(Image source: panoramic vision)
Economic Observer reporter Li Yao on the evening of July 22, the head of the State Drug Administration, Changchun Changsheng Biotechnology Limited Liability Company (hereinafter referred to as "Changsheng Biological") illegal production of lyophilized human rabies vaccine case related to the situation, said that it has been identified that the enterprise The company has been found to have fabricated production records and product inspection records, and arbitrarily changed process parameters and equipment.
The official said the enterprise is the second time in a year that it has been found to have problems with the quality of its products. In October last year, the former General Administration of Food and Drug Administration sampling test found that the enterprise production of a batch of DPT vaccine potency unqualified, the product is still in the suspension of production.
In the country, vaccines and other products to implement the batch issuance system, in such strict supervision why there are still unqualified vaccines on the market?
6 vaccines 2 shutdown
July 22 evening, the State Drug Administration responsible person's briefing that Changsheng Biological fabrication of production records and product inspection records, arbitrary changes in process parameters and equipment behavior is a serious violation of the "Chinese People's Republic of China *** and the State Drug Administration Law," the "Good Manufacturing Practices," the relevant provisions of the State Drug Administration has ordered the enterprise to stop production, recover the GMP certificate, and recalled the rabies vaccine that had not yet been used. The State Drug Administration in conjunction with the Jilin Provincial Bureau has opened a case on the enterprise to investigate, suspected of criminal transfer to the public security organs to pursue criminal responsibility.
Also on July 22, the afternoon of July 22, Changsheng Biological released an announcement in response to the Shenzhen Stock Exchange inquiry letter, said: although the freeze-dried human rabies vaccine, DPT combined vaccine have been discontinued, but the chickenpox vaccine is still on sale, at the same time, the company has obtained the tetravalent influenza virus cracked vaccine drug registration approvals, new drug certificates and GMP certificates, in the normal production and operation.2017 company Varicella Vaccine realized sales revenue of RMB572 million, accounting for 37% of the Company's operating revenue in 2017. As at the date of disclosure of this announcement, only two companies, including the Company, have obtained the production license of Quadrivalent Influenza Virus Lysate Vaccine, and the market competition pattern is good.
Changsheng Bio*** has six vaccines, two of which have been discontinued. Its previous products include lyophilized live attenuated varicella vaccine, lyophilized human rabies vaccine (Vero cell), lyophilized live attenuated hepatitis A vaccine, influenza cracked vaccine, adsorbed cell-free combined vaccine against DPT and ACYW135 group meningococcal polysaccharide vaccine, etc. 6, 2 due to quality problems have been successively called to a halt for adsorbed cell-free combined vaccine against DPT and lyophilized human rabies vaccine ( Vero cell).
Adsorbed cell-free DPT vaccine incident on November 3, 2017, the former State Food and Drug Administration issued "DPT vaccine potency index unqualified products disposal situation introduction", said recently received a report from the CIQ, in the drug sampling and testing detected Changchun Changsheng Biotechnology Company Limited, Wuhan Institute of Biological Products Limited Liability Company produced two batches of DPT vaccine The potency index did not meet the standard provisions. And as early as October 29, 2017, the State Food and Drug Administration, in conjunction with the National Health and Family Planning Commission, organized expert research and judgment, and to the relevant provinces and municipalities have issued a notice, requiring all localities to do a good job in the disposal of unqualified vaccines: firstly, ordering enterprises to ascertain the flow of the direction; secondly, immediately stopping the use of unqualified products; thirdly, ordering vaccine manufacturers to report on the results of factory inspection of two batches of unqualified vaccines, and to retention of samples for re-inspection. The fourth is to send an investigation team to the two enterprises to carry out investigations and on-site production system compliance checks; the fifth is to take samples of all the DPT vaccines produced by the two enterprises within the validity period for testing, and the conclusions of the test need to be made in six to eight weeks.
July 15, 2018, the State Drug Administration again issued a circular, saying that Changsheng Biological in the production process of freeze-dried human rabies vaccine records falsification and other serious violations of the "Good Manufacturing Practice" (drug GMP) behavior, and instructed the Jilin Provincial Food and Drug Administration to withdraw the relevant Changsheng Biological "drug GMP certificate".
On July 18, 2018, the Jilin Provincial Food and Drug Administration issued a penalty decision, making it clear that the adsorbed cell-free combined vaccine against DPT with batch number 201605014-01 produced by Changsheng Biologicals would be treated as an inferior drug, and confiscating the remaining adsorbed cell-free combined vaccine against DPT in stock of 186 vaccines, and confiscating 850,000 yuan of illegal income. At the same time, a fine of 2.584 million yuan was imposed on three times the value of the illegally produced drugs, and the total amount of confiscated money was 3.4429 million yuan. At this point, nine months have passed since the national bureau notification, and the rabies vaccine production record falsification has fermented.
By the close of trading on July 20, Changsheng Bio had suffered five consecutive losses, evaporating nearly 10 billion yuan in market value. It closed Friday at 14.50 yuan per share, capped by more than 550,000 sell orders.
For the DPT vaccine event, Changsheng Biological Company announced that in 2016 and 2017, the revenue of DPT vaccine was about 0.37 billion yuan and 0.30 billion yuan, respectively. Accounted for 3.62% and 1.95% of the company's operating income in that year, respectively, given that the combined vaccine of DPT accounted for a relatively small proportion of the company's total sales revenue, so the suspension of production matters on the company's production and operation has no significant impact.
Changsheng Bio also said that at present, the company's production plant of DPT has been suspended, and the company is actively researching the DPT component vaccine as well as the multiplex vaccine based on it. According to the current understanding of the situation, there are some areas of the disease control agencies have been temporarily suspended the company's other vaccine products.
With the July 15 announcement from the State Drug Administration, production of Changsheng Bio's freeze-dried human rabies vaccine has also been suspended. The recall of the product is expected to reduce the company's operating income in the first half of 2018 by about 200 million yuan or so, and net profit by about 140 million yuan. The discontinuation of production of the freeze-dried human rabies vaccine (vero cell) will have a greater impact on the Company's production and operation, and is expected to reduce the operating income in the second half of 2018 by approximately around RMB540 million. Under the quality storm of rabies vaccine and DPT vaccine, the remaining four vaccines, whether it can support the future of Changsheng Biologicals, may be yet to be tested.
Because of the impact of this rabies vaccine incident, Changsheng Biological has issued an announcement on the first half of 2018 performance forecast to amend, is expected to January-June 2018 attributable to shareholders of listed companies in the net profit change range of 210 million yuan -310 million yuan between, the change is revised to -20% -20%.
The more grim reality for Changsheng Biologicals also lies in the fact that, according to the current "Drug Administration Law", the production and sale of substandard drugs shall be subject to confiscation of the illegally produced and sold drugs and illegal income, and a fine of more than double and less than triple the amount of the value of the illegally produced and sold drugs; and if the circumstances are serious, it shall be ordered to stop production, suspend business and rectify the situation, or to revoke the document certifying the approval of the drug, revoke the "Drug Production License", "Drug Operation License" or "Medical Institution License". Drug Business License" or "Medical Institution Preparation License"; constitutes a crime, shall be investigated for criminal responsibility. At the same time, engaged in the production and sale of counterfeit drugs and the production and sale of substandard drugs in serious cases of enterprises or other units, their directly responsible for the supervisors and other personnel directly responsible for ten years shall not engage in the production and operation of pharmaceutical activities.
Why the batch issue is still unqualified vaccines
According to the Food and Drug Administration 22 informed that Changsheng Biological has been listed on the sales of products have been statutory inspection, no quality problems have been found, in order to further confirm the validity of the vaccine has been marketed, the State Food and Drug Administration has been initiated on the enterprise retained a sample of the product sampling for laboratory evaluation.
Changsheng Biological 22 announcement also said: the company has been listed on all human rabies vaccine products have been self-tested, the quality in line with national registration standards. In accordance with the provisions of the Administrative Measures for the Wholesale and Issue of Biological Products, the company's products will be marketed only after obtaining the Certificate of Wholesale and Issue of Biological Products issued by the China Academy of Food and Drug Control.
What does it mean?
About the current batch-issuance system for vaccines and blood products in China. Specifically, in accordance with China's Drug Administration Law and other laws and regulations, vaccine manufacturers must carry out a full program of tests on the safety and effectiveness of each batch of listed vaccines. After passing the self-inspection, the enterprise puts forward the application for vaccine batch issuance, the provincial drug administration will go to the pharmaceutical factory within five working days to organize the sampling, the samples will be sealed, and then sent to the CIQ or other authorized to carry out the batch issuance of the provincial drug inspection agency.
On May 24 this year, the Economic Observer reporter interviewed the China Food and Drug Testing and Research Institute (CFDRI) and learned that, for enterprises to send samples for testing, the staff of the Inspection and Quarantine Acceptance Hall of CFDRI will open the boxes on the spot to check whether the information and samples are complete and whether the vaccine samples are transported with a cold-chain transport during transportation, and so on. Accepted samples will be sent to the main part of the main inspection department for the relevant projects, the other part of the samples will be retained in a special low-temperature sample library, in order to be prepared for the future discovery of vaccines in the event of a quality problem to review the use of.
So why is it that every batch of the vaccine will still have unqualified potency?
A spokesman for the Food and Drug Administration said in a previous briefing on the disposition of products with unqualified validity indicators of the DPT vaccine that the China National Institute of Veterinary Inspection (CNIVI) had applied for the batch of vaccines for issue, and carried out batch-by-batch testing of safety indicators, and randomly selected 5% of the validity indicators of the validity of the vaccine in accordance with the internationally accepted practice for testing. After checking the records of the batch issue, the safety index of the 2 batches of vaccines meets the standard, and the validity index is not within the scope of sampling and testing.
The spokesman suggested that the failure of the validity index of the two batches of DPT vaccine may affect the effect of immune protection, but has no effect on human safety.
It is worth noting that biological products that do not pass batch approval will not enter the market and will be destroyed directly, while biological products with a previous "record" will be treated more strictly. According to the "Administrative Measures for Batch Issuance of Biological Products," China will carry out all the tests in accordance with the registration standards for biological products that have been ordered to stop production in violation of relevant laws and regulations and then resumed production after approval, and will carry out some of the tests only after at least three consecutive batches of the products have passed the batch-issuance test.
The quality of domestically produced vaccines should not be demonized
The fermentation of the Changsheng Bio vaccine has given rise to many problems, such as "turning over the vaccine book" has become a hot word in microblogging. Some consumers called 12331 to ask if they could check the specific batch number of the domestic rabies vaccine they received three years ago, as well as worrying about whether they would develop a disease in the future. Concerns about the quality of Changsheng Bio's products are rising into questions about domestic vaccines as a whole.
Is the quality of domestic vaccines really bad?
The Economic Observer reporter previously learned in an interview with the China Academy of Food and Drug Certification that China is one of the few countries in the world that can rely on its own ability to solve all the planned immunization vaccines, and domestically produced vaccines account for about 95% of the country's actual vaccination, and at present there are 45 vaccine manufacturers in the country***, which can produce 63 kinds of vaccines to prevent 34 kinds of infectious diseases, with an annual production capacity of more than 1 billion doses.
Vaccines marketed in China, whether domestic or imported, must undergo rigorous pre-market clinical studies in strict accordance with the requirements of the State Drug Administration (SDA) before they can be approved for marketing. Corporate production must also all meet Good Manufacturing Practice (GMP) requirements.
In 2017, China*** issued about 712 million doses of vaccines, 20 varieties of Class I vaccines were issued and marketed, totaling about 561 million doses, accounting for 78.79% of the listed vaccines; 34 varieties of Class II vaccines were issued and marketed, totaling about 151 million doses (recombinant hepatitis B vaccine, hepatitis A inactivated vaccine, and other Class I and II vaccines were available, so the varieties were double (recombinant hepatitis B vaccine, inactivated hepatitis A vaccine and other categories of both, so the varieties are double-counted); by place of production, of which domestic vaccines amounted to about 694 million doses, and imported vaccines were only 0.18 billion.
Shen Qi, director of the Institute of Biological Products Inspection and Certification of the CIQ, said that China has already established a regulatory system covering the whole life cycle of vaccine "research and development-production-circulation-inoculation", and has a relatively complete vaccine regulatory system, regulatory system and standards management. China has established a regulatory system covering the whole life cycle of vaccines, including R&D, production, circulation and vaccination, and has a relatively complete vaccine regulatory system, regulatory system and standard management, a scientific and rigorous vaccine registration and approval system, and the implementation of Good Manufacturing Practices (GMP) and Strict Good Manufacturing Practices (GMP), which are in line with the international advanced level. All listed vaccines have been subject to national batch-issuance management, and a monitoring and reporting system for abnormal reactions to vaccination has been established.
Official data show that it has been 40 years since China responded to a request from the World Health Organization in 1978 to implement immunization programs worldwide. Over the past 40 years, vaccine-preventable diseases have fallen to historically low levels across the country, and the country has relied on domestically produced vaccines to build an immunization barrier and effectively control the spread of vaccine-preventable diseases.
In 2000, China passed the confirmation of being polio-free; after the promotion of neonatal hepatitis B vaccination, the surface antigen carrier rate of hepatitis B virus in children less than 5 years old dropped from 9.67% in 1992 to 0.32% in 2014, and the number of hepatitis B surface antigen carriers dropped by 97% compared with 1992; the number of measles cases in 2017 was less than 6,000 cases, with the highest number of cases in the highest year ( 1959) was over 9 million cases; diphtheria had no reported cases after 2006, and the highest year (1960) was over 150,000 cases; less than 200 cases of rheumatoid encephalitis were reported in 2017, and the highest year (1967) had reported 3.04 million cases; only 1,000 cases of BSE were reported in 2017, and the highest year (1971) had reported nearly 200,000 cases of BSE; and in 2017 10,000 cases of whooping cough were reported, with the highest year (1973) being more than 2.2 million cases.
In terms of international recognition, the WHO has conducted two in-depth independent assessments of China's vaccine production regulation in the past six years, and both assessments showed that China's regulatory system meets WHO standards.
In 2013, the live attenuated encephalitis B vaccine from Chengdu, a subsidiary of China Biologicals, became the first Chinese vaccine to pass WHO pre-certification, followed by the influenza vaccine produced by Hualan Biologicals, the inactivated hepatitis A vaccine produced by Beijing Kexing Bioproducts Co Ltd, and the oral bivalent live attenuated polio vaccine produced by China Biologicals North Biologicals & Research Co Ltd, which also passed WHO pre-certification and were listed on the WHO's list, respectively, in 2015 and 2017. WHO pre-certification, listed in the WHO pre-certified products list, become the governments and international organizations to carry out the relevant procurement, used for reference, an important indicator to guide decision-making.
Pharmaceutical industry sources believe that the quality of many enterprise products has been close to or reached international standards, for individual enterprises should not rise to the illegal behavior of the entire domestic vaccine demonization. The ability to detect the production of fake products behind the inspection of qualified products, on the other hand, shows that the sensitivity of the regulatory system in the enhancement.