTICAL_IMPURITIES_AND_THEIR_CHARACTERIZATION_A_REVIEW/links/58df61bfa6fdcc41bf8ea462/PHARMACEUTICAL-IMPURITIES-AND-THEIR-CHARACTERIZATION-A-REVIEW.pdf
- https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255420/
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