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pda-tr-no-66-defining-leachables-risk-in-biologics-production
Extractables and Leachables 21 CFR 174.5 General Requirements for Indirect Food Additives – E&L21 CFR 175.300 Resinous and Polymeric Coatings – Leachables Control21 CFR 176.170 Substances in Contact with Aqueous Foods – Extractables21 CFR 177.1520 Leachable Migration Limits for Polyolefins21 CFR 177.1630 Polyethylene Terephthalate Polymers – Leachables LimitASTM D6288 Volatile Organic Compounds Determination by GC/MSASTM D6499 N-nitrosamines Extraction from Rubber ComponentsASTM D7823 Screening of Phthalates in Plastic ComponentsASTM D7896 Analysis of Leachables in Water by LC-MS/MSASTM D8147 Non-Volatile Extractables in Polymeric MaterialsASTM E2406 Leachables from Sterile Barrier SystemsASTM F1980 Accelerated Aging for Stability of ExtractablesASTM F2459 Extractable Residue from Metallic Medical ComponentsASTM F3136 Evaluation of Leachables in Drug Delivery DevicesEMA Guideline on Plastic Immediate Packaging Materials – E&LEP 2.9.47 Container Closure System Integrity Testing for ExtractablesEP 3.1.3 Polyolefins in Contact with Injectable PreparationsEP 3.1.4 Polypropylene for Containers in ParenteralsEP 3.1.5 Polyethylene Used in Pharmaceutical ContainersEP 3.1.6 Polyethylene Terephthalate Containers – Leachable SafetyEP 3.2.2 Plastic Containers and Closures for Pharmaceutical UseEP 3.2.8 Closures for Containers for Aqueous Parenteral PreparationsEP 3.2.9 Rubber Closures – Extractables AnalysisEP 5.1.1 Biological Safety – Leachables Toxicity AssessmentFDA 21 CFR 211.94 Container Closure System Suitability – Extractables RiskFDA Guidance: Container Closure Systems for Drug Products – E&L FocusFDA Guidance: Orally Inhaled and Nasal Drug Products – Leachables ReviewHealth Canada GUI-0069 Plastic Components in Contact with Drug ProductsICH Q3D Risk-Based Assessment of Elemental Impurities in LeachablesISO 10993-12 Sample Preparation for Extractables TestingISO 10993-13 Degradation Products Analysis for Polymeric Medical DevicesISO 10993-14 Identification of Degradation Products from CeramicsISO 10993-15 Identification of Degradation Products from MetalsISO 10993-17 Toxicological Risk Assessment for LeachablesISO 10993-18 Chemical Characterization of Medical Device MaterialsISO 11607-1 Package Integrity for Sterile Medical DevicesISO 11607-2 Manufacturing Validation for Sterile Barrier SystemsISO 11979-5 Extractables in Intraocular Lens MaterialsISO 14937 Sterilization and Extractables Safety AssuranceISO 15759 Analysis of Packaging for Contact with Parenteral DrugsISO 17664 Processing of Leachable-Safe Reusable Medical DevicesISO 18562-1 Leachables Testing for Breathing Gas Pathways in HealthcareISO 18562-2 Volatile Organic Compounds Testing from Medical DevicesISO 18562-3 Condensate Leachables Testing from Gas Pathway EquipmentISO 18562-4 Leachable Particulates in Medical Gas Pathway DevicesISO/TR 10993-33 Guidance on E&L Assessment Strategy for DevicesJP 2.20 Extractables from Rubber Stoppers by GC-MSJP 6.02 Aluminum Cap Material Leachables TestingJP 6.07 Plastic Containers for Aqueous Injections – Leachable StandardsJP 6.10 Gas Permeability and Volatile Leachable ReleaseJP 7.02 Residual Solvent and Leachable IdentificationJP 7.04 Container/Closure Leachable Migration EvaluationPDA TR No. 85 Extractables and Leachables in Manufacturing SystemsPh. Int. General Method 3.10 Leachable Profiling of Packaging MaterialsUSP <1031.1> Analytical Instrument Qualification for Extractables StudiesUSP <1031> Analytical Method Validation for Extractables StudiesUSP <1058> Analytical Instrument Qualification for Leachables TestingUSP <1079> Good Storage and Distribution Practices – Leachable RiskUSP <1086> Impurities – Extractables Risk ProfilingUSP <1088> Inhalation and Nasal Drug Products – Leachables TestingUSP <1207> Container Closure Integrity and Leachable EntryUSP <1231> Water for Pharmaceutical Purposes – Leachables RiskUSP <1661> Evaluation of Plastic Packaging Systems for Drug ProductsUSP <1663> Extractables Testing for Plastic Components in Drug PackagingUSP <1664> Leachables Analysis for Container Closure SystemsUSP <381> Elastomeric Closures for Injections: Extractable ProfileUSP <601> Aerosols – Extractables in Metered Dose InhalersUSP <661.1> Physicochemical Testing of Plastic Packaging SystemsUSP <661.2> Biological Reactivity Tests for Plastic MaterialsUSP <661> Packaging System Suitability for ExtractablesUSP <671> Stability and Buffering Capacity in Plastic ContainersUSP <800> Hazardous Drug Handling – Leachables from PackagingUSP <87> Biological Reactivity Test: In Vitro CytotoxicityUSP <88> Biological Reactivity Test: In Vivo Irritation & ToxicityUSP <905> Uniformity of Dosage Units – Leachable InfluenceWHO TRS 961 Annex 9 Guidelines on Packaging Materials – Leachables

Comprehensive Guide to PDA TR No. 66 Defining Leachables Risk in Biologics Production Testing Services

Provided by Eurolab

PDA TR No. 66, Defining Leachables Risk in Biologics Production, is a technical report issued by the Parenteral Drug Association (PDA) that provides guidance on evaluating and mitigating leachable risks in biologics production. This report is essential for ensuring the quality and safety of biologic products, particularly those intended for parenteral administration.

Relevant Standards:

  • ISO 14644-1:2015 - Cleanrooms and associated controlled environments

  • ASTM E2500-09 - Standard Practice for Sampling of Materials from Containment Devices (e.g., syringes)

  • EN ISO 10993-15:2009 - Biological evaluation of medical devices Part 15: Identification and quantification of degradation products from polymeric materials

  • TSE (Turkish Standards Institution) 1473:2017 - Pharmaceutical quality control

    • International and National Standards:

    The standards mentioned above are widely recognized and applied globally, with slight variations depending on the country or region. For example, in Europe, the EN ISO 10993-15 standard is used for biological evaluation of medical devices.

    Standard Development Organizations:

  • PDA (Parenteral Drug Association)

  • ASTM International

  • ISO (International Organization for Standardization)

  • TSE (Turkish Standards Institution)

    • These organizations play a crucial role in developing and maintaining standards related to biologics production and testing.

    How Standards Evolve and Get Updated:

    Standards are developed, reviewed, and updated periodically to reflect advances in technology, changes in regulatory requirements, or emerging industry needs. Standard developers engage with stakeholders, including manufacturers, regulators, and other experts, to ensure that the standards remain relevant and effective.

    Standard Numbers and Scope:

  • PDA TR No. 66: Defining Leachables Risk in Biologics Production

  • ISO 14644-1:2015: Cleanrooms and associated controlled environments

  • ASTM E2500-09: Standard Practice for Sampling of Materials from Containment Devices (e.g., syringes)

  • EN ISO 10993-15:2009: Biological evaluation of medical devices Part 15: Identification and quantification of degradation products from polymeric materials

    • Each standard has its specific scope, application, and requirements.

    Standard Compliance Requirements for Different Industries:

  • Biologics manufacturers

  • Medical device manufacturers

  • Pharmaceutical companies

  • Regulators (e.g., FDA, EMA)

    • Compliance with these standards is essential for ensuring the quality, safety, and efficacy of biologic products.

    Business and Technical Reasons for Conducting PDA TR No. 66 Testing:

    Conducting PDA TR No. 66 testing ensures that leachable risks are identified and mitigated, thereby:

  • Ensuring product quality and safety

  • Meeting regulatory requirements

  • Reducing risk of recalls and liabilities

  • Enhancing customer trust and confidence

    • Industries and Sectors Requiring this Testing:

    Biologics manufacturers, medical device manufacturers, pharmaceutical companies, and regulators require PDA TR No. 66 testing to ensure the quality and safety of biologic products.

    Risk Factors and Safety Implications:

    Failure to conduct PDA TR No. 66 testing can lead to:

  • Contamination and product failure

  • Patient harm or injury

  • Regulatory non-compliance

  • Financial losses

    • Quality Assurance and Quality Control Aspects:

    PDA TR No. 66 testing is an essential quality control measure that ensures the safety and efficacy of biologic products.

    Competitive Advantages of Having this Testing Performed:

    Companies that conduct PDA TR No. 66 testing demonstrate their commitment to product quality, safety, and regulatory compliance.

    Cost-Benefit Analysis of Performing this Test:

    Conducting PDA TR No. 66 testing provides a cost-benefit advantage by:

  • Reducing risk of recalls and liabilities

  • Enhancing customer trust and confidence

  • Meeting regulatory requirements

    • ---

    PDA TR No. 66 testing involves evaluating leachable risks in biologic products using a combination of analytical techniques, including:

    1. Sample Preparation:

  • Sample collection

  • Extraction and preparation for analysis

    • 2. Analytical Techniques:

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

  • Gas chromatography-mass spectrometry (GC-MS)

  • Inductively coupled plasma mass spectrometry (ICP-MS)

    • 3. Testing Environment Requirements:

  • Temperature control

  • Humidity control

  • Cleanroom environment

    • 4. Data Analysis and Interpretation:

  • Data processing and evaluation

  • Leachable risk assessment and mitigation

    • Analytical Techniques:

    LC-MS/MS, GC-MS, and ICP-MS are commonly used analytical techniques for evaluating leachables in biologic products.

    Testing Environment Requirements:

    A cleanroom environment with controlled temperature and humidity is essential for conducting PDA TR No. 66 testing.

    ---

    PDA TR No. 66 data analysis involves:

    1. Data Processing:

  • Data cleaning

  • Data normalization

  • Data transformation

    • 2. Leachable Risk Assessment:

  • Leachable identification

  • Quantification of leachables

  • Risk assessment and mitigation

    • 3. Reporting and Documentation:

  • Reporting of test results

  • Documenting test procedures and protocols

    • Data Analysis Software:

    Software such as Excel, R, or Python is commonly used for data analysis and processing.

    Leachable Risk Assessment:

    Risk assessment involves evaluating the potential impact of leachables on product quality, safety, and efficacy.

    ---

    PDA TR No. 66 reporting and documentation involves:

    1. Test Results Reporting:

  • Test results summary

  • Leachable identification and quantification

  • Risk assessment and mitigation

    • 2. Test Procedures and Protocols:

  • Description of testing procedures and protocols

  • Calibration and validation records

  • Standard operating procedure (SOP) documentation

    • 3. Regulatory Compliance:

  • Compliance with regulatory requirements

  • Reporting to regulatory authorities

    • Reporting Templates:

    Pre-designed reporting templates can be used for reporting test results.

    ---

    Conclusion:

    PDA TR No. 66 testing is an essential quality control measure that ensures the safety and efficacy of biologic products. Conducting PDA TR No. 66 testing provides a competitive advantage, reduces risk of recalls and liabilities, and enhances customer trust and confidence.

    ---

    References:

  • Parenteral Drug Association (PDA). (2015). Technical Report No. 66: Defining Leachables Risk in Biologics Production.

  • International Organization for Standardization (ISO). (2015). ISO 14644-1:2015 - Cleanrooms and associated controlled environments.

  • ASTM International. (2009). E2500-09 - Standard Practice for Sampling of Materials from Containment Devices (e.g., syringes).

    • ---

    Appendix:

    Additional resources, including standard operating procedures (SOPs), testing protocols, and regulatory guidelines.

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    Please note that this is a comprehensive guide to PDA TR No. 66 Defining Leachables Risk in Biologics Production testing services provided by Eurolab. It covers the business and technical reasons for conducting this testing, relevant standards, analytical techniques, data analysis and interpretation, reporting and documentation, and regulatory compliance.

    This guide aims to provide a detailed understanding of PDA TR No. 66 testing and its importance in ensuring product quality, safety, and efficacy.

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