Test Method Evaluation Report on In Vitro Pyrogen Test Methods

Cover of ICCVAM Test Method Evaluation Report on Pyrogen Test Methods

ICCVAM Test Method Evaluation Report:
Validation Status of Five In Vitro Test Methods Proposed for Assessing Potential Pyrogenicity of Pharmaceuticals and Other Products

May 2008 - NIH Publication No. 08-6392

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Complete Report

Main Body

Appendix A: Independent Scientific Peer Review Panel Assessment

Appendix B: Relevant Federal Pyrogenicity Regulations and Testing Guidelines

  • Appendix B1: U.S. Code of Federal Regulations
    • Appendix B1-1: 21 CFR 211.167 - Current Good Manufacturing Practice for Finished Pharmaceuticals: Special Testing Requirements
    • Appendix B1-2: 21 CFR 314.50(d)(1)(ii)(a) - Applications: Content and Format of an Application
    • Appendix B1-3: 21 CFR 610.9 - General Provisions: Equivalent Methods and Processes
    • Appendix B1-4: 21 CFR 610.13 - General Biological Products Standards: Purity
  • Appendix B2: International Organization for Standardization - ISO 10993-11 Biological Evaluation of Medical Devices - Part 11: Tests for Systemic Toxicity
    Document available from the ISO website
  • Appendix B3: U.S. Pharmacopeia
    Documents available from the U.S. Pharmacopeia website
    • Appendix B3-1: (85) - Bacterial Endotoxins Test
    • Appendix B3-2: (151) - Pyrogen Test
    • Appendix B3-3: (1041) - Biologics
  • Appendix B4: European Pharmacopoeia
    Documents available from the European Pharmacopeia website
    • Appendix B4-1: (2.6.8) - Pyrogens
    • Appendix B4-2: (2.6.14) - Bacterial Endotoxins
  • Appendix B5: FDA Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test for Human and Animal Parenteral Drugs, Biological Products, and Medical Devices
    Please note: In July 2011, the U.S. FDA withdrew the Guideline on Validation of the Limulus Amebocyte Lysate Test as an End-Product Endotoxin Test for Human Parenteral Drugs, Biological Products, and Medical Devices (1987) because the document no longer reflects the Agency’s current thinking on the topic.

Appendix C: ICCVAM Recommended Test Method Protocols

  • Appendix C1: The Human Whole Blood (WB)/Interleukin (IL)-1β In Vitro Pyrogen Test
  • Appendix C2: The Human WB/IL-1β In Vitro Pyrogen Test: Application of Cryopreserved (Cryo) Human WB
  • Appendix C3: The Human WB/IL-6 In Vitro Pyrogen Test
  • Appendix C4: The Human Peripheral Blood Mononuclear Cell (PBMC)/IL-6 In Vitro Pyrogen Test
  • Appendix C5: The Monocytoid Cell Line Mono Mac 6 (MM6)/IL-6 In Vitro Pyrogen Test

Appendix D: Federal Register Notices, Public Comments, and Relevant SACATM Meeting Minutes

Appendix E: ESAC Statement on the Validity of In Vitro Pyrogen Tests