The annual report of biological products in 2016
In this paper,
In 2016, the state food and drug supervision and administration bureau (hereinafter referred to as the "administration"), under the leadership of the school in the check and undertake biological products issued by the group of seven authorized provincial drug inspection institutions (Beijing, Shanghai, guangdong, sichuan, hubei, gansu and jilin) therelease of advance work, elaboration and gradually perfect the therelease of working procedures.
In 2016, a vaccine was issued for 3,949 batches of 646 million people. Blood products 4025 batches, approximately 5927.8 million bottles of blood sieve reagent 836 batches, about 878 million people. At present, the approved vaccines and blood screening reagents are mainly made of domestic products, and import products are less than 5%. The clinical supply of blood albumin is more than 50% of the blood products due to the deficiency of raw materials. The production standardization of batch products is better, the quality is stable and controllable, there are few unqualified products in recent years. Only 1 batch of domestic vaccines and 2 batches of imported blood albumin in 2016 did not meet the requirements.
On 6 kinds of biological products in China since 2001 (live attenuated measles, adsorption DPT vaccine, attenuated live vaccine, hepatitis b vaccine, polio intradermal injection with BCG and human blood albumin) trial batch issue. In 2006, the vaccine and blood products were issued in a comprehensive manner. At present, our country into the number of issued by management of biological products including vaccine products, domestic blood products and imported human blood albumin, blood screening with in vitro diagnostic reagents (hereinafter referred to as "blood screening reagents"). In 2016, it was decided by the general administration to implement the batch and issue management of hepatitis b/c/HIV testing blood screening reagents.
Since the implementation of the batch issuance system, the batch issuance system has been continuously improved and improved. The production enterprises of biological products and the national supervision and inspection institutions have generally established good consensus, constantly standardize the market of biological products and jointly promote the development of the industry. China has made great progress in vaccine production and research and development, and many vaccines have already gone to international market. The national regulatory system for the WHO vaccine was assessed in 2010 and 2014. On this basis, through several vaccine production enterprises or certification, is applying for the WHO vaccine will homebred vaccine in the United Nations and other international institutions purchasing list, for there is no vaccine production capacity of countries to provide more product support.
In 2016 after many years of practice, administration organization timely revision of the "measures for the administration of therelease of biological products, step into a clear thinking, clear responsibilities, therelease of refining process, in order to better work to lay the based therelease of biological products. As the main unit of the batch issuing work, the central court has actively participated in the relevant work of document revision under the leadership and requirements of the general administration. Courtyard in the check at the same time, according to the new regulations seriously than, combing therelease of workflow, timely and complete system of relevant supporting documents to revise, further improve and strengthen quality management of biological products.
In 2016, the state food and drug supervision and administration bureau (hereinafter referred to as the "administration"), under the leadership of the hospital and seven grant rights in the check for therelease of biological products issued by provincial drug inspection agency jointly promote group work and further refine and improve therelease of working procedures, to ensure the quality of biological products, promote the benign development of the industry, maintaining people's security. The details are reported as follows.
1. Batch and issue of vaccine products
The batch and issue of vaccine products is the main body of the batch work of biological products. The review, inspection and issuance of information are mainly focused on the central court. Among them, the two inspection items of aseptic and abnormal toxicity inspection are carried out by the authorized pharmaceutical inspection institutions in the jurisdiction of the production enterprises, and the results are summarized and issued by the central procuratorate. In accordance with the provisions of the drug administration law and the administration of drug import administration, the import of vaccine products shall be issued by the central inspection institute and shall be subject to the inspection and inspection of each batch.
(a) general situation of vaccine batch issuance in 2016
In 2016, the vaccine issued 51 varieties, with a total of 3,950 batches, of which 3949 of them were in compliance with the provisions and 1 batch of non-compliance (the non-qualified rate was 0.25 ‰). The 1 batch of the rejected vaccine (210048) is a combination vaccine for Changsheng bio-technology Co., Ltd., which is produced by Changsheng bio-technology Co., Ltd., and the non-conforming project is determined by the efficacy of the non-cell pertussis vaccine. Among them, the Chinese court issued the approval of all 51 vaccine varieties, total 3931 batches; A total of 19 batches (2.16 million people) of one variety of influenza virus vaccine were issued by the Shanghai food and drug inspection bureau. The results were in accordance with the provisions. The data analysis is summarized as follows:
1. The quality of the vaccine is stable, and there are fewer unqualified products
In recent years, the vaccine has been issued with a lower rate of disqualification, which was 0.03% in 2016. All the years were less than 0.5% (except in 2015, when 181 batches of rabies vaccine and b brain attenuated vaccine, which were applied for review by liaoning province, were refused to be signed, which was up 4.2%).
2. There was a general decline in vaccine issuance and there was no significant difference between 2016 and 2015
The analysis of vaccine batches from 2010 to 2016 reflects the stability of vaccine varieties. In the past years, the number of vaccine varieties was basically flat, at about 50 species. The second is the decline trend of batch issuance. From 2010 to 2013, about 5,000 a year, or about 4,000 a year for nearly three years. Compared with 2015, although the total number of batches declined slightly in 2016, the overall issuance volume did not decrease, with a total of 646 million people.
Table 1 overview of vaccine batch issuance from 2010 to 2016
Vaccine batches issued from 2010 to 2016
3. The listed vaccines are mainly domestic vaccines, and the proportion of imported vaccines is very low
First, domestic vaccines constitute the main body of the listed vaccine and support the implementation of national immunization programmes. In 2016, 33 domestic enterprises applied for vaccine approval. Issued 3808 batches of domestic vaccines and 631 million people; The import vaccine was 141 batches and 0.15 billion people. In the past years, the amount of imported vaccine accounted for only 5% of the listed vaccine, and the proportion in the last two years has been reduced, accounting for 2.1-2.3% of the listed vaccine.
Table 2: the issuance of domestic and imported vaccines in 2012-2016
From 2012 to 2016, domestic and import vaccine issuance
The second is the development and production capacity of vaccine manufacturers in China, and the domestic vaccine varieties basically cover the developed countries. In 2016, eight vaccine approvals were issued for six import enterprises. Among them, in addition to an immovable vaccine (adsorption cell free DPT, inactivated polio and haemophilus influenzae type b [combine] combined vaccine), the other seven are issued by domestic vaccine varieties vaccine, and most domestic vaccine batches and issuing amount is significantly higher than imported vaccines. It may also be a factor in the decline in imports. By analyzing the import vaccine situation, it is suggested that the production capacity of China's polio eradication vaccine needs to be improved, and the strengthening of joint vaccine development and production is one of the development directions of the vaccine industry.
Table 3 the introduction of vaccine varieties in 2016
4. State-owned vaccine production enterprises are the main suppliers of a kind of vaccine, and the private enterprises mainly supply the secondary vaccine
A total of 2150 vaccines were issued in 2016, nearly 51.2 million, accounting for 79.3% of the listed vaccines, with 90.3 percent of the vaccines produced by state-owned enterprises. The second type of vaccine was 1799 batches and 134 million people. In the second class vaccine, there were 1658 domestic vaccines and 119 million people (88.7%). The import vaccine was 141 batches, 0.15 billion people (11.3%).
As we all know, a type of vaccine, though large in quantity, does not account for a large share of sales. Therefore, the type of vaccine market in China is mainly composed of "six big research" by domestic production supply, 2016 issued the "six big research" for 1429 group, 455 million doses of vaccine, its share is about 88.9% of the type of vaccine market. In the case of batch issuance, private enterprises supply a kind of vaccine market mainly for hepatitis b vaccine, hepatitis a vaccine and cerebellum vaccine.
In 2016 issued by the 2 kinds of vaccine with je vaccine, hepatitis b vaccine, epidemic encephalitis vaccine (in addition to A group of epidemic cerebrospinal meningitis vaccine and A group of C group of epidemic cerebrospinal meningitis vaccine), influenza, the wild dog vaccine, haemophilus influenzae type b conjugate vaccine, chicken pox, and pneumonia.
5. The quality of domestic vaccines is too hard to be included in the procurement list of international agencies such as the United Nations, and the export volume increases
In 2010 and 2014, when the WHO vaccine national regulatory system was assessed (WHO NRA), the vaccine manufacturers in China had the qualifications to apply for the WHO vaccine pre-certification. After many years of extensive clinical application and technology accumulation, the production and use of domestic vaccines are confirmed by the world. In 2013, chengdu institute of biological products production of je vaccine is the first domestic through certification vaccine, WHO in 2015 biology of influenza vaccines through certification, WHO also have some domestic enterprises certification matters in preparation for the application for the WHO.
From the therelease of data analysis, chengdu institute of biological products in 2016 through the WHO live attenuated Japanese encephalitis vaccine, in the process of the certification issued by a total of 306 batches of 92.6959 million doses, 5950.60 doses of vaccine for export, exports accounted for 64.19% of total amount issued, visible international demand is higher.
Table 4 the sales and export status of the attenuated type b encephalitis in 2016
(ii) work done in the 2016 vaccine batch issue
The first is to strictly control the information of the data, review and audit the compliance of the production and quality control of enterprises, eliminate potential hidden dangers and urge the enterprise to regulate production. In 2016, the issue of the vaccine batch issue was issued in 13 copies, involving more than 20 batches of products. The main issues involved include the standardization of production and verification management, the consistency of the production process and the batch, and the implementation and approval of the new pharmacopoeia. For example, when the national photobiology first imported influenza virus to crack the vaccine, the data review found that the company's virus inactivation verification had a problem, which was verified and solved to eliminate the security risks.
2 by trend analysis method, monitoring the key data/production approval documents and the consistency of production process quality control, urge enterprises to strengthen the quality assurance and risk assessment in the process of production, make the risk in advance early ZhaDu loophole, ensure the quality of our system. For example, by analyzing the trend of vaccine efficacy, it is found that there is an abnormal decline in the efficacy of the vaccine, and even if it meets the standard, it is necessary for enterprises to check and analyze the reasons to ensure the stable quality of the vaccine. At the same time, we provide technical support for the processing of adverse events based on the batch issue inspection data. For example, data support is provided for the treatment of "suspected polio vaccine related cases (VAPP)".
The third is to advance the quality evaluation of new vaccines, better control the quality of products and promote the application of new vaccines. Timely launch of simultaneous batch issuance, shorten the vaccine listing process, and ensure the supply of vaccine market. For example, to alleviate the shortage of vaccine supply for polio program immunization, to ensure that the "polio vaccine conversion" work is carried out on schedule, to promote the listing of the enterovirus 71 vaccine.
Four is to actively participate in the management measures for therelease of biological products, on the premise of guarantee quality of biological products, adhering to the scientific supervision concept, further comb and therelease of planning system, and assist in administration of multiple biological products production enterprises, supervision departments of communication. In addition, our hospital is according to the new revision of the measures for the administration of seriously than, combing therelease of workflow, finish the process of making the relevant supporting documents, to ensure that the biological product batch of issuing the scientific, reasonable and efficient, further strengthen the biological products quality management.
Fifth, strengthen communication and exchanges to jointly maintain the quality of vaccines. During the batch issuance work, the central procuratorate promptly reports to the competent department of the general administration of the relevant working conditions, and submitted the relevant information in batches according to the requirements; On the premise of strictly abide by the honest self-discipline, in order to ensure the quality of biological products and biological products industry development, the written feedback, telephone communication or a communication or seminars and other forms, ensure therelease of works carried out smoothly; To ensure the smooth development of the approval of the batch issue; Further improve batch and issue public information through the hospital website. Therelease of related conference of 2016 or mainly includes: "measures for the administration of revised therelease of seminar", "implementation therelease of EV71 inactivated vaccines work symposium" and "western Pacific vaccines and blood products national quality control laboratory seminar", etc.
(iii) key varieties of vaccine batch issued in 2016
1. Bivalent polio vaccine (bOPV)
To fulfill the Chinese government for polio eradication put forward by the world health organization commitment, according to the unified deployment, to ensure that the discontinuation of trivalent OPV in May 2016 (tOPV), enabling the bivalent OPV (bOPV), to do a good job of transformation. As of the end of January 2017, bOPV133 batches were issued by our hospital, and 68 batches of products were verified by virus titer. By trend analysis shows that the courtyard with the temple of heaven in the check for 68 batch bOPV always drop test results are within the cordon, data are evenly distributed on average, reflect product has good consistency; Virus drops from thermal stability test decline in visible, in school and enterprise virus 68 batch bOPV falling drops degree detection results conform to the rules, show that the stability of the products is good, at the same time, each batch of results within the cordon, data are evenly distributed on average, shows that the product has good consistency.
2. Sabin plant poliomyelitis vaccine (sIPV)
On January 14, 2015, the general administration approved the first application for production registration of sIPV (single seedling) in the world. The three batches of sIPV issued by our hospital on June 25, 2015, which issued the first batch of applications, marked the official launch of the innovative sIPV in China's independent research and development. According to the requirements of the general administration, we continuously monitor and analyze the D antigen trend of the vaccine I, II and III in order to monitor the batch/production consistency. In 2016, the sIPV was issued 53 batches and the results were in accordance with the provisions; In addition, at present, the wIPV application of sanofi Pasteur in France has been issued, and 65 batches were issued in 2016. According to the trend analysis of D antigen content, the batch of IPV produced by the two enterprises is good, and the results of the self-examination are more consistent with those of the central inspection institute.
3. Enterovirus 71 vaccine (EV71 vaccine)
In 2016, 72 batches of the EV71 vaccine were issued in our hospital, 9755 million doses, and no serious adverse reactions were reported.
Table 5 overview of EV71 vaccine batch in 2016
According to the analysis of the results of vaccine test results of the two enterprises, the results of the detection of the key items of vaccine production and verification are well consistent. In kunming, the result of the antigen test was two discontinuities exceeding the warning limit, and the test results were in the warning line. The test results of the company have exceeded the warning limit of one batch, and the test results of the central inspection hospital have two consecutive batches exceeding the warning line. Neither the court nor the company has seen any of the three batches exceeding the limit of action. The trend did not see serious drift (six successive batches were either up or down, and eight batches of results were on the same side of the mean).
There are problems
1. We need to further improve the "national biological product batch and issuance management system", implement the network operation and maintenance funds and ensure the smooth operation of the system. In 2016, due to the administration of basic drugs platform network operational funds failed to timely implementation, compared with a national therelease of connected network system is to use the dedicated line, so in Beijing after the relocation of issues system cannot be connected, failed to timely find therelease of enterprise application information and summary inspection report, etc. After the multi-party communication, the method of temporary manual consolidation of the data by the central inspection institute was adopted to issue a batch report to reduce the impact of the issuing time. At present, the system problem has been solved. In 2016, the state administration allocated 5 million line fees to the central court, but the funding was not enabled due to lack of documentation support. At present, the central procuratorate is actively communicating with the general administration, implementing the funding problems as soon as possible, ensuring the normal operation of the national basic drug platform and the batch issuing system.
2. The communication mechanism should be further improved to strengthen communication with the vaccine production enterprises and the regulatory system of vaccines, while ensuring the quality of the vaccine and strict time limit management. In 2016, the time limit management was strengthened and the time limit was reduced. However, due to the shortage of animal supply, the inspection of multi-batch products has led to a backlog of tests, which still exists.
3. The efficiency of vaccine batch issuance should be further improved and resources should be properly allocated. In our country is vaccine production country, issued by batch quantity is big, in ensuring that the vaccine is safe and effective at the same time, according to the quality of vaccine, on the basis of literature review, can consider to adjust timely research test frequency.
4. Strengthen the scientific knowledge publicity of vaccines, guide correctly, and enhance public awareness and confidence in vaccines.
Issue of blood products
The approval of blood products shall be carried out by the central procuratorate and the seven authorized pharmaceutical inspection agencies, and shall divide the tasks according to the jurisdiction of the production enterprises. The central procuratorate undertakes the technical guidance, standard material and organization coordination of blood products approval, and extracts 10 to 20% batches of blood products.
(a) general survey of blood products in 2016
In 2016, 12 varieties of blood products were issued nationwide, and the number of batches of 4025 was 5927.802 million. Two of the rejected products were produced by Baxter AG, Austria, and the non-conforming project was a visible foreign object.
In 2016, 39 blood products manufacturing enterprises were issued and issued, including 27 domestic enterprises and 12 overseas enterprises. At present, a total of 28 domestic blood products enterprises, in addition to the xinjiang DE source biological engineering co., LTD. Has obtained GMP certificate issued by products, but not other 27 blood products manufacturing enterprises have product issue. In 2016, a total of 2564 batches of domestic blood products were issued, 3878.8277 million bottles, including 1593.5542 bottles of human blood albumin (10g/bottle). All imported blood products are blood albumin, with a total of 1457 batches of 2048.97.43 million bottles (at 10 g/bottle). The ratio of blood albumin to imported blood albumin was 43.75% and 56.25% respectively. It is basically flat compared to 2015.
Table 6. The issue of blood product approval in 2016
* : in 2016, two batches of blood products were rejected by Baxter AG/Austria.
(2) information on domestic pulp stations in 2016
In 2016, 28 domestic blood products production enterprises, total plasma station 218, the whole year slurry about 6212 tons. In the process of data review, our hospital summarized the distribution of plasma station of blood products enterprises. At present, the amount of plasma of 6212 tons can not meet the domestic clinical needs, and the difference is about 8000 tons of plasma. Imported human blood albumin 2048.97 million bottles, about 7,988 tons of plasma production, supplemental domestic deficiencies.
(iii) blood products of the year 2016
Human coagulation factor VIII
The human coagulation factor VIII is used in the treatment of hemophilia patients. Due to the shortage of domestic market, the general administration has paid close attention to the product.
At present, the domestic human coagulant factor VIII is under the batch issue management, the import person coagulant factor VIII is not included in the batch issue system, according to the normal regulation import product inspection. At home, there are five companies in the country that produce human coagulant factor VIII, which issued 98.86 million bottles in 2016, up 19.6 million bottles from 79.26 million bottles in 2015, up 19.8%. In 2016, the import volume of 68.59 million bottles has been increasing year by year. The factor VIII of imported coagulation factor accounted for 41%, effectively replenishing the market supply.
Table 7 statistics of factor VIII of recombinant human coagulation factor (200IU/bottle)
There are problems
First, we should strengthen the communication between the inspection agencies to ensure the consistency of the blood products of each drug inspection body and ensure the quality of the batch work. The study should consider timely adjusting the drug testing institution, namely, when the inspection capacity of a drug inspection institution is saturated or obstructed, timely communication of the agent, to ensure that the inspection time is transferred to other drug inspection organizations for approval.
Second, the central court should strengthen the technical guidance of each drug inspection institution, strengthen the business training, and improve the inspection ability of each inspection institution. For example, the training of test methods for the determination of immunoglobulin, rabies immunoglobulin and hepatitis b immunoglobulins were carried out in due course.
Thirdly, it is necessary to analyze and improve the quality of batch issuance and reduce the feasibility of the inspection proportion. From the international perspective, the United States has implemented the exemption and issuance system for some enterprises; Europe is dominated by documentation, with only key project verification. From the analysis of the results of the 2016 issue, only two batches of imported people were not qualified for the whole year, indicating that the quality of domestic blood products was controllable. In order to further improve the efficiency of the batch issue, reduce the inspection resources and the cost of enterprises, reduce the proportion of sample test and/or the inspection project.
3. Blood source screening is issued in vitro
(I) the issuance of blood source screening reagents in 2016
Drugadministration law according to the drug administration law and the regulations on the implementation of blood screening in vitro diagnostic reagent, according to the biological products management, and the implementation of batch issue, every batch of products are required to pass through in front of the public hospital in the check of the batch batch inspection. After years of strict regulation and supervision of the production enterprises, the overall stability of the production enterprises in recent years, the quality of blood source screening is better in vitro, and the qualified rate of batch approval is up to 100% for five consecutive years. In 2016, the total number of blood source screening and screening in vitro was 878 million, involving 9 varieties and 24 production enterprises. Among them, 64 batches of imported products (8% of the total number of issued batches), accounting for 0.03 billion (3.5% of the total number of persons issued), involved 6 varieties and 5 imported production enterprises. Compared with 2015, the two years of issuance have not been very different.
Table 8. Blood source screening in 2016 was issued with an in vitro diagnostic reagent
In 2016, domestic and imported blood source screening was issued in vitro
In 2015 and 2016, blood source screening was compared with in vitro diagnostic reagents
(2) batch and issue of HBV/HCV/HIV testing blood source screening reagents
On February 23, 2016, the "nucleic acid testing blood source screening reagent" was held, and the batch of blood source screening reagents was proposed. In order to guarantee the smooth progress of the work, according to the general conference spirit, our biological products offices shall be held on March 21, 2016, the source of blood screening for nucleic acid detection reagent therelease of implementation of communication ", related work and nucleic acid blood screening reagent production enterprise communication, to listen to your companies, to ensure that the nucleic acid testing blood screening reagents issued by laying a foundation for the smooth implementation of the work.
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