23-25 October 2019
On 2nd March 2017, the US FDA and the European Medicines Agency (EMA) informed that they concluded a so-called MRA (Mutual Recognition Agreement). As a consequence, a manufacturing site would be inspected by the local competent authority only (or other inspectorates not covered by an MRA). FDA inspections in the EU or EU inspections in the USA should then only be performed in exceptional cases. The MRA will start coming into force in November 2017.
What else is important for the Qualified Person (QP)?
The removal of the importation testing requirement
Will testing continue to be required on importation into some Member States and not others reflecting accession timelines?
There is a statement in Article 19 "Entry into force": "Notwithstanding paragraph 1, Article 9 [Batch testing] of this Annex shall not apply until the date on which all the EU Member State authorities for human pharmaceuticals listed in Appendix 2 have been recognized by the FDA." So nothing will change after November 1st in this regard because not all Member States have been accessed by FDA until then. Import testing needs to be performed until all Member States have been found equivalent. After implementation of this part of the agreement, the Qualified Person will be relieved of the responsibility for carrying out the controls laid down in Article 51 paragraph 1 of Directive 2001/83/EC and in Article 55 paragraph 1 of Directive 2001/82/EC with the following provisions:
At present marketing authorisation applications to EU authorities that list medicinal product manufacturers located in the USA are required to submit proof of the holding of an Establishment Licence issued by the FDA [Art. 8.3(k)/12.3(m) of Directive 2001/83(2)/EC] and a EU GMP certificate issued to the site. But, with full implementation of the MRA, those EU GMP certificates will not be issued anymore. And the FDA does normally not issue GMP certificates. Therefore an alternative approach will be needed (issuing of GMP certificates is not part of the current FDA system but work is ongoing to find a suitable alternative).
The holder of the manufacturing authorisation is responsible for the supplier qualification, but in fact the supplier qualification and respective audits are one of the tasks of the Qualified Person (which can be delegated) as defined in Annex 16 of the EU GMP Guidelines. The QP of the marketing authorisation holder is responsible for certifying the drug product for the market place and is being held accountable to ensure that all aspects of the supply chain have been taken into account under the appropriate GMPs. Audits will still be an essential part of this process. Another essential part is the verification of available GMP certificates. Here, the QP needs to see what will be available in future and what information can be used in the absence of an EU GMP certificate.
Quality defects also seem to cause some challenges. Although the two-way alert system from the original 1998 MRA is considered operational, it seems that this does not appear to be working optimally. The new MRA provides an opportunity for relevant experts in the EU and the FDA to discuss and agree on operational requirements.
So in future the QP needs to have an eye on what is available to qualify manufacturing sites in the US in the absence of a GMP certificate. Also testing of imported materials still needs to be performed until the MRA is fully implemented.
The MRA and other international developments and their possible impact on GMP, manufacturers and especially QPs will also be discusses at this year's QP Forum in Budapest.