In vitro diagnostic reagents (IVDRs) are products and services that obtain clinical diagnostic information by testing human samples (blood, body fluids, tissues, etc.) outside the human body, thereby judging diseases or bodily functions. In vitro diagnostic products mainly consist of diagnostic equipment (instruments) and diagnostic reagents.

As products supervised by the national drug regulatory system, in vitro diagnostic reagents are explained by the "Regulations on the Registration and Management of In Vitro Diagnostic Reagents (Trial Implementation)": In vitro diagnostic reagents managed as medical devices include those that can be used alone or in combination with instruments, appliances, equipment, or systems, used in the prevention, diagnosis, treatment monitoring, prognosis observation, health status evaluation, and prediction of hereditary diseases, for in vitro testing of human samples (various body fluids, cells, tissue samples, etc.), such as reagents, reagent kits, calibrators, and quality control materials.

For the general public, it can be explained as follows: Reagent kits used in the inspection department or other departments, combined with specific equipment or environment, cause human blood, urine and other body fluids to react with the components in these reagent kits, and then judge whether the human body is in a healthy state based on the data results. 。

Based on national regulatory classifications, the vast majority of in vitro diagnostic reagent products are managed as medical devices, with very few falling under drug management. At the same time, according to the degree of supervision, the national drug and medical device regulatory agency defines most in vitro diagnostic reagent products as Class II, with some classified as Class I and Class III. Furthermore, according to product types and methodologies, in vitro diagnostic reagents are generally divided into categories such as immunology, biochemistry, and gene testing.

Raw materials for in vitro diagnostic reagents are generally mainly various antigens, antibodies, secondary antibodies, enzyme conjugates, probes/primers, etc., corresponding to various products.

2 Current Situation and Problems of In Vitro Diagnostic Reagent Raw Material Enterprises

How to judge the quality of raw materials for in vitro diagnostic reagent products: According to the "Guiding Principles for the Analysis and Evaluation of In Vitro Diagnostic Reagents", the indicators to be analyzed and evaluated include detection limit, linear range, reportable range, accuracy (recovery experiment, method comparison), precision, interference test, stability, and reference values. Currently, in the research and development of in vitro diagnostic reagent products process the process is basically solidified, or several modes have limited choices becoming the trend, so the most critical issue determining product quality lies in the selection of raw materials.

Domestic in vitro diagnostic reagent manufacturers, starting in the 1980s, initially mainly used imported raw materials from foreign companies such as Merck, Sigma, and GE. Domestic in vitro diagnostic reagent raw material enterprises began to emerge in the 1990s and have been developing for more than 30 years. With the optimistic outlook for the domestic bioindustry at the beginning of this century, a number of large-scale bio-enterprises have also been born. For example, currently, only companies such as Fei Peng Biotechnology Co., Ltd., Novozan Biotechnology Co., Ltd., Shenzhen Ruiya Li Group Co., Ltd., and Tianjin Kangyuan Biotechnology Co., Ltd. have achieved a certain market scale , but they are still far from meeting the needs of domestic manufacturers, foreign raw materials still account for more than 60% of the domestic market share. 。

Why domestic raw material enterprises have not developed well, the author believes there are the following problems:

2.1 Management system of in vitro diagnostic reagent raw material enterprises, external demand and environmental issues

2.1.1 Users' raw material introduction ideas and technological level

When developing a new in vitro diagnostic reagent raw material product, in the initial stage, a mature system, including various component matrix formulas and process flows, is often used first, and then adjustments are made as needed, used for screening and matching raw materials, etc. However, currently, raw material R&D enterprises lack comparison with similar imported products in terms of application, making it difficult to guide users to treat them differently. In addition, the processes of most manufacturers' early products were explored based on imported raw materials, with little consideration given to the characteristics of the raw materials themselves, resulting in unique requirements for each raw material in terms of process and formula, which may lead to some deviations and cause some essentially excellent raw materials to be overlooked.

Immunodiagnostic raw materials are mainly divided into antigens, antibodies, and other special components. Among them, the quality of antigens and antibodies directly affects the core quality of the product: in actual production, the targets to be tested are all natural antigens, however, currently, the raw materials for immune antibodies are basically recombinantly expressed, which will bring many application problems that must be taken seriously. In addition, other special components in the reagents, such as Quillay, Tween, blockers, mouse serum, etc., although their performance has been evaluated in the initial stage of research and development, generally lack systematic experiments, therefore lacking supporting data for user research and development, and not being recognized by most users. Many raw material manufacturers cannot even provide product instructions, let alone guide users on how to use the raw materials; they cannot even describe the raw materials themselves, which further affects the R&D effect.

In addition, due to limitations in experimental conditions, some original work has not been done, resulting in an inability to provide data or explanations, such as the determination of antibody affinity constants, antibody subtypes, and monoclonal antibody pairing. Solid R&D data can give users a sense of reassurance, but domestic manufacturers are still lacking in this aspect. The biggest problem is that many manufacturers' products lack sufficient clinical data support, which is insufficient to win the trust of most customers, therefore many domestic raw materials are eliminated at the starting line. 。

2.1.2 Raw Material Manufacturing Workshop Management

The level of laboratory or production workshop on-site management is low and cannot meet the on-site audit requirements of medical device suppliers. The author has visited some companies for investigation and study, and found that the on-site management of domestic companies such as Feipeng, Medis, and Ruiya Li is relatively strict. However, on-site management of most domestic enterprises still needs to be improved. Currently, there are mainly three major gaps: The normativeness of quality control mentioned later (the main problems are whether to conduct inspections, whether the inspections are strict, and whether the inspection standards are higher than national standards, etc.), the management of controlled materials such as hazardous chemicals (mainly whether to truthfully declare management, supervision of the use process, and whether waste disposal is compliant), and aspects of production environment control (such as process water, clean rooms, three-waste treatment, etc.). )

2.1.3 Raw Material Packaging Management Standards

2.1.3.1 Inner packaging material verification

Inner packaging refers to the packaging that directly contacts the raw materials. The author has been engaged in the production of in-vitro diagnostic reagent products for many years. From a practical perspective, it is recognized that the quality of many raw materials, especially their stability, is related to the packaging used for storing them. However, based on the published information, few domestic raw material companies have conducted inner packaging validation. Currently, the inner packaging of domestic raw materials generally includes glass bottles, plastic bottles, and stoppers of different materials. To my knowledge, the antigen of a certain type of thyroid function series product cannot be stored in bottles sealed with butyl rubber stoppers; it can only be stored in bottles sealed with natural rubber stoppers. I believe this is unknown to many manufacturers. 。

2.1.3.2 Standardized Management of Packaging Issues

• Inconsistencies in product names on labels, instructions, outer packaging, inspection reports, delivery notes, and invoices, even differing from national standard names, can cause unnecessary trouble for users during later use.

• Missing items in labels, instructions, and outer packaging. The correct content should include, but is not limited to, product name, specifications, quantity, concentration, unit, whether light-sensitive, manufacturer name, precautions, etc.

• Quality issues with labels, instructions, and outer packaging. Because most biological raw materials require low-temperature storage, even below minus eighty degrees Celsius, higher quality requirements are placed on labels, instructions, and outer packaging; otherwise, they cannot withstand low-temperature environments, leading to confusion during shipment.

2.1.4 Raw Material Quality Inspection and Standardized Management

2.1.4.1 Quality Standard Management and Implementation Issues

Currently, domestic in-vitro diagnostic reagent raw material companies have problems with incomplete quality standards and non-standard quality inspection reports. According to regulations, quality standards must be clearly defined in raw material purchase and sales contracts. Moreover, this quality standard must meet or exceed the quality standard of the product using this raw material, and the corresponding batch's quality inspection report must be provided during the supply period. For example, the quality standard of type I-III collagen-coated monoclonal antibodies used in luminescence products must be equal to or higher than the national standard for type I-III collagen luminescence test kits. After the quality standard is established, the product quality must meet the agreed quality standard before shipment. This requires companies to enhance quality risk control, maintain quality control, and improve product quality.

This is also a common problem with biological raw materials internationally. Because many raw materials were not initially intended to be core materials for medical devices, there are no clear quality standards or standardized quality inspection reports. This has also led to some companies being unable to meet new requirements when new demands arise in the market.

2.1.4.2 Quality Information Lacks Clinical Data Support

The industrial chain of raw material companies, manufacturers, and clinical users has not formed a good feedback mechanism. Meeting clinical needs is essential, but because clinical trials are difficult to conduct, many companies do little of it. Therefore, in reality, raw materials have not undergone rigorous clinical validation. Currently, many domestic and foreign in-vitro diagnostic reagent raw material manufacturers produce a wide variety of raw materials; some manufacturers even launch seven or eight types of monoclonal antibodies for a single product. Apart from methodological reasons, the lack of clinical data makes it difficult to make optimal recommendations. As for how users use them, it's entirely up to the users themselves to screen and evaluate. This means that user R&D is largely taken up by raw material screening.

2.1.4.3 Falsification of Quality Data

Falsification of quality inspection data is also the current situation of some IVD raw material companies. This issue will not be analyzed in detail.

2.1.5 User Needs Management

2.1.5.1 Qualification Issues

The in-vitro diagnostic raw material industry has its particularities, so national supervision will have some special aspects, such as hazardous goods operating licenses and pharmaceutical packaging certificates. In-vitro diagnostic reagent manufacturers require suppliers to provide these qualifications. However, some suppliers do not pay attention to these qualifications or are unwilling to bear the potential costs, so they are unwilling to provide them. Some companies, due to a lack of responsibility, fail to provide users with the latest qualifications in a timely manner, which also affects the user experience.

2.1.5.2 After-Sales Technical Guidance and Feedback

The materials provided to users lack technical guidance, resulting in a lack of guidance during the use of raw materials, thus missing the optimal process system and affecting product quality.

2.1.5.3 Transportation Issues

Currently, the transportation conditions of in-vitro diagnostic reagent product raw materials are gradually being given attention and inspected by national regulatory authorities. Ideally, the professional cold chain transportation process should be verifiable, traceable, and recordable. Costs should be shared or negotiated by both supply and demand parties. Some companies may not yet realize this and have relatively low requirements for product transportation. Some companies are aware of the impact of refrigeration or freezing conditions on labels but do not pay attention to isolation, affecting the quality of product labels. The above operations may bring quality risks and may cause regulatory problems for in-vitro diagnostic reagent manufacturers.

2.1.6 Sustainable Production Capacity and R&D Investment of Raw Materials

Currently, the vast majority of domestic in-vitro diagnostic reagent raw material manufacturers are still in the era of small workshop economies. The non-standard breeding of experimental animals has resulted in insufficient sustainable production capacity of related companies, small batch production of products, and affected the stability of products over a period of time.

However, due to the outbreak of the COVID-19 pandemic, many companies have obtained sufficient funds and want to show off their achievements. However, I think many companies have spent their funds on buying land and building buildings, but actually spend less on R&D. This is a strange phenomenon in Chinese investment.

2.1.7   Difficulties in Customs Clearance for Some Biological Raw Materials

Difficulties in customs clearance for some biological raw materials and long approval times are also one of the reasons why effective materials cannot be obtained in a timely manner.

2.1.8   With a large influx of hot money, choosing which type of raw material to produce has also become a difficulty.

The influx of hot money has, to some extent, benefited the research and development of new raw materials. However, current antibody sequencing technology has deterred many raw material R&D manufacturers. Choosing which raw materials to develop and how to protect intellectual property rights have become the most headache-inducing problems in the current IVD industry raw material industry.

2.2 The Current Situation Facing the Industrialization Process of Domestic In-Vitro Diagnostic Reagent Raw Materials

2.2.1 The Importance of Promoting the Improvement of the In-Vitro Diagnostic Reagent Raw Material Industry Chain

The US-China trade war is raging, with the Western camp overtly and covertly assisting allied countries, and both sides are engaging in tit-for-tat moves. However, the most striking aspect is the battles related to the supply chain. Leaders of domestic in-vitro diagnostic reagent manufacturers must also fully realize that to develop and grow, they must control the supply chain, ideally by producing it themselves. However, I believe that most companies do not have the energy to produce upstream raw materials and can only rely on domestic companies, which has brought opportunities for domestic raw material manufacturers. At the same time, some foreign companies are establishing experimental platforms in China and carrying out direct production and transformation in China, which can also guarantee the domestic emergency needs. In addition, the country has already conducted pilot programs in Shenzhen. For example, the customs and Shenzhen Ruiya Li Group have cooperated to create a one-stop biopharmaceutical customs declaration platform, which has attracted the attention of many companies.

2.2.2 The Impact of Relevant Policies on the Domestic In-Vitro Diagnostic Industry Chain

From national policies to the cost-driven nature of medical institutions, coupled with the significant progress made by domestic in-vitro diagnostic reagent manufacturers, domestically produced in-vitro diagnostic reagents are beginning to gain a foothold in the mainstream market. However, long-term reliance on imported raw materials presents cost challenges, often hindering the achievement of a cost-effective advantage in competition with foreign products, and potentially leading to risks such as raw material shortages, product shortages, and shrinking enterprise sales. Therefore, the rapid development of domestic in-vitro diagnostic reagents has also created enormous demand for raw material manufacturers.

2.2.3 The urgent need for enterprises to introduce and optimize modern management

Profit is fundamental to the development of an enterprise. Enterprise management aims to optimize resource allocation under equal resource conditions to maximize profits. Chinese in-vitro diagnostic reagent raw material manufacturers also face survival and development challenges. Based on practical needs, they must also increase revenue and reduce expenditure to grow and expand, thus requiring improved management levels and optimization of various processes to adapt to the development of modern enterprises.

2.2.4 Market assessment of the in-vitro diagnostic reagent raw material industry

China's population accounts for 22% of the world's total population, but its share of in-vitro diagnostic reagents is only 2% of the world's total. Moreover, the rise and integration of various new technologies and methods in recent years have further promoted the development, application, and updating of in-vitro diagnostic reagents, The preliminary estimated market size of raw materials is between 2 and 3 billion . Against this backdrop, existing products may no longer meet market needs. Raw material manufacturers should take the initiative and pave the way for the subsequent development of diagnostic reagents. For example, drug tracking and animal detection products are only now becoming popular, but some related raw materials were developed more than a decade ago, especially by some foreign companies, which have already entered the field.

2.2.5 The capital market needs to see results

Since 2020, the IVD industry, including the raw material industry, has continuously reported explosive news of successful listings and large-scale acquisitions. Previously, this industry had low attention and rarely received capital recognition. Most enterprises relied on their own accumulation for development and expansion, resulting in steady steps and reluctance to easily venture into any direction. However, the influx of capital disregards this; its arrival demands immediate results, necessitating transformation and breakthroughs in existing product systems and models, as well as the emergence of new products—an inevitable trend.

3 Development prospects and suggestions for domestic in-vitro diagnostic reagent raw material manufacturers

Domestic in-vitro diagnostic reagent manufacturers face new situations and opportunities and should make the following adjustments:

3.1 Optimization of management in domestic raw material manufacturing enterprises

It's not just about improving the management level of on-site laboratories and production workshops; it's about enhancing the management level of the entire system, including system documents, on-site management, and on-site records. To achieve this, I believe it's necessary to establish regulations, conduct personnel training, implement SOPs, ensure equipment availability, provide supervision, and implement a reward and punishment system. Improving enterprise management levels is not simply to meet on-site assessments by users; it's about achieving efficiency and quality through management, effectively addressing the enterprise's inherent problems.

In-vitro diagnostic reagent raw material manufacturers should not be limited to the following aspects:

3.1.1 Internal and external packaging material verification

First, the relevant content must comply with national regulations and relevant policies. Second, a rigorous plan should be designed, and active internal and external packaging material verification should be carried out to eliminate quality hazards in their infancy. It is also necessary to start from the details, carefully review the enterprise's relevant outer packaging, and ensure that invoices and certificates match, strictly controlling quality, soliciting opinions from relevant personnel, and improving information.

3.1.2 Establish quality standards and rigorously issue quality inspection reports

Quality standards must be formulated based on relevant national and industry standards for products, combined with the actual situation of enterprise products, and must meet or exceed national and industry standards. After the enterprise produces raw materials, it should conduct inspections using the inspection methods and means specified in the quality standards, on designated equipment, and according to requirements.

If the inspection results are qualified during the inspection process, the quality inspection department can issue a qualified report and a release note, and the business department can proceed with sales. If the inspection is unqualified, an unqualified report should be issued, strictly controlling unqualified products from entering the sales channels.

3.1.3 Qualification certification and timely updates

Strictly abide by national regulatory requirements, actively participate in relevant certifications, and proactively and promptly provide users with relevant qualifications. For certifications that are not mandatory by the state, if required by the user, we should also cooperate as much as possible. After certification, relevant materials should be copied and stamped with the company seal before delivery to the user, and should not be copied again. At the same time, it is necessary to establish user information usage records and promptly update qualifications for users with needs based on the validity period of the qualifications.

3.1.4 Thoroughly address transportation and storage environment issues

Strictly abide by regulatory requirements, implement cold chain transportation regulations, plan and improve cold chain equipment, and add wireless monitoring and alarm devices. Carefully select cold chain suppliers and verify and confirm the transportation plans they provide. After meeting the requirements, sign a contract and cooperate with users for cold chain transportation as required.

3.1.5 Professional marketing

A new business perspective, different user groups, and marketing personnel require professional training. Unlike the marketing of finished in-vitro diagnostic reagents, the marketing of raw materials requires more professionalism. Therefore, it is necessary to equip technical experts and provide professional marketing training to ensure continuous growth in business capabilities.

3.1.6 Jointly building laboratories domestically and internationally

At the same time, some foreign companies have established experimental platforms in China, directly conducting experiments and production transformation in China, which can also guarantee domestic emergency needs.

3.2 Establish a third-party evaluation platform for in-vitro diagnostic reagent raw materials

In addition to good internal enterprise management, it is also necessary to strengthen mutual trust between enterprises and users. I believe that the current products in the in-vitro diagnostic reagent raw material industry are still in the stage of comparison with other manufacturers in terms of obtaining users, which has not been broken through and is not conducive to the development of the industry. . Therefore, it is recommended that an enterprise act as a third-party raw material evaluation center, playing an objective role and evaluating raw materials from a fair and impartial third-party perspective, using practical actions to support the credit building of both raw material buyers and sellers. On the one hand, the third party represents the basic point of independent expression of opinions; on the other hand, a platform-based and professional evaluation center will form a scale effect, forming a stable experimental approach and a more professional perspective.

The establishment of a third-party evaluation center may present the following opportunities and challenges:

3.2.1 Platformization brings possibilities for multi-platform testing of raw materials

Industry practice has shown that the fact that many raw materials cannot be used or are not easy to use on one platform does not mean that they will also fail on other platforms. However, it is extremely difficult for one enterprise to simultaneously cater to chemiluminescence, POCT, ELISA, turbidimetry, time-resolved fluorescence, radioimmunoassay, and colloidal gold methods. Therefore, cooperation among multiple parties can be achieved. Construction The model of a third-party evaluation center forms a new industrial chain to solve this problem and win trust.

3.2.2 Cooperation in the construction of a third-party testing center and a third-party in-vitro diagnostic reagent raw material evaluation center

With the vigorous construction of independent third-party testing centers in China, I think it has brought possibilities for platform-based raw material evaluation. Good division of labor: raw material enterprises provide evaluation raw materials, specifying evaluation methodologies and reference standards or other manufacturers' products as needed; third-party evaluation enterprises are responsible for designing schemes and preparing samples; third-party testing enterprises conduct testing and evaluation, and then return the results level by level, finally communicated to users by the raw material producing enterprise. This introduces new business for clinical testing centers, potentially bringing new growth points. In addition, the inherent advantage of clinical testing centers lies in their rich clinical samples, and an important aspect of raw material testing is the accuracy and stability of clinical measurements, which may solve the problem of clinical compliance in raw material testing.

3.2.3 The evaluation center needs to conduct market research.

Market research for this project is very necessary and must be conducted before market operation. Because the business is divided into three service targets: raw material manufacturers, reagent manufacturers, and some research institutions. Raw material manufacturers, in order to evaluate their products and have a "third-party evaluation" sign, may accept the business; reagent manufacturers, in order to develop new products, may take shortcuts or because initial R&D conditions cannot achieve accurate evaluation, therefore entrusting external evaluation; research institutions, in order to publish papers and evaluate raw materials or verify processes, but lack the corresponding personnel and experimental conditions, therefore entrusting external institutions. To clarify these needs and form a market, professional market research is needed to understand the thoughts of the target group and to take the initiative.

3.2.4 Application of platform data

Through third-party verification data, raw material manufacturers can obtain comparative information with other companies' competing products, and can use it as marketing materials based on comprehensive balance. Raw material using enterprises can save the process of screening raw materials during the development of new products and select the most cost-effective raw materials based on the results of third-party verification. Research institutions can integrate some experimental processes and results into research projects to verify research results.

3.3 Personnel trust

Currently, there is little communication between domestic in-vitro diagnostic reagent raw material enterprises and users, but analysis shows that more than 85% of sales targets are achieved mainly through proactive communication to gain trust. This view may not be true or may not reach such a high proportion in the purchase and sale relationship of in-vitro diagnostic reagent raw materials, because some good products really don't need to take the initiative, but the vast majority of products do not belong to this category, so proactive marketing is necessary.

3.3.1 Sincerity

To achieve trust, relevant raw material sales personnel must first be sincere. As the saying goes, "the buyer is not as shrewd as the seller." Many people misunderstand this saying. The true meaning is that the salesperson needs to do a lot of preparation work to be more thorough. The purchaser needs to know what the salesperson needs to know and even more, in order to achieve a deeper transaction. If both parties do this, at least they can smoothly express their thoughts and communicate effectively.

3.3.2 Continuously providing valuable information

To increase trust, salespeople must also continuously provide a lot of valuable things. To increase sales, salespeople need to let users know about new products and the latest promotional information, and consider how to let others know the purpose of the salesperson's visit.

3.3.3 Other issues

Sufficient trust, sufficient prior communication, and common ground between the two parties are necessary to reach the stage of actual procurement. From the perspective of marketing, there needs to be an environment for transactions, which means that both buyers and sellers need to have an intersection. The essence of the intersection is that the user's needs can be met by sales, and the user has the ability to pay for the needs, which will lead to a substantial transaction. For in-vitro diagnostic reagent enterprises, the transaction environment includes not only the intersection of both parties, but also legal permission, supplier assessment and review to enter the qualified supplier directory, possible resolution of previous disputes or reluctant acceptance, support from third-party data and comparative data, and the unification of the purchasing enterprise's R&D ideas and the sales enterprise's product intended use, etc. The completion of purchase and sale business, or even payment, is not the end of this type of business. If problems arise, communicate and solve them promptly; even if there are no problems, strive for feedback on usage experience to facilitate marketing for similar users.

4.  Conclusion

At the beginning of 2020, a sudden epidemic brought sadness to the world, but also brought opportunities to Chinese in-vitro diagnostic reagent related enterprises. Due to the large number of cases in China in the initial stage of the epidemic, it posed a strong challenge to in-vitro diagnosis. During this process, hundreds of manufacturers obtained international and domestic sales licenses, which in turn created a huge demand for upstream raw materials. Relevant in-vitro diagnostic reagent raw material enterprises rose to the challenge and basically met the raw material needs of the vast majority of COVID-19 products worldwide, verifying the enterprises' R&D capabilities, rapid response capabilities, and production capacity. Therefore, we believe that domestic in-vitro diagnostic reagent enterprises are a group with untapped potential.

This article analyzes some problems currently existing in China's in-vitro diagnostic reagent raw material production enterprises and introduces some existing opportunities. In view of the above situation, the author puts forward some measures to strengthen mutual trust between buyers and sellers, and especially suggests that aspiring individuals establish a professional platform-based "in-vitro diagnostic reagent raw material evaluation center" to meet new challenges!

Reprinted: Xiaojiedeng.com A Brief Analysis of the Business Situation of China's In-Vitro Diagnostic Reagent Raw Material Enterprises