National foreword

This British Standard is the UK implementation of ISO 11737‑3:2023.

The UK participation in its preparation was entrusted to Technical Committee CH/198, Sterilization and Associated Equipment and Processes.

A list of organizations represented on this committee can be obtained on request to its committee manager.

Contractual and legal considerations

This publication has been prepared in good faith, however no representation, warranty, assurance or undertaking (express or implied) is or will be made, and no responsibility or liability is or will be accepted by BSI in relation to the adequacy, accuracy, completeness or reasonableness of this publication. All and any such responsibility and liability is expressly disclaimed to the full extent permitted by the law.

This publication is provided as is, and is to be used at the recipient’s own risk.

The recipient is advised to consider seeking professional guidance with respect to its use of this publication.

This publication is not intended to constitute a contract. Users are responsible for its correct application.

Compliance with a British Standard cannot confer immunity from legal obligations.

This British Standard was published under the authority of the Standards Policy and Strategy Committee on 30 June 2023.

Foreword

ISO (the International Organization for Standardization) is a worldwide federation of national standards bodies (ISO member bodies). The work of preparing International Standards is normally carried out through ISO technical committees. Each member body interested in a subject for which a technical committee has been established has the right to be represented on that committee. International organizations, governmental and non-governmental, in liaison with ISO, also take part in the work. ISO collaborates closely with the International Electrotechnical Commission (IEC) on all matters of electrotechnical standardization.

The procedures used to develop this document and those intended for its further maintenance are described in the ISO/IEC Directives, Part 1. In particular, the different approval criteria needed for the different types of ISO documents should be noted. This document was drafted in accordance with the editorial rules of the ISO/IEC Directives, Part 2 (see www.iso.org/directives).

ISO draws attention to the possibility that the implementation of this document may involve the use of (a) patent(s). ISO takes no position concerning the evidence, validity or applicability of any claimed patent rights in respect thereof. As of the date of publication of this document, ISO had not received notice of (a) patent(s) which may be required to implement this document. However, implementers are cautioned that this may not represent the latest information, which may be obtained from the patent database available at www.iso.org/patents. ISO shall not be held responsible for identifying any or all such patent rights.

Any trade name used in this document is information given for the convenience of users and does not constitute an endorsement.

For an explanation of the voluntary nature of standards, the meaning of ISO specific terms and expressions related to conformity assessment, as well as information about ISO's adherence to the World Trade Organization (WTO) principles in the Technical Barriers to Trade (TBT), see www.iso.org/iso/foreword.html.

This document was prepared by Technical Committee ISO/TC 198, Sterilization of health care products.

A list of all parts in the ISO 11737 series can be found on the ISO website.

Any feedback or questions on this document should be directed to the user’s national standards body. A complete listing of these bodies can be found at www.iso.org/members.html.

Introduction

A pyrogen is any substance that can induce fever. Testing for pyrogens is required for release of many health care products. Pyrogens can be classified into two groups: microbial (e.g. bacteria, fungi, viruses) and non-microbial (e.g. drugs, device materials, steroids, plasma fractions; see the ISO 10993 series). The predominant pyrogenic contaminants encountered in the manufacturing of health care products are bacterial endotoxins, which are components of the cell walls of Gram-negative bacteria. Although Gram-positive bacteria, fungi, and viruses can be pyrogenic, they do so through different mechanisms (systemic effects) and to a lesser degree than Gram-negative bacteria. Only the Gram-negative bacterial endotoxins test (BET) using amebocyte lysate reagents from Limulus polyphemus or Tachypleus tridentatus is covered in this document. Other endotoxin detection methodologies, such as monocyte activation and recombinant Factor C (rFc), are not included (see B.12) in this document.

Endotoxins are the molecular weight lipopolysaccharide (LPS) components of the outer cell wall of Gram-negative bacteria, that can cause fever, meningitis, and a rapid fall in blood pressure if introduced into the blood stream or certain other tissues of the body. The outer cell wall components, which are composed primarily of proteins, phospholipids and LPS, are constantly released by the cell into the surrounding environment. Endotoxins are ubiquitous in nature, stable, and small enough to pass through conventional sterilizing filters. Sterilization processes will inactivate microorganisms on or in products, but usually do not inactivate endotoxin on products. With controlled processes, endotoxin contamination can be prevented.

The non-pyrogenicity of a health care product can be achieved through the following:

manufacturing techniques that prevent or control endotoxin contamination (e.g. contamination with Gram-negative bacteria);
depyrogenation by endotoxin inactivation (e.g. dry heat) or physical removal (e.g. rinsing, distillation, ultrafiltration).

The purpose of this document is to describe the requirements and guidance for testing for bacterial endotoxins. This includes product required to be non-pyrogenic based on either intended use or non-pyrogenic label claim, or both. Guidance is also provided on selection of product units, method suitability, use of techniques for routine testing, interpretation of test results, and alternatives to batch testing and risk assessment. Information on the following is provided in the annexes:

guidance on bacterial endotoxin testing (Annex A);
the history and background on the BET (Annex B);
guidance on out of specified limits (OSL) and failure investigation (Annex C);
guidance on in-process monitoring of manufacturing or component testing (Annex D);
guidance on conducting a risk assessment to support alternatives to batch testing (Annex E);
typical assignment of responsibilities (Annex F).

This document is based on ANSI/AAMI ST72. Several sections in this document have been restructured and extended or changed from ANSI/AAMI ST72.

1 Scope

1.1 Inclusions

This document specifies general criteria to be applied in the determination of bacterial endotoxins on or in health care products, components or raw materials using bacterial endotoxins test (BET) methods, using amebocyte lysate reagents.

1.2 Exclusions

1.2.1

This document is not applicable to the evaluation of pyrogens other than bacterial endotoxins. Other endotoxin detection methodologies are not included (see B.12).

1.2.2

This document does not address setting specific endotoxin limit specifications.

2 Normative references

3 Terms and definitions

4 General requirements

4.1

4.2

5 Selection of products

5.1 General

5.2 Selection of product units

6 Methods for BET

6.1 General

6.2 Consideration of an applicable endotoxin limit

6.3 Critical test parameters

6.4 Equipment and materials

6.5 Reagents

7 Method suitability for BET (BET validation)

7.1 General

7.2 Product and test method suitability

7.3 Sample preparation

7.4 Reagent and analyst qualification

8 Routine testing, monitoring and interpretation of data

8.1 Routine testing

8.2 Monitoring (test frequency)

8.3 Interpretation of results

8.4 Data analysis

8.5 Statistical methods

9 Maintenance of the BET method

9.1 General

9.2 Changes to either the product or manufacturing process, or both

9.3 Changes to the BET method

10 Alternatives to batch testing

10.1 General

10.2 Criteria for establishing alternatives to batch testing

10.3 Manufacturing process assessment

10.4 Change control

10.5 Maintenance of risk assessment

Bibliography

BS ISO 11737-3:2023

Sterilization of health care products. Microbiological methods - Bacterial endotoxin testing

Current

Published:

30 Jun 2023