GMP-Update - What's new in Germany and the EU? - Part 2

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The Mutual Recognition Agreement (MRA) EU - USA

With the recognition of Slovakia on 11 July 2019 all EU Member States were recognised by the USA on time. The EU has recognised the FDA already in 2017. This means that the MRA could enter into force as planned.

No more import testing

Main goal of the MRA was to mutually recognise the GMP inspection systems and to reduce the number of inspections. Another part which will provide some relief is that it is not required anymore to carry out a complete analysis of human medicines from the United States on import. A qualified person (QP) can rely on the release documentation and the decision of a US quality organisation for the batch certification. But in order to recognise or take over test results completely a few basic requirements need to be fulfilled. These are also mentioned in article 9 of the MRA document as well as in EMA's actual questions & answers document (EMA/395913/2019)1:

  • The analysis has been carried out in the United States;
  • The product has been manufactured in the United States;
  • Each batch/lot is accompanied by a batch certificate (in alignment with the WHO certification scheme);
  • This batch certificate has been issued by the manufacturer certifying that the product complies with requirements of the marketing authorization;
  • The batch certificate has been signed by the person responsible for releasing the batch/lot (in the USA). The Qalified Person has to verify in advance that these conditions are fulfilled.

No more inspections?

The FDA still may carry out inspections in the EU. The questions & answers document (EMA/395913/2019) mentioned above states that it is (only) "expected that the FDA will not duplicate inspections (...)." "(...) both the EU and FDA reserve the right to inspect in each other's territory at any time."  

What about pre-approval inspections?

So-called "application-specific inspections" such as pre-approval and post-approval inspections carried out by the FDA are within the scope of the MRA. But in its questions & answers document from July 20172 the FDA indicates that these inspections are based upon the application submitted to a specific regulatory authority, and that "additional coordination and assessments are required". Judging from the regularly updated website3 the FDA seems to be leaving all options open: "FDA will continue to perform some inspections in EU countries with capable inspectorates, such as product manufacturing assessment inspections to support marketing approval decisions". At least, the FDA expects to perform fewer routine surveillance inspections in EU countries.

Very important: FDA's date of recognition of EU inspections is 6 May 2019. This means that prior to this date local inspections do not have to be recognised and the FDA may visit to carry out inspections.

What are the next steps?

Further extensions of the scope are foreseen in the agreement and are currently being followed up. Examples for extensions are veterinary medicinal products, vaccines and plasma products intended for human use.

Actually, the FDA does not issue GMP certificates after inspections carried out in the USA. The introduction of these certificates known in the EU is not foreseeable currently. The exchange of information between authorities will be carried out using "GMP documents".

What are the consequences for EU marketing authorisation submissions listing US manufacturers? The following documents could be submitted (where available):

  • 90-day Facility Classification Decision Letter;
  • Screenshot of the FDA Inspection Classification Database (as a printout is not possible);
  • The most recent FDA Establishment Inspection Report;
  • The export certificate (Certificate of Pharmaceutical Products - CPP), if the same product is also authorised in the USA.

Revision of Annex 1 of the EU GMP Guidelines (Sterile Medicinal Products)

The long awaited draft of Annex 1 (Annex 1 "Manufacture of Sterile Medicinal Products; Targeted stakeholders consultation" ) was already published on 20 December 2017. There was comprehensive information on the planned changes in the GMP Journal so that these changes won't be addressed again in this article. The final version was published earlier this year.

In this context it is very interesting that the EMA has published a draft for a guideline on sterilisation processes in March 2019 (Guideline on the sterilisation of the medicinal product, active substance, excipient and primary container). It is valid since 1 October and replaces the decision trees for the selection of sterilisation methods from the annex of the Note for Guidance on Development Pharmaceutics (CPMP/QWP/155/96). The last draft did not refer to this document.

New Annex 21 of the EU GMP Guidelines (Guidance for Importers of Medicinal Products)

The completely new Annex 21 has been published as a new draft now. The concept paper was already published on 13 May 2015 (EMA/238299/2015) and the consultation phase ended in August 2015. The first draft concerning the regulatory consultation was published in November 2016.

The document addresses manufacturing import authorisation (MIA) holders which import human and veterinary medicinal products from third countries. Medicinal products which do not have an authorisation in the EU/EEA and are directly exported are not covered. The following points are supposed to be regulated:

  • Physical transfer from a third country into the EU/EEA;
  • Physical importation of the product;
  • Certification by a qualified person (link to the requirements of Annex 16);
  • Requirements on facilities and equipment;
  • Required documentation;
  • GMP requirements concerning manufacturers and exporters in the third country;
  • Qualification and audits are the responsibility of the importing business;
  • Testing during import if not coming from a third country with MRA or ACAA;
  • Contractual arrangements between all importers and businesses or persons concerned.

The question of "fiscal import" isn't addressed in the second draft anymore. This means that imports for fiscal reasons (imports taking place exclusively on paper) are not considered as import anymore according to the provisions of Annex 21.

ICH Q12

The International Council for Harmonization (ICH) met in Singapore from 16 to 20 November 2019. The milestone of this meeting was the adoption of the new ICH Q12 Guideline (step 4 of the ICH process) on the technical and regulatory considerations for a more flexible pharmaceutical product lifecycle management. The new ICH Q12 Guideline with two annexes complements the ICH Quality Guidelines Q8 to Q11. According to the ICH the guideline's goal is promoting innovation and continual improvement in the pharmaceutical sector, strengthening quality assurance and improving a reliable supply of medicinal products including proactive planning of global supply chain adjustments.

After publication of the final Q12 Guideline and its annexes on the ICH website the next phase will be the implementation of ICH Q12 in the ICH regions. But especially in the EU a revision of local regulations (such as the EU Variations Regulation) will be required in order to fully implement the concepts of Q12. In the USA, on the contrary, ICH Q12 is completely compatible with the existing legal framework.

Investigational medicinal products

The reorganisation of the requirements on clinical trials in the EU was decided upon already in May 2014. We have already informed you comprehensively on this topic and there are not a lot of new things to talk about. The new regulations will not apply until Regulation (EU) 536/2014 enters into force. The date of its entering into force is linked to the functioning of the new electronic Clinical Trials Information System the finalisation of which has now been dragging on for years.

Veterinary Medicinal products

Directive 2001/82/EC on the Community code relating to veterinary medicinal products will be repealed with effect of 28 January 2022 and replaced by Regulation (EU) 2019/06. An EU Regulation is valid directly and binding on all Member States. This means that no modifications are possible at national level and transposition into national law is not required. The regulation contains provisions on:

  • Authorisation;
  • Post-marketing authorisation measures;
  • Manufacturing;
  • Import and export;
  • Supply and use of veterinary medicinal products and regulates restrictions and penalties.

 

About the Author:
Wolfgang Schmitt
...
is Operations Director and organises and conducts courses and conferences on behalf of the ECA Academy in the areas QA and GMP.

Source:
1https://www.ema.europa.eu/en/documents/other/questions-answers-impact-mutual-recognition-agreement-between-european-union-united-states-11-july_en.pdf
2https://www.fda.gov/media/103391/download
3https://www.fda.gov/international-programs/international-arrangements/mutual-recognition-agreement-mra

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