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52 details Q & A: The official statement on the consistency evaluation of generic drugs



Medical Network September 8th. On July 26th, the State General Administration held a training course on the evaluation of the consistency and quality of generic drugs in Guangzhou. According to the Q & A recording, the notes are compiled as follows. No deletion, strive for objectivity. This question and answer arrangement is not perfect, but many of the answers have practical guiding significance. If there is an objection to a certain content, you can raise it, and I hope that everyone can discuss it together and change the inconsistent voice into consistency.
1. Among 1622 varieties, how to declare the problem again:
A: There are no separate rules for clinical production and R & D on-site verification in this consistency evaluation. The rules have been used in registered production site inspections, R & D sites, and clinical verifications, so the execution standard should be a standard, and there is no new standard The problem is the same as the old standard.
2. Search for reference preparations:
Answer: The homemade product is a capsule, but the reference is a tablet. Is it feasible? This variety of modified dosage forms needs further research.
3. Whether the prescription process and packaging must be consistent with the original research:
Answer: It is not necessary to agree in any explanation. This is not a necessary condition.
4. Is it consistent in quality and bioequivalent?
Answer: Specific analysis of specific varieties. Seeing him meant that there was no need to make a dissolution curve, but for us, the dissolution curve work was done carefully, carefully, and a characteristic dissolution curve was found to control the production quality, which is also the consistency evaluation this time. important content.
5. If discriminatory dissolution curves enter a quality standard that involves a change, where is the approved quality standard approved?
Answer: The final entry into the quality standard is dissolution. One or two points can be found on the dissolution curve to determine the dissolution. If there is no dissolution in the current quality standard (equivalent to the enhancement item), or there is dissolution, but the selected index is not very suitable, or the dissolution conditions have changed during the study of the dissolution curve, these are related to the quality standard The change belongs to the Pharmacopoeia Committee. If it is a Pharmacopoeia variety or a registration standard, you should contact the Pharmacopoeia Committee to propose a change standard.
6. Amoxicillin capsule "Chinese Pharmacopoeia" standard reaches 80% in 30 minutes, but the dissolution rate of the reference preparation is very slow, less than 80%. How does the consistency evaluation pass the pharmacopoeia?
Answer: Why is this product slow? What is the reason? Proper analysis is needed: Is it reasonable to dissolve 80% in 30 minutes. The dissolution limit of the Pharmacopoeia is not necessarily in place. Even if it dissolves at 80% in the past 30 minutes, maybe our conditions were severe at that time, or a solubilizing agent or a surfactant was added to the dissolution medium. I do n’t know the dissolution conditions of amoxicillin capsules, but whether it is suitable to reach 80% in 30 minutes, whether the dissolution conditions of the reference preparation are consistent with the dissolution conditions of the Chinese Pharmacopoeia, which is more reasonable. This requires specific analysis, and the answer can only be made after analysis.
7. The same variety is contained in Japanese orange peel. Can the consistency evaluation directly check the method of inclusion?
Answer: What method is used, where is it contained, where is the dissolution medium contained, or the literature you consulted, can be used as the dissolution curve method to establish the dissolution medium choice; can the dissolution rate be used directly? It can be used, the key is to see if the results made are suitable for your breed.
8. There is a large difference between batches of the reference preparation. The coefficient of variation of the first sampling point is greater than 20%, and the remaining sampling points are greater than 10%. How to compare f2?
Answer: First of all, it is necessary to confirm whether the reference preparation is really a large difference between batches, or whether the difference is caused by your own method, and whether it is a large difference between batches due to the method. If there is no problem in the method, it is a method of moderate discrimination, and the reference preparation does not have uniform batches in the batch. Then the sample cannot be used as a reference preparation in practice, and the reference should be changed.
9. The prescription and technology of the large and small capsules are exactly the same, but the loading is different. Can the in vitro dissolution profile be compared only with the large specifications?
Answer: In fact, both specifications need to be done. Although the prescription and process are exactly the same, their main drug content is different. It is possible that the main drug content is different and the in vitro dissolution is inconsistent, which needs to be verified by experiments.
10. Dissolution in vitro, in vivo and in vitro are not completely related:
Answer: The in vivo and in vitro are not completely related. The risk of doing BE directly is definitely a bit large, but it is not necessarily not equivalent. In this case, we of course take the BE result as the final judgment result, that is, the dissolution in vitro and in vivo. The difference is different, but we also need to establish a discriminative dissolution curve for this variety, which is different from BE. Does BE count? Of course, the test of BE is the final judgment. Then the establishment of the four curves is not exactly the same, but if it is discriminating, can it be passed? If the BE passed and is consistent, and the dissolution curve has the ability to distinguish, then we think it should pass, but your dissolution curve should be exactly the same for your later production as the sample that passed the BE, and the dissolution curve should be completely Again, this will ensure that future products are also bioequivalent.
11. Compared with the original preparation, the impurity profile of the drug substance has two impurities less than 1 / 10,000:
Answer: The analysis of the impurity spectrum needs to be compared with the original reagent under the same chromatographic conditions. If the impurity is small, according to the SOS regulations, as long as it is more than one thousandth, it is necessary to calibrate the impurity; if it is very small, it is lower than One in ten thousand impurities, if one in ten thousand is very sensitive (one in ten thousand has reached the detection limit), according to SOS regulations, one in ten thousand needs to be analyzed based on the daily dose. I think this is actually a comprehensive judgment: compared with the original research, what are the impurities you have, can you explain, in addition, whether the amount is relatively large, if the amount is relatively large, more than one thousandth or even one thousandth Two or more, then you have to make what the impurity is, whether it will affect the efficacy of the drug, whether there are toxic side effects; if it is very low or even one ten thousandth, then can it be reproduced, generally one ten thousandth is a basic inspection Limits, whether each batch can be repeated, or that it only happened by accident, which requires specific judgment based on specific problems. But if one ten thousandth is a known toxic impurity, according to foreign pharmacopoeia, such as USP, EP, their control of the drug substance, for the known toxicity, the lowest I can see can be controlled to 0.1PPM, Therefore, it cannot be said that we are in control of one ten thousandth. This needs to be based on the specific impurities (degraded or process), how toxic and the specific structure. So, I ca n’t sit here and tell you that less than one ten thousandth is not controlled, or two more can be. This is hard to say now, and you need to conduct further research yourself.
12. For domestic medicines manufactured on the same production line and marketed in the United States, European Union, and Japan, the original domestic listing application information was reported in 2005. It is slightly different from the recently approved application materials. Will this affect the approval conclusion:
Answer: The question is not too specific. I think it may be that there is a difference between domestic registration information and the latest foreign registration information. In this regard, in fact, I understand that the emphasis is now on the registration permission, and at the same time It also emphasizes that the same production line uses the same prescription technology and the same management to produce the preparations, and it is proved that this is consistent through the consistency evaluation, which is a prerequisite. The difference in the filing information, I do n’t know if you have a new process change in Europe and the United States, whether the changed process affects the quality of the product. In principle, you should use this consistency evaluation to list domestic listing data and foreign listings. The information is consistent with the premise. If it involves supplementary application for registration, this time it is necessary to add all relevant conclusions to the evaluation conclusion. The consistent conclusion is that the quality is consistent.
13. Consistent import registration was introduced in June. Foreign reference preparations were purchased before June. Can these reference preparations purchased before June be used for pharmaceutical research?
A: I think if it meets various requirements, but it is only a matter of time, then you have no problem doing research. As long as you guarantee the quality of this thing, you can do research.
14. Regarding the consistency evaluation, can the production inspection batch be used for marketing?
Answer: If the batches of the consistency evaluation are safe and effective, and the products are produced under the premise of legal compliance, then they can be sold on the market without saying that they cannot.
15. Specifications of reference preparations: The specifications contained in the Orange Book are different from those produced by our factory or enterprise. Some are large specifications, some are small specifications, some are small specifications, and some are Big size
Answer: This problem also includes the inconsistency of the dosage form. If viewed uniformly, there is a problem. This question was also mentioned just now, there is no clear conclusion, but it still needs to be researched, and we have less information, so we don't know where the approval of your specifications or the approval of the dosage form is reasonable, so it is recommended that you first There is another question for the record. I can choose both the United States and the European Union at the same time. Is it okay? I think there should be a sequence for this. When filing, it is necessary to explain what is preferred.
16. According to the document number of the General Administration, if the listing is approved before October 1, 2007, it is necessary to complete the consistency evaluation before 18 years. Then, if I obtain a marketing permission after October 1, do I not need to complete the listing at the end of 18 Will the application be rejected after 18 years?
Answer: The document makes it very clear that approval for listing before October 1, 2007 should be completed within 18 years. In fact, for these varieties, especially our compulsory requirements in the 287 directories, of course, if you have various conditions during the process, you can also reach 2021, these special conditions such as clinical trials, this is It takes time. In addition, if you deduct the wording of the document, after October 1st, you are not required to complete it by the end of 18th. There is no problem with this. However, in fact, everyone knows that there are many good policies for consistency evaluation. If people do not complete it, will it be unfavorable in the market, so this is not a mandatory requirement for us. In addition, when the document was just issued Some people also ask that some varieties are out of range. Can these varieties not participate in the consistency evaluation? Actually not.
17. Consistent imports:
Answer: Consistent import is a policy issued by our General Administration for everyone to carry out pharmaceutical research, which also includes consistency evaluation. Whether it is used for generic drugs or consistency evaluation, I have a foreign drug here. This situation, but if there are many inconveniences to go out and buy without a certificate and without a market authorization in China, everyone is concerned that there is a big change between the draft of the consensus evaluation document and the final release. I personally think that the main change is Remove many of the bottlenecks that originally restricted this matter, then there are two issues involved: for foreign countries to import control drugs to be approved to market to prove themselves (can provide the national drug marketing legal certification documents, as soon as possible drug import instructions for marketing or (The information published on the website of the State Drug Supervision and Administration Department) His question is whether all three items should be selected or selected by myself. I personally think that each of the three items can be used. Of course, you can get the best of all three items.
18. When will the submission channel for consistent import declaration materials be opened? What are the submissions of Guangdong Province? Is it 3 out of 1 or 1 + 2 out of 1?
A: This question was raised for our provincial bureau, which is very specific and needs to be docked with the provincial bureau.
(For referenced reference preparations, but the original manufacturer of the reference preparation does not provide his manufacturer's certificate, in other words, it does not have a commitment with domestic imports or origin. This commitment requires us, generic drug companies, to let the original research Pharmaceutical companies provide a consistent commitment to import drugs and drugs from the country of origin. This commitment is actually required to be submitted during the reference product declaration process.)
19. I can find a lot of standards, but the methods between these standards are quite different. How do I choose? How to choose the configuration method of the reference solution used in different media?
Answer: The reference or use of these selected literatures should be determined by the company, including work such as consistency evaluation. The experiments you perform, whether in vivo or in vitro, your purpose is to Prove to the approver that your product is consistent with the original research or reference. It is not that we have to set a limit, and then we can reach this limit. If we do not reach this limit, it will not work. Like the selection of different dissolution media and the choice of reference solution for different dissolution, one variety may be possible, but this method is not possible with another variety, so we follow certain guidelines when selecting these methods or parameters. The basic principle is not said to be a universal selection method.
20. RLDs in the United States are generally large specifications. Can small specifications from the same manufacturer be used for consistency evaluation?
Answer: (This question is not what I talked about, but I can tell my understanding) First of all, we should follow the guiding principles and various documents issued at the time of selection. The first choice of reference formulation for our consistency evaluation is The original research, here, if the same dosage form and specifications, in terms of method, the theoretical comparison error is the smallest, so we do not need to because the large specification abroad is RLD, then we only choose the large specification, obviously there are small specifications, We do not choose those with the same specifications. The selection of the reference preparation should also grasp its principles. It cannot be said that I only choose RLD and other specifications will not work.
21. How to determine the curve when there are differences between the three batches of reference? Are the three batches average, or how to choose?
Answer: If the reference difference is very large, then the first choice should doubt whether this variety can be used as a reference.
22. What kind of sample was used to establish the method? Is it a reference preparation or a home-made imitation?
Answer: As mentioned in the PPT just now, the pre-experiment establishment method we carried out uses a reference preparation.
23. Is the reference preparation used by the drug inspection institute provided by the enterprise or is it solved by the drug inspection institute itself?
Answer: The reference preparation at the time of audit was provided by the enterprise.
24. How is the sex ratio performed in the BE experiment? The original FDA audit report stated that there was no gender difference in the product, so how should the gender ratio be required in the actual test?
A: I just talked about why we have adjusted the subject, that is, there is experimental data that shows that women have greater variability than men in subjects. There is no difference in gender in the same drug in the original research approval report. Does it mean that there is no difference in his AUC and Cmax? Female subjects have greater variation than male subjects, so from a statistical point of view, a certain percentage difference is required. In addition, in the FDA audit report, the purpose of new drug evaluation and generic drug evaluation is different, so there may be some differences in experimental design. We have not set a strict limit on the proportion of female subjects. The main thing to look at is the indications, the pharmacological effects of the drug, and what kind of population will be used in the future. If it is a general population, then we will set an appropriate ratio. Exact data, and the current guiding principle is only a guide, that is to say, try to provide data for a representative population.
25. There is a specific drug with a low absorption rate in the human body, and the indicators adopted abroad are used for consistency evaluation. Can we also use this?
A: I think we can learn from some of the foreign guiding principles. You have to combine your own varieties. When designing the experiment, you must take the clinical efficacy evaluation as an indicator and the actual situation of the patient's medication. Then the indicator you choose is not sufficient enough, is it enough to explain the clinical effect, or should it be based on the pharmacological action of this drug, what is the mechanism of clinical action, and what indicators can be used in clinical observation? That is to say, the foreign guiding principles can be used as a reference, but as the applicant you know the best about your own breed, and you may have an expectation for his future clinical effect. At this time, you should use your subjective initiative to refer to foreign guiding principles.
26. Is one or more investigations of the stability of the dissolution curve conducted? Is the stability of the reference preparations one or more?
Answer: I said this morning that the reason for investigating the stability of the dissolution curve is for products with unstable physical and chemical properties. In the early stage, we will consult some literature. If there are reports that this is not very stable, then you have to be careful and do more work; but if it is very stable, you can do a test first, and do a more demanding one. Such as strong acid, see if the change is large. Actually, we do not require you to dissolve the stability is a must do, unstable to the physical and chemical properties; but if you are not assured, you better do it, we are not asking you to do all the curves, in order to know, You can do one or more, this is not mandatory, because this itself is the basis for your subsequent review, so we do not have to do it, you must do one or four, or more or less. If it is stable, you can also do it if you are confident. In addition, is the reference preparation one or more batches? If you only buy one batch, you may not be required to make multiple batches. In addition, the purpose of making multiple batches is to examine the uniformity and stability of the reference batches. Therefore, there is no compulsory standard, which is judged by everyone in the research process.
27. For special varieties, if there are important extracts, such as these preparations with Chinese characteristics, why do we need to evaluate the consistency?
Answer: Although these varieties are preparations in China, can their efficacy and quality be guaranteed. With whom to evaluate and agree with, this does not mean that there must be a fixed pattern. The question said, did the National Bureau publish some suggestions or information? In fact, these special preparations should be your company's main body of evaluation. You should know your own product best. How can you ensure quality and efficacy? This should be your own evaluation plan, so our company should Use your brain instead of what you want me to do. In fact, each breed is different. Each breed has its particularity, so we cannot give each breed a fixed pattern to say about this breed. Just do it, for example, compound glycyrrhizin tablets, I know it has very complicated extracts and so on. Then you ca n’t say that it is necessary to make four dissolution curves, which ca n’t be done at all. Is his quality controllable? Currently, there are more than 30 companies producing in the market, so these 30 are definitely not the same, and some of them have different appearances. So how to make all the same, this should be the role of each manufacturer or association, put forward a feasible evaluation method for this variety, such as quality control, the content of licorice extract includes its fingerprint, the fixation of the process And so on. These cannot use the conventional evaluation method, so we hope that the company can first propose an evaluation plan for this product. In fact, it is through this consistency evaluation work to improve our quality and improve our curative effect. This year's product feedback on the market and the efficacy of the hospital can be widely collected in the clinical hospitals of the users, which can be used as a basis for whether your product is safer and more effective. Then the quality standards are improved. Like these special varieties, there are special evaluation methods. Therefore, we need to use our company's brains. Each evaluation method needs to be proposed by yourself. You can also contact the relevant work unit to discuss and propose. A feasible and persuasive evaluation method, and then work accordingly. The consistency evaluation team then organizes relevant experts to evaluate your plan. Now our teacher cannot give you a more satisfactory answer, saying that your breed should do this, this is not very realistic.
28. The filing of the reference preparation is cumbersome and takes a long time, which affects the work progress of the enterprise. Can it be simplified?
Answer: Let me clarify one point here. The filing of a reference preparation does not mean that you must prepare it, you must prepare it, and you cannot carry out subsequent work if you do not prepare it. This is irrelevant. In other words, if the country has already published the catalogue of reference preparations, do we still need to record it? No need. Therefore, whether it is the filing of reference preparations or the recommendation of the association, and the original application or the internationally recognized generic drug company to make an independent declaration, it is mainly a multi-pronged approach. Many different subjects in different situations are for faster. Obtaining information on reference preparations, I believe that if all the channel information obtained by everyone is the same, sufficient literature data, then after expert review, it is easy to reach consensus. If you report different things, then the more things you report, the more complicated the situation will be. In addition, as far as I know, some companies that have put in a lot of work for the record have not started the relevant work before the publication of the reference preparations. Therefore, it may not be possible for the reference preparation to be filed for 60 working days, because the situation we are currently facing is quite complicated.
29. Do several enterprises jointly recognize the same product?
A: I ca n’t say whether the National Bureau of China admits it or not, but as far as I know, the National Bureau encourages industry to engage in alliances, and you may not do it for your family or every one. Then you can engage in this kind of communication, but You ca n’t just report this set of information. I personally think that this is possible, research, exchange, sharing, but you will definitely do it on your own production line and do your own BE experiment. Several joint ventures can report one document number, but you can't because you are the same and all are the same, so you need to approve three.
30. There are three varieties of a drug that have passed the consensus evaluation bidding for drugs that have not passed the consistency evaluation. One of the products is a new type 1 drug approved in 2007?
Answer: Class 1 new drugs are of a few points. If it is class 1.1, then you are the original researcher, and what consistency evaluation will be done. If you are not class 1.1, there are many situations, but the General Administration ’s announcement It is very clear that everything that is inconsistent with the original research needs to be done, but the pace of doing it is different, such as what should be done in 2018. There is another question here. I am an injection. Why don't you want me to do it? No one is not allowed to do it, and injections are also encouraged to do it, but the specific catalogue is introduced in stages. We first do it orally. One is that everyone is more concerned. The other is that everyone knows that there is an absorption process by oral administration. The process has a greater impact on the efficacy, so we first do it orally.
31. If the large size is BE, does the corresponding small size application require exemption?
Answer: BE is made for the large size, and the dissolution curve is also made for the small size. It must be proved to be consistent with it. Regarding the specifications, we also said today that first of all, your prescription must be exactly the same, and the ratio is changed in proportion. It is possible. If you have to do the relevant information about the BE test for the small size and the large size, it does not mean that you do not need to inspect the large size and the small size. This is not correct. Your small specifications must also be examined in relation to the large-scale dissolution profiles.
32. The large specifications have been completed and no approvals have been obtained. The ones that have been listed are the low specifications. Now that the application for the increase of the high specifications has completed the BE test, can the low specifications be exempted?
Answer: The first step to complete the BE test is to have detailed test data. In addition, there must be high specifications approved by you (that is, get approval). You must also prove that your low specifications are completely proportional to the high specifications. of. First you have to get approval, otherwise it is not enough to complete the BE test.
33. Different specifications, some specifications can reach the platform (ie all dissolve) at the paddle method 50rpm, but other 20mg specifications require 75rpm, that is, the two curves are inconsistent, then the 10mg energy of the two specifications Is the BE test waived?
Answer: The first choice is to confirm whether the prescriptions are the same. If they are the same but the sizes are different, the dissolution curves should be the same, but now the dissolution curves are 50rpm and 75rpm to dissolve. In this case, it cannot be said that 10mg is exempt, and the reasons for applying for exemption should not be sufficient.
34. Do pre-experiments need to be recorded?
Answer: Yes, it is needed. The pre-experiment also requires the approval and filing of the committee, and it also needs to be published on the clinical trial publicity platform.
35. If the pre-experiment fails, do I still need to re-file it?
Answer: Yes, every clinical trial needs the same treatment and the same record, approved by the committee, then publicized, and then the experiment.
36. Is the pre-experimental BE report also submitted in accordance with the new standard and the new CDE format?
Answer: There are no strict rules.
37. If clinical approvals have been obtained, do they still need to be filed?
A: I don't know why there is such a doubt. The two are complementary and can be filed with clinical approval. This does not affect the development of clinical experiments.
38. For situations where process changes are required, the consistency assessment report file requires research on processes and reference preparations after the change, and supplementary applications for process changes require space research before and after the change. Therefore, this consistency evaluation changes process Does it involve the need for research between pre-change, post-change and reference preparations?
A: For consistency evaluation, the purpose of any change is to research your changed product and reference preparations to see if they are consistent, so you don't need to research before the change; but if it is not consistency evaluation In terms of work, you are only submitting a supplementary application, then you need to research the product before and after the change. It depends on what you are doing.
39. Does the person performing the dissolution curve need qualification certification?
A: As mentioned earlier, personnel is a factor that affects the results of experiments, so the personnel must be trained. As for what kind of training, he feels that he can be suitable for this work. This is determined by the company itself. .
40. Can the dissolution curve be evaluated using a difference factor of F1 less than 15?
Answer: Yes. Not only the difference factor, but also the activity-dependent method. What method do you use, or jump out of this method and use other methods, but you have to say clearly. We use the similarity factor method, because everyone is familiar and using it, you do not need to explain too much, F2 is greater than 50, we think it is similar; for other methods we are not familiar with, you have to Explain clearly: first you have to let the reviewer understand that this method is applicable before you can use it.
41. The drug is unstable in the medium of ph1.2, that is, it may degrade 2% within 1 hour. How to study it?
A: As I said just now, when studying the dissolution curve, we must dissolve the changes in different organs and different parts of the human body, and he is examining the differences between the generic and reference formulations. Then, if we have Degradation, whether the original research or reference preparation also degraded, are we the same as him? After all, there is still a difference between the in vitro and the body: degradation in the body, it is likely that it dissolves as much as it dissolves, and it is too late to degrade. Therefore, it is sufficient to follow a principle here, and you can achieve the same dissolution behavior as the reference preparation or the original developer.
42. There is a difference in the external dimensions of the generic preparation and the reference preparation, such as a circular tablet and a shaped tablet?
Answer: This difference in appearance, including the difference in color (such as one coating and one without coating), is not the essential reason. What we want to examine is that his quality is consistent with the effect. The difference is not relevant, as long as the final effect is consistent.
43. How to build a dissolution curve with discriminating strength?
Answer: This is not an easy question to answer. It is difficult to elaborate in drug development, including the establishment of dissolution methods. I can only give an example: Take the number of revolutions as an example. If I finally chose 75rpm, the basket method 75rpm is possible, then why choose 75rpm? You have to make it clear, I have done all three of 50, 75, and 100. , 75 is the best discriminative power, then 75 is the best discriminative power of all the methods we have examined, so it is justified to choose it.
44. If there is imported original research, there must be a commitment on craftsmanship and origin. How can this commitment be obtained?
Answer: It may be that I did not make it clear when I said just now. This refers to when the original research enterprise declares that I want to use it as a reference preparation. We need him to provide such a commitment. The production country must be completely consistent with the country of origin. . Realized medicine also has this problem. You must have a certificate that is completely consistent with the original research. This commitment is provided by the original research company and the original research real estate company.
45. According to the drug registration management measures, do reference preparations in the pharmaceutical stage need to be reported when the generic drugs are declared?
Answer: At present, the filing procedure for reference preparations only evaluates consistency.
46. What to do with different specifications and what to do if the dosage form is changed? Or is it not a large dosage form, a small dosage form, such as a regular tablet changed to a dispersible tablet or an enteric tablet?
Answer: The complexity of these questions lies in how to do exactly the same, can be found, different proportions, that is, what to do if you can't buy, how much to buy. Some dosage forms are changed, such as capsules into tablets. Then, do I use different dosage forms to benchmark and make BE, or do they belong to the category of no reference preparations, because from the perspective of pharmaceutical equivalence, Tablets and capsules are not equivalent. Although they may be clinically replaceable, they are not considered pharmacologically equivalent. This is a situation. In addition, we have another situation. At that time, we may have some commercial ideas, or we would like to take advantage of clinical advantages, so in the end we made various changes, such as a self-discrimination that is easy to dissolve. To make a dispersible tablet, we do not need to make enteric tablets. We have to make enteric tablets. At this time, the consistency evaluation is coming, and everyone will be very entangled: Can we use ordinary tablets as reference preparations? If I can do it, can I do BE? If I can't do it, do I need to take clinical effectiveness, so these need to be studied. This is the first point. Second, according to the definition of the current guiding principles, we ca n’t take care of the original research, but it ’s really not found abroad, and it ’s the first of its kind in China, and even some varieties sell better, so can these varieties be used as original research or For reference, this is a new problem. There are also some varieties that are used more commonly in general medicine, but they are no longer available in foreign countries, or there are no foreign countries now. Not only do we have hundreds in our country, but we do not know who is the first to imitate according to the available resources. These need to be studied. The reference preparations are too complicated, because according to our new registration classification, or the generic drug laws in the United States in 1984, we also adopted the same generic requirements with them at that time, and there may be no such problems now. How to solve the problem of quality is definitely complicated. Some of these are slightly changed, some are changed a lot, and no comparable products can be found abroad. There are also some products, such as some chemical drugs, for a chemical medicine. No, but it is obviously a biochemical medicine, and it is a multi-component biochemical medicine, not our simple synthesis or fermentation by ourselves. At that time, some chemical medicine document names may have been given, which is not considered traditional significance. Whether you want to evaluate the chemicals on the board, these are all issues that need to be studied in the next stage.
47. The State Council issued the No. 8 document saying that it is impossible to find a reference to conduct a clinical effectiveness test. So, should the pharmaceutical research be conducted first or the clinical effectiveness test be entered directly?
Answer: The document makes it clear that there is a need to carry out a clinical effectiveness test for the need to find a reference. This is divided into two cases: First, it does not involve changes in the prescription process, then the next stage can be clinically effective through filing. Sex test, nothing has been changed, does not involve changes in the prescription process, what you are like now and what you will be in the future, but only for clinical effectiveness tests, then there is no need to carry out pharmaceutical research; Then you need to make a supplementary application in accordance with the existing registration management methods. You can do what you need to do with the supplementary application. You need to submit, approve, and then go to the clinic.
48. Is the clinical effectiveness test based on a cut-in test or a consistent evaluation of quality improvement?
A: Teacher Li Yu has made it clear this afternoon. His report contains it.
49. If the first three companies have passed the clinical effectiveness test, what can other companies do? Can they choose one of the first three companies as a reference?
A: I feel a bit late. All three clinical trials have been completed, and the time limit we may give is 2021. As for how to push our current reference preparations and what to do in accordance with existing guidelines, our clinical work is also constantly improved. In the next stage, we It is necessary to consider the formulation of the Orange Book of National Generic Drugs, how to prepare the Orange Book, and which can be used as a reference. I believe that we will focus on that stage, and it will be more accurate to answer this question at that time.
50. The period of purchase of the reference preparation must be shorter than his expiration date, so how long does it take to stabilize the reference preparation? Do you do it every month for long periods of 0, 3, 6, 9, 12, 24?
A: Actually, this morning I also mentioned that the reference preparation has no stability, only the dissolution curve. In order to prevent the reference preparation you bought from being different in the review process in the future, you need to do a stability study (dissolution curve). After the specific preparation is bought back, a dissolution curve will be made because of the pre-experiment. Then, during the pre-experiment, for example, the dissolution curve of the reference preparation can be made again after another one or two months to see if the reference is Is there any difference in the dissolution curve? It is not to say that the reference preparation is used for stability test, and there is no reference preparation stability check in the requirements of our application data. It is just that you have to do one after your prescription process is changed. Stability study. The reference preparation does not need to be checked for stability, but only for rechecking and repeating the dissolution curve test.
51. The raw materials used in the generic drugs produced by the company are produced by the company. What related experiments or precautions are needed for the raw materials?
A: You can do more in-depth research on the APIs that you produced yourself. Maybe you already did some research when you originally applied, but it may not be enough. In the new one, you can find the original research and reference. After reporting in the literature, compare his crystal form, particle size and other information. It is more convenient to make your own API. If you cannot get the original API, you can do some crystal form research based on the literature information and so on. In addition, impurity inspections and related substances such as the European Pharmacopoeia are more detailed. Some products make dozens or more of related substances, so from the source control of the drug substance, can your related substances reach foreign countries? These are the relevant research you can do. The more you do and the deeper you understand him, the greater your confidence in passing.
52. When selecting a reference preparation for a sustained-release variety, the original research has been discontinued. There is only one preparation with the same dosage form and specifications but different release mechanisms. Can it be used as a reference preparation?
Answer: This involves the issue of the release mechanism. We see that the guidelines we have given are all oral solid preparations. Slow-release preparations are relatively complicated. The industry also often discusses this issue, such as slow-release preparations and ordinary preparations. The release mechanism is different, so why should I be the same as your curve, or my curve is different but the same in the body, these problems are very confused in our early exploration process, although this statement is correct, However, if you do not use a curve to determine, especially for sustained-release preparations or other special varieties or preparation processes, it is difficult to draw the conclusion that the curative effect is consistent. The FDA has not said that in generic drugs, especially slow-release preparations, everyone The release mechanism must be the same, and this is not the key point of pharmacological equivalence. The release mechanism can be different. Therefore, if the sustained-release preparation is to be done, it is necessary to do BE, and if BE cannot be done, it is necessary to conduct clinical trials. The light from the perspective of the dissolution curve is not enough to prove his equivalence.