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Meaning of Toxicology Standards

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Medicines are the crystallization of important weapons for mankind to protect itself against the outside world; in its research process, many disciplines and systems engineering are refined. There are many pharmacological accidents caused by drug safety issues in history, and they also gave birth to many evaluation systems. Today we are going to talk about this topic ~ GLP, which is an important evaluation system spawned by this process, and has now become an important preclinical quality evaluation system for drugs.

1 GLP/Introduction

Good Laboratory Practice (GLP) is to ensure the high quality, truthfulness, completeness and reliability of the safety test data of new drug pre-clinical research and is aimed at the basic requirements formulated by non-clinical safety evaluation research institutions of drugs; Standardize the standardization, science and repeatability of non-clinical safety research of new drugs.

The preclinical safety evaluation of a new drug plays a pivotal role in whether the new drug can enter clinical research, predict the risk level of clinical research, and finally evaluate its development value. A high-quality safety evaluation must follow GLP, which is already in charge of various countries. The consensus of the department and the new drug research unit.

The implementation of GLP aims to standardize the entire process of drug safety research, including trial design, administration, observation, testing, recording, reporting, etc., to ensure that the test results can objectively, truthfully and comprehensively reflect the safety characteristics of the test substance. The test data generated on the basis of lack of science and standardization will directly affect the reviewer’s analysis, judgment and comprehensive evaluation. In this case, there will be many problems in the technical review of drug safety. It will affect the scientific nature of the evaluation; in other words, only when technical reviewers are faced with standardized, true and complete research data, can they eliminate many interfering factors or uncertain factors in the review process and focus on the main issues or deeper levels Problems, so as to make a more scientific and reasonable evaluation of the review object, and ultimately ensure the safety, effectiveness and quality controllability of the drug.

The quality structure of the GLP laboratory

2 “Thylan” promotes the rapid development of GLP!

In the history of the development of drug toxicology, the tragedy of “Thalidomide” is undoubtedly an important event that prompted humans to reflect on the safety evaluation of drugs…

In 1959, West German pediatrician Weidenbaeh first reported a rare deformity of a girl baby. This deformed baby did not have arms, legs, hands and feet directly connected to the body, much like the limbs of a seal, so it was called “seal limb deformity.” And “seal tires.” Medical research has shown that the cause of “seal fetus” is caused by women taking “thalidomide” (thalidomide) in the early pregnancy. It was first synthesized by a pharmaceutical company in West Germany in 1953. It is used to treat morning sickness during early pregnancy and has a good antiemetic effect. It has no obvious toxic side effects on pregnant women. It has been approved for sale in 51 countries.

From the entry of thalidomide into the market in 1956 to the withdrawal of the drug in 1962, more than 10,000 cases of “seal fetus” have been reported in more than 30 countries and regions around the world. The incidence of deformities in each country is positively correlated with the sales volume of thalidomide in the same period. For example, at least 6000 cases of teratogenicity were caused in West Germany, 5,500 such teratogenic cases were born in Britain, and about 1,000 cases in Japan. Thalidomide was the first drug to be clearly identified as human teratogenic. Since then, large-scale teratogenic studies have been conducted around the world. As a result, many drugs have been found to have varying degrees of teratogenic effects.

In fact, drug teratogenic experiments are not very complicated experimental methods. Such experiments can be carried out under the medical conditions at the time. Only the United States has not introduced such drugs due to the official cautious attitude. Therefore, except for bringing them from abroad Human users have caused several cases of teratogenicity, and almost no such cases have occurred.

A seal deformity in the UK and her father
A seal deformity in the UK and her father  (Image source: doi:10.3866/PKU.DXHX201904021)

3 U.S. FDA launches GLP and roll out in major countries around the world

After the thalidomide incident: In the 1970s, when the US FDA staff reviewed the safety research report submitted by a large pharmaceutical company to support two new drug applications, they found that the data in the report was inconsistent and there were experimental cheating. Signs, so the FDA has strong doubts about the reliability of the safety research reports of the products under its jurisdiction, and launched an investigation into national research institutions. The survey results show that although there are also cases of deliberately concealing experimental conclusions that are unfavorable to the product, a more serious problem that exists widely in various enterprises, research institutions, and schools is the flaws in the design, conduct and reporting of safety experiments. The credibility of the report is seriously reduced.

FDA Adverse Events ~ The main investigator assesses the reporting requirements to the Institutional Review Board (IRB)
FDA Adverse Events ~ The main investigator assesses the reporting requirements to the Institutional Review Board (IRB)

In response to this type of situation, the FDA promulgated the GLP regulations in 1976, which stipulated that the non-clinical safety research data of drugs issued by laboratories that did not meet the GLP standards would not be recognized. This regulation marks the emergence of modern GLP. By strengthening the quality management of non-clinical safety research, it has greatly improved the safety evaluation quality of drugs before clinical trials. Driven by the United States, the United Kingdom, Japan, France, Sweden and other countries have successively released their own GLPs, and GLP has gradually become an internationally accepted norm to ensure the quality of drug non-clinical safety research.

FDA and clinical practice
FDA and clinical practice

After the U.S. began to test GLP regulations in 1976, the U.S. officially took effect in accordance with federal regulations in 1979; then, between 1979 and 1980, the European Community formulated a principled document on the implementation of GLP. In 1981, the Ministry of Health, Welfare and Welfare of Japan formulated the GLP specification, which came into effect; subsequent revisions and improvements were made. In 1983, the European Organization for International Economic Cooperation (OECD) began to implement GLP. Britain, Germany, France, the Netherlands, Italy, Switzerland, and South Korea have successively implemented their GLPs.

4 The development history of China GLP

Due to the late founding of the country and the special development path of the pharmaceutical industry, my country only began to draft GLP in 1991, which was promulgated by the former State Science and Technology Commission in 1993 and became effective in 1994.

After the institutional reform of the State Council in 1998, the State Food and Drug Administration (called “SFDA” at the time), based on the development of international GLP and the actual situation in my country, promulgated the “Non-clinical Drug Research Quality Management Standards”, which was implemented in 1999.
In 2007, SFDA stipulated that chemical raw materials and their preparations and biological products that were not marketed in the country, and the active ingredients, effective parts and their preparations extracted from plants, animals, minerals and other substances that were not marketed in China, The non-clinical safety evaluation research of new medicines such as the active ingredients extracted from natural medicines and their preparations and Chinese medicine injections must be carried out in laboratories that have passed GLP certification and meet GLP requirements. This marks the beginning of GLP trials in my country to the current mandatory implementation .

The operating cost of a GLP laboratory is several times higher than that of an ordinary laboratory of the same kind. The investment in GLP certification is also very large. According to the data about 15 years ago, it will cost at least 50 million to 60 million yuan to build a laboratory that fully complies with the GLP specifications. Knowing how much investment is needed to build a GLP laboratory today. But even so, my country has already built dozens of GLP laboratories that meet national requirements. The number and distribution are shown in the figure below.

The distribution of domestic GLP laboratories that meet the requirements

5 Summary

my country is the country that announced the implementation of GLP late in the world. Compared with the GLP of developed countries, the gap is obvious; but we should see that after hard work, the level of GLP in my country is continuously improving; the regularization of the implementation of domestic GLP has also helped Scientific and regulatory compliance of drug candidate evaluation.

But here, the author has to say that the compliance of GLP is not just a collection of documents, it must be scientific. Many so-called GLP researchers, in a sense, are just an operator, and their operations often lack logic and thinking. While adhering to compliance, people tend to be rigid, dogmatic, not thinking, and even blind to mistakes. When something goes wrong, they will only take the accounts they have done and throw away the pot. The management of the GLP organization is very important; the personnel of GLP have great responsibilities; only by truly upholding the concepts and requirements of GLP and effectively implementing them in the test evaluation, will they truly maintain the original intention of GLP and truly be worthy of the new drug discovery process. Sweat!

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