Release date: 2015-11-19

On November 11th, “Breakfast Carnival Night” was an extraordinary night for the pharmaceutical industry. At about 21 o'clock that night, the CFDA official website published the "Notice on the Approval of 11 Drug Registration Applications for 8 Enterprises (No. 229, 2015)".

The first batch of penalties were the generic bioequivalence (BE) test, and it is incredible that the well-known Zhejiang Huahai Pharmaceutical is in the list, which is embarrassing. Huahai Pharmaceutical is recognized as the best domestic enterprise for oral solid preparations - so far it has received more than 10 US FDA and EU generic approval numbers (ANDA).

After the announcement, the industry people finally felt that the storm-like reform measures and the drastic policies that have been implemented this year have not been as arrogant and painless as they used to be. .

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Basically eliminate BE test fraud

Regarding the "unspoken rules" of the BE test that have almost failed, the author has heard about it ten years ago. Although the drug testing center (CDE) explicitly requested in April 2011 that multiple dissolution curves of the generic preparations must be consistent with the original development agent, it can be declared, but it is not required to be reviewed by the drug testing institute (currently it is only the quality standard of review) One": one medium, one time point, one dissolution amount), so many of the application materials "reported not to report worry" and bold fraud, leading to high levels of preparation developers have no use. To get the clinical approval to carry out the BE test, there is no failure, and it has already become the "inside" known to the industry. Even some serious and rigorous clinical trial institutions informed the client that after the failure of the BE test, the client refused to pay the final payment and searched elsewhere.

Therefore, the author is often told: "The 'multiple dissolution curve comparison method' you learned from Japan can really promote the development and quality improvement of generic preparations. However, due to loopholes in the above links, it is also a slap in the face and a mirage."

Nowadays, with the promulgation of the announcement, it is expected that there will be no more large-scale BE trial fraud in the future.

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Consistent dissolution behavior can greatly improve the success rate of BE test

The next question is: With the recent increase in the cost of the trial at least 1 time, how to ensure that it is as successful as possible at one time? Or how to improve the prescription process of the generic preparation after the first failure, so that the second test can pass smoothly? It is the focus and expectation of all developers!

The answer is: please let the pharmacy professionals of the R&D institutions down-to-earth and meticulously carry out the BE test on the in vitro multiple dissolution curves of the three batches of large-scale, large-scale production of the imitation preparations, and then do the BE test after the consistency of the original development agent. At least 90% success rate is guaranteed. In particular, the five most difficult varieties: poorly soluble oral solid preparations, enteric preparations, controlled release preparations, pH-dependent preparations, and therapeutic window narrowing pharmaceutical preparations, and more need to be continuously explored and repeatedly polished in the development of preparations.

In addition, when the in vitro dissolution behavior consistency study is not thoroughly carried out, and the first BE test is carried out after the first BE test, do not be discouraged. The author believes that: the significant difference between the two can be found under a certain dissolution test condition, and then continue to improve the formulation process and prescription, so that the dissolution behavior under this condition is consistent with the original development agent (of course, other dissolution conditions remain Consistently, when you go to the BE test, you can wait for the news of success with confidence and ease, without being as anxious as horse racing.

In fact, under the discriminatory dissolution test conditions, it is more difficult for the multiple dissolution curves of the imitation preparation to be consistent with the original development agent, which is far greater than the BE test - because the current domestic BE test is young and strong. As a subject, it is the best human environment and condition, that is, the minimum requirement; the actual situation is: the environment of middle-aged and elderly people is far from the young and strong (the gastrointestinal tract is weak, the pH is irregular, etc.) ), and at this stage, this group of people cannot be used as BE test subjects.

Therefore, at present, only through strict and targeted dissolution test requirements to promote the in-depth development and quality improvement of generic preparations, can the intrinsic quality be infinitely close to the original research and promote the therapeutic effect for various patients. At the same time, it can also save the high cost of BE test, and finally achieve a comprehensive clinical replacement of the original research drug, rather than the original research drug. This is the "dissolution test" as a lever to the "four or two pounds" that can be exerted by the entire oral solid preparation industry.

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How to ensure consistent industrial production

After the announcement, it is necessary to basically eliminate the fraud in the clinical trials in the future. But the core point is: how to ensure that the prescription, process, and production line of the bioequivalence test sample are consistent with commercial production (in the “Announcement on Certain Policies for Drug Registration Review and Approval [No. 230 of 2015], Issued the same day as Announcement 229).

That is to say, how to ensure that the samples used in the BE test are manufactured under the industrial production scale, and the non-declaration unit selects 200 pieces in the laboratory and then selects 200 pieces for CRO company or clinical base. Because the small test scale to achieve multiple dissolution curves and the original development agent is very simple, it is difficult: industrial pharmacy can be consistent after amplification. Because: "consistent" under the scale of industrial production is the real embodiment of the industry as a "high-end manufacturing"!

According to the author's understanding, the number of boards in the developed countries that require the declaration of generic preparations should not be less than 100,000 pieces as the research and development requirements. Then, how will China stipulate this aspect? This will further test the wisdom and courage of policy makers. Wait and see!

(The author of this article worked at Shanghai Food and Drug Administration)

Source: Pharmaceutical Economics

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