Development Investigation of Biomedical Reference Material in

Promoting National Health

Peilei Fan

, Haibo Zhao

, Yujia Zhao

, Liang Liang

and Shuai Chen

Beijing Institute of Metrology, No.A10 Lishuiqiao, Chaoyang, Beijing, China

Keywords: Traceability, Biomedical Metrology, Invitro Diagnostic Reagents.

Abstract: Biomedical reference material is a kind of important tool used in biopharmaceutical companies and health

service centres to ensure the accuracy and reliability of measurement instrument. It can be traced to the source

of quantity value through an uninterrupted traceability chain. Firstly, based on the detailed discussion of the

development status of reference materials, it is focused on the classification and characteristics in this paper.

Secondly, the management methods and application status in COVID-19 have been detailed. Finally, it

explores the application research invitro diagnostic reagents and the key contents of biomedical metrology in

national health service.

1 INTRODUCTION

Metrology is the key for human beings to explore the

world, and measurement is the basis for realizing the

unity of units and ensuring the accuracy of quantities.

With the continuous pursuit of the reliability and

comparability of results, reference materials, as an

important tool for measuring instrument calibration

and measurement method evaluation and

confirmation, are being more and more widely used.

The proposal of "Precision Medicine" and "National

Health" promotes the importance of metrology field

on the accuracy and reliability of clinical medicine,

chemical analysis and biological analysis measuring

instruments.

As the main carrier to ensure some medical

instruments’ reliability used by medical institutions,

biopharmaceutical companies and health service

centers, biomedical reference materials are always in

the core and key position. By the uninterrupted

traceability chain, they can be traced to the source of

value source for maintaining the consistency and

accuracy of global measured value.

https://orcid.org/0000-0002-2910-0916

https://orcid.org/0000-0003-2110-4362

https://orcid.org/0000-0002-6606-5697

https://orcid.org/0000-0002-2444-4103

https://orcid.org/0000-0003-1369-4120

2 REFERENCE MATERIALS

At present, measurement technology institutions at

home and abroad have a wide variety of types and are

distributed in different countries, among which the

American Institute of standards and Technology, the

German Federal Institute of physics and Technology

and the British Government Chemist Laboratory have

developed most rapidly. They have invested a lot of

human, material and financial resources, and become

a technical leader integrating measurement standards

and laboratory capability verification.

According to foreign research hotspots,

investigation direction of reference materials is

different, as summarized below:

(1) United States: inorganic solution, organic

solution, acidity and materials, dyes, sediments,

minerals, soil and particles;

(2) Germany: water, acidity, conductivity, metals

and metal alloys, advanced materials;

(3) Japan: advanced materials, food, sediments,

minerals, soil and particles;

(4) Other countries: research has been carried out

in advanced materials, gases, food, films and

engineering nano materials.

Fan, P., Zhao, H., Zhao, Y., Liang, L. and Chen, S.

Development Investigation of Biomedical Reference Material in Promoting National Health.

DOI: 10.5220/0011374900003443

In Proceedings of the 4th International Conference on Biomedical Engineering and Bioinformatics (ICBEB 2022), pages 973-978

ISBN: 978-989-758-595-1

973

The development of reference materials in China

also started earlier, paying great attention to the

preparation of reference materials, and carrying out

legal management on the approval and production.

We have invested a lot of funds for long time. After

about ten years of efforts, fruitful results have been

achieved, and the types of national reference

materials have increased year by year.

According to uncertainty range of reference

materials, China classifies them into two categories:

national primary reference materials (GBW XX....)

and national secondary reference materials (GBW(E)

XX....). According to different characteristic values,

reference materials are usually divided into 13

categories, which are numbered by large category

number, small category number and approval time

sequence. As shown in the Tab.1 below, the category

of reference materials can be identified according to

numbering rules.

Table 1: Classification table of reference materials.

Category Numbering Rules Category Numbering Rules

steel composition

GBW01~

GBW(E)01~

environmental chemistry GBW08~

GBW(E)08~

gas composition and

metals

GBW02~

GBW(E)02~

biomedical and drugs GBW09~

GBW(E)09~

building material GBW03~

GBW(E)03~

food ingredients GBW10~

GBW(E)10~

composition analysis and

radioactivity of nuclear

materials

GBW04~

GBW(E)04~

composition analysis and

physical properties of coal

and petroleum

GBW11~

GBW(E)11~

properties of polymer

materials

GBW05~

GBW(E)05~

engineering technical

characteristics

GBW12~

GBW(E)12~

chemical product

composition

GBW06~

GBW(E)06~

physicochemical

properties

GBW13~

GBW(E)13~

geological and mineral

composition

GBW07~

GBW(E)07~

3 BIOMEDICAL REFERENCE

MATERIALS

3.1 Development Analysis

Internationally, developed countries such as Europe,

America and Japan have taken the lead in technology.

Their biomedical reference materials have many

types and high quality. They have covered all

measurement fields, including small molecules,

macromolecules, inorganic, organic, pure products

and matrix, and most of them have been used in

clinical practice. For example, reference materials in

the European Union are the main ones, and the

development of reference materials in metabolites,

non-peptide-hormones, electrolytes, enzymes, drugs,

etc. is relatively complete; Singapore, France and

other countries are also catching up. They have

developed corresponding reference materials lists in

terms of metabolites and conducted strict

interchangeability research, which could provide

more interchangeability information.

At home, the technology of reference materials

has been very mature, especially the reference

materials for small molecular metabolites are

relatively complete, but there are still many fields that

are very scarce or even blank. They are mainly

developed by National Institute of Metrology (NIM),

the first hospital of Peking University, Beijing

Institute of medical device inspection, etc. And some

projects have been used to improve clinical practice.

In the research of certified clinical reference

materials, NIM and the clinical laboratory center of

the Ministry of health have developed metabolites

and non-peptide hormone reference materials by

using isotope dilution mass spectrometry; Taking

Beijing Aerospace general hospital and Beijing

Chaoyang Hospital as representatives, some

metabolites and electrolyte reference materials were

developed by using other principles, which played a

role in the quality control for clinical laboratories;

The clinical enzymology reference material was

developed by using the network fixed value of

enzymology reference laboratory established in

China.

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Figure 1: COVID-19.

Since the outbreak of COVID-19, biological

nucleic acid reference materials have developed

rapidly, and various life invitro diagnostic reagents

have emerged one after another. How to quickly

extract virus DNA by pharyngeal swab method,

realize rapid virus detection and develop biological

vaccine has become a common problem all over the

world. Nucleic acid detection is an effective method

to detect pathogenic microorganisms in clinic. In

particular, the detection of COVID-19 and bacterial

16SrNA genes has been considered the gold standard

for detection by real-time fluorescence quantitative

PCR. China's newly developed New Coronavirus

matrix reference material, reference material of

circulating tumor DNA containing EGFR (L858R)

Mutation and reference material of pathogen

microorganism plasmid DNA have provided

qualitative and quantitative reference standards for

the accuracy of epidemic prevention and the accuracy

of the existing IVD test kit and the traceability of the

value.

On the one hand, the number of reference material

has gradually increased. So far, there are about 2944

kinds of first-class reference materials in China,

including 365 kinds of biomedical reference

materials accounting for 22.7%. On the other hand,

biomedical reference materials involve more and

more various items in clinical testing fields.

Figure 2: Distribution of reference material in China.

3.2 Organization Management

In order to apply metrological principles and

reference materials to clinical medicine and health

care, the International Federation of Clinical

Chemistry and laboratory medicine (IFCC) was

established internationally. IFCC is a global, non-

political organization of clinical chemistry and

laboratory medicine. It supports the development of

key technologies and technical breakthrough of

clinical chemical and biological reference materials,

and it has made major breakthroughs in medical care.

For example, the use of cholesterol reference

materials can save 1.5 billion yuan per year, IFCC has

become a leading organization in clinical medicine

and laboratory medicine, and has improved the

diagnosis, treatment level and quality of patients all

over the world.

EU invitro diagnostic instrument directive

requires that calibrators for in vitro diagnosis should

be traceable to high-level reference materials or

reference methods. In 2002, International Joint

Committee on Traceability of Laboratory Medicine

(JCTLM) was established in cooperation with

metrology, laboratory accreditation and testing. The

purpose is to establish a platform to review high-

grade reference materials, reference methods and

reference laboratories, and publish the results in the

Development Investigation of Biomedical Reference Material in Promoting National Health

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JCTLM database for promoting the realization of

equivalent and consistent test results.

The review of biomedical reference materials and

the formulation of relevant reference methods and

measurement technical specifications are mainly the

responsibility of clinical medical measurement

technical committee and national reference material

management committee, which are responsible for

reviewing reference materials and reference methods

according to different division.

3.3 Interchangeability Evaluation

Due to the complexity of measurement methods and

measurement system composition in individual

differences of human body, there might be great

differences between reference materials and actual

samples, so biomedical reference materials pay more

attention to the interchangeability evaluation of

reference materials, The main purpose is to avoid the

lack of consistency between the actual sample

measurement results after the same biomedical

reference material calibrates different measuring

systems.

Interchangeability evaluation refers to the

characteristics of reference materials expressed by

the consistency between the measurement results

obtained by two given measurement procedures and

the measurement results obtained by another

specified substance for the specified amount of a

given reference material. It is more to compare with

the clinical trial data to ensure that the characteristics

of reference materials are consistent with the natural

samples, avoid the lack of comparability of

measurement results after calibrating different invitro

diagnostic systems.

The interchangeability results of biomedical

reference materials are closely related to the

evaluation methods. At present, the most widely used

interchangeability evaluation schemes are ep30-a,

ep14-a3 and IFCC schemes.

The validity standards of samples, measurement

procedures and measurement data used to evaluate

interchangeability are basically similar, but the

evaluation methods and judgment basis are slightly

different. Therefore, appropriate sample quantity,

type, sample status and evaluation method should be

selected according to specific conditions to ensure the

interchangeability on different in-vitro diagnostic

systems.

4 DIFFICULTIES AND

CHALLENGES

Biomedicine is developing rapidly at home and

abroad. It’s focus is mostly on the development of

clinical reference materials, measurement and

detection technology of measuring instruments for

biological analysis, molecular biological reference

materials and clinical application. Biomedical

reference materials emerge one after another, and

biometric technologies and methods have also been

significantly improved.

Although many biomedical reference materials

have been applied in biomedicine, clinical laboratory,

inspection and quarantine and other fields, there are

still many difficulties and challenges, such as:

1) Traceability: many characteristic values of

reference materials are given in the form of mass

fraction, molar concentration, etc., but there are few

reference materials in non-SI units.

2) Valuation Technology: the valuation method of

biomedical reference materials is complex, which

requires expensive experimental equipment and

consumables, and the development cost is high.

Although the existing fluorescence quantitative PCR

technology has been widely used, many

experimenters did not evaluate the applicability of the

method and optimize the test scheme in the

development process. In fact, nucleic acid quality,

primers and amplification efficiency directly affect

the measurement results. So, it is necessary to

strengthen the formulation of evaluation and

preparation standards and specifications.

3) Raw materials: the raw materials of many

biomedical reference materials come from blood,

urine, etc., with great individual differences. It is

difficult to ensure a stable source. Some enzyme

active reference materials are easy to denature, which

leads to the shortage of active components.

4) High-accuracy biomedical reference materials:

The focus of this part is to develop peptide and

protein reference materials for cardiovascular and

renal disease diagnostic markers and related auxiliary

diagnostic reference materials; Through high-

throughput gene sequencing technology, we should

study gene fragments for specific diseases, lock

individual lesion genes, formulate personalized

treatment plans, establish gene sequencing

measurement methods, and carry out the

development of high-accuracy and high-grade

reference materials to ensure the accuracy and

reliability of sequencing results and provide guidance

for the implementation of targeted therapy.

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5) Application in epidemic prevention:

biomedical reference material of the viral crown of

the medical crown virus has the physical structure of

the virus like and the specific nucleic acid sequence

of the new crown virus, and ensures the reliable

biological safety and stability of the fake viral target

through the gene transformation technology, so that

the standard value can reproduce the process of the

detection of the new crown virus nucleic acid to the

maximum extent, and achieve the quality control

from nucleic acid nucleic acid extraction to nucleic

acid quantification. It provides accurate rulers for the

results of COVID-19 nucleic acid diagnosis, and

effectively reduces the probability of false negative.

Figure 2: Process of gene transformation.

5 CONCLUSION AND PROSPECT

To sum up, it has been more than 60 years since the

comprehensive introduction of medical reference

materials abroad. There is still a long way to go

between the research of medical reference materials

and the needs of health protection, prediction and

diagnosis of disease development. There are more

than 1000 kinds of clinical testing items, which is

obvious compared with the number of biomedical

reference materials.

The purification and preparation of biomedical

reference materials is difficult, and its determination

components and matrix are also unstable. Now the

gap of reference materials for invitro diagnostic

reagents is too large to meet the needs of market

testing, so the development of reference materials

related to clinical testing has a long way to go.

With the rapid development clinical diagnosis

demands, biomedical reference materials provide

rulers and weights to meet the measurement value

and accuracy, promote the upgrading and updating of

national health, inspection and quarantine and

intelligent medical industries and have become the

gold standard for precision medicine.

In the future, we should focus on the research of

reference materials urgently needed in the biomedical

field, build the technical system through high-

accuracy certificating technology, strengthen the

research of biomedical reference materials in clinical

testing, and improve the technical level of

preparation, stabilization and mutual recognition.

ACKNOWLEDGEMENTS

This work was financially supported by the

Foundation of China (2019YFF0216703).

REFERENCES

Chen Baorong (2016). Influence of different evaluation

methods on interchangeability evaluation results of

reference materials. Journal of clinical laboratory,

34:808-812.

Chen Baorong (2016). Some problems that should be paid

attention to in the interchangeability evaluation of

laboratory medical reference materials. Journal of

clinical laboratory, 11:801-803.

Chen Liyuan (2019). Development of sodium benzoate

reference material in water. Stoichiometric analysis,

28:6-10.

Chen Yu (2017). Development status of reference materials

at home and abroad, Journal of environmental hygiene,

4:156-162.

Han Lu (2018). Research progress of vitamin reference

materials. Journal of food safety and quality inspection,

8:3883-3890.

Li Weiwei (2018). Difficulties in the development of

biological reference materials. China metrology, 8:83-

85.

Wang Bin (2009). Overview of the development of

reference materials in China since 2001. China

metrology, 9:71-72.

Wu Hai (2016). Study on preparation method of

multicomponent volatile organic compound gas

reference material. Measurement technology, 6:7-11.

Yan Mingcai (2006). Preparation and certification of

biological reference materials. Rock and mineral

analysis, 25:159-172.

Development Investigation of Biomedical Reference Material in Promoting National Health

977

Yang Yimei (2019). Development of reference materials

for fat composition analysis in infant formula milk

powder. Food industry, 40:145-148.

Zhang Qinghe (2013). Current situation and trend of

certified reference materials in chemical measurement

related fields. Chemical reagents, 35:865-870.

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