1988: Back to the human world for a few years

Chapter 405: The article behind “Original Research Localization” (3)

When talking about "drug dissolution curve", we must first understand the concept of "dissolution".

Dissolution rate refers to the rate and extent of dissolution of active drugs from common preparations such as tablets, capsules or granules under specified conditions... In preparations such as sustained-release preparations, controlled-release preparations, enteric-coated preparations and transdermal patches, it is also called release rate.

The dissolution behavior of drugs in vitro can be used to predict the disintegration, dissolution and absorption in vivo; at the same time, the dissolution behavior of drugs in vitro can reflect the quality of the preparation to a certain extent;

Therefore, dissolution testing is the most useful method for monitoring dissolution behavior at different stages of the drug life cycle, and is even considered by the industry to be the only batch release test method that can monitor the rate and extent of in vitro drug release. This test is usually used to ensure the consistency of in vivo performance of surrogates. Therefore, it is widely used in drug development, stability studies, interchangeability evaluation, routine quality control, batch expansion and post-approval changes.
Moreover, the application scope of dissolution determination is very wide, and it is suitable for various dosage forms, such as tablets, capsules, transdermal preparations, oral suspensions, suspension injections, etc. Therefore, with the development of the times, "dissolution" has become an important means to evaluate the quality of oral solid preparations.

So as the name suggests, the "drug dissolution curve" is the curve of the relationship between drug dissolution amount and time in the drug dissolution test.

Since the dissolution determination method is based on the dissolution curve method in the quality standard of drugs, so to some extent, dissolution is a simplification of the dissolution curve. Moreover, since the dissolution curve is a curve fitted by multiple points, it is more intuitive than dissolution in expressing the trend of drug dissolution behavior and reflecting the changes of raw materials, prescription ratios, and process parameters in the drug production process.

"Bioequivalence" refers to the statistical differences in the extent and rate of drug absorption between the test preparation and the control standard preparation under the same test conditions...When the difference in absorption rate has no clinical significance, certain drug preparations with the same absorption extent but different rates can also be considered bioequivalent.

Of course, bioequivalence is not completely equivalent to pharmaceutical equivalence. Pharmaceutical equivalence refers to the same drug and the same dosage form, but the inactive ingredients are not necessarily the same. For preparations that meet the same specified standards in terms of content, purity, uniformity, disintegration time, and dissolution rate, pharmaceutical equivalence sometimes cannot reflect the situation of drug preparations in the body, but requires bioequivalence to reflect this.

In short, the two pieces of data, "drug dissolution curve" and "bioequivalence", are considered by the pharmaceutical industry to be the most biological standards that reflect drug preparations, and can even provide direct proof of clinical efficacy; their significance is invaluable.

………………

So, when the fat old man called Director Liu threw out this killer move, Tugou was immediately caught in a dilemma.

It is undeniable that there is a clear gap between generic drugs and original drugs in terms of the two data of "drug dissolution curve" and "bioequivalence". This is a real major problem and an unavoidable problem at this stage... Not to mention now, even for a long time in the future, these two things will be the "two mountains" weighing on generic drugs.

But there is no way. It is really difficult, very difficult to pursue data consistency in these two areas.

Take in vitro dissolution as an example. There are differences between batches of original research drugs. In addition, the condition for passing dissolution is that the F2 factor is greater than 50... 51 is also qualified, 95 is also qualified, which is also a difference.

In addition, the dissolution of generic drugs only needs to be compared with one batch rather than multiple batches of original drugs. The superposition of multiple differences will magnify the differences.

The same is true for in vivo tests. When comparing single batches, the Cmax interval also has a qualified range with upper and lower fluctuations.

This means that there will inevitably be a gap between the research and development results of generic drugs and the original drugs in terms of drug dissolution curves and bioequivalence data... With so many variables superimposed on each other, how difficult is it to pursue perfect consistency! ?
Of course, there are many details that are not known to outsiders, which lead to the gap in data... For example, there are differences in dissolution and permeation between drugs classified in different BCS categories; for example, there is no bioequivalence for injections, and there is no need to conduct BE studies, etc.

But no matter what, with the current level of technology and the financial strength of Dahua, with strong support, it may be possible to concentrate firepower to try to narrow the data gap in drug dissolution curves and bioequivalence of several generic drugs. But how can we expect hundreds of generic drug products to narrow the gap in drug dissolution curves and bioequivalence with original drugs?
What a joke!

After thinking about it, Tugou could only helplessly defend himself: "Leaders, although drug dissolution curve and bioequivalence are very important, I think that the current emphasis on generic drugs is too much, which is not realistic for China at present..."

The fat old man suddenly laughed: "Manager Lu, your company cares about the society and the hard-working people. We naturally see your sincerity and are very pleased... To be fair, there are very few companies like yours that actively assume their social responsibilities. If other companies can learn from your company, the social atmosphere will surely be much better."

"But, let's be clear, there are some things we can talk about based on the heart rather than the deeds, but there are some things we must talk about both the heart and the deeds!"

"As a member of Dahua Company and as a half-practitioner in the pharmaceutical industry, we all see Manager Lu's [expectations], but what about ordinary people?"

"When you are really ill and facing a life-or-death decision, when there may be a significant difference in actual clinical effects, what is your choice between domestic injectable drugs and solid drugs?"

At this point, the fat old man's tone became slightly stern: "Admittedly, I know that Manager Lu's original intention was to allow the rural poor with meager incomes to buy cheap generic drugs;"

"But Manager Lu, please face a problem... Once reorganized, the generic drugs produced by these pharmaceutical factories cannot be supplied only to your rural grassroots chain drugstore project... To be frank, your company's project does not have such a large digestion capacity at present."

After implicitly pointing out the infrastructure flaws of the project, the fat old man sighed: "If other units proposed this project and this cooperation, we would naturally not be so worried, nor would we repeatedly question the real efficacy of generic drugs... The reason is very simple. The people are not fools. As long as our medical staff and pharmacy practitioners stick to the bottom line, when faced with generic drugs and original drugs, the people will naturally know how to choose according to their actual situation and symptoms."

After another pause, the fat old man's tone suddenly became stern:
"But you are different!"

"who are you?"

"Drilling Company, Qingfeng Food, Xialiu Sales Agency, these companies are well-known and influential in the grassroots rural areas of Dezhou and Lanling. I don't need to say more, right?"

"Drugs are no different from other things. Once there are quality problems or relatively serious medical accidents, and this happens in a project under your company's name, the social impact and trust crisis caused will be ten or even a hundred times greater than other ordinary projects. With so many people pushing forward, the consequences may even be catastrophic... We have no choice but to be cautious!"

Everyone present knew what Director Liu meant by "Qunlan boosting the company". Even though his words sounded sincere and heartfelt, he was actually trying to put a label on the company and did not want those small and medium-sized pharmaceutical companies to divest and restructure, his words still made them hesitate.

At least what Director Liu said was right. The Drilling Company and Dahua Company were no different from other companies. Their reputation and influence in the Dezhou area were unrivaled. This was a double-edged sword. The good mass base that they all envied could certainly allow the young man Yang Mo to promote the project he wanted to promote with minimal help, but once a serious safety accident occurred, the negative impact and chain reaction caused would definitely not be comparable to that of ordinary units.

Moreover, Director Liu made it very clear that given the extremely sensitive domestic and international situation, once something happens, those with ulterior motives will certainly fan the flames. Once they take advantage of the situation to elevate an ordinary medical accident to a height and breadth that it should not have risen to, and use Dahua's status as a central enterprise to make derivative articles, then... I am afraid that these people will inevitably be severely punished.

………………

But it was obvious that Tugou, who had always been well protected by Yang Mo, was still thinking about the project at the level of "sticking to the facts". Therefore, after hearing what Director Liu said, he did not realize that at this point in time, he actually needed to adopt a roundabout strategy to hide some topics. Instead, he took a serious attitude and continued to argue with the fat old man in front of him about professional matters.

"Director Liu, first of all, I am very grateful for your care and affirmation for our Dahua Company and Drilling Company. I also agree with what you said... The more the people trust us, the more responsible we should be to them."

"However, I would like to emphasize that the gap between generic drugs and original drugs in terms of dissolution curves and bioequivalence is caused by many factors. Although it is unlikely to completely narrow the gap between them in a short period of time, we can use other means to minimize the gap as much as possible... turning 59 points into 60 points, or even 60 points into 80 points."

Tugou showed the persistence and seriousness that is common among technical personnel, and then took out a document and handed it to the staff: "Based on our visits and investigations, as well as consulting professionals in the industry and the information we got from Sankyo Co., Ltd., we can come up with a relatively objective view;"

"That is, the gap in actual clinical effects between generic drugs and original drugs, and the gap in drug dissolution curves and bioequivalence are actually caused by a variety of reasons, and a large part of the reasons are closely related to the detailed control of the formulation process."

"For example, in the production of generic drugs, the intermediate process control of raw materials and auxiliary materials... Please note that this is not about the intermediate product standards, but the intermediate process control... According to our visits and investigations, many small and medium-sized pharmaceutical factories have employees with lax work attitudes, and batches of medicinal materials are put in the wrong way, resulting in the scrapping of the entire batch of finished drugs. As for the order, time, and specifications of the main and auxiliary materials, deviations occur from time to time... If you don't strictly follow the process standards, how can you produce drugs that meet the standards?"

"For example, they are reluctant to invest in R&D, and pharmaceutical research is left in the air. The so-called pharmaceutical research of a considerable number of generic drugs is nothing more than changing the configuration or dosage form... The targets and even the mechanisms are ready-made, so it should not be difficult to make small improvements and innovations. However, even so, there are still many drugs that arbitrarily change the dosage form and excipient ratio without conducting in-depth research, resulting in the innovative generic drugs that cannot even achieve half the clinical effect of the original drugs."

"In addition, even the generic drug factories under the joint ventures in the past few years have many problems in the production process..."

"For example, workers' haphazard operation caused equipment and machinery to malfunction frequently, delaying production. Then, because they were unwilling to scrap the entire batch of drugs, the drugs' effective substances met the standards, but the actual clinical effects were not ideal.

"Although these joint venture factories have introduced GMP equipment and management systems, they have become lax about GMP compounding over time, and even stopped doing GMP compounding verification. This is also a very important reason that affects the clinical effects of drugs leaving the factory;"

"In short, there are many problems in the production process of domestic generic drug companies... If the production standards of original drugs are 10, then our domestic generic drug factories can only achieve 5 at most... This is the main reason why there is such a big gap between the drug dissolution curve and bioequivalence of my country's generic drugs and original drugs."

“Therefore, if we introduce GMP equipment in subsequent work and strictly control each link according to GMP standards, even if the generic drugs produced cannot perfectly replicate the effects of the original drugs, it is not impossible to achieve 80 points!”

"besides……"

Hearing this girl arguing with Director Liu on professional topics in a daze, and even extending the topic to the directions of "people" and "management", even Ye Tao couldn't help but feel a headache.

Silly girl, even if what you said makes sense, don't forget that according to the plan, the preventive drugs in your drug store chain in the future will be produced by those small and medium-sized pharmaceutical companies after business divestitures and reorganizations... Aren't you just making yourself uncomfortable by leading the topic in this direction?

If the topic is really directed to this aspect, Director Liu can find ten thousand reasons to prevent this project from being approved.

Seeing that the fat old man opened his mouth, obviously wanting to change the subject, Ye Tao finally couldn't help it and coughed lightly before the other party opened his mouth.

After all, he was a general manager. As soon as Ye Tao coughed, the whole meeting room suddenly became quiet. The fat old man who was about to speak stopped, and the other two middle-aged men who were eager to try also sat up straight again.

As for classmate Tugou...

No matter how stupid she was, she was not so stupid as to keep talking nonstop when she saw the leader wanted to speak.

After looking around at everyone, Ye Tao fixed his gaze on classmate Tugou, whose face was glowing red.

It can be seen that this girl is very confident about what she just said, as if as long as advanced equipment is introduced and GMP management is implemented, the generic drugs produced will definitely benefit the public.

With a slight sigh in his heart, Ye Tao looked at Lu Yingying with a complicated look in his eyes.

Although this girl's performance today was a bit too eccentric and confused, and the gap between her level and that of a little fox like Yang Mo was quite large, in his opinion, this childhood friend of Yang Mo did not even have the ability to become the person in charge of a large project.

But he actually had no aversion to this girl.

The reason is simple, there are fewer and fewer people with light in their eyes these days;

And various past situations have shown that the light in this girl's eyes is not fake.

That's enough.

He had seen many people with great abilities;
But people who are capable and still have light in their eyes are like giant pandas these days... Even Yang Mo didn't give him that feeling.

Besides, even if his abilities are temporarily insufficient and his vision is relatively narrow, isn’t he still young?

As long as we can keep the light in our eyes, the future is worth looking forward to.

Thinking of this, Ye Tao pondered for a moment, and suddenly raised his head: "Manager Lu, colleagues, Director Liu is right. Generic drugs are also drugs after all, and the matter is of great importance... So, Manager Lu, why don't you call General Manager Yang on the spot and ask for his opinion?"

Tugou was dumbfounded. Didn’t they just agree that strictly implementing GMP standards and controlling each production link would improve the clinical effects of generic drugs? The things that Director Liu was worried about could obviously be avoided as much as possible, so why did he suddenly ask to call Yangshidan?

However, Ye Tao was the executive director and the host of the hearing, so she had to answer the other party's words. She nodded and said, "Okay, Executive Director Ye, I will take a 15-minute intermission and then ask for instructions from our General Manager Yang."

Ye Tao looked at the time on his watch, but shook his head: "Manager Lu, there's no need to adjourn the meeting. Just play here."

As he spoke, he looked around at the others and laughed: "It's almost time to get off work, and we have to take a fifteen-minute break. I'm afraid that some comrades will report to the higher-ups that our work arrangements violate the work and rest regulations... Besides, Mr. Yang is not an outsider. If you have anything to say, we can communicate on the phone here!" Silly girl, you can call Yang Mo during the fifteen minutes of halftime, so can't other people go out and make calls?
After this hearing, there were more than one or two comrades who became concerned and shaken because of Director Liu’s words. Fifteen minutes was enough to complete one or two rounds of exchanges and then attract a group of reinforcements.

Aren't you asking for trouble?

Hey ~
The struggle experience is still too lacking!
Tugou was stunned when he heard that. He saw the staff considerately untie the telephone wires that were originally bundled together, and then handed him a white landline phone that was originally placed on the left side of the conference room door. Only then did he dial the number with some discomfort.

"Hello~ Vice President Yang, hello, it's me, Lu Yingying."

Since the handset was on speakerphone, Tugou used the honorific somewhat awkwardly.

"Eh~!?? Girl, did you take the wrong medicine? Why don't you call me Yangshidan today?"

"This isn't right...it's already time to get off work!"

Yang Mo's surprised voice came from the phone.

"Hmm... could it be?"

Following a sound of gnashing teeth, Yang Mo's terrified voice came from the phone: "Hello, hello, country girl, have you been kidnapped?"

"If you are kidnapped and robbed of your money, just blink your left eye; if you are kidnapped and raped, just blink your left eye... Hmm, that doesn't seem right. There is no video call function now. Girl, I can't see you even if you blink."

Hearing the funny voice mixed with sly laughter coming from the phone, all the participants including Ye Tao couldn't help but tremble their lips.

It is hard to imagine that such a frivolous remark was uttered by a super powerful figure who controls hundreds of millions of funds, hundreds of large, medium and small projects, and secretly controls a company with a production value of tens of billions.

Girl?

Sheep shit?
Hearing Yang Mo's unguarded tone, everyone looked at Lu Yingying with increasingly strange eyes, yet more solemn than before.

Although everyone knows that this girl is Yang Mo's childhood friend and they are very close; but given Yang Mo's current status, he still behaves so intimately with this childhood friend.

The importance of this girl in Yang Mo's heart is probably even more important than he thought before!

Thinking of this, the fat old man couldn't help but let out a sigh of relief.

Fortunately, I showed some discretion and did not push this girl to the point of being completely embarrassed. Otherwise, if Yang Mo really held a grudge against me, it would not be so easy for me to carry out my future work!

Unlike the participants in the conference room who were seven or eight years old every second, Tugou was pissed off by Yang Mo on the other end of the phone. He managed to hold back the urge to curse and said through gritted teeth, "Vice President Yang, I'm in a meeting in the city right now. I need to ask you about something... Also, the phone is on speakerphone, and the leaders are listening in!"

Eh?
There was a sudden silence on the other end of the line, and then the voice that came from the other end seemed to be a different person: "Manager Lu is still in the city for a meeting? Um...is there anything you need to ask me?"

Seeing this, Ye Tao couldn't help but laugh.

And classmate Tugou also had a stern face and gave a general account of the situation.

………………

five minutes later.

After a brief silence, Yang Mo's voice came from the phone: "Leaders, especially Director Liu's concerns are very necessary; therefore, I would like to propose three improvement ideas on behalf of Dahua Company."

Hearing that Yang Mo came up with a solution so quickly, not only Director Liu and Ye Tao, but everyone else also held their breath and concentrated.

"First, the production plan of generic drugs, which focuses on the divestiture and reorganization of local small and medium-sized pharmaceutical companies, remains unchanged. However, for the laid-off workers generated during the divestiture and reorganization process, Dahua will work with the competent authorities to provide them with retraining services for their re-employment."

"If they meet the skill assessment standards after 3-6 months of training, our company will provide them with jobs as drug shopping guides or deputy store managers in rural grassroots chain drugstores;"

"According to the first phase plan, 500 grassroots pharmacies will be opened. Based on the full scale of five employees per grassroots pharmacy, apart from the fact that the store manager must be specially designated by us, a total of 5 re-employed employees can be accommodated."

"In addition, chain drug stores also need manpower for a series of operations, including quality inspections of drugs on sale, inventory statistics, distribution, publicity, door-to-door services, store inspections, etc. Therefore, in addition to the 2000 shopping guides, we can also provide about 600 new jobs."

Call ~
Just the first improvement plan made Director Liu breathe a sigh of relief.

2000+600, that is 2600 jobs. Although it may not cover all the laid-off employees in the process of restructuring, it has at least solved to percent of them, which can be said to have helped him solve a huge problem... Don't think that the re-employment of people is an easy task. As an old industrial area, Texas already has the problem of industrial imbalance. In terms of creating new jobs, it cannot compare with Dahua Company/Drilling Company which are full of weird ideas. The resettlement of more than people is already a big headache for them.

………………

“Second, after the rural grassroots chain drugstore project is implemented, we will openly invite the masses in rural areas to actively participate in the Phase III clinical trials including generic drugs and self-developed drugs, and open up the public’s right to know and supervise;”

“It should be noted that this type of phase III clinical trial uses the demand inversion method.”

"That is, we will calculate what functional drugs are needed at the grassroots level in rural areas, and what improvements need to be made on the basis of existing similar drugs; after packaging the demands to cooperative pharmaceutical companies, the relevant pharmaceutical companies will conduct targeted scientific research;"

"And because these needs are real and urgent, pharmaceutical companies can recruit a sufficient number of volunteers through us by paying only the minimum basic nutrition fee;"

"At the same time, since the public's right to know is open, during the phase III clinical trial, pharmaceutical companies must regularly and truthfully publish clinical results and then accept public supervision... Although there are certainly some troubles in the operation process, from the perspective of the operating system, it is currently the most win-win method."

Upon hearing this, Director Liu hesitated slightly, but finally nodded.

The benefits of this demand inversion method are obvious. It is applicable to those drugs that are commonly used in rural areas but whose prices or effects are not satisfactory in some aspects.

With the good reputation and appeal of the drilling company and Dahua Company in the rural areas of Texas, as long as they are willing, they can easily recruit a large number of low-cost volunteers... Of course, the prerequisite is that you have to be willing to accept the supervision of the masses. Otherwise, even with the guarantee of the drilling company, not many people are willing to be your guinea pigs for such a little basic level of nutrition.

Although it is difficult for many pharmaceutical companies to regularly publish clinical results and accept supervision from the public and volunteers, the benefits are obvious... It is unlikely that you will be able to do anything fancy with this kind of generic drug improvement or original drug research work that is oriented towards actual results.

What will it mean if pharmaceutical companies can no longer play tricks in this area?
This means that a large portion of the obscure scientific research funding can be saved;
This means that these pharmaceutical companies must really engage in academic research and innovation;

It also means that once there is real innovation and improvement, it is easy for new drugs to accumulate enough Phase III clinical cases at a very cost-effective cost, and then naturally pass the CDE review, enter the medical channel, and become a recommended drug in a certain aspect... If you are ambitious, you can directly apply to the FDA, and after clinical verification, it is not impossible to enter the American market.

In a word, Yang Mo’s second improvement plan, once implemented well, will be a great success!
Thinking that he might be able to make further progress, the fat old man couldn't help but breathe faster.

…………

"Third, since we are promoting the divestiture and restructuring of local small and medium-sized pharmaceutical companies, a lot of non-performing assets will certainly be generated in the process."

"As compensation, I would like to express on behalf of Dahua that I am willing to assist you leaders in disposing of the non-performing assets generated after the restructuring is completed."

"Of course, since it is an assistance, it is basically unlikely that Dahua Company will spend its own money to purchase these non-performing assets;"

"So my idea is that it would be better if the competent authorities of DZ City introduced policies to transform these non-performing assets into production capacity for pharmaceutical raw materials production/purification/pharmaceutical food processing in township enterprises in the form of industrial transfer, and disperse them into the fine chains of Western medicine, food, health care, and even traditional Chinese medicine industries, and finally transform them into the driving force for industrial upgrading."

Some things should only be said briefly. After saying these words, Yang Mo on the other end of the phone fell silent.

Although Yang Mo's words sounded high-sounding, everyone present was a smart person. How could they not hear the trick?

As expected, he is Yang Mo. Although a lot of room for operation is reserved in favor of Dahua Company, it must be said that these three suggestions for improvement take all aspects into consideration... It is really generous!

Ye Tao smiled with satisfaction and looked around at the people around him: "Everyone, do you have any questions that you need to discuss with Mr. Yang?"

Although the question was directed at the big guy, his eyes were fixed on the fat old man.

How could Director Liu not understand what Ye Tao meant?

He shook his head slightly and said, "No, I have no questions about this project."

What a joke, there has to be a limit to what one does. Yang Mo has already shown enough goodwill and also given a lot of compensation in a roundabout way. In addition, Ye Tao has made it clear that he wants to support the other party. If he doesn't know when to stop, then he will have lived in vain in this half of his life.

Seeing everyone nodding, Ye Tao nodded slightly.

After raising his wrist to check the time again, Ye Tao stood up, walked in front of Tugou, and then smiled and stretched out his right hand: "Congratulations!"

Eh?
Student Tugou stared blankly at the people in the room with kind smiles on their faces, and his mind was suddenly confused.

what's the situation?
Weren't they just having a heated argument?

How come Yang Shidan made a 180-degree turn after only talking on the phone for less than three minutes?

See what this means...

The hearing on this project...is over?

------

PS: This chapter has been partially edited, please forgive me if it is not smooth to read.

(End of this chapter)