* Corresponding author: Wang shuling, associate professor. Major research area: medicine circulation management direction, etc. Tel:13998302138, E-mail: lingyi50@163.com.

Abstract Objective To analyze laws, regulations and the responsibilities of relevant authorities for vaccine quality control and to provide suggestions for improving vaccine quality control system in China. Methods Laws and rules issued by related authorities were classified and studied. Results and Conclusion There are still some problems in the basic laws and regulations, including the lack of legal basis, the unclear responsibilities of relevant authorities and so on. We should improve the current laws, regulations as well as the responsibilities of the authorities so as to build up a sound system of vaccine traceability gradually.

Keywords: vaccine; quality control; law and regulation; relevant authority

Vaccines are active immune preparations for the prevention of infectious diseases that are made of pathogenic microorganisms (such as bacteria,rickettsia, viruses, etc.) and their metabolites through artificial attenuation, inactivation or genetic engineering. Vaccination is highly efficient and costeffective in preventing disease, and has been highly valued in every country’s public health sector. WHO evaluated China’s drug regulatory authorities in 2010 and 2014 and the evaluation results fully met the standards. However, several vaccine adverse events in recent years once again aroused great concern of the society, which also exposed some problems in China’vaccine quality control. This paper analyzes the laws and regulations and the related department’s functions from the perspective of vaccine quality process control, so as to provide reference for improving vaccine quality control system.

1 Status of vaccine quality control in China

1.1 Concept and main steps of vaccine quality control

Vaccine quality control refers to a series of technical and management measures taken to ensure the safety, effectiveness and quality of vaccines in the process of research and development, registration,production, storage, circulation, marketing,vaccination and post-marketing evaluation. In quality control science, there is the concept of quality control point, known as a witness point and a termination point. The difference between them is that when the supervisor does not appear, the former has the right to perform subsequent work, while the latter does not[1].Due to the particularity of the vaccine, it is necessary to ensure that the vaccine is in a standard environment at all stages. Therefore, all detection points should be the termination points, which can help to stop vaccine from flowing to the next link if there is no inspection during the process of circulation.

Generally, there are eight main steps in vaccine quality control: research and development,registration, production, storage, circulation, listing,inoculation and post-market evaluation. The main control links include four aspects. (1) The quality control of vaccine R&D and registration is reflected in laboratory tests (pre-clinical trials), clinical trials and the review of registration applications by the Center for Drug Evaluation. (2) The quality control in the process of vaccine production shall follow the relevant laws in the Pharmacopoeia of the People’s Republic of China, to establish a sound cell bank system and seed batch system, and manage the raw and auxiliary materials, production technology and production environment. (3) The quality control of the storage and circulation requires drug regulatory authorities,producers and distributors to jointly supervise whether the condition and other operations conform to relevant regulations during storage and transportation; (4)The quality control of vaccine listing refers to the relevant regulations on the issuance of vaccine batches. Besides, the quality of vaccine, records,and application materials shall be inspected by the pharmaceutical supervision and administration department. The quality control of vaccination and post-marketing evaluation refers to the management of vaccine storage by the authorized departments, the handling of adverse reactions after vaccination and the accountability of the problematic vaccines, etc.

The broad sense of vaccine quality control includes the above eight steps, and the narrow sense of vaccine quality control refers to the supervision and management of vaccine quality in the production and circulation. The vaccine quality control in this paper is the broad sense.

1.2 Development and current situation of Chinese laws and regulations on vaccine quality control

1.2.1 Emphasis on disease prevention and neglect of vaccine quality

Since the founding of the People’s Republic of China, China has been attaching great importance to the work of planned immunization. As early as the beginning of new China (1950), the instruction on launching autumn vaccination campaign was issued,which greatly reduced the incidence of smallpox. In 1963, the Ministry of Health promulgated the Measures for the Implementation of Vaccination, and from then on, the immunization project in some regions of China was gradually planned[2]. In 1980, the Ministry of Health promulgated the Measures for the Implementation of Vaccination Work, which further improved the vaccination project and related matters.After the reform and opening up, China put forward the concept of planned vaccination. China promulgated the Regulations on National Immunization and launched the plan of four vaccines against six diseases in 1982. At this stage, China attached great importance to the preventive vaccination work, but ignored the quality of the vaccine. In the process of promoting this policy, there were some events such as the live attenuated oral poliovirus vaccine leading to death, but they did not receive attention of the government.

1.2.2 Establishing a legalized vaccine quality control system gradually

In 1984, the Standing Committee of the National People’s Congress adopted the Drug Administration Law of the People’s Republic of China, symbolizing the beginning of the legal process of drug supervision.In 1989, the Standing Committee of the National People’s Congress adopted the Law of the People’s Republic of China on the Prevention and Control of Infectious Diseases, stressing that vaccines must meet the national quality standards. In 1994, the Ministry of Health promulgated the Measures for the Management of the Production and Supply of Biological Products for Preventive Use, which stipulated a series of matters in the production, circulation and use of vaccines, marking the establishment of China’s vaccine supervision and management system. In 2001,the circulation of biological products for prevention under special management was written into the Drug Administration Law, and the quality management of vaccines gradually gained the attention of the government. In 2005, the State Council formally issued Regulations on the Administration of Vaccines Circulation and Vaccination, the Opinions on the Supervision of Vaccine Management, and the Specification for Vaccination Work. In 2006, the Ministry of Health, in collaboration with the State Food and Drug Administration, issued the Code for the Administration of Vaccine Storage and Transportation.In 2008, the Ministry of Health issued the Measures for Identification of Immunization Abnormal Reaction. At this point, China has established a more standardized vaccine regulatory system, but there are still many problems from the legal point of view and the responsibilities and cooperation between different supervision departments.

After the outbreak of the Shandong vaccine incident in 2016, the public reacted strongly, and the quality of the vaccine was taken seriously.The Regulation on the Administration of Vaccine Circulation and Vaccination was revised for the second time in 2016, and the Regulation on the Administration of Vaccine Storage and Transportation was revised for the second time in 2017. Therefore, the supervision and management of vaccine circulation were refined continuously. The incident of rabies vaccine from Changsheng Company caused anger and panic in the society in July 2018. Three months later, the Vaccine Management Law of the People’s Republic of China(draft for consultation) was issued by the State Administration for Market Regulation, which for the first time upgraded the supervision of vaccine quality to the status of maintaining national security.

1.3 Related departments of vaccine quality control and their responsibilities in China

During the NPC and CPPCC sessions in 2018,China adopted a series of decisions on the reform of state institutions. China Food and Drug Administration(CFDA) was abolished, and the State Administration for Market Regulation was established. The National Medical Products Administration (NMPA) was also set up. The National Health Commission of the People’s Republic of China was established to integrate the functions of the National Health and Family Planning Commission. The preventive biological products are mainly supervised by the National Health Commission and NMPA. The National Health Commission has the Bureau of Disease Prevention and Control which mainly focuses on setting the development direction and building a trigger mechanism for large accidents from macroscopic perspective. NMPA just works on supervision and management more comprehensively from the details, and is also responsible for the flight inspection and other matters.

Table 1 Relevant department of vaccine quality control

Table 2 Summary of the functions of the official agencies involved in vaccine quality control

On the evening of November 11, 2018, the draft of Vaccine Administration Law of the People’s Republic of China (hereinafter referred to as the draft) was issued by the State Administration for Market Regulation, which stipulated all responsible parties in details. The system of Vaccine Marketing Authorization Holder was carried out. It means the marketing authorization holder should supervise and manage vaccine’s whole life cycle according to laws.The vaccine quality control system will be supervised and administrated jointly by the Department of Science and Technology under the State Council, the Department of Industry and Information Technology,local people’s government, the National Medical Products Administration, and the National Health Commission, as shown in the Fig. 1.

Fig. 1 Draft for comments on the vaccine - related responsibility of the main body and its responsibilities

2 The problems of vaccine quality control in China

2.1 Laws and regulations on vaccines are not perfect

2.1.1 Some laws and regulations are not specified

Before the official release of the Vaccine Administration Law of the People’s Republic of China, China’s vaccine quality control is mainly based on the Regulations on the Administration of Vaccine Circulation and Vaccination and the Vaccine Storage and Transportation Management Standards(2017 edition), focusing on the quality control of vaccine storage, circulation and vaccination. But in the regulations, some contents are not specified. For example, according to the regulations, provincial Center for Disease Control agencies should put temperature control labels on vaccines that have long cold chain transportation time to remote areas,but it did not specify time span and the distribution distance. In the Vaccine Storage and Transportation Management Standards (2017 edition), it required companies should establish automatic temperature monitoring systems if they have certain conditions.For cost-saving, most companies will not set up the system to have regular temperature detection every six hours. But in view of the specificity and sensitivity of vaccines to temperature, they should have the realtime detection of temperature. The above-mentioned problems have not been further solved in the draft for consultation, which may cause the quality controlsubjects to avoid stricter control and higher costs.

2.1.2 Provincial authorities did not formulate detailed rules in accordance with the law

The Regulations on the Administration of Vaccine Circulation and Vaccination, formulated,by the State Council, also should be improved by pharmaceutical administrative departments and health departments at all levels. For instance, regional guidelines for vaccine use should be formulated by provincial health departments according to their own conditions. Meanwhile, the technical specifications of national vaccine traceability system should be jointly worked out by pharmaceutical administrative department of the State Council and health department. However, until the release of the draft, no related regulations have been published on the official websites of these relevant departments.

2.1.3 Lack of relevant laws and regulations in some links of vaccine

The lack of vaccine laws and regulations is reflected on the relief system for vaccination victims. The current laws and regulations, such as the Drug Administration Law, Regulations on the handling of Medical Accidents, the Regulations on the Administration of Vaccine Circulation and Vaccination, the Vaccine Storage and Transportation Management Standards (2017 edition), and the Measures for Identification of Immunization Abnormal Reaction didn’t stipulate the treatment and compensation for the victims in the event of a vaccine accident, nor did they specify how to determine the person responsible for the incident and the amount of compensation, etc. Therefore, after the occurrences of vaccine incidents in China, many problems arose,such as complicated handling process, no laws to rely upon, avoiding responsibilities and unconvincing punishment. And these problems further cause public discontent with the relevant institutions and the government. The new draft for consultation points out that vaccination should be carried out with nofault compensation principle. Without a detailed compensation mechanism, it is necessary to establish the national trust fund of vaccine injury compensation.Before improving vaccine insurance system, the nofault principle has great moral hazard because it may lead to a series of problems affecting the construction of social integrity.

2.2 The responsibilities of vaccine quality control department are not clear

Most of the departments involved in vaccine quality control in China have superior and subordinate responsibilities, and they all run through the whole process of quality control. The same phenomenon also exists in the new draft for comments. Although vaccine departments at all levels have their own functions, they are involved in all aspects. In the introduction of the function of official websites of various departments, some are directly presented in the form of the original documents of the superior departments, while others are listed in a few general phrases with the core concept of prevention disease among the public. The responsibilities are not specific to each step of vaccine quality control, which results in the overlapping of most functions of various departments. This makes the supervision of vaccines prone to loopholes. Once vaccine events occur, there will be the phenomenon of shirking responsibilities.Because there wasn’t such a traceability system for vaccines in China before November 2018, the expired vaccines on the market would undoubtedly increase the risk of vaccinators. After November 2018, the Draft for Comments stipulated how to destroy expired vaccines, and proposed that the State Council’s drug regulatory department and the health administration department should establish a nationwide electronic traceability coordination platform, and formulate unified vaccine traceability standards and norms. It stipulated that the main responsibility of a vaccine traceability system was the vaccine Marketing Authorization Holder (MAH).

2.3 Inadequate supervision channels and lack of professionals

China has not established an informationbased vaccine whole-process traceability system, or will not be open to the public after it is established in the future. Therefore, vaccinators cannot monitor the real-time technical data of the whole process of the vaccine they use. Thus, there are no social supervision channels. For the informer within the illegal enterprise, China has not issued a detailed restriction mechanism (to avoid malicious reporting)and protection mechanism, which makes the interests of the informer unable to be guaranteed by law.

There is a lack of professional supervision personnel and high-tech applications in the process of vaccine quality control. Enterprises engaged in vaccine research and development, production and distribution need professional personnel to guide the self-inspection and supervision process of vaccines, and drug regulatory departments also need professional personnel to supervise and check vaccines. In addition, one of the important reasons for China’s inability to establish an informationbased vaccine whole-process traceability system is the backwardness of science and technology, which makes it impossible to integrate data related to the whole process of vaccine, such as machinery and equipment,transportation map and computer system.

2.4 Enterprises lack awareness of recall

In foreign countries, drug recalls occur from time to time. However, in China, enterprises lack the awareness of recall. Once the problem drugs are recalled, it will inevitably cause adverse social impact, which will seriously damage the reputation of enterprises and cause greater losses. At the same time,the Internet cynical will also make use of the problem,and criticize the government. Therefore, enterprises generally do not want to recall the problem drugs, but rather bear the loss of the possible drug harm events.

3 Foreign experience in vaccine quality control

In terms of vaccine quality management, UK department of health has the absolute authority. As the only buyers of all vaccines, the ministry of health not only buys the vaccine at a price lower than the market price released by the manufacturers, but also has strict requirements for the manufacturers. Their development ability, production equipment, capital and so on must pass strict examination. Therefore,only seven manufacturers obtained production qualification. At present, China has not merged a large number of vaccine manufacturers, but combined with the new concept of MAH, the supervision of vaccines has been further strengthened and improved.

As to vaccine storage and circulation management, these developed countries such as the United States, Germany, Japan, the United Kingdom and Australia all have the whole-course traceability system. The circulation plan of the United States is very detailed. There are detailed regulations on the temperature record of vaccine transportation, the unpacking inspection at the time of receiving, the cold chain storage after receiving, the reasonable selection of refrigerator and freezer, the power supply for the protection of cold chain, the report of cold chain accidents, and other related matters during internal transport. Germany has strict requirements for transport equipment. Japan applies advanced bar code technology, temperature sensor technology and GSP positioning technology to the traceability system. Meanwhile, its distribution route is also strictly planned, which does not allow nationwide transportation but only within the region, reducing the risk caused by long distance in the transportation process greatly[3].

In terms of post-marketing quality management,the above mentioned countries have their own relief systems and compensation methods due to their welldeveloped traceability systems, which facilitate the rapid recall of problem vaccines and the handling of vaccine incidents. At present, China has also emphasized the gradual establishment of a wholeprocess information traceability system for vaccines in article 10, 14, 24 and 52 of the Draft for Comments.In chapter 7 and 10, the contents of compensation and compensation are further improved.

4 Recommendations for vaccine quality control

4.1 Establishing a better system of laws and regulations related to vaccine

A better system of laws and regulations related to vaccine will be established gradually so that the quality control of vaccine research and development,registration, production, storage, circulation,marketing, vaccination and post-marketing evaluation can have a legal base. Laws and regulations must be as detailed as possible, and vague words such as should,conditional and distant should be used less, so as to make the terms clear. The rapid recall system, relief system, compensation fund raising and conditions of the vaccine should be improved as well. Once a major vaccine event occurs again, the defective vaccines can be recalled in the shortest time, and the investigation,accountability, compensation of the event can quickly enter legal procedures to appease the public.

Before the introduction of the new vaccine management law, China’s national conditions should be fully considered to improve the existing relevant policies. For example, compulsory insurance system is required to be implemented in the Draft for Comments.However, China’s social insurance and commercial insurance systems are not yet perfect, and there is a gap in the regulations of insurance companies in vaccine-related fields. Due to the moral hazard in the compensation system, insurance companies are unwilling to bear the potential risks. All these require the government, the license holder and the insurance company to reconsider and coordinate. After the introduction of the new vaccine administration law, a series of regulations and guidelines should be issued as soon as possible.

4.2 Clarifying the functions of various departments involved in vaccine quality control

Whether it is through the supervision by superior and subordinate departments, or supervision by various departments at different stages of vaccine quality control, the functions of all departments should be improved to avoid putting the original document issued by the State on the official website of departments. They should not use broad terms like maintaining people’s health to describe their functions. At the same time, the responsibilities of the ethics committee should be improved to strengthen the management of research and development and clinical trials. It is stipulated that consent form must cover the content that cannot be written in. Different consent forms for must be made for vaccinators, medical staffand researchers, and the issuance of consent forms should be supervised. Only by constantly refining the functions of institutions can the quality control of vaccines be strengthened, and at the same time, it is easy to facilitate the investigation of the responsibility of the incident.

4.3 Establishing an open information vaccine traceability system

The information traceability system shall include the public R&D information filling, production,storage, procurement, distribution, circulation (cold chain), vaccination, adverse reaction detection and effect evaluation after vaccination. After the construction of traceability system, it can be open to the public and accept social supervision. The establishment of vaccine information traceability system requires not only the standardization of the system, but also the support of high-tech and training of high-quality disease prevention and control team.Learning from foreign experience, we can integrate high-quality transportation equipment, temperature monitoring technology and positioning system into the traceability system. Meanwhile, technical training for equipment operators, service training for medical personnel and legal training for regulatory personnel should be strengthened to build a sound vaccine health service system.

In a word, the laws and regulations in the process of vaccine quality control in China are still not perfect. Besides, the responsibilities of relevant departments are not clear which lead to the poor supervision. Therefore, China should establish an information traceability system for vaccine as soon as possible. In addition, a supervision system with laws and regulations for vaccine quality control should be set up to clarify the responsibilities of departments and protect the legitimate interests of vaccinators and people’s health.