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usp-476-impurity-profiling-for-new-drug-applications
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 <467>: Residual Solvent Testing in APIs and ExcipientsUSP <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 <476>: Impurity Profiling for New Drug Applications Laboratory Testing Service Provided by Eurolab

Overview of USP <476>

The United States Pharmacopeia (USP) <476> is a standard that outlines the requirements for impurity profiling in new drug applications. Impurity profiling involves the identification and quantification of potential impurities present in pharmaceuticals, which can impact their safety, efficacy, and regulatory compliance.

Legal and Regulatory Framework

The USP <476> is based on international standards such as ISO 9001:2015 (Quality Management Systems) and ICH Q3A (Impurities in New Drug Substances). Regulatory agencies worldwide, including the US FDA, EU EMA, and Japanese PMDA, require compliance with these standards for pharmaceuticals.

International and National Standards

The following international and national standards govern impurity profiling:

  • ISO 9001:2015 (Quality Management Systems)

  • ICH Q3A (Impurities in New Drug Substances)

  • USP <476> (Impurity Profiling for New Drug Applications)

  • EU GMP (Good Manufacturing Practice) for pharmaceuticals

  • Japanese PMDA guidelines for impurity profiling

    • Standard Development Organizations and Their Role

    Standard development organizations, such as the International Organization for Standardization (ISO), play a crucial role in developing and maintaining standards. These organizations facilitate international cooperation and harmonization of standards.

    Evolution of Standards

    Standards evolve over time to reflect advancements in technology, changes in regulatory requirements, and industry best practices. Eurolab, as an accredited laboratory, stays up-to-date with the latest standards and guidelines through ongoing training and professional development.

    Specific Standard Numbers and Their Scope

    Some key standard numbers related to impurity profiling are:

  • ISO 9001:2015 (Quality Management Systems)

    • Scope: Requirements for quality management systems

  • ICH Q3A (Impurities in New Drug Substances)

    • Scope: Guidelines for the identification and quantification of impurities in new drug substances

  • USP <476> (Impurity Profiling for New Drug Applications)

    • Scope: Requirements for impurity profiling in new drug applications

    Standard Compliance Requirements for Different Industries

    Compliance with standards is essential for various industries, including:

  • Pharmaceuticals: Compliance with USP <476>, ICH Q3A, and EU GMP guidelines

  • Biotechnology: Compliance with ISO 9001:2015 and ICH Q3A guidelines

  • Cosmetics: Compliance with ISO 9001:2015 and European Cosmetic Regulation

    • Standard-Related Information Table

    Standard Scope Industry

    --- --- ---

    ISO 9001:2015 Quality Management Systems Pharmaceuticals, Biotechnology, Cosmetics

    ICH Q3A Impurities in New Drug Substances Pharmaceuticals

    USP <476> Impurity Profiling for New Drug Applications Pharmaceuticals

    Standard-Related Information Figure

    Figure 1: Standard Development Process

    Insert figure

    Why This Specific Test is Needed and Required

    Impurity profiling is essential for ensuring the quality, safety, and efficacy of pharmaceuticals. Potential impurities can impact the stability, potency, and bioavailability of drugs.

    Business and Technical Reasons for Conducting USP <476> Testing

    Conducting USP <476> testing ensures compliance with regulatory requirements, reduces the risk of product recalls or market withdrawal, and protects brand reputation.

    Consequences of Not Performing This Test

    Failure to perform impurity profiling can lead to:

  • Product recalls or market withdrawal

  • Regulatory non-compliance

  • Loss of customer trust and confidence

  • Financial losses due to costly rework or replacement

    • Industries and Sectors that Require This Testing

    Pharmaceutical, biotechnology, and cosmetics industries require impurity profiling.

    Risk Factors and Safety Implications

    Impurities can pose serious health risks to consumers, including:

  • Toxicity

  • Allergic reactions

  • Carcinogenicity

  • Genotoxicity

    • Quality Assurance and Quality Control Aspects

    Quality assurance and control are crucial for ensuring the accuracy and reliability of test results.

    How This Test Contributes to Product Safety and Reliability

    Impurity profiling ensures that products meet regulatory requirements, reducing the risk of adverse events or product failures.

    Competitive Advantages of Having This Testing Performed

    Companies that invest in impurity profiling demonstrate a commitment to quality, safety, and regulatory compliance, enhancing their market position and reputation.

    Cost-Benefit Analysis of Performing This Test

    The benefits of conducting USP <476> testing far outweigh the costs, considering the risks associated with non-compliance.

    Detailed Step-by-Step Explanation of How the Test is Conducted

    1. Sample preparation

    2. Instrumental analysis

    3. Data processing and interpretation

    Instruments Used for Analysis

  • High-performance liquid chromatography (HPLC)

  • Gas chromatography-mass spectrometry (GC-MS)

  • Liquid chromatography-tandem mass spectrometry (LC-MS/MS)

    • Sample Preparation Methods

  • Solvent extraction

  • Solid-phase extraction

  • Enzyme-linked immunosorbent assay (ELISA)

    • Instrumental Analysis Conditions

  • Column type and size

  • Mobile phase composition

  • Detector settings

    • Data Processing and Interpretation

  • Peak identification and quantification

  • Method validation

  • Result reporting and documentation

    • Test Conditions and Methodology Figure

    Figure 2: Test Workflow

    Insert figure

    Test Conditions and Methodology Table

    Instrument Sample Preparation Method Instrumental Analysis Conditions

    --- --- ---

    HPLC Solvent extraction Column type: C18; Mobile phase: 0.1 formic acid in water

    GC-MS Solid-phase extraction Column type: DB-5ms; Temperature program: 50C - 280C

    LC-MS/MS ELISA Column type: Acquity UPLC BEH C18; Mobile phase: 0.1 formic acid in water

    Test Conditions and Methodology Figure

    Figure 3: Instrumental Analysis

    Insert figure

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