The EU Falsified Medicines Directive (2011/62/EC) introduced some amendments to the EU Human Medicines Directive (2001/83/EC) in order to prevent the entry into the legal supply chain of falsified medicinal products. Among other issues regulated in the 2011 directive, there was particular concern about the entry into the European Union of active ingredients that did not follow the EU standards of good manufacturing practice (see Statements 7, 9 and 20).
One of the adopted measures was the requirement that, as of January 2 2013, all imported active ingredients must have been manufactured in compliance with standards of good manufacturing practice at least equivalent to EU good manufacturing practice. In order to give effect to this measure, as of July 2 2013 and according to the wording of Article 46ter of the Human Medicines Directive, as a rule:
"[a]ctive substances shall only be imported if the following conditions are fulfilled:
(b) the active substances are accompanied by a written confirmation(1) from the competent authority of the exporting third country of the following:
(i) the standards of good manufacturing practice applicable to the plant manufacturing the exported active substance are at least equivalent to those laid down by the Union pursuant to the third paragraph of Article 47;
(ii) the manufacturing plant concerned is subject to regular, strict and transparent controls and to the effective enforcement of good manufacturing practice, including repeated and unannounced inspections, so as to ensure a protection of public health at least equivalent to that in the Union; and
(iii) in the event of findings relating to non-compliance, information on such findings is supplied by the exporting third country to the Union without any delay."
As an exception, written confirmation will not be required in the following cases:
- if the exporting country is in a list of non-EU countries published by the European Commission that includes non-EU countries which applied to be part of it and, after evaluation by the commission, have demonstrated good manufacturing practice requirements equivalent to those of the European Union (Article 46ter(3));(2) and
- exceptionally and where necessary to ensure the availability of medicinal products, where a plant manufacturing an active substance for export has been inspected by a member state and was found to comply with the principles and guidelines of EU good manufacturing practice and the member state in question has expressly made use of this possibility. This waiver from the written confirmation shall not exceed the validity of the certificate of good manufacturing practice, and the member state expressly communicates the use of this exception to the European Commission (Article 46ter(4)).
The European Commission published a useful question-and-answer document,(3) which defines the active ingredients subject to the written confirmation and other issues regarding the import of active substances for medicinal products for human use.
Spain has used the exemption from the written confirmation for the import of active ingredients from non-EU countries only in exceptional circumstances, and where necessary to ensure the availability of medicinal products according to Article 46ter(4).
In this regard, on June 7 2013 the Spanish Medicines and Sanitary Products Agency (AEMPS) published an informative note.(4) The note includes a link to a copy of the letter that the AEMPS director sent to the general director of the European Commission Directorate General of Health and Consumers on May 31 2013 in order to inform the European Commission that Spain had decided to make use of the exemption.(5)
The note envisaged the required provisions to be subject to the exception used by Spain in the following terms:
"[T]he companies that: (i) import active ingredients to be used in the manufacture of medicinal products for human use (ii) do not have the written confirmation issued by the third exporting state and (iii) the exporting state is not included in the list referred in Article 111bter of the before mentioned Directive (published by the European Commission), must send to the Department of Inspection and Medicinal Products Control's e-mail email@example.com, at least 10 days prior to the first import of the active ingredient/s from a plant of a third state, the following documentation:
- Identification of the importing company.
- The active ingredient/s and data of the manufacturing plant (full address and country).
- Certificate in force of the EU standards of good manufacturing practice of the manufacturing plant of the active/s ingredient/s.
- Medicinal Products that will be manufactured with the imported active ingredient/s.
Once this information is reviewed, if necessary, AEMPS will contact with the importing company.
On the other hand, please note that, from July 2, these importing companies of active ingredients to be used in the manufacture of medicinal products of human use, must submit, in addition to the things envisaged in the provisions of the Order SPI/2136/2011 of July 19, by which it is established the procedure of health control at customs by the pharmaceutical inspection and regulates the Informatics System of Pharmaceutical Inspection of Exterior Health and in the Circular 1/2008 regarding the external trade of medicines, the following documents in the pharmaceutical inspection of customs:
- Written confirmation of the third exporting state, or failing that,
- Certificate in force of the EU standards of good manufacturing practice of the manufacturing plant of the active ingredient/s."
(1) The template for the written confirmation is available at http://ec.europa.eu/health/files/gmp/2013_01_28_template.pdf.
(2) The list is available at http://ec.europa.eu/health/human-use/quality/index_en.htm#ias.
(3) The question-and-answer document is available at http://ec.europa.eu/health/files/gmp/2013_04_12_qa_en.pdf.
(4) The note is available at www.aemps.gob.es/informa/notasInformativas/industria/2013/NI-ICM-CONT_03-2013-principios-activos.htm.
(5) The letter is available at www.aemps.gob.es/industria/principios-activos/docs/carta-directora-AEMPS-CE-31-05-13.pdf.