Suggestions on the verification and management of pharmaceutical production process of CFDA

Recently, I saw the general office of the General Administration of food and Drug Administration solicit the opinions of the announcement on the implementation of the verification of drug production process (Draft for comments), and I also saw many articles in this regard Based on many years of drug production quality management practice, and from the understanding of the drug management law, I would like to briefly talk about the views of the verification management of drug production process of the General Administration of food and drug administration 1、 Article 10 of the Drug Administration Law: in addition to the processing of Chinese herbal pieces, drugs must be produced in accordance with the national drug standards and the production process approved by the drug regulatory department under the State Council, and the production records must be complete and accurate Where a pharmaceutical manufacturing enterprise changes a production process that affects the quality of a drug, it must report to the original approving department for examination and approval Chinese herbal pieces must be processed in accordance with the national drug standards; if there are no provisions in the national drug standards, they must be processed in accordance with the processing standards formulated by the drug regulatory department of the people's Government of the province, autonomous region or municipality directly under the central government The processing specifications formulated by the pharmaceutical supervisory and administrative departments of the people's governments of provinces, autonomous regions and municipalities directly under the central government shall be reported to the pharmaceutical supervisory and administrative department of the State Council for the record How to correctly understand the "provisions on the production of drugs in accordance with drug standards and approved production processes" in this article? The first paragraph of this article stipulates the basic requirements for the production of drugs other than the processing of Chinese herbal pieces, including: 1 Drugs must be produced in accordance with the national drug standards In accordance with the provisions of Article 32 of the drug administration law, the Pharmacopoeia of the people's Republic of China and drug standards promulgated by the drug regulatory department under the State Council are national drug standards National drug standards are the technical regulations of the state on drug quality specifications and inspection methods, and are the legal basis for drug production, supply, use, inspection and management departments to follow As drugs are special commodities related to human health and personal safety, drug standards are mandatory standards that must be implemented According to the provisions of this article, except for the processing of Chinese herbal pieces, the production of all drugs must comply with the approved national standards 2 Drugs must be produced in accordance with the production process approved by the drug regulatory department under the State Council The "production process" mentioned here refers to the basic production process of drugs which directly affects the quality of drug production and is approved by the drug regulatory department under the State Council at the time of drug approval It does not refer to all process operation details of drug production Because the production process of drugs, like that of other products, includes not only the basic process, but also the specific requirements of production operations It is required that every small operating procedure should be approved by the drug regulatory department of the State Council, which is not necessary and difficult to achieve in practice Whether the production of drugs conforms to the basic production process approved by the drug regulatory department under the State Council is directly related to the quality of drugs Drug manufacturing enterprises must carry out production according to the production process approved in accordance with the law, and shall not change without authorization When a drug manufacturing enterprise changes the production process that may affect the quality of drugs, it must report to the original approval department for examination and approval in accordance with the provisions of the drug administration law On the premise of conforming to the approved basic production process and according to the specific production technology characteristics of the enterprise, any pharmaceutical manufacturer that adopts or changes the auxiliary production process that is helpful to ensure the quality of pharmaceutical production and improve the production efficiency does not need to report to the pharmaceutical supervision and Administration Department of the state Council for approval, but the enterprise shall make relevant changes and confirmation, if necessary Carry out process validation to check whether it has impact on product quality 3 The production records of drugs must be complete and accurate Drug production record is the basic data of drug production management The establishment of complete and accurate drug production records can truly reflect the actual situation of the whole process of drug production, which is conducive to strengthening the control of drug production quality by the enterprise, as well as the supervision of drug supervision and administration departments on drug production quality; in case of drug quality disputes, it can also provide evidence for handling the disputes Therefore, the drug administration law clearly stipulates that drug manufacturers must have accurate and complete drug production records According to the provisions of the drug production quality management standard (revised in 2010), drug manufacturers must establish batch production records and batch inspection records of drugs in accordance with the provisions, and make specific provisions on the basic contents that should be stated in the records This requires drug manufacturers to establish and fill in drug production records in accordance with the provisions of the drug administration law and the drug production quality management standard (revised in 2010), and strictly implement them The second paragraph of this article makes special provisions on the processing standards of Chinese herbal pieces The so-called decoction pieces of traditional Chinese medicine refer to the finished products processed by special processing of traditional Chinese medicine under the guidance of the theory of traditional Chinese medicine, according to the needs of syndrome differentiation and treatment, adjustment and preparation of traditional Chinese medicine Chinese herbal pieces are also the raw materials of many Chinese patent medicines Because of the different requirements of Chinese patent medicine and TCM syndrome differentiation, the processing of Chinese herbal pieces is quite special At present, if all the processing standards are formulated by the state, the conditions are not yet available and do not conform to the actual situation Corresponding management measures shall be taken according to the specific conditions of each traditional Chinese medicine variety For the varieties of traditional Chinese medicine pieces with mature conditions that can be standardized by the state Where the State formulates the standards for the processing of Chinese herbal pieces, the drug regulatory department under the State Council, together with the Chinese herbal medicine regulatory department under the State Council, shall incorporate them into the catalogue of varieties under the administration of approval number in accordance with the provisions of Article 31 of the drug administration law Meanwhile, the State Drug Standards shall be promulgated For Chinese herbal pieces with existing national standards, the processing shall be in accordance with the national drug standards For other varieties of Chinese herbal pieces that do not have national standards, the pharmaceutical supervisory and administrative departments of the people's governments of provinces, autonomous regions and municipalities directly under the central government shall formulate processing specifications, and the production enterprises of Chinese herbal pieces shall organize production in accordance with the relevant processing specifications of each region The processing specifications formulated by the pharmaceutical supervisory and administrative departments of the people's governments of provinces, autonomous regions and municipalities directly under the central government shall be reported to the pharmaceutical supervisory and administrative department of the State Council for the record, so as to facilitate the pharmaceutical supervisory and administrative department of the State Council to fully grasp the processing and specifications of Chinese herbal pieces throughout the country 2、 The historical evolution of the production process of Chinese pharmaceutical manufacturers China's management and specification of drug manufacturing enterprises are changing with the improvement of standards, GMP certification and social progress! 1 There are generally two types of product approval number obtained by enterprises One is the past imitation The process is relatively simple when submitting for approval, and the detection standard is relatively low The year of submitting for approval is also earlier The most original data of many enterprises can not be found at present The other is to obtain approval through the application of new drugs The level of technological research is inconsistent, with high and low level, small-scale test, medium-sized test and large-scale production, and the technological level is also unequal Some of the raw material production process or cost or new requirements of safety and environmental protection have changed, resulting in passive changes in the enterprise In 2007, the production process and prescription verification organized by the State Bureau and provincial bureaus all over the country, most of the enterprises improved under the new environment of standard improvement and GMP 2 Four major factors change, enterprises improve technology! (1) Standard improvement! China's drug quality standards are constantly improving! From local standards to ministerial standards to Chinese Pharmacopoeia, from trial standards to formal standards The progress of quality inspection level and advanced testing instruments also promotes the improvement of quality standards However, the improvement of quality standards has a direct impact on whether the enterprise can produce qualified products and products that meet the quality standards If the original process cannot produce qualified products, it will inevitably promote the enterprise to continuously optimize the production process to meet the requirements of product quality standards, and the result can only be forced to adjust the process! (2) GMP requirements are improved! The requirements of the new GMP for plant facilities and equipment have been greatly improved In the past, the equipment used in many processes has not met the requirements of the new GMP, and has been eliminated in the new round of plant construction and transformation On the other hand, according to the requirements of environmental protection and safety, the production environment has changed, some engineering media have changed, and the production process has to be changed! (3) Accessories progress! In the past, most of the excipients used by enterprises were edible, which was safe With the progress of excipients production technology, the state has standardized the pharmaceutical excipients Because there are many kinds of pharmaceutical excipients, some of which are not included in the national pharmaceutical excipients, the pharmaceutical production should use excipients that meet the pharmaceutical standards At the same time, with the research and development of excipients, new excipients with better performance should be used Gradually, new and better excipients have been introduced into drug production These changes make the drug production process constantly change with the progress of laws and regulations and technology! (4) Equipment progress! The progress of pharmaceutical manufacturing cannot be separated from the development and progress of pharmaceutical machinery The implementation of the new GMP promotes the rapid development of the pharmaceutical machinery industry in China The new GMP concept is applied to pharmaceutical machinery manufacturing, and the production equipment is more advanced In the GMP transformation of enterprises, the vast majority of enterprises have adopted the equipment of domestic first-line and second-line brands, and even introduced some international advanced production equipment, these high-performance equipment To produce qualified and high-quality products is a challenge to the original process In order to apply advanced production equipment, the process is changing! 3、 How to implement Article 10 of the law of the people's Republic of China on the administration of reference drugs to manage the production process, so as to achieve the interaction between the regulatory authorities and the production enterprises! In order to produce qualified and high-quality products, a process research department is set up in the enterprise The technology management department constantly optimizes and improves the production process to ensure the continuous stability, safety and effectiveness of product quality! Drug regulatory departments at all levels, in order to prevent safety problems of enterprise products, have set up relevant functional departments to manage the production process, and have a series of comprehensive rules and regulations! At present, many of the flight inspection results reported by the State Bureau or provincial bureaus are "enterprises change technology without authorization!" In fact, the vast majority of enterprises do not report after the change of production process or because of policy factors, or even dare not report, there are subjective and objective conditions! So how to solve this dilemma, I have three suggestions 1 The idea of process management is changed from registration system to record system The actual process of all products produced by the enterprise shall be reported to the provincial drug regulatory department The enterprise shall be responsible for the product quality and the authenticity of the process! For filing process, signature of enterprise legal person, person in charge of production and person in charge of quality! The enterprise is responsible for the consistency of production process, and the drug supervision department is responsible for the management! 2 The pharmaceutical supervision and administration department has changed the registration system from the filing system to the registration system for the excipients used in the process that are not listed in the catalog of pharmaceutical excipients in China, and there are no relevant pharmaceutical standards, and the solvent medium is not traditional! In order to promote the continuous improvement of quality standards and production process of pharmaceutical excipients 3 Pay attention to scientific and technological innovation, protect the intellectual property rights of the enterprise, and control the filing process or registered process content with the core points For example, the preparation product should include raw materials, auxiliary materials, and the total proportion of auxiliary materials, main process of the process, etc.; the raw materials should include raw materials, auxiliary materials, solvents, main process of the process, etc., so as to relax the innovation space of the enterprise and constantly optimize its production process! At the same time, consider the intellectual property rights of the enterprise, such as the proportion of auxiliary materials used in the process, temperature and other technical parameters without filing requirements, so as to reduce the concerns of the enterprise! The enterprise is the main body of the market, responsible for the product quality and consumers of the enterprise, supervision department