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YY/T 0618-2017Test methods for bacterial endotoxins of medical devices—Routine monitoring and alternatives to batch testing (English PDF)

医疗器械细菌内毒素试验方法常规监控与跳批检验

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Issued by

NMPA

Level / Type

Industry · Recommended

Issue date

February 28, 2017

Implementation date

January 1, 2018

Scope

YY/T 0618-2017 is the English-translated version of 医疗器械细菌内毒素试验方法常规监控与跳批检验.

YY/T 0618-2017 is the Chinese pharmaceutical industry standard that gives the basic guidance on bacterial endotoxin test methods as they are applied to medical devices, their components and their raw materials.

It sets out the extraction of the device, the choice between the gel clot, turbidimetric and chromogenic techniques, the validation of the method for the sample including the test for interference, the controls and the calculation and expression of the result. Issued on 28 February 2017, it has applied since 1 January 2018.

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Document preview — YY/T 0618-2017

National Standard of the People's Republic of China

Replacing: YY/T 0618-2007

Issued by: National Medical Products Administration of the People's Republic of China

Foreword3
Introduction4
1 Scope6
2 Normative references6
3 Terms and definitions6
4 Principles of quality management system11
5 Non-pyrogenic label13
6 Selection of product unit14
7 Choice of technique15
8 Methodological validation15
9 Use of technique20
10 Alternatives to batch testing24
Appendix A (Informative) Background information on bacterial endotoxin testing28
Appendix B (Informative) Guidelines for test methods, routine monitoring, alternatives to batch testing32
Appendix C (Informative) Out-of-specification (OOS) and failure investigation guide : References50

Foreword

This standard was drafted in accordance with the rules given in GB/T 1.1-2009.

This standard replaces YY/T 0618-2007 "Bacterial endotoxins - Test methodologies routine monitoring and alternatives to batch testing". The main differences from YY/T 0618-2007 are as follows.

- MODIFY the name of the standard into. Test methods for bacterial endotoxins of medical devices - Routine monitoring and alternatives to batch testing;

- MODIFY the scope;

- ADD the terms, Control standard endotoxin (see 3.4); geometric mean endpoint (see 3.11); investigation test (see 3.14); out of specification (see 3.21);

- MODIFY "Appendix B -- Test methods, routine monitoring and guidelines for alternative to batch testing";

- ADD "Appendix C -- Out of specification (OOS) and failure investigation guidelines".

1 Scope

This standard specifies basic guidelines for test methods for bacterial endotoxins, which are applicable to the determination of medical devices, components or raw materials.

Note. Although the scope of this standard is limited to medical devices, the requirements specified in this standard and the guidelines given may also apply to other medical products.

This standard does not apply to the evaluation of pyrogens, other than bacterial endotoxin.

2 Normative references

The following documents are essential to the application of this document. For the dated documents, only the versions with the dates indicated are applicable to this document; for the undated documents, only the latest version (including all the amendments) is applicable to this standard. Pharmacopoeia of the People's Republic of China 2015 Edition

3 Terms and definitions

The following terms and definitions apply to this document.

3.1 Bacterial endotoxin test; BET

Tests for the determination of active bacterial endotoxins, by mixing a liquid test sample with Limulus amebocyte lysate, wherein the results of proportional responses are measured by visual inspection, turbidity, chromogenic or other validated test methods.

3.2 Batch

A specified quantity of raw material, intermediate or finished product, which is expected or claimed to be produced in a specified production cycle with uniform characteristics and quality.

3.3 Chromogenic technique

A BET method, for quantification or detection of endotoxin, based on the principle that the measured color reaction is proportional to the reaction -- between the limulus amebocyte lysate and endotoxin.

3.4 Control standard endotoxin; CSE

Endotoxin preparations, which are calibrated on the basis of national standards.

3.5 Depyrogenation

Validated process for removing or inactivating endotoxins.

4 Principles of quality management system

4.1 Document formation

4.1.1 The bacterial endotoxin test procedure shall be described in detail.

4.1.4 Calculations and data transfer shall be properly controlled. If electronic data is used, the software used shall be validated and a record of validation shall be kept.

4.3 Product realization

The steps for procurement shall be detailed. These steps shall be consistent with the quality management system requirements.

4.5 Equipment

4.5.1 All equipment which is required for the proper conduct of the specified tests, shall be available. The planned maintenance and calibration shall be carried out, in accordance with documented procedures. Maintenance and calibration records shall be kept.

4.6 Reagents and materials

4.6.1 The material preparation method, which is used in the bacterial endotoxin test, shall be specified, including the corresponding identification test.

4.6.2 All Limulus amebocyte lysates used in the test shall be licensed.

4.7 Measurement, analysis, improvement

Procedures shall specify the handling requirements for abnormal, unexpected or out-of-specification results, including corrective and preventive actions.

5 Non-pyrogenic label

5.1 For the products, that come into direct or indirect contact with intravascular, intralymphatic or intrathecal products, OR products that may come into contact with similar systemic contact (such as infusion sets, transfer devices, catheters, implants, infusion components), OR ophthalmic products for intraocular use (e.g., silicone oils, viscoelastic products, intraocular lenses), it shall evaluate endotoxins.

5.3 Any product, that is labeled as being nominally non-pyrogenic, shall have definitive proofs, which may include.

5.4 All components of the product claimed to be non-pyrogenic shall be included in the test procedure. Any item of product within an exempt package shall be documented (e.g., a handle or strap). Claims of "non-pyrogenic fluid circuits" shall be supported by appropriate evaluation of the associated components and surfaces of the fluid circuits used.

5.5 For multi-component kits, the labels and claims shall be consistent with the documented evaluation of the components, in the package in contact with the circulatory, lymphatic or cerebrospinal fluid system.

5.6 Product endotoxin limits shall be determined, in accordance with appropriate regulatory requirements.

6 Selection of product unit

6.1 The sampling criteria for the selection of product units, in the bacterial endotoxin test, are based on the premise that the production process is controlled and the requirements of the quality management system are met.

6.4 Test samples should be selected from the finished product, which includes all factors that may affect or increase endotoxin levels (e.g., packaging).

6.5 Samples may include pre-sterilized and post-sterilized products. The sterilized sample contains all the factors that could affect the product or endotoxin testing.

6.6 In the inspection of multi-component kits (program packages) or complete sets of products, depending on the use of the product, sometimes each component can be evaluated individually, sometimes all the contents can be regarded as a whole for evaluation.

7 Choice of technique

7.1 Testing laboratories currently have three bacterial endotoxin testing techniques to choose from. The selection of each technique should be based on adequate evaluation of laboratory skills, experience, sample size requirements, data handling requirements, test sample properties.

7.2 The selected method shall be confirmed, in accordance with Chapter 8: If the test method or technique is changed, validation/verification shall be carried out (see 8.6).

8 Methodological validation

8.1 Identification of test endotoxin limits

8.1.1 The test endotoxin limit is defined as the maximum allowable concentration of

8.2 Maximum validated dilution factor (MVD)

8.2.2 If a product is tested according to MVD, the endotoxin test should be regarded as a qualitative test. Results are expressed as pass/fail.

8.2.3 When a product is tested, at a dilution lower than the MVD, additional dilutions may be required, to determine whether a positive result meets the test requirements.

8.2.1 The product may sometimes interfere with bacterial endotoxin tests

(inhibition/enhancement). Interference is usually mitigated by diluting the product extract, with endotoxin testing water (LRW) or other suitable diluents.

Dilution can be used to obtain a valid test result. Additional dilutions may not require validation. Diluents other than water may interfere with use AND shall be re-validated.

8.4 Product identification/validation

8.4.1 General

Each product or product parent (see B.6.3) shall be identified/validated, to fully confirm that the test sample itself will not inhibit or enhance the bacterial endotoxin test system; otherwise, it will interfere with the accuracy and lambda of BET. See 8.5, for sample interference information.

8.4.2 Gel-clot technique

8.4.2.1 Prepare the solution, according to Table 1.The dilution of the sample solution shall be less than or equal to the MVD, meanwhile the test system shall not contain any detectable endotoxin. Dilution series and negative controls for each endotoxin dosage are tested.

8.5 Sample interference

If there is interference in the bacterial endotoxin test, the sample extract can be diluted and/or treated appropriately, to remove the inhibition or enhancement effect.

8.6 Maintenance of identification/validation

8.6.2 A batch shall be taken for validation, under the following circumstances.

9 Use of technique

9.1 Key test parameters

9.1.1 Temperature

The general incubation temperature for bacterial endotoxin test methods is (37 ± 1) °C.

Refer to the reagent manufacturer's instructions for selection of appropriate parameters.

9.2 Equipment and reagents

9.2.3 The product label of the Limulus amebocyte lysate manufacturer will give storage requirements for lyophilized and reconstituted reagents. If the storage conditions in the laboratory are different from those recommended by the manufacturer, the storage conditions shall be confirmed.

9.3 Sample preparation

9.3.2 Medical devices

9.3.2.1 The instruments are usually leached together, for routine endotoxin testing.

When the test determines the endotoxin level per device or the variability between devices, the device needs to be tested separately. See Appendix B or relevant regulations, for guidelines on the appropriate sample size.

9.3.2.5 The volume of LRW, which is used for leaching instruments, depends on the size of the instrument. Calculate the test endotoxin limit, in accordance with 8.1, OR the maximum amount of extract, that can be used after pooling. To overcome interference, the sample extract may be further diluted to a level not exceeding the calculated MVD, as shown in 8.2.

9.4 Routine inspection and monitoring

9.4.3 Color development and turbidity techniques

See 8.4.3 for routine test methods.

9.4.4 Test frequency

Bacterial endotoxin testing shall be performed, in accordance with a documented sampling plan (see Chapter 6), which has a defined sampling frequency and sample size.

9.5 Interpretation of results

9.5.1 A valid routine test needs to observe the following results.

9.5.2 For the gel limit test, it is acceptable, if the validity of each parameter of the test product complies with 9.5.1 AND both test tubes of the sample solution are negative.

If a positive result appears in any sample tube, see Appendix C.

9.5.4 In the chromogenic method and the turbidimetric method, if the average endotoxin concentration of each tube of the sample solution is less than the product endotoxin limit, after the dilution, AND concentration is corrected, the test preparation meets the test.

9.6 Change control

See 8.6, for specific requirements for maintaining product identification/validation.

9.7 Out-of-specification values and failure investigation

When a sample exceeds the endotoxin limit of the product, it shall be investigated (see Appendix C).

......
This preview omits tables, figures, formulas and parts of the technical clauses. The complete document — 53 pages — is available in the English PDF.

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Editions of YY/T 0618

Edition	Title	Revision	Status
YY/T 0618-2017	Test methods for bacterial endotoxins of medical devices—Routine monitoring and alternatives to batch testing	current edition	Current
YY/T 0618-2007	Test methods for bacterial endotoxins of medical devices—Routine monitoring and alternatives to batch testing	previous edition	Superseded

This page sells the current edition, YY/T 0618-2017. Earlier editions are listed for reference only.

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