The reform process of pharmaceutical excipients management and the analysis of the impact of the filing system on the pharmaceutical industry

Do you remember the "Qi Er Yao" incident in 2006? There are two kinds of excipients of "leucine a injection" produced by Qiqihar Second Pharmaceutical Co., Ltd., one is propylene glycol, the other is PEG400 Propylene glycol is often used as adjuvant in injection, PEG400 is less used Therefore, the incident initially focused on the toxicity of PEG400 But there is no evidence that PEG400 is toxic According to further analysis of infrared spectrometer, Guangdong Institute of drug control finally determined that there was a large amount of industrial diethylene glycol in liangjunjia injection produced by Qiqihar Second Pharmaceutical Co., Ltd., which resulted in the death of patients with acute renal failure Diethylene glycol is the main reason for the world famous "sulfanilamide elixir event" The frequent occurrence of "drug harm" has aroused the thinking of the domestic drug regulatory department So, what kind of supervision mode should be adopted for auxiliary materials? In China, the registration system is implemented for pharmaceutical excipients, which to a certain extent solves the requirements for technical confidentiality of excipients manufacturers and the need for registration of pharmaceutical enterprises However, the "Qi Er Yao" time exposed the shortcomings of the registration system: (1) the first factor for preparation enterprises to select accessories is whether there are registration approval documents, which makes preparation enterprises form "stereotyped thinking" and "inert thinking", thinking that accessories with approval documents are legal and qualified accessories, and on the premise of approval documents, supplier audit is ignored, and the pursuit of blindly reducing Profit; (2) the auxiliary material enterprises pay more attention to obtain more auxiliary material approval documents than to really study the characteristics of auxiliary materials To some extent, the registration system of excipients with approval as the first factor has affected the research and development of Chinese pharmaceutical preparations, so the reform of management system of excipients is of great significance The DMF model of the United States and the MF model of Japan have been running successfully for many years, which has certain reference significance Since 2008, China's drug regulatory authorities have begun to explore the reform of the management mode of pharmaceutical raw and auxiliary materials In 2010, the former State Food and Drug Administration drafted and formulated the regulations on the record management of pharmaceutical raw and auxiliary materials (Draft for comments), and again in 2011 for public comments In 2012, the relevant regulations on strengthening the supervision and management of pharmaceutical auxiliary materials were issued, which respectively clarified the work of pharmaceutical production enterprises, pharmaceutical auxiliary material production enterprises and pharmaceutical regulatory departments Responsibility Further clarify the regulatory model of pharmaceutical excipients, and also set up a working mechanism of information disclosure, extended supervision and the use of social resources to strengthen supervision, further strengthen the fight against illegal activities In the aspect of clarifying the responsibility of enterprises, we should focus on the implementation of the responsibility of enterprises as the main body of drug quality and safety It is pointed out that the manufacturer of pharmaceutical preparations is the person in charge of pharmaceutical quality For pharmaceutical preparation enterprises, we must strictly control the excipients used in pharmaceutical production It is required to audit the suppliers of auxiliary materials, accurately grasp the product information, and comprehensively understand the application of standards, including the quality management of auxiliary material production The purchased auxiliary materials must pass the standard inspection before they can be used in drug production In 2015, the State Council issued the opinions on the reform of the review and approval system for pharmaceutical and medical devices, which clearly defined the goal and direction of the reform of the management mode of pharmaceutical excipients at a higher level, and clearly pointed out that efforts should be made to simplify the drug approval process The independent Approval Mode of drug packaging materials and pharmaceutical excipients list was changed to be reviewed and approved together with the drug registration application In January 2016, in order to implement the opinions on the reform of the review and approval system for pharmaceutical and medical devices, the independent Approval Mode of packaging materials, containers and pharmaceutical excipients that directly contact with drugs was changed to the associated review and approval mode at the same time of drug registration application The General Administration of food and Drug Administration organized the drafting of the application data requirements for the associated review and approval of pharmaceutical packaging materials and pharmaceutical excipients (for consultation In May 2017, the General Administration of food and Drug Administration publicly solicited the relevant policies on encouraging the innovation of medical devices and accelerating the review and approval of new drug medical devices on the market (Draft for comments), clearly proposed: to formulate the measures for the record management of medical raw and auxiliary materials and packaging materials, and establish the record information of medical raw and auxiliary materials and packaging materials Platform, relevant enterprises shall submit the filing materials as required and be responsible for the authenticity of the filing information The drug evaluation institution shall review and approve the raw and auxiliary materials and packaging materials recorded on the information platform together with the drug registration application Pharmaceutical production enterprises shall be responsible for the quality of the selected raw and auxiliary materials and packaging materials Further clarify the main responsibility of drug manufacturers for drug quality In the related review, the manufacturer of pharmaceutical excipients shall record the relevant starting materials, production process research, application in preparation production, etc., so that the drug registration applicant can quickly transfer part of the data to improve the efficiency After the implementation of the related review and approval, the information provided by the auxiliary material enterprises is less, while the compatibility, pharmacology and toxicology research of the preparation and auxiliary materials are provided by the preparation enterprises This means that pharmaceutical companies can not only consider the cost in the future, and the selection of raw and auxiliary materials needs to be very rigorous It is necessary to investigate whether the production of raw and auxiliary material suppliers is standardized, whether the raw material sources of raw and auxiliary materials are guaranteed and standard, and whether the quality is stable, especially the work related to the consistency evaluation of generic drugs However, as the main body of responsibility, the quality audit of pharmaceutical enterprises will inevitably increase the management cost of pharmaceutical enterprises The audit scope of pharmaceutical enterprises includes not only the audit of the production qualification of pharmaceutical excipients, but also the audit of the upper and lower levels of distributors, agents, sub packers and other intermediate links in the supply chain, so as to ensure the quality of the whole production and circulation of excipients In addition, it is also necessary to require the excipients production enterprises to strictly implement GMP in production, so as to ensure that the industrial diethylene glycol is used in similar "Qi Er Yao" events The drug damage event that used propanediol as auxiliary material instead of medicine no longer occurred The state should also speed up the support of the third-party audit certification of pharmaceutical excipients to help the smooth implementation of the filing management of pharmaceutical excipients in China; promote local pharmaceutical enterprises to understand and accept the new mode of reducing the risk of drug supply chain and audit cost of enterprises; encourage pharmaceutical enterprises to adopt the third-party audit Certification Form for raw and auxiliary material suppliers to control the safety of supply chain And risk At the same time, drug manufacturers should be prevented from indirectly transferring the research work that should have been carried out by drug manufacturers to the suppliers of auxiliary materials, such as compatibility of preparations and auxiliary materials, pharmacological and toxicological research In addition, the domestic filing system should learn from the management experience of the United States and Japan For example, for generic drugs, the United States chooses "use precedent" to prove the safety and effectiveness of excipients and ensure the limit of excipients There is a large space for the development of pharmaceutical excipients in China Enterprises, governments and other social parties should seize the opportunity to promote the rapid and healthy development of pharmaceutical excipients industry Original statement: This article is the original manuscript of yaozhi.com, welcome to reprint, reprint please indicate the source and author, thank you!