The production process verification is officially started. What about the inconsistency?

Source: e drug manager 2017-01-12 on January 10, 2017, the official website of the drug review center of the State Food and Drug Administration (hereinafter referred to as "CDE") issued a notice on Soliciting Opinions on the technical guidelines for research on production process change of listed chemicals (hereinafter referred to as "guidelines") In response, CDE said that in order to ensure the safety and effectiveness of public drug use, improve and standardize the management of drug production process, serve and guide the applicant to carry out the research on process change after the registration of chemical drug production process information, CDE has drafted the "guiding principles" and now solicits opinions from the public Feedback to CDE is required by February 28, 2017 This is the first "technical guidelines for production process change research" since the announcement on the implementation of drug production process check (for comments) was issued on August 9, 2016 (hereinafter referred to as "process check announcement"), which means that the drug production process check has entered the practical operation stage The previous process check announcement clearly stated that "if the pharmaceutical production process is consistent with the production process approved by the regulatory authority, it can continue to produce or import, and be filed with the local provincial regulatory authority"; if not, the relevant pharmaceutical manufacturers shall carry out sufficient research and verification in accordance with the relevant documents“ After research and verification, if the change of production process has an impact on the quality of drugs, the enterprise shall immediately stop production " Now, the production process check is officially started If it is inconsistent, what will happen? 1 how to conduct process change research? The guiding principle is mainly for the research and verification of the proposed production process change, and the main direction is that the change of production process may affect the safety, effectiveness and quality controllability of drugs The scope of coverage includes changes in the production process of chemical APIs and chemical preparations However, it is worth noting that the guiding principle only describes the relevant research and verification work to be carried out when the production process of the product is changed from a technical point of view, and does not involve specific punishment and other measures CDE divides changes into three categories in order to grasp the possible impact of changes on product safety, effectiveness and quality controllability: Category I changes are minor changes, which have little impact on product safety, effectiveness and quality controllability; category II Class III change belongs to moderate change, which shall be proved to have no impact on product safety, effectiveness and quality controllability through corresponding research work; class III change belongs to major change, which shall be proved to have no negative impact on product safety, effectiveness and quality controllability through a series of research work The guiding principle points out that the classification of change categories is to help drug manufacturers carry out targeted change research Since the guiding principles are aimed at listed chemicals, the research on change and change is based on the research and data accumulation in the previous drug registration stage and the actual production process In addition, if the conclusion obtained through other scientific research can prove that the change does not have a negative impact on the safety, effectiveness and quality controllability of drugs, CDE believes that it is not necessary to conduct the change research in full accordance with the requirements of the guiding principles on the basis of sufficient basis As for the basic principles of the research on the production process change of listed chemicals, we mainly adhere to the following: first, the drug manufacturing enterprises are the main body of the research on the production process change and the self-evaluation of the research results Drug manufacturing enterprises should have a comprehensive and accurate understanding of the R & D and production of the products and the nature of the products When considering the change of the production process of the products, drug manufacturing enterprises should be clear about the reasons for the change, the extent of the change and the impact on the products In addition to studying the product quality, stability and biology before and after the process change, the production enterprise also needs to pay attention to the comprehensive analysis of the research results, evaluate the impact of the change, whether it conforms to the current international standards, whether it is consistent with the quality of the original research product, and whether it is clinically equivalent The second is to comprehensively evaluate the impact of production process change on drug safety, effectiveness and quality controllability Due to the close relationship between drug development and production, the change of production process may have a comprehensive impact on the safety, effectiveness and quality controllability of drugs Therefore, CDE requires enterprises to further study and comprehensively evaluate the impact of production process change when they cannot accurately judge the impact of change on products It mainly evaluates any change in product chemistry, physics, microbiology, bioequivalence and stability In addition, it also evaluates the equivalence or equivalence between the product and the original research product after the process change It is required that the product after the process change should maintain the same quality and clinical equivalence with the original research product The selection principle of samples for the third research is that the samples of commercial scale shall be used for research and verification Specifically, the quality comparative study (such as dissolution and release comparative test) of the products after the change of production process and the changed products / original research products generally adopts the three batches of production scale samples before the change and the one to three batches of samples after the change The fourth is the research principle of association change CDE points out that a change of production process often does not occur independently, so the guiding principle calls other changes accompanying or caused by a change as related changes For related changes, the guiding principles require that the research work can be carried out in accordance with the basic ideas of each change in the guiding principles In fact, through the detailed analysis of the "guiding principles", this time we mainly start from the results, mainly to ensure the "safety, effectiveness and quality controllability" As a whole, it is the effect comparison before and after the change, and the comparison between the imitation and the original research From the results to be achieved, this process consistency involves the problem of "generic consistency", that is, it is required to be consistent with the original research in the process stage, if not, it is necessary to compare the results, that is, the consistency of generic drugs 2 what will happen if the process is inconsistent? The guiding principles are issued to coordinate with the verification of pharmaceutical production process, so that the verification of production process can be followed After the research, if the consistent requirements cannot be met, or if the "safety, effectiveness and quality controllability" are negative, will it be as stated in the announcement on the implementation of drug production process verification (for comments)? According to the process check announcement, if it is consistent, "the drug manufacturer shall complete the self check before October 1, 2016 and report the self check to the local provincial food and drug regulatory authority The provincial food and drug administration shall summarize the self inspection of the enterprise and report to CFDA before November 1, 2016 " If there is any inconsistency, "if the production process has an impact on the quality of drugs after research and verification, the enterprise shall immediately stop production." However, after the announcement stirred the industry like a gust of wind, the process check did not cause substantial problems for pharmaceutical enterprises However, this guiding principle is in line with "the enterprise shall complete the research and verification of product process, submit the supplementary application and other related work before June 30, 2017, and the process verification of other non production products shall be completed before December 31, 2017" in the "process verification announcement" If "not completed on time, production shall be stopped." In other words, process verification is entering a new stage However, how much influence does process check have on the enterprise? At this year's annual meeting of Chinese pharmaceutical entrepreneurs, Wu Zhen, deputy director of CFDA, said that the process self-examination being carried out "is to enable enterprises to fix their production processes, so that those who have changed their processes do not have risks." If there are risks, we have ways to prevent and correct them " For the process self inspection announcement that has been issued before, Wu Zhen said that CFDA does not need to change anything through process inspection, but needs to know clearly the reason and purpose of the enterprise's process change from the regulatory level, so as to achieve a targeted supervision Generally speaking, "process is a process of manufacturing products, which must be fixed and cannot be changed without authorization According to the law, if the change of process does not affect the quality, the enterprise can file; if it affects the quality, it can be submitted for approval according to the ordinary application."