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YY/T 0618-2017: Test methods for bacterial endotoxins of medical devices—Routine monitoring and alternatives to batch testing
YY/T 0618-2017
YY
PHARMACEUTICAL INDUSTRY STANDARD
OF THE PEOPLE’S REPUBLIC OF CHINA
ICS 11.040.01
C30
Replacing YY/T 0618-2007
Test methods for bacterial endotoxins of medical devices -
Routine monitoring and alternatives to batch testing
ISSUED ON: FEBRUARY 28, 2017
IMPLEMENTED ON: JANUARY 01, 2018
Issued by: China Food and Drug Administration
Table of Contents
Foreword ... 3 
Introduction ... 4 
1 Scope ... 6 
2 Normative references ... 6 
3 Terms and definitions ... 6 
4 Principles of quality management system ... 11 
5 Non-pyrogenic label ... 13 
6 Selection of product unit ... 14 
7 Choice of technique ... 15 
8 Methodological validation ... 15 
9 Use of technique ... 20 
10 Alternatives to batch testing ... 24 
Appendix A (Informative) Background information on bacterial endotoxin testing .. 28 
Appendix B (Informative) Guidelines for test methods, routine monitoring, alternatives
to batch testing ... 32 
Appendix C (Informative) Out-of-specification (OOS) and failure investigation guide
... 50 
References ... 53 
Test methods for bacterial endotoxins of medical devices -
Routine monitoring and alternatives to batch testing
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
The abnormal phenomenon of bacterial endotoxin test, which is caused by non-
endotoxin-related factors (usually caused by the characteristics of the test sample),
making the test response higher than the actual total amount of endotoxin present.
3.10
Gel-clot technique
The BET method for quantification or detection of endotoxin, which is based on the
principle that the resulting gel-clot reaction is a proportional reaction -- between the
Limulus amebocyte lysate and the endotoxin.
3.11
Geometric mean endpoint
The mean value, which is obtained from repeated serial dilutions, as converted to a
base 10 endpoint logarithm value; it is used for determining the central tendency or
mean value, from a test solution.
3.12
Inhibition
The abnormal phenomenon of bacterial endotoxin test, which is caused by non-
endotoxin-related factors (usually caused by the characteristics of the test sample),
so that the test response is lower than the actual total amount of endotoxin present.
3.13
Inhibition/enhancement test
A test, which is used to determine whether a specific bacterial endotoxin test sample
contains factors that reduce the accuracy of the test. That is, whether it inhibits or
enhances the test system.
3.14
Investigation test
Reanalysis of a sample extract or preparation, to verify the original test results.
3.15
LAL reactive material; LAL-RM
Any non-endotoxin component that activates the Limulus amebocyte lysate and
causes enhancement.
3.16
LAL reagent water; LRW
Purified water or other identified solvents, diluents and/or extractants, for use in
BET, which shall be non-reactive and non-interfering in the method used.
3.17
Lambda
The nominal lambda of the LAL gel reagent, expressed in EU/mL. OR, for
chromogenic and turbidimetric methods, refer to the nadir of the standard curve
(endotoxin concentration).
3.18
Limulus amebocyte lysate; LAL
Reagents which are extracted from the circulating blood amoeba of horseshoe crab
(Limulus polyphemus or Tachypleus tridentatus). It interacts with endotoxin to
produce gels, for bacterial endotoxin assays to determine bacterial endotoxin levels.
3.19
Lipopolysaccharide; LPS
Gram-negative bacterial cell wall components, which are typically composed of
lipid A, core polysaccharide, and O-side chains.
3.20
Maximum valid dilution; MVD
The maximum dilution of the sample, at which the specified test endotoxin limit can
be detected, in relation to the lambda of the BET.
3.21
Out of specification; OOS
Samples with valid BET test results exceeding the specification for product
endotoxin limits.
Note: The term OOS applies only to this document. It is different from other regulatory
guidance that deals with OOS results, such as the U.S. Food and Drug Administration (FDA)
"Studies of OOS Test Results for Drug Manufacturing".
3.29
Standard control series
Serial dilutions of RSE or CSE, which are used for validating endotoxin lambda.
3.30
Test endotoxin limit
The maximum endotoxin concentration is allowed in the extract. This determined
limit is used to calculate the maximum effective dilution factor, for sample leaching
(mix or one unit).
Note: This limit is determined by dividing the product endotoxin limit by the volume of
LRW used per unit of sample extract.
3.31
Turbidity technique
The BET method, for quantification or determination of endotoxin, which is based
on the principle that the measured color reaction is a proportional reaction -- between
the Limulus amebocyte lysate and the endotoxin.
3.32
Validation
Establish documented procedures for obtaining, recording, interpreting results, to
ensure that products conform to predetermined specifications.
4 Principles of quality management system
4.1 Document formation
4.1.1 The bacterial endotoxin test procedure shall be described in detail.
4.1.2 The documents and records which are required in this standard shall be reviewed
and approved by designated personnel (see 4.2.1). Meanwhile, it shall be under the
control of the specified quality management system requirements.
4.1.3 The retention of original data, calculated and derived data, final data records shall
be specified, in the quality management system requirements. Records shall include
information on those involved in sample preparation and testing.
The inspection technique steps and instructions used are approved. All relevant
equipment for use and operation shall be available.
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.
4.2 Management responsibilities
4.2.1 Responsibilities and rights to complete and carry out the steps, which are
described in this document, shall be specified. Responsibility shall be given to those
who meet the requirements of the quality management system.
4.2.2 If an organization, which has a separate quality management system, undertakes
the requirements of this standard, the responsibilities and rights of each individual shall
be specified.
4.3 Product realization
The steps for procurement shall be detailed. These steps shall be consistent with the
quality management system requirements.
4.4 Personnel
4.4.1 The responsibilities of personnel, who are assigned to perform bacterial endotoxin
testing, shall be specified in the quality management system requirements.
4.4.2 The training shall be carried out in accordance with the documented procedures.
The records of the relevant identification, training, and experience of the technical
personnel shall be kept.
4.4.3 The analyst shall qualify the bacterial endotoxin test (see 8.3.2), before
undertaking it.
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.
4.5.2 All equipment shall be operated in accordance with the document specifying the
guidelines.
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.
Note: The corresponding identification test includes the identification of the lambda of the
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. This label should be consistent
with the intended clinical use of the package and its components.
5.6 Product endotoxin limits shall be determined, in accordance with appropriate
regulatory requirements.
Note: Endotoxin limits for medical infusion (blood) and injection equipment are recommended
in GB/T 14233.2-2005.
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.
6.2 The selection of test product units shall be based on the criteria, as specified in the
sampling plan, which may be based on regulatory requirements, published statistical
programs or guidelines, or validation of production runs.
6.3 The sampling parent (group) is generally defined as the production batch. If data
support different selection bases or alternatives for batch testing is selected, sample
selection can be based on the sampling parent being not a production batch. If
alternatives for batch testing is selected, see Chapter 10, B.6 ~ B.8, B.10.
Note: Sampling specifications, where the sampling matrix is not a production batch, should
include a risk assessment, to evaluate the suitability of the criteria for establishing the sampling
matrix (see Appendix B).
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).
Note: Samples for endotoxin testing may be selected from products, which are rejected in other
production quality items, provided that the rejected samples represent non-rejected products.
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. If
sample testing before sterilization is selected, the acceptability of the sample to
represent the endotoxin level of the final product shall be documented. The inspection
procedures performed should consistently reflect pre-sterilized or post-sterilized
samples. See B.6.5 for guidance on validation of equivalence.
Note: For products that promote microbial growth, it may not be appropriate to select samples
prior to sterilization.
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. Standard test procedures should be applied to each component case. When
using a product kit or kit as a stand-alone unit, consideration shall be given to sample
preparation and applicable product endotoxin limits, without changing the method. See
B.6.6, for more guidance.
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. Current techniques and methods include:
a) Gel-clot technique: Limit test and determination method;
b) Chromogenic techniques: Kinetic and endpoint methods;
c) Turbidity techniques: Kinetic and endpoint methods.
See Appendix B, for information on the three methods.
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
endotoxin, which may exist in the extract of a product, which is related to the product
endotoxin limit. See Appendix B, to determine product endotoxin limits.
8.1.2 Once the product endotoxin limit is determined, the test endotoxin limit can be
calculated, according to formula (1):
Medical device test endotoxin limit (EU/mL) = KN/V ………………………… (1)
Where:
a) BET testing laboratory changes;
b) Changes to BET materials, equipment that may affect the test; and
c) Changes to lambda of Limulus amebocyte lysate.
Note: Product positive controls (PPCs) are available for validation in some cases. PPC may
adequately detect that a change has occurred.
9 Use of technique
9.1 Key test parameters
9.1.1 Temperature
The general i...