Fang Hanmin believes that drugs are special products that treat diseases and save lives, and there is no room for negligence. No matter how high the price is, the various ingredients in them must be understood.
First of all, once the composition of this impurity is known, it can be determined how it was generated during the synthesis reaction. By changing the process conditions, the generation of this impurity can be minimized or eliminated, which will help further improve product quality.
In addition, after the drug is successfully developed, it needs to be registered with the regulatory authorities. At that time, the analysis and test results of the drug must be presented to the regulatory agency. Because it involves the evaluation of toxic and side effects, each ingredient, including impurities, must be clearly identified. Determined, otherwise, the regulatory authorities will not grant registration approval.
Fang Hanmin explained the reasons for the failure to colleagues in the generic drug research team and analytical testing institutions. He asked Wang Gong to contact relevant domestic institutions as soon as possible to conduct qualitative analysis of the impurities in the samples as soon as possible.
After consulting his university teachers, Wang Gong quickly contacted a top scientific research institution. After explaining his intentions on the phone, the other party said that they could conduct qualitative analysis of their samples, but the fee was relatively high. In addition, it is required that the content of the substance to be qualitatively detected in the sample shall not be less than 50%.
Fang Hanmin doesn't care about the charge, but the content of the unknown substance in the sample is only 1%, which is far from the requirements of the testing agency!
"Normally, the entrusting party only provides samples for inspection, and everything else is the entrusted party's business. How could they make such a request?" The time traveler has experienced similar incidents in scientific research work in his previous life, and is no stranger to the relevant procedures. Fang Hanmin didn't understand this.
"My teacher in college had a lot of dealings with this scientific research institution. According to his analysis, there are only five or six such instruments in the country. In recent years, domestic scientific research work has been unprecedentedly active, and there is a long queue of businesses that require qualitative analysis. In order to reduce the workload, the staff of the entrusted agency asked the entrusting party to concentrate the components that need to be characterized in the sample to more than 50%, so that they can improve the detection efficiency."
"No, trace components can also be subjected to qualitative analysis!"
"Yes, trace components can also be subjected to qualitative analysis, but the qualitative testing process is more cumbersome because the main components in the sample have a great interference with the test results. In order to get the correct conclusion, it is often necessary to test multiple times and repeat the test results. Compared."
Fang Hanmin nodded in agreement, "Asking the client to concentrate the tested components in the sample to more than 50% can greatly reduce interference and eliminate the need for multiple tests, thus saving a lot of time in analysis and comparison. It can indeed reduce the workload. This is a good idea. .”
"The problem is to concentrate the unknown substance content in the sample from 1% to more than 50%. This task is not easy!" Guo Peng stood aside and shook his head.
After a brief silence, Fang Hanmin said helplessly: "The difficulties are not small, but if people have such requirements, we have to comply with them."
Fang Hanmin certainly knew the difficulty of this work. To concentrate the unknown substance content in the sample to more than 50%, the only methods were recrystallization and multiple extraction. The principles of the two methods are basically the same, but it is very difficult to find a suitable solvent. not easy.
After analyzing the characteristics of the two methods, Fang Hanmin believed that the recrystallization method was too cumbersome and required a lot of experiments to find a suitable solvent. Although the screening of extraction solvents is still a difficult task, the extraction method is relatively Simple and easy.
Theoretically, as long as a suitable solvent is found, all that is left is to repeat the extraction operation and then concentrate the extract. However, because the physical and chemical properties of unknown substances are not known, screening can only be carried out through trial and error, which is cumbersome and time-consuming.
After putting forward some guiding opinions and suggestions on specific operations, Fang Hanmin asked the analysis and testing agency to cooperate closely with the research team and seize the time to carry out the test. ...
After leaving the laboratory, Fang Hanmin saw Hou, the head of the personnel department, walking towards him in the corridor. Lao Hou was the middle-level leader Fang Hanmin first met. There was a special relationship between the two. Although Fang Hanmin has now become the head of Red Star Pharmaceutical Factory, he respects Lao Hou every time they meet.
"Chief Hou, where are you going?" Fang Hanmin greeted proactively and enthusiastically.
"Director Fang, I went to your office just now and saw that you were not there. I guess you are in the technical center. Do you have time now? I'm here to report to you."
"Oh, come in and talk." Fang Hanmin also had an office in the technology center, and he let Lao Hou into the room.
After closing the door, Section Chief Hou briefly reported to Fang Hanmin the statistical verification results of "young and promising" scientific and technological personnel, and handed several pages of forms bound together to Fang Hanmin, "Here is a brief introduction to the relevant personnel."
Fang Hanmin glanced through it briefly and felt quite satisfied, "The tasks assigned last week were completed so quickly. You guys are very efficient at work!"
"Red Star Pharmaceutical Factory has not officially allocated housing for more than 20 years. Regarding matters related to housing allocation, the staff in Corey are very resolute and rush to do it. Everyone hopes to finalize the plan as soon as possible."
"Are the situations reflected here true? Have you verified it carefully? Don't let those opportunistic people take advantage of the loopholes!" Fang Hanmin seemed very cautious in this matter.
In order to dispel Fang Hanmin's doubts, Section Chief Hou introduced the implementation process of this work in detail. After receiving the task, Lao Hou discussed the investigation plan with the technical section chief Wan Cheng. Wan Cheng was young and had little administrative experience and could not come up with a feasible method, but he was willing to listen to Lao Hou's opinions with an open mind.
Section Chief Hou believes that it is best to carry out this work separately. First, the technical department will issue a questionnaire to each grassroots team according to the spirit of the factory's instructions. The conditions for "young and promising" should be noted in the questionnaire. The employees You can compare it with your own situation. As long as you feel that you meet the conditions, you can apply for the "Young and Promising" Talents of Red Star Pharmaceutical Factory. However, you must explain your contribution in detail in the application form, and have the signatures of grassroots leaders and at least one colleague to vouch for it. .
The Technical Section is only responsible for issuing questionnaires and collecting declaration forms, and then forwarding the declaration forms to the Personnel Section for verification.
Based on the declaration form received, the staff of the Human Resources Department found the parties and witnesses and verified them one by one. If the situation was true, the parties were confirmed to be "young and promising" talents.
"Well, this is a good method! But during the verification process, did you find any fraudsters or opportunists?" Fang Hanmin was very satisfied with the work of the two departments.
"Not only are there, but there are several production teams at the grassroots level. For example, there is an employee named Lai Qingyuan in the second workshop. He also filled out the declaration form. We verified based on the content he filled in the form, and found that the grassroots leaders The signatures he signed with the witness were all fake, because the leader of the second workshop never signed for him at all, and the witness he filled in was not found in the second workshop!"
"Hahaha!" As soon as Section Chief Hou finished speaking, Fang Hanmin burst out laughing, "When you mentioned the name Lai Qingyuan, I thought that something would definitely happen, because I know this person too well! However, although the grassroots leaders The signatures and witnesses are fake, but are the contributions he said true? Although I have a bad impression of him, I can't bury his contributions."
Lao Hou waved his hand, "What a contribution! What he said is completely false. The two leaders of the second workshop and his team leader have never heard of it!"
"Did you see? This trick of yours is very effective. It completely eliminates those speculators who commit fraud. However, in order to make this matter more fair, just, open and transparent, I suggest that this list be publicized throughout the factory. If If there are no objections within a week, it will be considered passed.”
Lao Hou felt that the personnel department had done enough serious verification, but he did not expect that Fang Hanmin's requirements would be even stricter. "Okay, I will print this list and send it to every grassroots team to see if there are any different opinions."
...
Although the generic drug research team started trials, there was no progress in several trials. The scientific and technical personnel of the research team were helpless. Fang Hanmin also felt incredible, "None of the five extraction agents that have been used is effective?"
The twists and turns of the test process made Guo Peng and other scientific and technical personnel feel dejected. "I have used several extraction agents and the results are similar. What else can be done next?"
Fang Hanmin read the test records, thought for a while, and then said: "Alcohol solvents are not very effective. You can try ethers, lipids and nitrogen-containing solvents, because what is to be extracted is an unknown substance that can only be extracted through many solvents." Only after several experiments can we find a suitable extraction agent, everyone must be patient and don’t be discouraged.”
Following Fang Hanmin's ideas, the research team conducted more than twenty experiments and finally found a lipid solvent that has a very good extraction effect on unknown substances.
This result encouraged the staff of the research team. They worked hard and quickly concentrated the unknown content in the sample to more than 50% using this extraction agent.
The staff sent the samples that met the requirements to the authoritative identification agency. A week later, the qualitative analysis results came. It turned out that the unknown substance was an aromatic nitrogen-containing organic substance. Judging from the molecular structure, the substance was indeed a synthesis reaction. generated during the process.
After checking the toxicity data, Fang Hanmin was shocked, "Fortunately, we found out in time that if the current sample of the original drug is submitted to the regulatory authorities for filing, once it is approved and put on the market, the toxicity of this substance will affect people who take the drug. Patients cause great harm!”
Knowing the molecular structure of this impurity, we can judge its source. Fang Hanmin, together with Guo Peng and other scientific and technical personnel, searched for the cause from the reaction mechanism, improved the synthesis process, and minimized its production amount, while looking for ways to eliminate the impurity and remove it. The content in the original drug is reduced to a minimum.
After several explorations, it was finally discovered that the raw material ratio and synthesis reaction time are two key factors that affect the generation of impurities. In subsequent experiments, the optimal material ratio was first determined. Under these conditions, as long as the synthesis reaction time is controlled within six hours, the formation of toxic impurities will not be detected. Once it exceeds six hours, such impurities will gradually increase. .
"It's easy now. By controlling the synthesis reaction time within six hours, toxic impurities are completely eliminated." Guo Peng seemed very happy.
Fang Hanmin reminded: "You have ignored the fact that when the synthesis reaction time does not exceed six hours, the conversion rate of the main raw materials is only about 45%, not even 50%, which will hinder the subsequent separation. Purification brings great trouble!”
"Although the conversion rate of raw materials is relatively low, the unconverted raw materials can be recycled without causing waste. I think as long as the generation of toxic impurities can be eliminated, the process is reasonable."
Fang Hanmin disagrees with this view, "You have to remember that what we do is applied research, which has a different purpose from basic research. Applied research must emphasize both purpose and practicality, and neither can be neglected."
