The most stringent generic drug evaluation system in the world -- requirements of Japan Drug Administration (Ⅰ)

This paper is compiled by Mr Xie Mufeng of Shanghai food and Drug Inspection Institute Due to its long length, it will be pushed continuously for three days This is the first part     The article "because Japan implements the strictest generic evaluation system in the world, the quality of approved generic drugs in China is no different from that of the original drugs" published by Mr Qingliu in September 2003 aims to introduce "the strictest generic evaluation system in the world is in Japan, not in the United States", and to appeal to the industry not to give up its attention to Japan There are still many practices that we can learn from in different countries For example, there are a lot of valuable documents on the website of the Japanese drug review center (PMDA) If you miss this "scenery", you will regret it ——Xie Mufeng Title: as Japan implements the strictest generic drug evaluation system in the world, the quality of generic drugs approved by us has no difference from the original drugs Author: Qing Liu, chief of the first office of the Ministry of medicine, National Institute of pharmaceutical and food health Brief introduction of the author: one of the authors of the current edition of the guiding principles for bioequivalence test of generic drugs; the first office of the Ministry of drugs is the Department that studies the quality evaluation system of preparations and scientifically formulates the quality standards of preparations [interpretation] the highlight of the Japanese version of the guidelines for bioequivalence test of generic drugs is "how to measure multiple characteristic dissolution curves of the original research preparation", which is also the unique content in the world so far After returning to China in February 2004, after more than two years of translation, I completed more than 70000 words of translation, which was first published in the "dingxiangyuan dissolution column" founded in 2009, and delivered to "national drug review center" and "China National Institute of inspection quality and efficacy consistency evaluation office of generic drugs" in 2010 and 2012, respectively I am very pleased to learn and apply them Since 1960s, Europe and the United States began to pay attention to the differences in clinical efficacy between generic drugs and original research drugs; unlike Japan, its medical and drug management systems are separate, so the medical system has higher expectations for generic drugs and hopes that the quality can be consistent with the original research drugs In order to avoid problems, Europe and the United States have established a method for the detection of blood drug concentration However, due to the low sensitivity of analytical instruments at that time, the test results were not very reliable, so it can be said that the research at that time did not make a breakthrough, or even some of it was just a formality It was not until the appearance and popularization of liquid chromatograph that the determination of blood drug concentration could be carried out accurately to a certain extent, so that people began to explore whether the quality of generic drugs was consistent with the original drugs from a scientific point of view   At that time, the situation in China was that the quality of generic drugs could not be approved because a complete drug evaluation system had not been established, and the concept of generic drugs was also very vague at that time, for example, the society expressed doubts about "some people said that there would be differences in the efficacy of drugs containing the same ingredients", because there was no objective data support and calculation formula to prove this Difference Since the concept of bioequivalence has not been established at that time, the standard to judge whether a drug is equivalent is that as long as it contains the same principal component of the same specification, the drug will play the same effect At that time, even the state could not come up with a specific detection method, so only enterprises were required to carry out a general study But all the drug regulatory bureaus in the world think of it in the same way, "what other requirements should be put forward?" Therefore, in the evaluation of generic drugs in China, enterprises are required to provide animal experimental data to prove the equivalence with the original drugs Although there is such a requirement, it is impossible to judge whether the data is accurate because there is no accurate detection method at that time Japan began to pay attention to equivalence since 1975, when it was learned that the United States began to conduct human be test Since animal experiments are still widely carried out in China, beagles are allowed to replace human body, even though the results are quite different from that of human Since then, there has been no progress in relevant research Until 1980, the Ministry of health and welfare suddenly made a decision that human body must be used as bioequivalence test object In retrospect, it's a long time ago So historically, 1980 was the first year of Japan's official implementation of human bioequivalence test Although there was a liquid chromatograph at that time, the sensitivity at that time was far lower than that at present, making the accurate determination still far away How to carry out bioequivalence test? First, collect the same drug of different brands, i.e from different sources (such as generic drugs and original research drugs), mark and mix them, and then let the subjects take blood samples respectively for verification At this time, there are two problems of "data fluctuation" and "poor absorption of drug itself" But the first research is basically good absorption of drugs (mostly bcs i), so the impact of data fluctuation is very small because of good absorption of drugs themselves The most ideal oral preparation is that the drug can be absorbed after being completely dissolved in the body, but it is difficult to achieve more than 80% absorption due to the different environment in the human body What problems have been found in the bioequivalence test? The biggest problem is the difference in bioavailability between the two If only from the data, the absorption rate of some products will even be close to 0, because the pH value when the preparation disintegrates is not considered Why pH? Because in Japan, there are many people with low gastric acid secretion and high gastric pH The latest research results show that: in China, with the increase of age, the proportion of people without gastric acid is increasing By the age of more than 50, there are nearly 60% of the population The fact that the absorption rate of some drugs is close to 0 will be revealed if the subjects without gastric acid are used in the bioequivalence test Pharmaceutical factories usually produce according to the quality standard of Japanese Pharmacopoeia For example, for sugar coated tablets and film coated tablets, only disintegration test and ph1.2 medium were specified at that time, and the products produced by the pharmaceutical factory will be completed as long as they are qualified under this condition In this way, the disintegration of these drugs in the normal gastric acid secretion, i.e low pH body is no problem, but it is not clear for the lack of gastric acid secretion, i.e high pH body Although 1.2 is the approximate value of human gastric environment, the actual situation is numerous As long as it is in line with the Japanese Pharmacopoeia, there is nothing wrong with the manufacturer's practice, but the objective fact that there are still many people without gastric acid is not taken into account However, no one has ever studied "the disintegration, dissolution, or absorption of drugs in people without gastric acid" [interpretation] it seems that Japanese pharmaceutical companies are also inert - only to meet national requirements In fact, this also reflects the essence of the pharmaceutical industry: an interdependent competition between referees (governments) and athletes (enterprises) To be honest, there was no cro company at that time (i.e an outsourcing company that called healthy young people as subjects to complete the full set of be tests), so all the research could only be completed in the laboratory If all the subjects can find young volunteers to take part in the experiment, it's natural However, due to the low budget of the experiment, they usually have to ask their colleagues in the laboratory to help them participate, which makes the age range of the subjects wider [interpretation] Japanese scholars can act as subjects for their colleagues' be experiments This dedication to scientific research is admirable! At that time, it was found that: the older subjects will have poor drug absorption What is the reason? After research, we found that it was due to the lack of gastric acid secretion Therefore, investigation of gastric acid secretion, i.e full range verification of pH value, can explain the above phenomena, but we are deeply surprised that "how far is the number of people without gastric acid beyond expectations" About Xie Mufeng From 1990 to 1995, he majored in five-year Japanese pharmacy; from 1995 to 1998, he majored in pharmaceutical analysis; since 1998, he has worked in Shanghai food and Drug Inspection Institute; from August 2003 to February 2004, he went to the Pharmaceutical Department of the National Institute of pharmaceutical and food health of housheng province (i.e the Japan Institute of Chinese Medicine) for further study and studied under the two core experts of the Japanese pharmaceutical quality re evaluation project, Mr Hiroshi Komatsu The division (then head of the drug department) and the teacher (then head of the first room) studied the project comprehensively and systematically Its core idea is "the failure rate of the bioequivalence (be) test will be extremely low after the dissolution is consistent", which is the "academic crystallization" obtained by a group of elite pharmaceutical experts who established a special dissolution test research group in 1993 and confirmed after several years of implementation and validation; since February 2004, it has been committed to the quality improvement of domestic generic drugs