YY/T 17092020 (YY/T17092020)
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Evaluation of measurement uncertainty of calibrators for in vitro diagnostic kits

YY/T 17092020
 Valid 
YY/T 17092020

YY/T 17092020: PDF in English (YYT 17092020) YY/T 17092020
YY
PHARMACEUTICAL INDUSTRY STANDARD
OF THE PEOPLE’S REPUBLIC OF CHINA
ICS 11.100
C 44
Evaluation of measurement uncertainty of calibrators
for in vitro diagnostic kits
ISSUED ON: JUNE 30, 2020
IMPLEMENTED ON: DECEMBER 01, 2021
Issued by: State Drug Administration
Table of Contents
Foreword ... 3
1 Scope ... 4
2 Normative references ... 4
3 Terms and definitions ... 4
4 Evaluation process ... 6
5 Uncertainty of changing batch of calibrator ... 20
Annex A (informative) Examples of uncertainty introduced by uniformity ... 21
Annex B (informative) Examples of uncertainty introduced by stability ... 23
Annex C (informative) Example of uncertainty evaluation introduced in process
of valuing ... 26
Bibliography ... 30
Evaluation of measurement uncertainty of calibrators
for in vitro diagnostic kits
1 Scope
This Standard specifies evaluation methods of measurement uncertainty of
calibrators for in vitro diagnostic kits.
This Standard is applicable to evaluation of measurement uncertainty of
product calibrators for in vitro diagnostic quantitative kits.
2 Normative references
The following referenced documents are indispensable for the application of
this document. For dated references, only the edition cited applies. For undated
references, the latest edition of the referenced document (including any
amendments) applies.
GB/T 21415, In vitro diagnostic medical devices  Measurement of quantities
in biological samples  Metrological traceability of values assigned to
calibrators and control materials
3 Terms and definitions
For the purposes of this document, the following terms and definitions apply.
3.1 product calibrator; calibrator
The calibrator intended for the manufacturer's final product.
NOTE: The product calibrator here includes the calibrator used by the manufacturer for
final product calibration. The calibration information of the calibrator will be transmitted to
the measurement of the clinical sample through ways such as electronic carrier.
3.2 working calibrator; master calibrator
Measurement standard used for calibration of manufacturer's permanent
measurement procedures.
3.3 metrological traceability
Absolute value of standard uncertainty divided by measured value.
[JJF 10012011, definition 5.23]
3.9 combined standard measurement uncertainty; combined standard
uncertainty
The standard measurement uncertainty of the output obtained from the
standard measurement uncertainty of each input in a measurement model.
[JJF 10012011, definition 5.22]
3.10 expanded measurement uncertainty; expanded uncertainty
The product of the combined standard uncertainty and a digital factor greater
than 1.
NOTE: “Factor” refers to coverage factor.
[JJF 10012011, definition 5.27]
3.11 coverage probability
The probability that the measured set of values is contained within the specified
containment interval.
[JJF 10012011, definition 5.29]
3.12 coverage factor
A number greater than 1 multiplied by the combined standard uncertainty, in
order to obtain expanded uncertainty.
[JJF 10012011, definition 5.30]
4 Evaluation process
4.1 General
4.1.1 Basic flow
According to the flow shown in Figure 1, evaluate the measurement uncertainty
of in vitro diagnostic calibrator.
repeatability standard deviation sr of the test method can be used to estimate.
If there are more than 2 concentrations of the product calibrator, it needs to
conduct uniformity inspection on the calibrator of each concentration (except
for zero concentration calibrator).
If the product calibrator contains multiple test items, it needs to evaluate the
uniformity between bottles of each test item separately, unless there is a clear
distribution relationship between the two items.
4.2.2 Test scheme
4.2.2.1 Test method
The test method shall meet the following requirements:
a) It can use manufacturer’s permanent measurement procedures or other
measurement procedures that set values for product calibrators.
Complete the test under repeatable conditions.
b) The reportable concentration range shall cover the expected
concentration of the product calibrator. If the expected concentration of
the product calibrator is higher than the concentration range of the test
system, it can, under strictly specified test conditions, use weighing
method to accurately dilute the product calibrator. And ensure that the
dilution will not change the interchangeability of the calibrator and thus
affect the uniformity test results.
c) The method precision shall reflect the difference between bottles and not
be inferior to the precision of the valuation method. Under ideal conditions,
, where sr is the repeatability standard deviation of the test method,
ud is the target standard uncertainty of the calibrator.
d) The minimum sampling amount that can guarantee uniformity shall be
specified. It is recommended not to be higher than the sampling volume
when calibrating the matching kits.
NOTE: If the calibrator is diluted and then used in the calibration kit, then the minimum
sampling volume for uniformity testing is not higher than the minimum sampling volume for
the dilution operation (for gradient dilution, take the minimum sampling volume for the first
dilution operation).
4.2.2.2 Sample extraction
According to random stratification method, extract the calibrator from the
smallest packaging unit for uniformity inspection. Number the samples in
If there are more than 2 concentrations of the product calibrator, it needs to
inspect the stability of each concentration of calibrator (except zero
concentration calibrator).
If the product calibrator contains multiple test items, it needs to evaluate the
stability of each test item separately, unless there is a clear distribution
relationship between the two items.
4.3.2 Test scheme
Stability test can choose "classic" scheme or "synchronous" scheme design.
The classic scheme is to put the samples prepared at the same time under the
expected storage conditions. Take some samples for measurement over time.
It is realtime tracking test of sample stability under reproducibility conditions.
The synchronous scheme takes samples in timesharing and place them under
certain reference conditions. It is considered that the influence of instability is
not considered under these conditions. Take them out together after the
expected stabilization time. Conduct simultaneous measurement under the
repeatability conditions. The specific choice depends on the precision of the
method and the stability of the sample. Accelerated stability studies or
experience gained from similar in vitro diagnostic kits can only be considered
for estimating the initial expiration date. It cannot substitute the realtime
stability test.
The expected stable timeliness of the calibrator can be preliminarily determined
by referring to the experience of literature and other materials in combination
with the use of requirements. According to the principle of dense first then
sparse, within at least 5 timeintervals of expected stable aging, randomly select
at least 2 calibrators of the smallest packaging unit for stability test. Perform 3
measurements for each packaging unit. The test system used for stability
inspection can choose the same test system as the uniformity inspection. The
precision is not lower than the fixed value system, with good sensitivity and
stability. Pay attention to the consistency of each experiment operation and
experiment conditions.
NOTE: For calibrators with poor stability, increase the frequency of monitoring
appropriately. For calibrators with poor uniformity between bottles, increase the amount of
extraction at each time point. And for test systems with poor precision, the number of
measurements per package can be increased.
4.3.3 Result statistics
Check test data. Test data shall not be excluded for nontechnical operation
reasons.
Use t test to analyze the significance of the trend. Suppose there are stability
When the user needs it, the manufacturer shall provide the user with the
uncertainty of the calibrator assignment and be able to provide the uncertainty
component results and uncertainty evaluation process.
It is recommended that the uncertainty of the product calibrator be reported in
the form of standard uncertainty "(digital value assigned ±uc) unit". If it is
reported in the form of expanded uncertainty "(assignment ± U numerical value)
unit", it needs to specify the value of coverage factor k.
If the measurement uncertainty of the calibrator is less than the preset target
uncertainty, the traceability of the calibrator’s set value is confirmed. Otherwise,
analyze and find the reasons, improve the preparation process or test system.
Change the traceability chain if necessary and reassign the calibrator
assignment and uncertainty evaluation.
5 Uncertainty of changing batch of calibrator
Usually the calibrator needs to reevaluate the uncertainty.
If the historical batch data of uncertainty component or combined uncertainty is
used, the following conditions must be met:
a) The characteristic value of the calibrator varies within ±10%;
b) The source of key raw materials and article numbers have not changed,
and the preparation process has not changed;
c) The calibrator assignment system (including traceability chain, working
calibrator, equipment and operating procedures) has not changed;
d) There are 3 consecutive batches and above calibrator uncertainty
evaluation data, showing that the variation of the combined standard
uncertainty is within the allowable range specified by the manufacturer.
If both a) and b) are satisfied, the stability uncertainty component of historical
batches can be quoted. But the stability shall still be monitored in real time. The
manufacturer can accumulate multiple batches of stability data as the basis for
evaluating stability and introducing uncertainty components.
If a)~d) are satisfied, the maximum uncertainty of the historical batch can be
selected as the uncertainty of the future batch of calibrators. The manufacturer
shall still periodically verify the validity of the uncertainty. Ensure to meet the
requirements of target uncertainty and reflect changes in technical capabilities
in a timely manner.
Annex B
(informative)
Examples of uncertainty introduced by stability
The uncertainty evaluation introduced by stability takes the calibrator of the
Follicle Stimulating Hormone (FSH) project product of XX company as an
example.
B.1 Scheme
The calibrator is a lyophilized powder matrix. Store at 2°C~8°C. Expect good
storage stability. Use the magnetic particle chemiluminescence method of the
XX company's test system to test the longterm stability and shortterm stability
(including transportation stability and reconstitution stability) of the calibrator.
B.1.1 Longterm stability
The calibrator shall be stored in accordance with the stipulated 2°C~8°C. Take
out 2 bottles at 0, 3, 6, 9, 12, 15 and 18 months respectively. Each bottle is
tested 3 times.
B.1.2 Transport stability
Although cold chain transportation is adopted, changes in the transportation
environment and time are considered to investigate transport stability at room
temperature and 37°C. At 0d, 1d, 2d, 3d, 4d, 5d, 6d and 7d respectively, take
out 2 bottles each at the simulated temperature. At the 7d, uniformly test under
repeatable conditions. Each bottle is tested 3 times.
B.1.3 Reconstitution stability
Use weighing method to reconstitute 2 bottles of calibrators. Store at 2°C~8°C.
At 0d, 1d, 2d, 3d, 4d, 5d, 6d and 7d respectively, take out to test. Each bottle is
tested 3 times.
B.2 Inspection results
See Table B.1~Table B.4 for the results.
Annex C
(informative)
Example of uncertainty evaluation introduced in process of valuing
The uncertainty evaluation introduced in the valuing process takes the valuing
process of the calibrator of XX company's total bilirubin (TBiL) project as an
example.
C.1 Valuing process
Perform product calibrator valuing with permanent measurement procedures.
The permanent measurement program consists of a testing system composed
of Beckman AU5800 automatic biochemical analyzer and supporting kits. It has
been verified that the batch difference between the kits used can be ignored.
Assignment experiment uses the same batch of kits. Use the company's
working calibrator to calibrate the permanent measurement program. Take 2
product calibrators of the smallest packaging unit. Each unit is tested 5 times
on 1 instrument each. Complete 5d experiments continuously. Daily test needs
to be recalibrated. Get a total of 50 test data. Obtain the product calibrator
assignment after analysis.
Use new product calibrators and routine measurement procedures to form a
measurement system. Directly test the national frozen human serum total
bilirubin standard substance GBW09184. Compare with target value for
assignment confirmation.
C.2 Results
The specific assignment data is shown in Table C.1. Conduct statistics on
suspicious value of 5d data. No need to exclude data for outlier review.
Calculate its total mean value as the initial assignment of the calibrator.
...... (Above excerpt was released on 20201128, modified on 20210607, translated/reviewed by: Wayne Zheng et al.) Source: https://www.chinesestandard.net/PDF.aspx/YYT17092020
