July 26，The State Administration of General Administration held & ldquo; the quality and efficacy consistency evaluation training course & rdquo;，Recording according to questioning，Set up notes as follows。No deletion，Strive for objective。This question is not perfect，But many answers have practical guidance。If you have any objection to a certain content，can be proposed，I hope everyone can discuss it together，turn the inconsistent sound into consistent。

 

  1. In 1622 varieties，How to declare the question again:

 

  Answer: The clinical production and development site verification is not formulated in this consistency evaluation，The rules have always been checked at the registered production site、The development site and clinical verification，So the execution standard should be a standard，There are no problems with new standards and old standards，The standard is the same。

 

  2. Search for reference preparations:

 

  Answer: Homemade products are capsules，But the reference is tablet，Is it feasible? This variety of dosage type needs to be further studied。

 

  3. Prescription process、Whether the packaging must be consistent with the original research:

 

  Answer: No explanation said that it must be consistent，This is not a necessary condition。

 

  4. Is the quality of quality and the equivalent of biology?

 

  Answer: Specific analysis of specific varieties。Seeing him does not need to be dissolved，But for us，The work of dissolution curve is done carefully、a little more meticulous、Find out a feature -dissolved curve，To control the quality of production，It is also an important content of this consistency evaluation。

 

  5.，Where to approve the quality standard of the change?

 

  Answer: Finally enter the quality standard for solubility，One or two points can be found on the dissolution curve to formulate the solubility。If there is no solubility in the quality standard (equal to the promotion project)，or now there is a solubility，But the indicators selected are not very suitable，Or the dissolution conditions of the solubility during this dissolved curve changed，These involve changes in quality standards，belonging to the Pharmacopoeia Committee，If it is a variety or registered standard，It should be to contact the Pharmacopoeia Committee to propose the change standard。

 

  6. Amoxicin Capsule "Chinese Pharmacopoeia" standard is 30min to 80%，But the dissolution speed of the reference preparation is very slow，less than 80%，How is the consistency evaluation?

 

  Answer: Why is this product slow，What is the reason，Need to make appropriate analysis: 30 minutes dissolve to 80%reasonable。The dissolution limit of the pharmacopoeia is not necessarily very in place，Before 30 minutes reached 80%, even if it was dissolved，But maybe our conditions were more intense at that time，or add a solvent or surfactant to the dissolved medium。I don’t know the dissolution conditions of amoxicillin capsules，but 30 minutes is 80%suitable，The dissolution of the reference preparation is consistent with the dissolution conditions of the Chinese Pharmacopoeia，Which is more reasonable，This requires specific analysis，Analysis can be made to answer。

 

  7. The same variety is collected in Japanese orange peel，Consistency evaluation can be directly learned?

 

  Answer: What kind of method is used，Where to collect it，Where is the dissolved medium collected，or the literature you checked，All can be used as a choice of soluble medium as a solubility curve method; can the solubility be used directly to use，You can use，The key after use is to see if the result is suitable for your variety。

 

  8.，The first sampling point mutation coefficient is greater than 20%，The rest of the sampling points are also greater than 10%，How to compare F2?

 

  Answer: First of all, to confirm whether the reference preparation is really a big difference in batch batch，or this difference is generated by your own method，Whether it is due to the large differences in batch batch。If there is no problem with the method，is a method of moderate distinction，The reference preparations are indeed uneven in -approved，So the sample can actually be used as a reference preparation，Should need to change the ginseng。

 

  9. Large specifications and small specifications capsules are exactly the same as that of the prescription and process.，Can the in vitro dissolution curve only compare with large specifications?

 

  Answer: In fact, both specifications must be done，Although the prescription and process are exactly the same，But their main medicine content is different; the main medicine content is different，It is possible to dissolve in vitro that is inconsistent，This still needs to be verified by experiments。

 

  10. In vitro dissolution、Inside and outside the body is not completely related:

 

  A:，Being directly to be risk is definitely a bit big，But it doesn’t mean that it must not be equal to，In this case，Of course we use BE results as the final judgment result，That is, the excess of the body is different from the body，But we also have to establish a distinctioned dissolved curve for this variety，This is two different things to do with BE。So bes? Of course, still use BE's test as the final judgment。So the establishment of 4 curves is incomplete，But with distinction，Can it pass? If BE passed and consistent，and the dissolution curve has a distinction ability，So do we think it should be passed，But your dissolution curve should be exactly the same as you can produce in the future with your sample，The dissolved curve should be exactly the same，This can ensure that future products can also be equivalent to biology。

 

  11. The impurity spectrum of the raw medicine and the comparison of the original research preparation，Impuerment spectrum has two more impurities less than one tenth of 10,000:

 

  Answer: Analysis of impurities spectrum，It is necessary to compare it under the same chromatography as the original developer，If the impurities are small，According to SOS regulations，As long as one thousandths or more，What the impurities are required for the impurities; if it is very small，impurities below one in 10,000，If one thousandth is very sensitive (one thousandths have arrived below the test limit)，According to SOS regulations，One in 10,000 needs to be analyzed according to the dosage of the daily dose。I think this is actually a comprehensive judgment: compared with the original research，What are your many impurities，Can you explain，Another，Is the quantity relatively large，If the amount is relatively large，More than one thousandths or even more than two thousandths，So what are you going to make this impurities，Whether it will affect the efficacy，Whether there are toxic side effects; if very low or even one thousandths，So can you reproduce，Generally one thousandth is a basic detection limit，It can appear repeatedly in each batch，Or is it just a chance to appear，This requires specific judgments based on specific issues。But if one thousandth is a known toxic impurities，According to foreign pharmacopoeia，such as usp、EP，Their control of raw medicines，For the known toxicity，The lowest can be controlled to 0.1 ppm，So we can't say that we control it in one thousandth，This needs to be based on specific impurities (whether degraded or process)，How big is the toxicity，Specific structure，This is all。So，I can’t sit here to tell you that I will not be controlled by one in 10,000.，or two more you can，This is hard to say now，You need to conduct further research。

 

  12. Use the same production line production in China，stake betting appIn the United States、EU、Drugs listed in Japan，The original listing declaration information was reported in 2005，It is somewhat different from the recently approved application information，Whether this will affect the approval conclusion:

 

  Answer: The question is not too specific，I think it may be that domestic registration materials and the latest registered materials abroad are different，For this point，Actually，What I understand is the current emphasis on registration permit，At the same time, emphasize the same production line，Use the same prescription process and the same management to produce preparations，Prove that this is consistent through consistency evaluation，This is the premise。Differences on the application information，I don’t know if you are changing in new crafts in Europe and the United States，Whether the change of this change affects the quality of the product，In principle, you should use this consistency evaluation to consistent the premise of domestic listing information with foreign listing information，If it involves supplementary application registration，This time, we must also add all related to the evaluation conclusion，Consistent conclusion is that these quality are consistent。

 

  13. The consistency import registration is introduced in June，Foreign reference preparations were purchased before June，So can the reference preparations purchased before June can be used for pharmacy research?

 

  Answer: I think if it meets various requirements，It's just a problem with time，Then you have no problem in doing research，As long as you guarantee that you use the quality of this thing，Doing research is possible。

 

  14. Can the consistency evaluation production inspection approval be used for listing and sales?

 

  Answer: If the batch of consistency evaluation is safe and effective，and the product is produced under the premise of legal compliance，So it can be sold for sale，No say can't say it。

 

  15. Specifications of reference preparations: The specifications loaded in the orange book are different from the fact that the factory or the company's production，Some are collecting large specifications，What you do is small specifications，Some are carried by small specifications，I do large specifications

 

  Answer: This problem also includes inconsistency of the dosage type，If you look at it unified，means that there are problems。This question also mentioned just now，There is no clear conclusion，Instead, you still need to study，and we get less information，So we don’t know where your specifications or the rationality of the approval of the dosage type，So I suggest you fix it first，There is another question，I can choose the United States at the same time，You can also choose the EU at the same time，Is it possible to，I think this is best to have a sequence，What to explain when filing is the first choice。

 

  16.，Approved to be listed before October 1, 2007，Need to complete the consistency evaluation before 18 years，So I got a listing license after October 1，Is it not necessary to complete the listing declaration at the end of 18 years，If it will not be accepted after 18 years?

 

  Answer: The file is very clear，For the approved listing for listing before October 1, 2007，It must be completed in 18 years。Actually，For these varieties，Especially for our compulsory requirements in 287 directory，Of course，If you happen in various situations in the process of doing，You can also reach 2021，These special circumstances such as clinical trials，This takes time。Another，The word of the file of the file，After October 1，I did not ask you to complete it at the end of 18 years，This is no problem。but，Actually everyone knows，Evaluation of consistency，There are many good policies，If people are done, you haven't done it，Whether it will be unfavorable in the market，Therefore, although we have no mandatory requirements; in addition，The file was just introduced，Some people also ask some varieties that are not within the range，So do these varieties cannot participate in consistency evaluation? Actually not。

 

  17. Consistency import:

 

  Answer: Consistency imports are the General Administration of Pharmaceutical Research for everyone，There are also consistency evaluations，Policies introduced，Whether used for generic drugs or consistency evaluations，I have a foreign medicine here，If there is a certificate, it is a situation，But if there is no prove、How inconvenient to buy in China without listing in China，Everyone is paying attention to the consistency evaluation document solicitation document and the final release draft.，I personally think that the main change is to remove the many bottlenecks that were restricted to this matter，So there are two problems in this: for the foreign country's approved listing certificate for importing control drugs (can provide a legal certification document for national drug listing、Pharmaceutical Import Manuals listed as soon as possible or disclosed information on the website of the National Drug Supervision Department) His questions are that these three are or choose them or choose themselves，I personally think that every one of the three items can，Of course you get the best in three items.。

 

  18. When is the Submitting channel for the submission of consistency imports，What are the submitted information in Guangdong Province，Is choosing 1 or 1+2 to choose 1?

 

  Answer: This question is given to our provincial bureau，Very targeted，Need to connect with the provincial bureau。

 

  (Refesting preparations for references，But the original manufacturer of the reference preparation does not provide his manufacturer's certificate，In other words, it has not promised to import or origin with domestic imports，This commitment requires us to let the original research pharmaceutical companies provide a promise of imported drugs with the consistency of the native country.，This promise actually needs to be submitted in the process of reference preparation declaration。）

 

  19. I can find a lot of standards，But the differences between these standards are large，How to choose? How to choose the configuration method of control products used in different media?

 

  Answer: These selected documents reference or used，All should be determined by the company's side，Including a work of consistency evaluation，Those experiments you do，Whether it is inside or in vitro，Your purpose is to prove to the approval person that your product is consistent with the original research or reference，Not we have to set a limit，Then you can reach this limit，It will not work without reaching this limit。Selection of different dissolved medium，Selection of the controlled solution selected by different solubility，Maybe a variety can，But the method of changing a variety is not possible，So we follow a certain basic principle for these methods or parameters，No said it is a general choice method。

 

  20. American reference agent RLD is generally large specifications，Can the small specifications of the same manufacturer be a consistency evaluation?

 

  Answer: (This question is not what I said，But I can tell everyone about my understanding) First of all，We should follow the principles of guidance when choosing and various files currently introduced，We do consistency evaluation reference preparations to choose the first choice is the original research，Here，If the same dosage form and the specifications，From a way to persist，The theoretical comparison error is the smallest，So we don't need to have a large specification of large specifications because of his large scale in foreign countries.，Obviously there are small specifications、We do not choose the same specifications。The choice of reference preparation should also grasp its principles，I can't say that I only choose RLD and other specifications will not work。

 

  21. Three batches of references have differences，How to determine the curve? Three batches are average，How to choose?

 

  Answer: If the difference is very large，So you should doubt whether this variety can be compared。

 

  22. What sample is the establishment method，Is it a reference preparation or a homemade imitation preparation?

 

  Answer: Actually, I said it in the PPT just now，The method of establishing the tests we carried out uses a reference preparation。

 

  23. The reference preparation used by the drug inspection is provided by the enterprise or solved itself?

 

  Answer: The reference preparations at the time of review are provided by the enterprise.

 

  24. BE experiment，How to perform the proportion of gender? The original stake sports betting appFDA audit report said that the product has no gender difference，So how should the gender ratio be required during actual test?

 

  Answer: I just talked about why we have adjusted in this aspect，means experimental data indicates，The mutation of women in the subject is greater than men。The same drug in the original research approval report has no difference in gender，Is there no difference between his AUC and CMAX? Female subjects are greater than men，Therefore, from a statistical perspective，It requires a certain proportion difference。Another，FDA review report，The purpose of new drug evaluation and generic drug evaluation is different，Therefore, there may be some differences in the experimental design。The proportion of female subjects does not do strict limits，The main depends on indications、The pharmacological effect of the drug、What are the applicable people in the future，If it is a general population，Then we stipulate a proper proportion，No exact data，The current guidance principle is just a guidance，means to provide a data with a representative crowd as much as possible。

 

  25. There is a specific medicine，The human body's absorption rate is low，An indicators used abroad for consistency evaluation，So can we also use this?

 

  Answer: I think some of the guidance principles abroad can reference. We can learn from，You have to combine your own variety，During the experimental design, be sure to use the clinical efficacy evaluation as the indicator，To combine the actual medication of the patient。So the indicator you choose is not enough，Is it enough to explain the clinical efficacy，Still depending on the pharmacological effect of this drug、What is the mechanism of clinical effects、What indicators are available in clinical observation to refer to。That is to say, foreign guidance principles can be used as reference，Just as the applicant, you know the most of your own variety，There may be a expectation for his future clinical efficacy，At this time, you have to use your subjective initiative to refer to the guidance principles abroad。

 

 

  26. Is the stability inspection of the dissolution curve?、Is the stability of the inspection reference preparation a batch or multiple batches?

 

  Answer: I said this morning，The reason why the stability of dissolving curves is inspected，It is a product with unstable physical and chemical properties。We will consult some literatures in the early stage，If there are reports that this is not very stable，So you have to be careful，Do more work; but if it is very stable，You can do a try，Do a more harsh，such as strong acid，See if the change is big。Actually，We don’t ask you to dissolve stability.，Unstable in the nature of chemical and chemical; but if you are not assured，You better do it，We don’t ask you to do all the curves，For the number of in my heart，You can do one or more，This has no mandatory requirements，Because this is the foundation for the review behind you，So we have no need to do it，One or four must be done，or more and less。If it is stable，You can also do it，If you are very confident。Another，Is the reference preparation a batch or multiple batches? If you only buy a batch (only)，It is impossible to ask you to do multiple batches，Another，The purpose of making multiple batches is to examine the uniformity and overall stability of the reference batch。So there is no compulsory standard，This is the judgment of everyone's own research process。

 

  27. For special varieties，If there are important extracts，Like these preparations with Chinese characteristics，Why do you need consistency evaluation?

 

  Answer: Although these varieties are preparations in China，But can its curative effect and quality be guaranteed。Who evaluates with，Who is consistent with，This is not to say that there must be a fixed mode。Say in the question，Have the National Bureau announced some suggestions，or information? In fact, these special preparations，It should be the main body of your company itself，You should know the most about your own products，How to ensure quality and efficacy，This should be a plan for your own evaluation，So our company should have brains，instead of you let me do it, what can I do，In fact, each variety is different，Each variety has his particularity，So we can't give each breed a fixed mode that this variety is done，For example, compound licorzide tablets，I know it has very complicated extracts and so on，Then you must not say that you can also make four dissolved curves，This cannot be done at all，So how to evaluate it? Is his quality controlled，At present, more than 30 companies in the market are produced，So these 30 people are definitely not the same，Some appearances are different。So how do you make everything the same，This should be the role of each manufacturer or the association，Putting a feasible evaluation method for this variety，If control quality，Licorice molecoping its content includes its fingerprint map、Fixed control of crafts, etc.。These unable to use conventional evaluation methods，So we hope that companies can propose an evaluation plan for this product，In fact, it is also through this consistency evaluation work to improve our quality、Improve our efficacy。The feedback of this year's products in the market、The efficacy of the hospital, etc.，It can be widely solicited from the feedback of the clinical hospital of the unit，This can be used as your product to provide some basis for your products。Then improve the quality standard，These special varieties have special evaluation methods，So we need our company to move their brains，Each evaluation method needs to be proposed，You can also contact related work units，Discuss，Put forward a feasible and convincing evaluation method，Then carry out the corresponding job。Then the consistency evaluation team will organize relevant experts to evaluate your plan。Now our teacher can't give you a more satisfactory answer，Say your variety should do this，This is not very realistic。

 

   28. Reference preparation filing is cumbersome、Long time，Affecting the progress of the company，Can it simplify?

 

  Answer: I'm here to clarify a little，The filing of the reference preparation does not mean that you must prepare，Must be prepared，Can't do subsequent jobs if you don't have any trouble。This is okay，In other words，If the state has announced the directory of the reference preparation，Do you still need everyone to record? unnecessary。So whether it is the record of the reference preparation or the recommendation of the association、and the original research enterprise or internationally recognized generic drug enterprise to make independent declarations，Mainly a multi -measure，Many different subjects with different situations，All to get information of the reference preparation faster，I believe that the channel information you get is the same，Full Literature Data，So after the expert review，So it is easy to reach consensus。If the things you report are uneven，So the more things you report, the more things you report，So the more complicated this situation。Another，As far as I understand，Some companies that have made relatively large kung fu records，No waiting for the announcement of the reference preparation will start related work。So 60 working days of reference preparations will not be able to come down，Because the situation we are currently facing is quite complicated。

 

  29. The same variety，How many enterprises are united to recognize the National Bureau?

 

  Answer: I'm hard to say that the State Administration is recognized or not，But as I know，The National Bureau is to encourage the industry to engage in the alliance，I don’t necessarily do it as just your family or every family，Then you can engage in this communication，But you ca n’t want everyone to report this set of information，I personally think this is OK，Research research、Communication of communication、Share sharing，But you must eventually do it on your own production line，Do your own BE experiment，Several joint enterprises can report a number number，But you can't because you are together，All the same，So one of them must be criticized for three。

 

  30. A variety has three medicines that have been bidded through consistency evaluation work that have not passed consistency evaluation，A variety is a new category approved in 2007?

 

  Answer: Class 1 new medicine is 1 point，If it is Class stake sports betting app1.1，Then you are the original research，What are the consistency evaluations of what else; if you are not in category 1.1，Then there are multiple situations，But the announcement of the General Administration is clearly written，Anyone who is inconsistent with the original research needs to be done，Just the rhythm is different，For example, what should be done in 2018。In addition, there is another problem here，I am an injection，Why don't you do it? No let everyone do，Injecting agents also encourage everyone to do，But the specific directory introduction is performed in stages，Let's do oral first，First, everyone is more concerned，Second, everyone knows that there is a process of absorption，The general absorption process has a great impact on the efficacy，So let's do it first。

 

  31.，So does the corresponding small specification application exemption still need relevant information?

 

  Answer: BE was made on large specifications，Small specifications must also be dissolved，It is necessary to prove that it is consistent with it。About specifications，We also said today，You first are the prescription must be exactly the same，The proportion is the change of equal proportion，Yes。If you have the relevant information about your small specifications and large specifications of BE test，Not to say that there is no need to examine the large specifications of large specifications，This is wrong。Your small specifications must also do related inspections of large -scale dissolved curves, etc.。

 

  32.，Low specifications are already on the market，The high specifications applied now have been completed by the BE test，So is the low specifications exempt?

 

  Answer: First of all, the BE test must have the test data，In addition, there must be high specifications that have been approved for you (that is, get batch)，You also have to prove that your low -specification and high specification prescription is completely proportional。First of all, you have to get a approval，Otherwise, it is not enough to finish the BE test。

 

  33. Different specifications，Some specifications can reach the platform (that is, all dissolved)，But the other 20mg specifications need 75rpm，That is, these two curves are inconsistent，So can 10mg of these two specifications be exempted from BE test?

 

  Answer: To confirm whether the prescription is the same，If it is the same as the size is different，The dissolved curve should be the same，But now the dissolved curve is 50rpm and the other is 75rpm to dissolve，Explain that your craft should be a bit inconsistent。So in this case, it cannot be explained that 10mg can be exempted，The reason for applying for exemption should not be enough。

 

  34. Do you need to record pre -experiments?

 

  Answer: Yes，Need。Preparation also requires the approval of the committee and filing，It also needs to be announced on the clinical experimental publicity platform。

 

  35. If the pre -experiment fails，Do you still need to re -record?

 

  Answer: Yes，Each clinical experiment requires the same treatment、The same filing，Approve by the committee、Then publicize、Perform experiments。

 

  36. Whether the BE report of the pre -experiment is also in accordance with the new standard、New CDE format submission?

 

  Answer: There are no strict regulations.

 

  37. If clinical approval has been obtained，Do you still need to record?

 

  Answer: I don’t know why there are such questions，These two are complementary，If you have clinical approval, you can also record，This does not affect the development of clinical experiments。

 

  38. Consistency evaluation and declaration data required for the situation that needs to be changed，Research on Crafts and Reference Preparations，Replenishing application for changing technology needs to be changed before and after the study，Therefore, whether this consistency evaluation process involves needs to be changed、Research between the three after changing and the reference preparation?

 

  Answer: For consistency evaluation，The purpose of any change is to study your changing products and reference preparations，See if they are consistent，Then there must be no need to study before changing; but if it is not for the work of consistency evaluation，Just your application for supplementary application，So you need to study the products before and after change。It depends on what you use。

 

  39. Does the personnel of the dissolved curve need qualification certification?

 

  Answer: Just mentioned just now，Personnel is a factor that affects the results of the experiment，Then the personnel must have to be trained，As for what kind of training, I feel that he can be suitable for work in this area，This is determined by the company itself。

 

  40. Can the dissolution curve be evaluated by the method of F1 less than 15?

 

  Answer: Yes。Not only the difference factors，Activity dependencies can also。What method do you use，or jump out of this method to use other methods，Both，But you have to make it clear。We use the similar factor method，Because everyone is familiar with、All are using，You don’t need to do too much explanation，F2 is greater than 50，We think it is similar; for other methods we are not familiar with，You have to explain it clearly: First of all, you have to let the reviewer understand that this method is applicable，Then you can use。

 

  41. Drugs are unstable in the medium of pH1.2，that is, it may be degraded 2% within 1 hour，How to study?

 

  Answer: I just said it just now，When studying the dissolution curve，Be sure to be different organs in the human body、Solubility and changes in different parts，And he examined the difference between the imitation preparation and the reference preparation，So，If we have degradation，Whether the original research or reference preparation is degraded，Are we down like him，After all, there are still differences from the body in vitro: degradation in the body，It is likely how much is it dissolved and how much is it absorbed，Before -degraded。So follow a principle here，You can do the same dissolving behavior as the reference preparation or the original development agent。

 

  42. There are differences in the shape and size of the imitation preparation and the reference preparation，For example, one is a round film、One is a alien film?

 

  Answer: The difference in appearance，Including color differences (such as a coat and one without a coat)，These are not essential reasons。What we want to examine is the consistency of his quality and efficacy，Differences have nothing to do，As long as the final efficacy is consistent。

 

  43. How to build a dissolved curve with distinction?

 

  Answer: This is not a question that is too easy to answer。During the establishment of the drug research and development, the establishment of the solubility method，It is difficult to explain in detail。I can only give an example: take the rotation as an example，If I finally chose 75rpm，Basketball method 75rpm is possible，Then why choose 75rpm, you have to make it clear，I will 50、75、100 of these all did，75 is the best distinction，So 75 is the best division of all the methods of all our investigations，So choosing it is a reason。

 

  44. If there is an imported original research，Be sure to have a commitment to a process and origin，How to get this promise?

 

  Answer: Maybe I didn't tell clearly when I just said，This refers to the original research company. When I declare it as a reference preparation，We need him to provide such a commitment，It must be promised that the production of the country is completely consistent with the country of origin。Real estate medicines also have such problems，You have to have a proof of exactly consistent with the original research，This is provided by the original research enterprises and the original real estate enterprises to provide this commitment。

 

  45.，Is the reference preparation during the pharmaceutical stage of the pharmaceutical pharmaceutical stage need to be reported?

 

  Answer: At present，The filing procedure of the reference preparation only evaluates the consistency。

 

  46. What to do if different specifications，What should I do if I change the dosage form? In other words, the dosage type that is not large is a small dosage type，If ordinary tablets are changed to decentralized or enteric tablets?

 

  Answer: The complexity of these problems lies in，Exactly the same、I can find it、How to do different proportions，What should I do if I can't buy it、How much to buy。Some modified dosage type，If the capsule is changed into a tablet，Then I use different dosage forms to go benchmark、Do be，Still say that this belongs to the scope of the reunification preparation，Because from the perspective of pharmacy,，Tablets and capsules are not equal Stake Sports Bettingto，Although they may belong to clinical replacement，but not the equivalent effect of pharmacy，This is a situation。Another，We still have another situation，We may have some commercial ideas at that time，or want to use the advantages of clinical aspects，So finally made a variety of changes，For example, I have to make a decentralized tablet、We do not need to do enteric -soluble.，At this time，Consistency evaluation is coming，Everyone will be very entangled: Can we use ordinary films as reference preparations，If you can do it, you can do it，If you can't do it, is it necessary to go clinical effectiveness，So these are all needed research，This is the first point。Second，According to the definition of current guidance principles，Original research, we can not care about the original research，But it is indeed not abroad、The first domestic，And even some varieties sell better，So can these varieties be used as the original research or reference，This is a new problem。There are also some varieties that are used in more medicines、But abroad is gone，or now there are no more than hundreds of in our country，and according to existing resources，I don’t know who is the first imitation，These are all needed research。The reference preparation is too complicated，Because according to our new registration classification，or after the imitation drug bill in the United States in 1984，We also used the same imitation requirements as them at the time，Maybe there are no current problems，How to solve several quality problems is definitely complex，Some of these are slightly changed，Some are changed a lot、Unable to find a product that can be compared abroad，There are some products，Some chemical medicines，Give a chemical medicine number，But it is obviously a biochemical medicine，and is a biochemical drug of multiple components，Not our simple synthetic or fermented，It might also give some chemical number number at the time，Then this is not a traditional chemical medicine，Do you want to comment，These are a problem that needs to be studied in the next stage。

 

  47.，Unable to find a reference requires clinical effectiveness test，So is it first carried out pharmacy research or directly entering the clinical effectiveness test?

 

  Answer: The file is very clear，For the need for unable to find a reference, clinical effectiveness test，This is divided into two situations: one、Not involved changes to the prescription process，Then the next stage can be conducted through the record of clinical effectiveness test，Nothing changed，Not involved changes to the prescription process，What do you look like now，What will be like in the future，Just do the clinical effectiveness test，Then there is no need to carry out pharmacy research; two，Change of the prescription process，So you need to make a supplementary application in accordance with the existing registration management measures，Supplement application, you can do what you do，Need to submit、Approval、Re -clinical。

 

  48. Is the clinical validity test conducting the clinical test clinical effectiveness test or the consistency evaluation of rising quality?

 

  Answer: This afternoon Teacher Li Yu has said it very clearly，His report is available。

 

  49. If the first three have passed the clinical effectiveness test，How to do other companies，Can you choose a certain part of the first three houses?

 

  Answer: Personally feel a bit late。Three clinical trials have been done，Maybe the time limit we give is 2021，As for how to push our current reference preparation，How to do it according to the existing guidance principles，Our clinical work is also continuously improved，In the next stage, we must also consider the formulation of the orange book of national generic drugs，How to formulate the orange book、Which can be used as a parameter，I believe that at that stage we will all be concentrated，At that time, answering this question will be more accurate。

 

  50. The deadline for buying the reference preparation must be less than his validity period，So how long does it take to do the stability of the reference preparation? Is it according to long -term 0、3、6、9、12、24 every month?

 

  Answer: This is actually mentioned this morning，Reference preparations are not stable，Only dissolved curve，To prevent the reference preparations you bought in the future, there will be differences in the review process，So you need to do a stable inspection (dissolved curve)，After the reference preparation is bought back, it will be dissolved due to pre -experiments.，Then in the process of doing the test，For example, after another one or two months, you can do the dissolution curve of the reference preparation，See if the reference is dissolved in the curve different，Is it not to say that the ginseng comparison preparation is used to do stability test，and in the requirements of our application information, there is no reference preparation stability inspection，Just when your prescription process is changed, you have to do a stability inspection。Reference preparations do not require stability inspection，Just to review，Repeat the test on the dissolved curve。

 

  51. The raw medicine used by the generic drug produced by the company is produced by the company，What related experiments or precautions are needed for the raw medicine?

 

  Answer: You can do a deeper research for the raw medicine you produced，May，But it may not be enough，After the new research and reference literature report you found in the new，Crystal type for him、granularity and other information for comparison，It is more convenient for your own raw medicine，If you can't get the original raw medicine medicine，Then you can do some crystal research based on the document information。Another，Ins an impurities check like European Pharmacopoeia、Related material, etc.，Some products make more than a dozen or more related substances，So from the source control of the raw medicine，Can your matter meet foreign requirements，These are related research that you can carry out。The more you do，The deeper the understanding of him，Then the greater the grasp you pass。

 

  52.，The original research has been discontinued，There is only a preparation with the same dosage form and the same specifications but the release mechanism is different，Can it be used as a reference preparation?

 

  Answer: This involves the problem of the release mechanism，We see the guidance principles we give are oral solid preparations，Slow -release preparation is relatively complicated，I often discuss this in the industry，For example, the release mechanism of a slow release preparation is different from the release mechanism of ordinary preparations，Then why should I be the same as your curve，or my curve is different but the body is the same，These problems are very confused in our early exploration process，Although this statement is correct，But if you do not use the curve to determine，Especially slow -controlled release agents or other special varieties or preparation processes，The curve consistent efficacy is consistent. It is difficult to give this conclusion，FDA also did not say that in generic drugs，Especially the slow release preparation，Everyone's release mechanism must be the same，Not the key point for the equivalent of pharmaceuticals，Democracy mechanism can be different。So if you need to do the slow -release preparation, you need to do be，BE cannot do clinical trials，The angle of light from the dissolution curve is not enough to prove his equivalent。