修订/更新CEP的要求 新版EDQM指南研讨会问答环节附属稿（整理）与概要

Q1. Whether you could actually request an extension of the time which you got allowed to respond for any request for additional information?
A1. This is something which may be necessary in some situations. We do encourage full complete data package at submission for rapid acceptance of the change. But if when you read the deficiency letter, you realize that you have more relevant work that you have to contact the supplier, then contact us and explain the situation and we can often give you an extension for the time for you to respond to our request for additional information.
CEP持有者可酌情向EDQM提供合适理由、请求延长缺陷信的回复期限。

Q2. What we understand to ‘being substantially different route of synthesis’?
A2. Now we have made it clear that we’re gonna give further guidance in the near future as to what we understand. Currently, if you look into the document, we do give examples as to where a substantially different route of synthesis will be introduced, which are likely to change the specifications of the final substance, and examples there do include changing synthesis strategy. It’s quite clear that if you are gonna change synthesis strategy, which is to say, you got different synthetic intermediates, you could have different  starting materials. Then this would definitely be considered as substantially different. But then what comes afterwards, new reagents, and there is an example submitted at a question where you go from sodium hydroxide to using potassium hydroxide. You know. This is obviously something that could have no affect really at all upon the  impurity profile at all. And then the examples continue with different  solvents are being used or different materials, and I think really that, just explain from my experience, lifecycle management is becoming something really important that we need to pay attention to and that a separate certificate where you are introducing a substantially different route of manufacture would be the preferred way forward for lifecycle management. And this is what we would encourage. But there are some examples, lithium to sodium hydroxide whereby you could be accepted continuing to describe in the same file. So we’ve got a spectrum of different examples which we are hoping to tie down in the near future and give guidance where we would be considering this to be substantially different. And where maybe even though you could be changing the  solvents, we could accept that as not being substantially different. We are going to tie this down in the near future. But what I would say is that the reason for doing this is lifecycle management. It facilitates lifecycle management for CEP holders but also for us. And if you are in doubt, please do contact us before hand, before submission. And if you are going to submit something which you consider not to be substantially different, it’s your interest to really explain to us why it is not substantially different. So really to take a massage to the various questions we received on this issue is we are gonna be trying to get clarity on this in the near future. There are some examples which are clearly a substantially different route of synthesis but there could be others that are much less obvious. And therefore you may wish to justify why it’s not substantially different, and then contact us. So that what I'm gonna say on this issue.
“合成路线具有本质上的区别”是如何定义？（案例广泛，情况复杂）EDQM计划对这方面内容推出指南。

Q3. Item 4.II.1.4 of the revised guidance does not include the changes of manufacturing process of a starting material under which item the changes of manufacturing process of starting materials are evaluated.
A3. The answer to this question really is, if the supplier of the SM is making changes to the manufacturing process, it’s for the CEP holder to be informed by these changes and then for the CEP hold to evaluate whether the  specifications of the SM are going to be impacted. And if the specification of the SM are gonna be impacted, they have to be declared to us accordingly. And if following the changes in the specifications of the SM which are gonna be impacted, you may have to also look at what the specifications of the final substance are also impacted. So if the specifications of the SM after you have evaluated them as CEP holder, if the specifications of the SM remain unchanged, you don’t have to inform us about that. If you are actually going to change some information which has been submitted, you would need to notify us of that. But if the specifications of SM need to be changed, you declare accordingly.
CEP持有者有责任对 起始物料的 工艺变更进行评估、进行相应行动，并酌情通知EDQM。

Q4. If micronization is included in the ASMF, if the process reviewed by EDQM, if the grade micronized is not applied as CEP name.
A4. Now we expect manufacturers to be declaring what they are doing to obtain the grade of substance, if there are physical process steps carried out, you should be declaring that. But as you probably know it’s optional to include in the subtitle a grade like  micronized. Now, if we have not included that subtitle in the CEP, that means we have not evaluated that part of the process, we have not taken a critical review on that. And therefore (without) this information if you are going to be using the certificate for a micronized grade of material, you need to be providing to your customers all of the information dealing with micronization, you need to be providing the description of the method which is used to determine whether the material meets the specification for micronized grade material. And this information has to be submitted to the national competent authorities in the context of the medicinal product, and it is them who would be evaluating this. So we expected things to be declared in the file. So if physical processes are being carried out, you should be declaring it in the file. But if you’re not gonna put subtitle on the certificate, we will not evaluate that.
如果 申报人想要将API微粉级别体现在CEP证书副标题，就应提交相应信息。如果证书副标题上显示API微粉级别，则表明EDQM已审评并批准相应内容；反之亦然 , 则申报人就应将微粉工艺描述提供给申报制剂的客户 , 由国家主管机构进行审评。

Q5. The revised guideline gives various examples dealing with biological drug substances.
A5. And I confirm that has been no change in the acceptability of the certificate suitability for a biological substance. We cannot acceptance applications for biological substances. This is following a clarification made in 2004 in the ASMF guideline document, it was included in an annex. And Heads of Medicines Agencies has published what probably is a known exhaustive list, giving a list of substances they consider to be biological, and we cannot accept that applications, so the examples which are included in this revised variation is for the existing CEPs prior to 2004.
该指南不针对 生物药。HMA在2004年列出过定义生物药的清单。

Q6. If we submit an application for another CEP e.g. sister file, can the validation batches for the sister file be sold in the EU market after we get approval for the certificate?
A6. The answer is YES. Those batches have probably been described in the sister file application. But once you have got approval for the sister file, batches manufactured according to what you have descried in the sister file including the  validation batches are then covered by the certificate of suitability.
申报（包括sister file）批准后 ,  工艺验证批可以用于销售。

Q7. If there is a deletion of noncritical raw material from the last stage of the active substance, what's the type of change?
Firstly, again, the question is what is considered as noncritical. What you need to be doing is looking at the impact of deletion of this  raw material. So is there any impact on the  impurity profile of the final substance, for example? If there is indeed some impact, you should be considering it as change 4.II.1.4 c) which would be major revision. If it is something which has no direct impact, zero impact on the impurity profile of the final substance, then it could be something submitted as a minor change by default. However, since this is something impact the last stage of the process, it could not be submitted just as Annual Notification. It is something for which an evaluation is needed.
对最后一步工艺删除 物料的变更分类：应评估该物料的影响。

Q8.Can we demonstrate equivalence for only one batch for revision of the application?
A8. As you see in the guidance, we always ask for batch analysis data for at least three batches of the final substance. And we recommend that you give appropriate level of equivalence with three batches.
证明等同性通常需要3批数据。

Q9. If there is a change in the name of manufacturer for different group during the ongoing review process for alternative sites, what do we do?
A9. Firstly, it should be stressed that changes which are declared during an ongoing evaluation process generally cannot be accepted and should be submitted as a separate request for revision or notification depending on the change. Now in certain cases, such as this, where there is a change in the name of manufacturer during the ongoing review process. I’d like to refer back to slides in Nataliia’s presentation, where of course, when the guidance is once implemented, it will not be possible to have an alternative manufacturers for final substance from different groups. However, if it’s an intermediate manufacturer, then the requirements for this change would be submitted as a change 4.II.1.2.b). So you will be looking at the documentation and conditions to be met for that change. Now if it is during an ongoing evaluation, well, we recommend that you contact EDQM, explain the situation, explain that there has been a change in the name of manufacturer, and ask if it is possible to submit supplementary information. So that would be submitted as support. Again it depends the status of the evaluation, depends on the nature of the change. But, what we recommend, for instance, is to contact EDQM You talk to EDQM, explain your scenario, and see if exception this change could be taken into account during the course of the evaluation.
审评期间不允许递交变更。无法判断上报方式的特殊情况下建议咨询EDQM。

Q10. Can you repeat what is meant by ‘the same group of companies’?
A10. As you can see in the revised guidance, we have reference to if new suppliers are part of the same group. What we mean by this is that, is the proposed manufacturers part of the same legal entity. So it would be the CEP holder's responsibility to demonstrate how a company is part of the same group. If it is part of a different group, then it should be appropriately categorized. But it's the CEP holder's responsibility to show this newly proposed company is part of the same group. So, for example, the new company may have a different name, but part of the same holding company, the same nature of company.
“同一公司集团”的定义。　

Q11. For baseline sequences, do we need a complete set of module 1 documentation?
A11. Just to briefly remind people that ‘Yes’. For baseline submission, if it's part of a minor revision for example, we do need, of course, the application form, a cover letter, appropriate supporting documentation. And what I would recommend to people is to refer to the existing webinar ‘Electronic submission’ which is available on EDQM website, before preparing a baseline submission.
全套递交（尤其在纸质转电子递交时）需要完整的M1资料。　

Q12. If a new starting material manufacture uses a solvent which is already used by the existing starting material manufacturer and the API process, is it necessary to monitor that solvent again?
A12. Again, this depends on the nature of the solvent and the  package prepared by the applicant. When there is a  control strategy in place for that solvent in the API manufacturing process, this could be used as a reason to justify why it is not specifically controlled in the starting material. Although, it really depends on the solvent, (and) really depends the nature of where the starting material is introduced into the process as well.
对新增 起始物料中使用的 溶剂，如果在现有起始物料或在API中已经使用，其控制策略取决于溶剂本身属性、现有 控制策略、起始物料使用点等。　

Q13. Does this new revision guideline has impact on the EMA’s variation guideline, for example, the DMF procedure?
A13. What must be reminded to people is that this guideline apply only to CEP procedure. So if you are applying for  variations for  DMF, you should refer to the EMA variation guideline. Although, there are a number of changes which are similar. The guideline we are talking today is exclusive to CEP procedure.
该指南只针对CEP程序 , 不针对EMA的DMF程序（虽两者有相似之处）。

Q14. Is it considered as a minor change if we use a new starting material from the current approved manufacturer, with the same specification but different  analytical methods for some of the parameters?
A14. If there is different analytical method for some parameters, of course, it depends on what the parameters are. If they are critical parameters, related substances, for example. We do not expect cross validation for starting material methods, so we wouldn't consider a complete package, like, if there were alternative related substance methods used in final substance, we would expect much more complete package.
新增起始物料方法改变的影响大小取决于对应检测项目的重要性。EDQM对起始物料方法的数据量要求少于对API的。

Q15. In the new guideline, the revision for addition or replacement of quality control testing sites has been deleted?
A15. In fact, it's been moved slightly. So if you refer to the guideline, in section 4.II.1.3, you will see change related to where relevant to change in  quality control testing sites.
质控场地的新增或替换的变更 , 其描述在新版指南里移动了位置 , 并没有删除。　

Q16. Which kind of change is the change of temperature during manufacturing process if the specification of the final substance remain the same?
Basically, if the synthetic route remains the same, and if you are doing adjustment of operation conditions such as  temperature, taking into account the parameter change, data can be proceeded as notification. However, you should check that the conditions we state are all fulfilled.
工艺温度改变的变更类型。　

Q17. Has the application form for renewal or revision been updated?
A17. We are currently using application form for request for revision of CEP 056 Revision 12, in 2018.
变更申请表的现行版本。　

Q18. The section 1.1 in the application form, does the application for new CEP correspond to grade?
A18. Just to make it clear, if you want ‘grade’ to be stated as a subtitle, fill in the text that would correspond to your grade.
在申请表的1.1部分可按照需求填写API级别，它将成为证书的副标题。

Q19. Can we apply your guideline for submission occurring before January 2019?
A19. For the reasons of being equal with all of our applicants, and to avoid administrative issue, we strongly recommend you to keep to the version 6R during 2018, and only to submit your applications in line with the version 7R starting from January 1st. so up to the end of this year, please use the current version 6R, and 7R would be applicable next year.
EDQM强烈建议在2019年1月1日新执行之前 , 也就是在2018年内仍然使用目前的6R版本指南。　

Q20. If CEP is due for renewal, whether major revision can submitted before renewal or after renewal application?
Q20. We remind you that major changes cannot be included in your renewal application. When you are submitting renewal, you are only authorized to include the certifications or minor changes. So you should check what is the  expiry date of your certificate. Normally, you will be submitting your request for renewal six and half to seven months before expiry date. Major revision can be submitted before that date. But you should be reminded that you will have procedure for assessment of major revision which will take two months, and in some cases, we would need additional information, so you would need time to provide to us the additional information, and we would need time to assess that additional information. So we would strongly advise you to evaluate the time frame of submitting major revisions. In some cases it is better to do after renewal. In some cases, it might be done before, but you should ensure yourself that there is sufficient period left before the renewal to be submitted.
在renewal递交前夕或期间，不建议递交重大变更。应做好重大变更递交的时间计划。

Q21. Is transfer of holdership required in the case of change of administrative status of the current holder, same site of manufacturing, but social reason changed?
Q21. In case if the CEP holder itself is not changed, so you are not transferring your holdership. If it is the social status that is changed, I guess, that would have impact on the name of the company, so that should be declared to us as administrative change of the name of the company, if that is impacted. But if the holder name remain the same, there is no change.
CEP持有者的行政状况变化。

Q22. We wish to know the current thinking of EDQM on equipment variations used in original submission, for example, changing drier used for drying a final substance.
Often, we get a pretty generic description of equipment which is being used in the manufacture of the substance. Sometimes, we get a bit more detail given by the applicants about the type of equipment which is being used. We're not gonna look for details into the equipment which is being using. A generic description is sufficient to tell us what you are using to manufacture the substance. But the example in the question, for example, changing drier used for drying of final substance. This is something which immediately jumps out, that could have a high risk here, or you could be changing the technology of the drier, it could be that the final substance is a sterile grade of substance. So this is really something which is going to be attracting our attention a lot more, because we are dealing something used to obtain the final substance. So it could be the changes which have been made to the description of the equipment in the original submission, could be declared as an annual notification. It might be, that you are not going to be able to say it’s a non-significant change to do description of equipment, therefore you would have to declare it’s a minor change. If you are going to include some new technology, to dry the final substance, if you are dealing with sterile grade of material, this could well be a major variation which has to be declared. So a generic description can be acceptable. If you are changing the technology which is being used then you are going to justify, it could be a minor, it could be a major.
EDQM对CEP文件中的设备信息只需概况，但是设备变更也可能是重大变更。

Q23. Is there any procedure possibility to ask for an accelerated review in case of major change?
A23. Basically, the answer is No. we have two months in which to evaluate major change. If you want to get rapid acceptance of the major change, we encourage you to supply a full data package. We are currently respecting our deadlines, in which case, there will be a response within two months from us. If the data package is incomplete, there should be positive response. However, if for public health concerns, there is an authority which is awaiting acceptance of the change, then you should inform us of this. And then we will be looking to with national authority whether there is need to get this down as quickly as we can. So if there is public health issue should national authority expecting a revise CEP, please notify us of that.
EDQM不具有对变更的进行加快审评的程序，但是在影响公共安全情况下（CEP持有者应告知EDQM），会酌情加快程序。

Q24. Different routes of synthesis with different manufacturers
A24. If you are gonna have different route of synthesis, we will be looking for new certificate. And something that we are going to revising will be requirement for a new application to make it clear that, in the new application you cannot have different routes of synthesis even if the impurity file is the same. So the procedure for the new applications will get revised next year to take on board the fact that we are looking at when there is a substantially different variation you need separate certificate, and we will corporate this in this guidance as well.
对于新申报程序，EDQM计划在明年开始不允许一个CEP中同时上报具备不同ROS的多条工艺。