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  • Types of Impurities in Pharmaceuticals: Organic, Inorganic and residual solvents

    In the pharmaceutical industry, the presence of impurities in both Active Pharmaceutical Ingredients (APIs) and formulations is a critical consideration for drug development and regulatory compliance.

    Impurities can either exist inherently in the raw materials or may develop during the manufacturing process. Therefore, the isolation, identification, and quantification of these impurities are paramount to ensure the safety and efficacy of the final drug product.

    Comprehensive impurity profiling is essential to establish control over the quality of APIs and finished pharmaceutical products. This rigorous analysis aids in meeting regulatory requirements, safeguarding patient well-being, and ultimately contributing to the successful development and commercialization of pharmaceuticals.

    Formation of impurities


    The formation of impurities in pharmaceuticals is a critical aspect that can occur at various stages of drug development and manufacturing. This includes during the synthesis of Active Pharmaceutical Ingredients (APIs), as well as throughout the formulation process of the final drug products. Impurities may originate from multiple sources, including intermediate steps in the synthesis pathway or the specific route of synthesis chosen for API production. Throughout the synthesis process and the preparation of pharmaceutical dosage forms, impurities can emerge from a variety of origins.

    Impurities present in pharmaceuticals can be broadly classified into organic or inorganic compounds, alongside residual solvents. These materials are distinct and separate from the intended drug substances or formulation ingredients.

    The classification of impurities in pharmaceuticals is typically divided into three main categories: inorganic impurities, organic impurities, and residual solvents. Each of these classifications requires careful identification, isolation, and quantification to ensure the quality and safety of the final pharmaceutical product.

    Types of impurities in pharmaceuticals

    • Organic impurities in pharmaceuticals can originate from various sources, including starting materials, by-products formed during synthesis, different stages of intermediates, and degradation products that may arise during the manufacturing process or storage.
    • Inorganic impurities, are typically acquired during the manufacturing process. These impurities are often identified as reagents, inorganic salts, ligands, heavy metals, charcoal, catalysts, and other inorganic substances used in the synthesis or manufacturing of pharmaceuticals.
    • Residual solvents are impurities introduced with solvents used in various stages of the pharmaceutical manufacturing process.

    The number of permissible inorganic impurities and residual solvents is usually limited and strictly regulated to ensure the safety, efficacy, and quality of the final pharmaceutical product.

    Organic Impurities

    Organic impurities in pharmaceuticals pose a potential and actual risk, and they are most likely to arise during the synthesis process or storage of the drug substance. The synthesis of drug substances involves various chemical reactions. Therefore impurities associated with raw materials can contribute to the overall impurity profile of the drug substance.

    One subset of organic impurities is represented by organic volatile impurities, which are residual solvents used in and produced during the synthesis of drug substances or in the excipients used in the production of drug formulations. These solvents can persist in the final product and need to be carefully controlled.

    Impurities from intermediates or starting materials may carry through to the drug substance if not effectively removed during the multiple steps of synthesis. Therefore, a thorough understanding of the synthesis process is crucial to identify and eliminate potential impurities.

    In some cases, the degradation of final products can lead to the formation of impurities during bulk drug manufacturing. These degradation products may arise from factors such as storage conditions, the synthesis process itself, or the formulation of the drug product.

    Inorganic Impurities

    Inorganic impurities in pharmaceuticals, including heavy metals, residual solvents, and traces of catalysts, are crucial aspects of quality control. These impurities, often originating from excipients and the manufacturing process, necessitate rigorous detection and quantification using established pharmacopeial standards.

    Catalyst traces from the development of the drug substance must also be carefully managed. Adherence to stringent quality standards, routine testing, and compliance with regulatory guidelines are imperative to ensure the effective control and minimal presence of these inorganic impurities, safeguarding the overall quality and safety of pharmaceutical products.

    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

    Residual solvents in pharmaceuticals are organic volatile chemicals that, while present in trace amounts, are considered potentially undesirable substances and require removal. Even in minute traces, these residual solvents have the potential to influence the efficacy and safety of pharmaceutical products. Their presence can impact various properties of the drug substance, such as crystalline structure, dissolution rate, and color.

    Therefore, stringent control measures are essential to ensure the complete removal of residual solvents during the manufacturing process, preserving the intended quality and characteristics of the pharmaceutical product. This meticulous approach is crucial in maintaining the safety and effectiveness of the medication for end-users

    Classification of residual solvents as per ICH guidelines 

    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.

    types of impurities

    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.

     

    Fig 1

    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.

    Conclusion

    Controlling impurities is a critical challenge currently faced by the pharmaceutical industry, and addressing this issue is essential for product safety and efficacy. International guidelines, such as those provided by the International Conference on Harmonization (ICH), offer frameworks for impurity control, with various regulatory authorities emphasizing the importance of identifying and maintaining purity in APIs.

    Consequently, impurity profiling and testing have become indispensable steps in pharmaceutical manufacturing, contributing to the production of high-quality pharmaceuticals that meet stringent regulatory standards for market release. Rigorous monitoring and control measures are essential to prevent and manage the formation of these impurities, ensuring the quality, safety, and efficacy of pharmaceuticals throughout their lifecycle.

    FAQs:

    What are the impurities in Pharmaceuticals?

    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.

    Which are the types of impurities in Pharmaceutical manufacturing processes?

    Impurities in pharmaceuticals are classified in three different types which includes Inorganic impurities, Organic impurities and from the Residual solvents.

    What are Organic Impurities?

    Organic impurities in pharmaceuticals pose a potential and actual risk, and they are most likely to arise during the synthesis process or storage of the drug substance. The synthesis of drug substances involves various chemical reactions, and impurities associated with raw materials can contribute to the overall impurity profile of the drug substance.

    What are Residual Solvents?

    Residual solvents in pharmaceuticals are organic volatile chemicals that, while present in trace amounts, are considered potentially undesirable substances and require removal. Even in minute traces, these residual solvents have the potential to influence the efficacy and safety of pharmaceutical products. Their presence can impact various properties of the drug substance, such as crystalline structure, dissolution rate, and color.

    Reference:

    1. https://database.ich.org/sites/default/files/ICH_Q3C-R8_Guideline_Step4_2021_0422_1. pdf
    2. 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
    3. https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3255420/

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