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  • Residual Solvents in Pharmaceuticals

    In pharmaceuticals, residual solvents are the volatile organic compounds used or produced during the manufacturing of drug substances or excipients or during the preparation of drug products. Numerous organic solvents are utilized in the synthesis of drug substances or drug products. These organic solvents have poisonous properties and are also harmful to the environment.

    Residual solvents in pharmaceuticals are organic volatile chemicals and are potentially undesirable substances that are present in trace amounts 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.

    Understanding the Impact of Residual Solvents on Pharmaceutical Quality

    Residual solvents can affect the physicochemical properties of pharmaceuticals, potentially leading to variations in dissolution rates, bioavailability, and therapeutic effectiveness. By comprehending the impact of residual solvents on pharmaceutical quality, manufacturers can proactively address potential concerns and optimize their processes accordingly.

    During the manufacturing process, residual solvents are not completely removed by the manufacturing techniques and also it is very difficult to get rid of organic solvents completely from the finished product. If organic solvents aren’t removed completely from the finished product then the quality and safety of the product are at risk and finally unsafe to the consumer.

    Pharmaceutical manufacturers also need to ensure that the drug substance or excipients or drug products are free from the toxic levels of volatile organic compounds. The selection of an appropriate solvent for the synthesis drug substance or excipients may increase the purity, yield, solubility, and crystal form.

    In the production of pharmaceutical products mainly in the last processing and purification stage the content of the residual solvent in the final product should be analyzed and the acceptability limit to be followed as per the ICH guidelines. 

    Sometimes the solvents may be an important element of critical parameters in the synthesis process. The residual solvents should be tested for drug products, drug substances, and excipients during the production stage or purification stage. Analytical techniques like gas chromatography are used to identify the solvents present as residual solvents.

    Classification of Residual Solvents by Risk Assessment:

    There are certain guidelines issued by the regulatory authority to make sure that it’s safe to use organic solvents. Permitted daily exposure (PDE) is defined as a pharmaceutically suitable consumption of residual solvents.

    Class 1 SolventsClass 2 SolventsClass 3 Solvents
    Class-1 solvents are to be avoided because of their predictable and assumed to be human carcinogens and environmental risks.Class-2 solvents are a smaller amount of genotoxic carcinogenic agents of other irrevocable toxicity like neurotoxicity.Class-3 solvents with less poisonous and at lesser risk to human health.
    The class-1 solvent should be avoided within the manufacture of drug substances, excipients, and drug products.Class-2 solvents are a smaller amount of genotoxic carcinogens agents of other irrevocable toxicity like neurotoxicity.Class-3 solvents are safe for humans with their generally accepted limit in drugs. PDEs are specified as 50 mg per day (5000ppm) would be acceptable without justification.
    e.g. Benzene, Carbon tetrachloride, 1,2-Dichloroethane 1,1-Dichloroethene, 1,1,1-TrichloroethaneClass-2 solvents are assumed as further substantial but revocable toxicities. PDEs are stated to the adjacent 0.1 mg/day, and concentrations are given around 10 ppm.e.g. Acetonitrile, Chlorobenzene, Cyclohexane, Dichloromethane, Hexane, Methanol, N-Methyl pyrrolidone, Tetrahydrofuran, Toluene, Xylene

    Regulatory Guidelines and Standards: Safeguarding Against Residual Solvents

    Regulatory authorities such as the United States Pharmacopeia (USP), the European Pharmacopoeia (EP), and the International Conference on Harmonisation (ICH) have established guidelines and standards to control residual solvents in pharmaceuticals. These guidelines categorize solvents into classes based on their toxicity levels, allowing manufacturers to mitigate risks effectively.

    Recently the International Council for Harmonisation (ICH) published ICH guideline Q3C(R8) on impurities: guidelines for residual solvents for establishing new permitted daily exposures (PDEs) for three residual solvents.

    Residual solvents as per the pharmacopeia to be reduced or removed to the extent possible to meet the product specifications and meet the ingredient, good manufacturing, or based on quality requirements, as the residual solvents do not provide any therapeutic advantage.   

    Minimizing Health Risks: Risk Assessment of Residual Solvents in Drug Formulations To ensure patient safety, manufacturers conduct comprehensive risk assessments for each residual solvent employed in the production process. These assessments evaluate toxicological properties, permissible exposure limits, and potential impacts on product quality and stability. By adopting a risk-based approach, manufacturers can minimize health risks associated with residual solvents.

    FAQs:

    What are residual solvents in pharmaceuticals?

    Residual solvents are volatile chemicals that may be used or generated during the manufacturing process of pharmaceuticals. These solvents can remain in trace amounts in the final product.

    What are the FDA solvent classes?

    As per the guidance, solvents are divided into three classes: Class 1 Solvents which are known to cause unacceptable toxicities and usage must be restricted; Class 2 Solvents which are associated with less severe toxicity and Class 3 Solvents with low toxic potential and regarded as less toxic and of lower risk to human health.

    Why are residual solvents a concern in pharmaceuticals?

    Residual solvents pose potential health risks to consumers. Depending on their nature and concentration, these solvents can have toxic effects, including organ toxicity, carcinogenicity, and developmental or reproductive toxicity.

    Why are residual solvents to be removed from drug preparations?

    Residual solvents (RS) analysis in drug preparation is necessary as the residual organic solvents constitute a potential risk to human health due to the toxic and undesirable side effects. 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.

    How are residual solvents identified and quantified?

    Sophisticated analytical techniques such as gas chromatography and mass spectrometry are employed to identify and quantify residual solvents in pharmaceutical products. These techniques provide accurate measurements and help ensure compliance with regulatory limits.

    References:

    1. ICH, Q3C(R6) Impurities: Guideline for Residual Solvents,
    2. ICH, Q3C(R8) Impurities: Guideline for Residual Solvents, PDE for 2-Methyltetrahydrofuran, Cyclopentyl Methyl Ether and Tertiary-Butyl Alcohol, Draft Version,
    3. The United States Pharmacopeia (USP) general chapter <467> Residual Solvents,
    4. Posiva Panovska; Acevska J; Stefkov G; Breszovska K; Petkovska R; Drimitrovska. A, Optimization of HS-GC-FID-MS Method for Residual Solvent Profiling in Active Pharmaceutical Ingredients Using DoE, Journal of Chromatographic Science, 54, 2016,
    5. “USP–NF | USP-NF.” Uspnf.com, 2023, www.uspnf.com/. Accessed 30 May 2023. https://www.uspnf.com/sites/default/files/usp_pdf/EN/USPNF/generalChapter467Current.pdf
    6. Committee for Medicinal Products for Human Use ICH Guideline Q3C (R8) on Impurities: Guideline for Residual Solvents Step 5. 2021, www.ema.europa.eu/en/documents/regulatory-procedural-guideline/ich-guideline-q3c-r8-impurities-guideline-residual-solvents-step-5_en.pdf.
    7. ‌MANUAL of POLICIES and PROCEDURES CENTER for DRUG EVALUATION and RESEARCH MAPP 5015.8 POLICY and PROCEDURES OFFICE of PHARMACEUTICAL QUALITY Acceptance Criteria for Residual Solvents www.fda.gov/media/75126/download#:~:text=The%20guidance%20divides%20solvents%20into. Accessed 30 May 2023.