There was no need to test at all. Judging only from the appearance and smell of the sample, the results were far from the expected results. Fang Hanmin decided to temporarily stop the test and find out the reason first.
Since the patent protection for generic drugs is about to expire and the patent details have long been made public, Fang Hanmin dug out the original text of the patent and read it carefully, and checked it one by one with the formulated test plan, and found no problems.
"Director Fang, is it possible that the original patent description was inaccurate and led to us being misled?" Guo Peng analyzed.
Fang Hanmin did not answer, but shook his head thoughtfully.
The time traveler was very familiar with the various synthesis processes of this calcium antagonist antihypertensive drug in his previous life. The process route selected for the imitation test is a classic preparation method for this drug, which has been fully verified in actual production and has been widely used.
"The inventor of this preparation method has applied for patents in many countries. I compared several major versions and the content is completely consistent. Therefore, there should be no problem with the patent description." Fang Hanmin said with certainty.
Guo Peng frowned and was helpless, "It seems that imitation is not simple. So, what is the problem?"
After pondering for a long time, Fang Hanmin turned to ask: "Do you have test data for all the raw materials used in the test?"
Guo Peng picked up two test reports and handed them to Fang Hanmin, "This is the quality test data of the two raw materials we developed ourselves." He opened the drawer and flipped through it. "There are also test results for several other purchased raw materials. This is the quality inspection report."
Fang Hanmin repeatedly checked the quality inspection data of each raw material, but he did not see any problems in the black and white letters of the report, which made him deeply confused.
With his head lowered and pacing back and forth in the laboratory, Fang Hanmin suddenly thought of a question. The original patent specification only indicated the amount of various raw materials added, but did not indicate the specifications, content and impurity control indicators of the raw materials. However, various kinds of ingredients used in the imitation test were not specified. Raw materials, quality indicators are available in three specifications: 96%, 97% and 98%.
Stopping, Fang Hanmin suddenly asked: "According to the test results, the content of the two raw materials developed by ourselves is only 96%. Can we improve the quality?"
"Director Fang, do you suspect that the quality of the raw materials is substandard?"
"When looking for the reason, we have to think of various possibilities. Of course, the quality of raw materials is one of the factors that is questionable."
"But...," Guo Peng hesitated, looking very embarrassed.
"If you have anything to say, you might as well say it directly, why are you hesitating?" Fang Hanmin looked at the other party in confusion.
"Director Fang, our research team is only responsible for the synthesis of the original drug, regardless of the quality of the raw materials!"
Fang Hanmin nodded in agreement, "You are right. Whether the quality of raw materials can be further improved is a matter for the raw material development research team. I have to discuss it with them."
The raw material development research group is now jointly supervised by Xu Hui, deputy director of the technology center, and Gong Jianchang, the team leader. When Fang Hanmin asked them to continue to improve the quality of raw materials, the two shook their heads in unison, "Director Fang, these two raw materials can achieve 96% The content is already very difficult, and it will be too difficult to improve the quality!”
"I know this. If it wasn't difficult, wouldn't it be that the content would have been over 99% long ago? But I want to remind everyone that our current job is in the technology center of Hongxing Pharmaceutical Factory! The mission of the technology center is to develop new products and new technologies New processes will inevitably encounter many technical problems in the process, and our task is to solve the technical problems!" Fang Hanmin did not give his subordinates any reason to retreat.
"But Director Fang, we have tried our best to reach this level. If you ask us to further increase the content, we really have no choice. We don't know where to work."
Fang Hanmin understands the personalities of Gong Jianchang and Xu Hui, and they will not back down if they can still come up with some solution. "Okay, I will work with everyone to find a solution, Jianchang, let me see the test records during this period."
From the end of last year to now, in less than three months, the technical staff and test workers of the raw material development research team worked day and night, and finally prepared samples of the two raw materials in advance, so that the generic drug trial could be carried out as planned.
However, from several large test records, Fang Hanmin found that many aspects of the test process were not precise and rigorous enough. "If the process conditions are further optimized, the sample content may be increased."
Gong Jianchang was the leader of the research project for the first time. His technical level and work ability were limited, and he lacked confidence in himself. He thought Fang Hanmin was blaming him for not doing the test well, so he hurriedly defended: "Director Fang, we strictly followed your rules. If you are testing the experimental plan, you don’t know what aspects should be optimized?”
The plan given by Fang Hanmin only provided directional guidance for the test process, without going into too many details. It ignored the fact that the research leader Gong Jianchang was inexperienced. This was due to his poor consideration. Of course, he did not mean to blame Gong Jianchang.
"It's not that you didn't strictly implement the test plan. It was precisely because you conducted the test according to the formulated plan that you successfully developed samples of the two raw materials in such a short period of time. However, to further improve the quality of the samples, the preparation process can only be improved. Optimize and work hard on details." Fang Hanmin didn't want Gong Jianchang to have any mental burden.
"To optimize the process conditions, what do we need to do next?"
Fang Hanmin thought for a while, "For example, we can analyze which process conditions can be improved to reduce the generation of by-products? In addition, we can also do some calculations to see if the current fractionation tower is high enough during the sample purification stage? Is it Can we increase the height of the tower to increase the sample content?"
Because he holds the two important positions of factory director and technical center director, Fang Hanmin cannot cover everything during the technology development process. He can only point out the general direction and let the technical personnel of the research team implement it.
Following Fang Hanmin's prompts, Gong Jianchang first increased the height of the fractionation tower in the next test. The obtained sample passed the test and its content indeed reached 97.5%.
Gong Jianchang told Fang Hanmin the news happily, but he seemed very calm, "One result can't explain anything. Let's continue the experiment and see how reproducible the results are."
In the following tests, Gong Jianchang's research team obtained almost consistent test results. Multiple batches of samples of the two raw materials developed reached a content of 97.5%.
Although this is exciting news, Fang Hanmin is not satisfied with this. He knows very well that as pharmaceutical raw materials, it is related to the efficacy and toxic and side effects of the drugs. No matter how high the quality requirements are, he is determined to develop the raw materials. While working on the preliminary work of the group, Fang Hanmin believes that they still have a lot of work to do.
"Director Fang, we have improved the fractionation tower and increased the sample content. What else do we need to do next?" Gong Jianchang looked worried.
"You should know that there are many factors that affect the content, and the height of the fractionation tower is only one of them. For example, I said before that optimizing the synthesis process can also reduce the generation of by-products. This factor is worthy of your careful study. .”
Although he was very reluctant in his heart, Gong Jianchang could not refuse Fang Hanmin's request, so he had no choice but to agree.
Returning to the research group, Gong Jianchang conveyed Fang Hanmin's instructions to the employees. As soon as he finished speaking, the people below started talking a lot. Not only the technicians thought that the next work was a bit redundant, but even the experimental workers felt that Fang Hanmin's quality requirements were too strict. Harsh.
Xu Hui has only recently joined the raw material development research group. Although he is the deputy director of the technology center, his task is to assist the research group in applying the laboratory's small-scale test results to industrial production. At this stage, he is very concerned about the work of the research group. He is still in the familiarization stage, so he generally does not express opinions on the affairs of the group.
Xu Hui had worked with Fang Hanmin for two or three years in the past few years. He not only learned advanced pharmaceutical technology knowledge and experimental skills from Fang Hanmin, but Fang Hanmin's rigorous and pragmatic scientific research spirit had a profound impact on him.
After listening to the discussions of the employees, Xu Hui felt that he needed to stand up and say something fair, "You may have misunderstood what Factory Director Fang meant. He just wanted to further increase the sample content by optimizing the process conditions, and did not deliberately embarrass everyone. I was also present when the next step of work was explained just now. Director Fang has already pointed out the general direction of the work. In the next test, we only need to try to change the test conditions based on the existing conditions until we get the best process conditions. "
After all, Xu Hui is the deputy director of the technology center. He strongly supports Fang Hanmin's decision. All employees of the raw material development research team, including Gong Jianchang, can't say anything more, at least on the surface.
After more than ten days of repeated experiments, it was finally discovered that allowing the synthesis reaction to be carried out in an inert solvent can suppress the occurrence of side reactions to the greatest extent. Not only does it maintain a high conversion rate of raw materials, but also the product has the least impurities, which can be separated by distillation. , the purity of the final sample is as high as 99%!
When reporting the results to Fang Hanmin, Gong Jianchang seemed to have some regrets, "Although the purity of the sample has been improved, the solvent must be recovered first, and the separation and purification process has been doubled. Is it worth it?"
"Of course it's worth it!" Fang Hanmin said without hesitation, "Why do many imported drugs have better efficacy than domestic drugs and lower side effects? One of the main reasons is that imported drugs have higher content of original drugs and fewer impurities. Control should start from the source, that is, the raw materials for synthetic drugs! Therefore, as long as the generation of impurities can be reduced, it is worthwhile even if the refining and separation process is prolonged!”
...
After improving the purity of the self-made raw materials, the research team led by Guo Peng started the generic drug test again. Fang Hanmin told them to strictly control the process conditions and pay attention to the abnormal phenomena that occurred during the test.
At around ten o'clock in the morning, Fang Hanmin had just returned to his office from the technical center laboratory. Deputy Director Liang, who was in charge of logistics, opened the door and handed Fang Hanmin a stack of manuscript papers in his hand, "Look at this, is it appropriate?" I will modify it if necessary."
Fang Hanmin looked at the other party inexplicably, "What is this?"
"You can take a look at my preliminary housing allocation plan."
"We've just started digging the foundation, right? The house won't be completed until the end of the year at the earliest. Isn't it too early to discuss the housing allocation plan now?"
"It's not early at all. Even though there is still more than half a year left, this housing allocation plan is not so easy to determine. After soliciting your opinion, I will also seek the opinions of other members of the team. Only after comprehensive consideration can it be submitted to the team meeting. The discussion was approved. After soliciting opinions back and forth, the draft will inevitably change several times. It will be good if it can be finalized in half a year!"
Fang Hanmin thought for a while and felt that what Lao Liang said made sense, "Let's put it here first. I'll take a look at it when I have time."
"Director Fang, you'd better take a look at it as soon as possible and put forward your opinions. After I modify it, I will let you review it."
On the surface, Lao Liang asked for opinions, but in fact he was dictating Fang Hanmin's work. These words made people feel very awkward.
