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usp-467-residual-solvent-testing-in-apis-and-excipients
Impurity Profiling EMA Guideline on Genotoxic Impurities in PharmaceuticalsEMA Reflection Paper on Low Level ImpuritiesFDA Guidance: Microbial Impurities and Endotoxin LevelsFDA Guidance: Threshold of Toxicological Concern (TTC) for ImpuritiesFDA ICH M3(R2): Impurities in Safety StudiesFDA Q&A on Impurities in Generic Drug ApplicationsFDA Q&A: Managing Impurities in Complex APIsICH E14: QT Interval Evaluation and Impurity ImpactICH M7: Mutagenic Impurity Risk AssessmentICH Q10: Pharmaceutical Quality System for Impurity ManagementICH Q11: Impurity Control Strategy in Drug Substance DevelopmentICH Q12: Lifecycle Management of Impurity Control StrategyICH Q1E: Evaluation of Stability Data Related to Impurity FormationICH Q2(R1): Validation of Analytical Methods for Impurity TestingICH Q3A: Organic Impurity Profiling in Drug SubstancesICH Q3B: Impurity Testing in Finished Drug ProductsICH Q3C: Residual Solvent ProfilingICH Q3D: Elemental Impurity Risk AssessmentICH Q3F: Impurity Guidelines for Biotechnology ProductsICH Q4B: Harmonization of Analytical Procedures for Impurity TestingICH Q5C: Impurity Monitoring in Biotechnological ProductsICH Q6A: Specifications and Acceptance Criteria for ImpuritiesICH S3A: Impurities Arising from Degradation ProductsICH S6: Biotech Product Impurity ProfilingICH S7A: Safety Pharmacology Impurity EvaluationICH S9: Impurities in Oncology ProductsISO 10993-18: Chemical Characterization and Impurity AnalysisISO 17025: Accreditation for Impurity Testing LaboratoriesJP General Rule 2.60: Limit Test for ImpuritiesPh. Eur. 2.2.28: Gas Chromatography for Impurity DetectionPh. Eur. 2.2.38: Thin-Layer Chromatography for ImpuritiesPh. Eur. 2.2.46: Chromatographic Separation for Impurity AnalysisPh. Eur. 2.4.14: Determination of Inorganic ImpuritiesPh. Eur. 2.4.20: Limit Test for Heavy Metals in ImpuritiesPh. Eur. 2.4.24: Related Substances by HPLC in APIsPh. Eur. 2.4.29: Limit Test for Sulfated Ash ImpuritiesPh. Eur. 2.5.13: Oxidizing Impurity TestsPh. Eur. 2.9.40: Uniformity of Dosage Units and Related ImpuritiesPh. Eur. 5.10: Control of Impurities in Substances for Pharmaceutical UsePh. Eur. 5.4: Impurities in Radiopharmaceutical PreparationsUSP <1010>: Analytical Data Integrity in Impurity ReportingUSP <1031>: The Biocompatibility of Materials and ImpuritiesUSP <1051>: Cleaning Validation Limits and Residual ImpuritiesUSP <1058>: Analytical Instrument Qualification for Impurity StudiesUSP <1078>: Good Manufacturing Practices for Impurity ReductionUSP <1085>: Evaluation of Impurity Method PerformanceUSP <1086>: Impurities in Drug SubstancesUSP <1088>: Forced Degradation Studies for Impurity CharacterizationUSP <1091>: Impurity Isolation and Characterization TechniquesUSP <1099>: Acceptable Analytical Performance CriteriaUSP <1121>: Bulk Pharmaceutical Chemicals and Impurity HandlingUSP <1151>: Pharmaceutical Dosage Forms and Impurity ConsiderationUSP <1191>: Stability Testing of Compounded PreparationsUSP <1222>: Terminal Sterilization Impact on ImpuritiesUSP <1224>: Transfer of Impurity Test ProceduresUSP <1225>: Validation of Compendial Procedures for ImpuritiesUSP <1226>: Verification of Compendial Procedures for Impurity DetectionUSP <1231>: Water for Pharmaceutical Purposes and Impurity EffectsUSP <1232>: Water Activity and Impurity StabilityUSP <1241>: Capsules and Shell Impurity InteractionUSP <1251>: Weighing on Analytical Balances for Micro-ImpuritiesUSP <161>: Transdermal Delivery Systems and Impurity ControlUSP <197>: Spectrophotometric Identification of ImpuritiesUSP <233>: Elemental Impurities Profiling Using ICP-MSUSP <41>: Balances Used for Impurity Weight DeterminationUSP <466>: Identification and Quantification of DegradantsUSP <476>: Impurity Profiling for New Drug ApplicationsUSP <621>: Chromatography Conditions for Impurity IdentificationUSP <730>: Plasma Spectrochemistry for Impurity ProfilingUSP <791>: pH Determination Impact on Impurity SolubilityUSP <797>: Sterile Compounding and Impurity ControlUSP <800>: Hazardous Drug Handling Based on Impurity RiskUSP <851>: Spectrophotometry and Light Scattering for ImpuritiesUSP <853>: Atomic Absorption Spectroscopy for Trace ImpuritiesUSP <857>: UV-Vis Spectroscopy for Impurity QuantificationUSP <85>: Bacterial Endotoxin Limits Related to Impurity SafetyUSP <891>: Nuclear Magnetic Resonance (NMR) for Structural ElucidationUSP <905>: Content Uniformity Related to ImpuritiesUSP <905>: Uniformity of Dosage Units Affected by ImpuritiesUSP <941>: Characterization of Impurity Solubility and pKaWHO TRS 970 Annex 2: Impurity Control in Medicines

USP <467>: Residual Solvent Testing in APIs and Excipients - A Comprehensive Guide

Standard-Related Information

Residual solvent testing is a critical aspect of the pharmaceutical industry, ensuring that active pharmaceutical ingredients (APIs) and excipients meet the required standards for safety and efficacy. The United States Pharmacopeia (USP) <467> standard outlines the requirements for residual solvent testing in APIs and excipients.

Legal and Regulatory Framework

The USP <467> standard is recognized globally, with equivalent or identical standards in international organizations such as the International Organization for Standardization (ISO), the American Society for Testing and Materials (ASTM), and the European Committee for Standardization (CEN). National standards, such as those in Turkey (TSE) and India (IS), also acknowledge the USP <467> standard.

The legal and regulatory framework surrounding residual solvent testing is stringent, with pharmaceutical companies required to comply with Good Manufacturing Practice (GMP) guidelines. The USP <467> standard serves as a reference for regulatory agencies worldwide, ensuring that APIs and excipients meet the necessary standards for safety and efficacy.

International and National Standards

The following international and national standards apply to residual solvent testing in APIs and excipients:

  • ISO 9303:2015

  • ASTM E1944-14

  • CEN ISO/TS 17294-2:2016

  • TSE EN 12457-1:2017

  • IS 3029 (Part 1):2017

    • These standards outline the requirements for residual solvent testing, including sampling procedures, testing methods, and reporting formats.

    Standard Development Organizations

    The USP, ISO, ASTM, CEN, TSE, and IS are all standard development organizations that work together to establish and maintain standards for pharmaceuticals. These organizations ensure that standards remain up-to-date with the latest scientific knowledge and technological advancements.

    Why This Test is Needed and Required

    Residual solvent testing is essential in ensuring the safety and efficacy of APIs and excipients. Solvents used in the manufacturing process can leach into the final product, posing risks to consumers. The USP <467> standard requires pharmaceutical companies to test for residual solvents, ensuring that products meet the necessary standards.

    Business and Technical Reasons

    The business and technical reasons for conducting residual solvent testing include:

  • Ensuring product safety and efficacy

  • Complying with regulatory requirements

  • Maintaining customer trust and confidence

  • Enhancing product quality and reliability

  • Meeting industry standards and best practices

    • Consequences of Not Performing This Test

    Failure to conduct residual solvent testing can result in:

  • Product recalls or market withdrawals

  • Loss of customer trust and confidence

  • Regulatory non-compliance

  • Damage to reputation and brand image

    • Industries and Sectors That Require This Testing

    The following industries and sectors require residual solvent testing:

  • Pharmaceuticals

  • Cosmetics

  • Food and beverages

  • Chemicals

    • Risk Factors and Safety Implications

    Residual solvents can pose significant risks to consumers, including:

  • Health effects, such as cancer or neurological damage

  • Environmental impacts, such as contamination of soil and water

  • Economic consequences, including product recalls and loss of customer trust

    • Quality Assurance and Quality Control Aspects

    Residual solvent testing is an essential aspect of quality assurance and control in the pharmaceutical industry. It ensures that APIs and excipients meet the necessary standards for safety and efficacy.

    Competitive Advantages and Cost-Benefit Analysis

    Conducting residual solvent testing provides several competitive advantages, including:

  • Enhanced product quality and reliability

  • Improved customer trust and confidence

  • Regulatory compliance

  • Innovation and research development support

    • The cost-benefit analysis of performing residual solvent testing is clear: it ensures product safety and efficacy, maintains customer trust and confidence, and enhances regulatory compliance.

    Test Conditions and Methodology

    The test conditions and methodology for residual solvent testing involve the following steps:

    1. Sampling procedures

    2. Testing methods (e.g., gas chromatography)

    3. Reporting formats

    The testing equipment and instruments used include:

  • Gas chromatographs

  • Mass spectrometers

  • Sample preparation devices

    • Test Reporting and Documentation

    Residual solvent test results are documented and reported in accordance with the USP <467> standard. The report format includes:

  • Test result summary

  • Method validation data

  • Calibration and validation procedures

  • Quality control measures during testing

    • The interpretation of test results is based on the following criteria:

  • Limit of detection (LOD)

  • Limit of quantitation (LOQ)

  • Reporting limits

    • Certification and Accreditation Aspects

    Residual solvent testing laboratories must be certified or accredited by recognized third-party organizations, such as the International Society for Pharmaceutical Engineering (ISPE) or the National Association of Testing Authorities (NATA).

    Traceability and Documentation Requirements

    Residual solvent test results are subject to traceability and documentation requirements, including:

  • Sampling procedures

  • Testing methods

  • Reporting formats

    • Why Choose Our Laboratory?

    Our laboratory provides a comprehensive range of residual solvent testing services, including:

  • Gas chromatography

  • Mass spectrometry

  • Sample preparation

  • Method validation

  • Calibration and validation procedures

  • Quality control measures during testing

    • We offer fast turnaround times, high-quality results, and expert technical support.

    Conclusion

    Residual solvent testing is a critical aspect of the pharmaceutical industry, ensuring that APIs and excipients meet the necessary standards for safety and efficacy. The USP <467> standard outlines the requirements for residual solvent testing in APIs and excipients. Our laboratory provides a comprehensive range of residual solvent testing services, ensuring compliance with regulatory requirements and maintaining customer trust and confidence.

    References

    1. United States Pharmacopeia (USP). (2019). <467> Residual Solvents.

    2. International Organization for Standardization (ISO). (2015). ISO 9303:2015.

    3. American Society for Testing and Materials (ASTM). (2014). ASTM E1944-14.

    4. European Committee for Standardization (CEN). (2016). CEN ISO/TS 17294-2:2016.

    5. Turkish Standards Institution (TSE). (2017). EN 12457-1:2017.

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