Table 1.

Examples of guidance documents and international standards for the measurement of impurities in therapeutic products. International standards (IS) and Guidance for Industry (GI) provided through the U.S. FDA, the U.S. Pharmacopeia (USP), and the International Organization for Standardization (ISO) describe the risks of endotoxin and pyrogen contamination in therapeutic products and outline the assays, protocols, and detection limits which have been standardized and approved for universal application in therapeutic safety and purity measurements.

Document	Type	Purpose	Reference
USP 85 Bacterial Endotoxins Test	GI	Describes method validation and sample preparation requirements for turbidity, chromogenic and gel-clot LAL assay	[63]
USP 151 Pyrogen Test	GI	Describes method validation and sample preparation requirements for the rabbit pyrogen test	[64]
FDA Immunotoxicity Testing Guidance (FDA-modified version of ISO-10993)	GI	Summarizes general types of toxicity and subsequent testing that should be considered for medical devices or constituent materials	[35]
FDA Guidance for Industry: Pyrogen and Endotoxin Testing: Questions and Answers	GI	Provides bacterial endotoxin and pyrogen testing recommendations (gel-blot, photometric, and kinetic tests) and acceptance criteria	[65]
FDA Endotoxin Testing Recommendations for Single-Use Intraocular Ophthalmic Devices	GI	Provides recommended endotoxin limits for the release of intraocular devices and single-use intraocular ophthalmic surgical instruments/accessories	[66]
FDA Questions and Answers on Quality Related Controlled Correspondence	GI	Provides answers to common scientific and regulatory questions around the manufacture and quality control of generic drug production including endotoxin testing	[67]
FDA Immunogenicity Assessment for Therapeutic Protein Products	GI	Outlines approaches to evaluate and mitigate adverse immune responses/immunogenicity associated with therapeutic protein products; discusses the importance of IIMI detection	[62]
ISO-10993-1 Biological Evaluation and Testing Standards for Medical Devices (prepared by ISO/TC 149)	IS	Outlines the potential biological risks arising from the use of medical devices and provides a framework to plan biological evaluation, testing methods, and acceptance criteria	[68]
ISO-29701 Endotoxin Standard (prepared by ISO/TC 229)	IS	Describes application of LAL assay for evaluation of endotoxin levels in nanomaterials intended for use in vitro	[29]
ISO-21582 Pyrogenicity Standard (prepared by ISO/TC 149)	IS	Specifies the principles and methods for pyrogen testing of medical devices and their materials	[72]