1. Is the QP authorization of the plant of production and release of a finished product mandatory for the use of an intermediate imported from another site?
Annex 21 applies also to intermediate medicinal drug products and therefore a QP confirmation (not authorization) by the site of importation has to be performed prior to further manufacturing steps at the site of importation or any different site of manufacturing within EU.
2) New Annex 21 - It is written that a custom documentation/customer import declaration is necessary for the QP - What is your opinion? Is this a quality related document?
The document itself from customs is not a GMP document. Once you file it as part of your certification assessment it needs to be kept and archived following GMP rules.
3) Customs Clearance/ documents: what does the EU QP need to review/know for the Certification of a batch?
According to Annex 21 the certifying or confirming QP needs to have assurance, that customs clearance has been completed before he can certify a batch. For this you need to know which entity performs this step and you need an established relationship to this entity.
4) If a batch is certified in the EU, then exported to Switzerland or a third country and reimported in the EU. Should it be EU certified again for importation? Is full batch documentation necessary to be reviewed by QP after import to EU again? Is it acceptable to rely on previous EU QP release?
Each physical bringing from outside EU (import) requires a new QP-batch certification under full Annex 21 & Annex 16 requirements. As there is no exception for the described case, also in this case full requirements apply. Even EU-retesting is necessary again, because for this import the batch was not tested in Switzerland. Testing was only performed for first importation, but testing is required for each import. In addition, things could have gone wrong during transport. For this reason not only batch documentation, but also testing is required again. Regarding previous QP-release one could assume acc. Chap. 1.5.2 from Annex 16 (see below), that reliance on QP-certification from first importation might be possible. Initial certification can then be seen as a CoC for second importation, but QP-certification of second importation has to be performed in addition.
1.5.2 In accordance with the principles described in Section 1.4 of this Annex, the QP certifying the finished medicinal product batch may take account of the confirmation by, and share defined responsibilities with, other QPs in relation to any manufacturing or importation operations taking place at other sites in the EU and other manufacturing authorisation holders defined in the relevant MA.
5) IMPs: do we need to do testing after importation? Do we need a PQR?
Both, testing for importation and PQR no requirement is defined by the Clinical Trial Regulation.
6) If a bulk product is imported from a 3rd country, finally packaged in the EU (CMO) and then certified by another site in the EU, do Annex 21 requirements apply for the Final Certification?
Annex 21 applies in such scenario to the physical importing site. The site of final certification will here not be registered as site of importation. Though, Annex 21 applies for the importation of bulk product from 3rd-country.
There are requirements specifically for the site of QP certification in Annex 21. Those need to be followed. Also, the site of batch certification (sometimes called „Batch Release Site“) is mandatory in MAAs.
7) What about countries covered with MRA? Is full batch documentation required? What about re-testing and comparison of analytical test results?
MRAs do not cover any relief from responsibilities for importers with one exception: testing can be established and registered on the territory of the MRA country instead of the territory of the EU.
8) Full batch review documentation: Can it be omitted, if the person performing batch confirmation in the third country belongs to same company as the EU QP performing batch certification? Could it be delegated to an Audit service organization? Or should it be delegated to someone from the same site of the QP certification site?
We need to clarify: a company in a third country can legally never belong to the same legal entity than a site established in the EU. The importing site has to take care to hold the batch documentation and based on risk also review it. Delegation within this organization is possible but does not help the QP to understand the document. Delegation of this only periodically executed batch record review seems not to meet the intent and meaning assigned to this requirement. Any QP responsibility delegated, can only be delegated to a site which holds an EU-MIA.
9) Should the whole transportation route from origin and temperature records be reviewed for the batch certification or just be available?
Control of conditions during transportation should be ensured. To my imagination only a review of such data can provide such assurance. But transportation documents must be available at site which performs importation activities for each batch. Documentation of transport must cover complete route from 3rd-country CMO up to physical site of importation.
10) If we receive API with revision of CEP which is in the meantime replaced with the new revision of the CEP by which there was no change in the quality (no changes in specification, no change in the route of the syntheses…). Is it ok to use this API with the old revision of the CEP in the production or it is major regulatory non-compliance?
Not topic of Annex 21. Annex 21 covers medicinal product importation only.
Import should be on the basis of the current CEP.
11) How to assure that QP is informed on all deviations and changes that are linked to specific batch? For example, deviations and CC that include PW system, power failures, inadequate storage conditions in warehouse (raw materials). Batch documentation is reviewed by QC and Production, and those departments do not possess all information mentioned.
Ensuring that all are available via SOPs and contractual arrangement. The second sentence that QC and Production does not possess all information should be once recognized addressed via deviation management. Root cause analyses and improved via CAPA implementation.
12) You said that retention samples have to be located in EU. That is not in line with the guidelines. Retention samples can also be kept in a country with an MRA agreement if they are available rapidly (Switzerland for example). Only the release samples should be kept in the EU.
Annex 19 differentiates reference samples and retention samples. It is clearly stated that retention samples have to be located within the EU even if an operational MRA is in place. This is not dependent from distance or speed on availability.
7. Reference Samples – General Points 7.1 Reference samples are for the purpose of analysis and, therefore, should be conveniently available to a laboratory with validated methodology. For starting materials used for medicinal products manufactured within the EEA, this is the original site of manufacture of the finished product. For finished products manufactured within the EEA, this is the original site of manufacture. 7.2 For finished products manufactured by a manufacturer in a country outside the EEA; 7.2.1 where an operational Mutual Recognition Agreement (MRA) is in place, the reference samples may be taken and stored at the site of manufacture. This should be covered in a written agreement (as referred to in section 6 above) between the importer/site of batch release and the manufacturer located outside the EEA.
8. Retention Samples – General Points 8.1 A retention sample should represent a batch of finished products as distributed in the EEA and may need to be examined in order to confirm non-technical attributes for compliance with the marketing authorisation or EU legislation. Therefore, retention samples should in all cases be located within the EEA. These should preferably be stored at the site where the Qualified Person (QP) certifying the finished product batch is located. 8.2 In accordance with 8.1 above, where an operational MRA is in place and reference samples are retained at a manufacturer located in a country outside the EEA (section 7.2.2 above), separate retention samples should be kept within the EEA.
13) Can a batch be imported or exported under quarantine?
No.
14) Regarding the stability review requirements in Annex 21: is it sufficient to include a summary in the PQR?
On the one hand side the QP should be continuously aware on any stability trends but also the confirmation that no unexpected trend is occurring. I do not know how this analyses and discussion required to be documented in a PQR can be performed on the basis of short summary only.
Only summary is not sufficient (see below):
Annex 21, chap. 6.1: Details of the ongoing stability program, such as protocols, results and reports should be available for inspection at the site responsible for QP certification.
15) Why would the transfer of a batch from NI to an EU country be considered an Import to EU as shown in David’s slide?
The UK, which includes Northern Ireland, is a third country. Slide 11 is intended to show the differentiation between GB and NI as a result of the Ireland/Northern Ireland protocol in which the latter is managed as if it were a member state with respect to the movement of goods.
16) If a bulk batch is packed in different finished product batches for different MAHs, is it possible to gather representative samples of all the finished product batches in order to perform an unique analysis in the EU?
In this case each import relates to a specific finished product (from different MAHs). As an import does always only relate to a specific batch (and therefore to a specific product), importation-testing has to be performed for each import, even if originating from same bulk. Also, for the reason, that different packaging operations (which is part of manufacturing) and therefore different manufacturing operations are applied to each and every finished product batch. In addition, sampling is to be done after importation, which can only be from each and every finished product, which underwent different packaging operations. Also, in third country sampling for finished product testing must be done from finished product, because it must reflect the whole manufacturing process, which includes packaging.
There may be a possible but rare scenario where this would be possible if all the finished batches were transported together to the same importer. For agreement contact the respective inspectorate.
17) Regarding the import testing and the comparison with "internal" tests of the MAH. How is an "allowed" difference defined?
Based on your product knowledge and experience.
18) Could a local authority force a site of QP certification to be the fiscal owner of an imported medicinal product as prerequisite for QP certification? Argumentation: site of QP certification should have power of disposition over the product until it is certified.
Not to my knowledge. If so, not based on GMP rules. Annex 21 does not consider any fiscal activities.
19) Can analytical results from MRA countries be accepted for importation into EU and QP certification?
A: In the case of applicability of the MRA, yes. Applicability is limited to specific products as defined in the MRA (each MRA is different) and direct shipment from the 3rd country into EU/EEA.
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