1. DMF request by the Chinese on API and Excipient, can you clarify is one DMF covering all or a DMF per API, Excipient, product?
Either separate or together. Both options are possible.
2. For a final granulate or powder that is intended to be used for the manufacture of tablets a contamination by packaging Material is detected. Is the manufacturer allowed to use optical separation techniques (validated), that are not registered, for this single batch? Is health authority notification/approval required?
How can a corrective action on an one-off deviation be validated? This means for inspectors, that this type of deviation occurs on regular basis.
How can you validate, if you cannot be sure about the particle-size of contaminating material?
Normally competent authorities would not accept such a procedure.
3. On MAH Responsibilities Concept Paper a couple of questions:
a. Regarding the de-harmonised approach across EU on MAH inspections, is there official information published on which countries are routinely inspected? Do the local authorities use a risk based approach to target those inspections? Is there anywhere published which are the most common finding?
b. When inspectors as yourself inspect a virtual MAH "who" would you held responsible for the implementation of a Quality System, is the Head of Regulatory? Marketing Director?
Acc. EU-GMP Guideline Part I, chap. 1 responsibility lies with the Head of Quality (Assurance) Unit.
c. Is the advertisement material management within scope of MAH routine inspection?
That depends on type of advertising material and the additional national legislations in the respective EU-member state (e.g. some member-states have special “advertising laws for medicinal products”).
4. What is the current status of Annex 1 and what is the anticipated implementation date and transition period? Is the draft Annex 21 available for the general public?
Current (December 2019) status Annex 1: Post GMDP-IWG review and prior to “restricted stakeholder consultation” (restricted public consultation).
No, current Annex 21 DRAFT is at the moment not available to public.
5. GMP for MAH: published as draft in 2016. Any information when a final version will be published and in which form? Reflection paper or more legally binding format?
Form will be “reflection paper”, because all information in this reflection paper originates from already legally binding documents (e.g. regulations, directives, guidelines)
Reflection paper is only summary of already existing requirements with some additional explanations
No information on publishing-date
6. In the presentation there is a reference to the recognition date for EU inspections by US-FDA from 06. May 2019 and the comment made that this is applicable for GMP inspections carried out in Germany / by the German authority. What triggers this date as FDA confirmed the capability in Germany on 26th June 2019? What would be the cut-off date for Spain for ex?
US-FDA defines recognition date for each EU-member-state individually. EU has no influence on setting this recognition date
Individual recognition dates should be available on US-FDAs homepage
7. Is there news on the timeline to Serialization in Russia? Rumors tell serialization is postponed again.
We recommend waiting for final publication by Russian Health Authorities rather to follow rumors.
8. When you have enough stock of Drug substance version A that you cannot transform it in DP and then FG before the end of the agreed 6 month implementation with EU, is it the release date which is to be respected in regards to release of version A vs version B or is it not possible to use this DS (released within the 6 months) after the end of the 6 months in DP manufacturing (after the 6 months)?
The implementation period is applied to the finished good. Finished goods to EU and export markets are certified by the QP. The QP certification always has to refer to the Marketing Authorization valid at the exact day of certification. After the agreed implementation time only new material version B can be certified, if both versions have not been approved as valid alternatives to be used in parallel. This is the mechanism for any change implementation.
9. Annex 21: Physical Import: If certification or batch confirmation is unrelated to import, what is regarded an accepted documented evidence for importation?
The question is understood in such a way, that certification is performed at a different location of the physical importation. QP certification stays therefore related to the importation. In such a case full Annex 16 applies to assess compliance of such batch. In relation to the importation site documented evidence of temperature control covering the shipments involved and some evidence that the material has arrived at that place should be shared with the site of certification. The first is governed by GDP regulations; the second is relevant because certification can only happen on material, which is physically available on EU/EEA soil. Dependent on any other activity performed by the information site, this may include any handling of samples, additional evidence is needed. You have to carefully assess the relevant activities on ensure transparency to the site of certification and QP.
10. What level of investigation is expected from companies with regards to serialisation alerts where the cause is not shown to be due known errors e.g.no batch number or lower case characters? Given >5000 reported by end of Sept in this category, is a documented investigation / rationale required to justify why the pack is not a counterfeit?
The regulation is built on the assumption and purpose of the system, that alerts are rare cases and if they happen are nearly sure an indication of falsification. Therefore the MAH´s first priority and responsibility is to drive down the number of false alerts. To achieve this goal for sure you have to invest and focus on such cases, which are not easily understood. The number of alerts should not be taken as an excuse. Of course in the situation of today you will not be able to fully investigate 5000 cases, but you may classify the alerts and you have the obligation to sort out all root cause as soon as possible.
This system protects your own business from falsification; your company is paying for it. The interest to the system should be high and not supporting additional efforts during this early phase after system go-life. You therefore should invest what is needed, that the system can deliver soon as intended. Not all your competitors report such an amount of alerts; therefore it is likely that you can still solve some significant root causes in-house.
11. What is your opinion regarding the certification of batches which have its final production step within the EU but not marketed in the EU? Is certification for Export batches needed or is it ok to just issue a QP GMP Statement for these batches?
EU law does not distinguish between manufacture for EU and manufacture for export. Both require a manufacturing authorisation and the accompanying obligations including QP certification. Appendix 2 of Annex 16 provides a recommended format for QP certification. Oddly, this format suggests that for export markets, certification that EU GMP requirements have been met is sufficient without going on to certify compliance with the marketing authorisation. On the other hand the GMP directive clarifies that EU GMP requires compliance with the marketing authorisation. My opinion is therefore that QPs should be satisfied that third country marketing requirements are known and being complied with and should certify accordingly and ignore Appendix 2 of Annex 16.
12. I understood that the legal document is the Supply agreement and that the TQA is a GMP document but legally (civil and penal) may not have the same power as the supply agreement? Is it correct?
I am not a qualified lawyer but I suspect that you are correct. It is clear however that either party may need legal redress in case there is a failure by the other party to fulfil their agreed obligations within a technical agreement. As it makes little sense for lawyers to draw up technical agreements, the advice I have consistently given in the past is that the overarching supply agreement should cross refer to the relevant technical agreement(s) which should be drawn up by appropriate experts with input from the QP.
13. In case the UK will leave WITH deal, can CoCs signed by UK QPs (e.g. partial release) be accepted in the interim as EU CoCs - meaning the certifying QP (EU) shares responsibility with the UK QP according to Annex 16? Interim period - day of Brexit until availability of MRA EU/UK.
If the UK leaves with an agreement there will be a transition period during which the future relationship will be negotiated. In the November 2019 agreement this period ends on 31 December 2020 (although it could be extended). During this transition period UK will be a third country but will follow all EU rules. So there will still be a UK QP certifying each batch. All EU MAs will have been varied to change the “Batch Release Site" (meaning site of QP Certification) to somewhere in the EU. Nevertheless the certifying QP within the EU will be able to use this as “Confirmation” in the same way as if it had come from a QP within the EU.
14. Bulk product, manufactured in DK and release tested in UK. After Brexit - can company still use QC release testing of bulk in UK?
During any transition period (see above), the answer is yes. After the transition period it will depend on the agreed new trade arrangements. If no agreement is reached the answer will be no. Otherwise, it is very likely that acceptance of release testing will be possible as it currently is with MRA partner countries.
15. You talked about a “normative document” that is required for Russia. In case the normative document is only submitted for Drug Product and not for the API, are the requirements in the ND also applicable to the API? For example the Russian pharmacopeia has specific requirements for water. In the normative document water is mentioned. Are the water requirements than also applicable to the API since water is used to make the API and not to make the drug product?
Normally the information of the current specification of API is also included in the Drug Product dossier. The use of the same water quality is recommended, unless the water being used in the API is added in a very early stage of the process. It is however recommended to have a dialogue with the Russian health authority to get an official answer.
16. How would you certify the batch which is contaminated with another API? PDE is 4 times bellow allowed quantity. Risk assessment shows that there is no danger for patient. This batch contains antihipertenzive API and diuretic API. Contamination API is analgesic API.
Normally an API that has been contaminated should not be used, since this means that either your cleaning validation is not sufficient or that some other deviation has occurred. If there is a very strong need to use the API (risk of drug shortage of an essential medicine), you should contact your local health authority and discuss the situation.
17. For MP a wholesaler (or manufacture) has the responsibility to check the receiving entity. Is this also the case for IMP's and what kind of document will be sufficient and how can these documents required and send to the RP and or QP?
Depending on what is meant by “the receiving entity” various plausible scenarios might exist:
a) Depot in the EU receives IMP post QP certification & distributes IMP directly to clinical sites:
depot on the List of Approved Service Providers (available to QP)
depots qualified & managed by a companies’ Contract Manufacturer and thus again on this List.
A Quality Assurance Agreement (QAA) (part of the Product Specification File) determines procedures, roles & responsibilities to cope with any potential incident that may occur during transportation (e.g. temperature excursion, loss, incorrect delivery, wrong recipient, etc.), including definition in which circumstances which documents (e.g. temperature monitoring data) have to be provided to the QP.
b) Clinical site receives IMP post QP certification and 2nd step of IMP release:
Each clinical site is qualified & managed by GCP colleagues including respective contracts set up. Procedures, roles & responsibilities likewise to be laid down in a (global) SOP (if intracompany) or intercompany QAA to ensure respective document flow in case of potential incidents during transportation.
c) EU depot receiving IMPs manufactured in third countries (e.g. importation from US to EU):
IMP requires release by an IMP QP. The QP needs all relevant documentation to conduct full IMP batch certification.
Furthermore, it may be useful to exactly define the IMP receipt process at clinical sites, e.g. proof of delivery procedure & confirmation of receipt including time control and document the IMP receipt in the Interactive Response Technology (IRT) system.
EudraLex 10 will include the “Guideline on the responsibilities of the sponsor with regards to handling and shipping of investigational medicinal products for human use in accordance with Good Clinical Practice and Good Manufacturing Practice” EMA/202679/2018, draft link.
18. Why it is mandatory to EU re-test commercial batches, coming from outside of EU, but IMPs do not have this mandatory requirement? Isn’t the risk the same?
Dir 2003/94/EC Art. 11 (2) last paragraphs says “For investigational medicinal products …. When the products are imported from third countries, analytical control shall not be mandatory.” This requirement will carry over in the Commission Delegated Regulation (EU) 2017/1569 Art. 10 (3).
Thus, it is up the IMP importer to define extend and scope of re-testing upon importation based on a respective risk assessment.
Currently, it is still required for comparators sourced from outside the EU/EEA to register “information on the analytical methods needed for at least reduced testing (e.g. identity) in the IMPD and with doing so conduct respective testing, refer to IMPD Guideline CHMP/QWP/185401/2004 final, sec. 3, second paragraph.