YY/T 1737-2020 English PDF (YYT1737-2020)

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YY/T 1737-2020: Analytical method for bioburden control level of medical device
YY/T 1737-2020
YY
PHARMACEUTICAL INDUSTRY STANDARD
OF THE PEOPLE’S REPUBLIC OF CHINA
ICS 11.080.01
С 47
Analytical method for bioburden control level of medical
device
ISSUED ON: SEPTEMBER 27, 2020
IMPLEMENTED ON: SEPTEMBER 01, 2021
Issued by: National Medical Products Administration
Table of Contents
Foreword ... 3
Introduction ... 4
1 Scope ... 6
2 Normative references ... 6
3 Terms and definitions ... 6
4 Factors affecting product bioburden ... 8
5 Risk of product bioburden ... 8
6 Bioburden monitoring ... 9
7 Correction treatment ... 11
8 Change assessment ... 11
9 Regular review ... 11
Appendix A (Informative) Examples of statistical methods for alert level and acting
level ... 12
Appendix B (Informative) Examples of establishing alert level and acting level without
historical data ... 18
Bibliography ... 19
Analytical method for bioburden control level of medical
device
1 Scope
This Standard stipulates the analytical method for bioburden control level of medical
device.
This Standard applies to the analysis of bioburden control levels of sterile and
implantable medical devices.
This Standard is not applicable to the analyses performed to validate bioburden test
values for products during the development phase.
2 Normative references
The following referenced documents are indispensable for the application of this
document. For dated references, only the dated version applies to this document. For
undated references, the latest edition (including all amendments) applies to this
document.
GB/T 19971, Sterilization of health care products - Vocabulary
GB/T 19973.1, Sterilization of health care products - Microbiological methods -
Part 1: Determination of a population of microorganisms on products
YY/T 0287, Medical devices - Quality management systems - Requirements for
regulatory purposes
YY/T 0316, Medical devices - Application of risk management to medical devices
3 Terms and definitions
For the purposes of this document, the following terms and definitions, as well as those
given in GB/T 19971, apply.
3.1
colony forming unit; CFU
The microbial colony formed by the reproduction of one or several microorganisms
after microbial culture, abbreviated as CFU, and usually expressed in number.
The time or dose required to inactivate 90% of the total number of test microorganisms
under specified conditions.
4 Factors affecting product bioburden
There are many factors that affect the product bioburden. The risk sources that affect
bioburden as identified in YY/T 0316 include but are not limited to the following
aspects:
-- personnel clothing, personal hygiene, and personal habits;
-- equipment and work surfaces;
-- raw materials, packaging materials, components;
-- cleaning, assembly, packaging, handling and other operation methods;
-- environmental conditions, storage conditions, storage time;
-- process media (process gas, process water, cleaning agents, disinfectants, etc.);
-- monitoring and measuring equipment and methods, etc.
5 Risk of product bioburden
5.1 Risks associated with the sterilization method of the product
5.1.1 If the product is sterilized by overkill, from the perspective of sterilization, as long
as the bioburden of the product does not exceed the spore count on the biological
indicator (BI) for sterilization and the resistance does not exceed the D value of the BI,
it can be effectively killed.
5.1.2 When a combined bioburden and biological indicator sterilization method is used,
the bioburden shall not exceed the predetermined limit and the resistance shall not
exceed the D value of the BI.
5.1.3 For sterilization methods based on bioburden, such as radiation sterilization, since
the sterilization dose is determined by factors such as the amount and/or resistance of
the bioburden, it is recommended that the amount and/or resistance of the bioburden be
equivalent to that during the initial sterilization confirmation, otherwise there is a
possibility of increased dose.
5.2 Risks related to the nature of contact between the product and the human body
5.2.1 Products that come into contact with the human body can be divided into three
main categories: surface contact device, external access device and implantable device.
Among them, surface contact device is divided as per: skin contact, mucosal contact
and damaged surface contact; external access device is divided as per: indirect blood
contact, tissue/bone/dentin contact, circulating blood contact; implantable device is
divided as per: tissue/bone contact and blood contact.
5.2.2 Medical devices of different contact categories have different bioburden
requirements. Low-risk devices, such as skin contact devices, have relatively low
bioburden requirements. High-risk devices, such as implantable devices that come into
contact with blood, have relatively high bioburden requirements. In addition, the impact
of endotoxins shall also be considered, and the product bioburden control level shall be
adjusted and controlled in combination with the endotoxin control level.
6 Bioburden monitoring
6.1 Documents
Manufacturers shall establish product bioburden monitoring documents.
6.2 Monitoring frequency
Sampling and bioburden testing can be performed at regular intervals or according to
production frequency. The selection of bioburden monitoring frequency may take into
account factors such as product material characteristics, production process
characteristics, production frequency, seasonal and environmental changes, and
sterilization methods.
6.3 Sampling
6.3.1 Select a representative product (or equivalent product) from the product family
for bioburden testing. If the product is not available (e.g., not produced during the
specified testing period), an acceptable alternative product (equivalent product) for the
product family shall be defined in the documentation to represent the normal production
process for testing.
6.3.2 Routine monitoring of bioburden levels typically uses 3 ~ 10 samples. The
production and treatment of samples shall be representative of normal production.
Note: Samples may be selected from products rejected due to other production quality
issues, provided that the rejected samples are representative of the regular
products and have no impact on the bioburden test results, and the samples are
initially packaged according to the regular production process for bioburden
testing.
6.3.3 Wherever possible, for sterile medical devices, the time between sample
collection and bioburden determination should reflect the time period between the
completion of the last step of the product and the sterilization of the product. In
particular, for medical devices that can support microbial growth, the storage time
7 Correction treatment
7.1 When the monitoring result exceed the acting level, it is necessary to investigate the
cause, including laboratory investigation. If it is proven that there is no abnormality in
laboratory operations, further investigation including the production process will be
required. Where applicable, the investigation may include, but is not limited to, the
following:
a) process control of product sampling and transfer/transport to the laboratory;
b) any abnormal data;
c) changes in production process;
d) key process and production records, etc.
7.2 The situation where the acting level is exceeded should be handled in accordance
with corrective, preventive measures and/or non-conforming product control in YY/T
0287.
8 Change assessment
When a product is changed, the impact of the change on the product bioburden shall be
assessed and recorded.
9 Regular review
Product family, validation method and associated alert level and acting level shall be
regularly reviewed and recorded to ensure their continuing applicability. The review
may include:
a) assessment of the product family and representative product (or equivalent
product);
b) monitoring frequency;
c) test method validation/verification;
d) deviation events;
e) non-conformities;
f) alert level and/or acting level (if applicable).
the advantage of allowing analysts to visually inspect the data, thus facilitating data
review and trend analysis. The individual value chart is taken as an example for analysis
here.
Control chart: Individual value chart.
Obtain an individual value chart by using the Y-axis to represent an individual
observation value, and the X-axis to represent the corresponding parameter, such as
time, batch number, etc. Use these graphs when there is only one value per observation.
Therefore, they are suitable for bioburden monitoring data analysis and can be prepared
manually or using statistical software using the following formula.
Individual value chart calculation: Use the bioburden data of the linear cutting stapler
in Table A.1 as an example for calculation. To prepare the graph, first calculate the
average value and the average range of the raw data. The average range is calculated
by averaging the ranges of each group. Then, use the following formula to calculate the
alert level and the acting level.
Alert level = 𝑋ത + 2 (𝑅ത/d2)
Acting level = 𝑋ത + 3 (𝑅ത/d2)
Where X is the average value; 𝑅ത is the average range; d2 is the conversion factor used
to estimate the standard deviation (d2 can be obtained by referring to the tables and
charts in Appendix II and Chart A of Juran's Quality Handbook (Sixth Edition) to
calculate the factors for each line in the control chart). For the subgroup of 10, this value
is equal to 3.078. For the bioburden data of the linear cutting stapler in Table A.1, the
average value is 41.1 and the average range is 73.17. Therefore, the alert level and the
acting level are calculated as follows:
Alert level = 41.1 + 2 × (73.17/3.078) = 88.6
Acting level = 41.1 + 3 × (73.17/3.078) = 112.4
Then, prepare a chart as shown in Figure A.2. Reviewing the chart, the analyst might
observe several instances where the alert level and the acting level are exceeded. These
observations can alert the analyst that, in the event of a deviation from the acting level,
further investigation and/or correction is required.