Veterinary pre-submission Q&A: 1-20
This page lists questions 1 to 20 of the European Medicines Agency's questions and answers on pre-submission guidance for veterinary medicinal products.
The page is updated regularly to reflect new developments, to include guidance on further pre-authorisation procedures and to reflect the implementation of new European legislation. New and revised topics are marked as “New” or “Rev.” on publication.
- More information on this pre-submission Q&A.
Regulation (EC) No 726/2004 of the European Parliament and of the Council lays down a centralised Union procedure for the authorisation of medicinal products for which there is a single application, a single evaluation and a single authorisation allowing direct access to the single market of the Union.
Article 3 of Regulation (EC) No 726/2004 defines the scope and eligibility of applications for evaluation under the centralised procedure through which medicinal products must ("mandatory scope") or may ("optional scope" or "Generic/Hybrid") be authorised by the Union.
Mandatory scope (Article 3(1), Annex):
For veterinary medicinal products falling within the mandatory scope of the Regulation (EC) No 726/2004, applicants are obliged to use the centralised procedure by submitting their marketing authorisation application to the European Medicines Agency.
These are veterinary medicinal products developed by means of one of the following biotechnological processes:
- Recombinant DNA technology.
- Controlled expression of genes coding for biologically active proteins in prokaryotes and eukaryotes including transformed mammalian cells.
- Hybridoma and monoclonal antibody methods.
And in addition:
- Veterinary medicinal products intended primarily for use as performance enhancers in order to promote the growth of treated animals or to increase yields from treated animals.
Any veterinary medicinal product which contains a proteinaceous constituent obtained by means of one of the biotechnological processes listed above falls under the mandatory scope, irrespective of whether or not the constituent is an active substance of the veterinary medicinal product. This also applies where a biotechnology manufacturing step is introduced into the manufacture of a proteinaceous product after the granting of a marketing authorisation.
Examples of new biotechnological products which would be considered mandatory for the centralised procedure are given below:
- Products intended for gene therapy;
- Vaccines from strains developed by means of recombinant DNA technology, including gene deletion;
- Any veterinary medicinal product for which a monoclonal antibody is used at any stage in the manufacturing process;
- Cell therapy products, which are the result of any biotechnological process referred to in the Annex to Regulation (EC) No 726/2004.
Optional scope (Article 3(2)):
For veterinary medicinal products falling under the optional scope, applications for the following categories may, at the request of the applicant, be accepted for assessment under the centralised procedure.
The following categories of medicinal products for use in animals are eligible:
(a) Medicinal products intended for use in animals, containing a new chemical, biological or radiopharmaceutical active substance which, on the day of entry into force of the Regulation (20 May 2004), was not authorised in the Union for use in a medicinal product intended for use in animals.
A new chemical, biological or radiopharmaceutical active substance, as defined in Annex I of Chapter 1 of Volume 6A of the Notice to Applicants, includes:
- A chemical, biological or radiopharmaceutical substance not previously authorised (i.e. not authorised on 20 May 2004) in a veterinary medicinal product in the Union.
- An isomer, mixture of isomers, a complex or derivative or salt of a chemical substance previously authorised in a veterinary medicinal product in the Union but differing in properties with regard to safety and/or efficacy from that chemical substance previously authorised.
- A biological substance previously authorised in a veterinary medicinal product in the Union, but differing significantly in properties with regard to safety and/or efficacy due to differences in one or a combination of the following: molecular structure, nature of the source material or manufacturing process.
- A radiopharmaceutical substance, which is a radionuclide or a ligand not previously authorised (i.e. not authorised on 20 May 2004) in a veterinary medicinal product in the Union, or the coupling mechanism to link the molecule and the radionuclide has not been previously authorised in the Union.
A biological active substance is considered new if:
- the antigen or antiserum is contained within a product indicated against a newly emerging species of pathogen, or
- a new antigen or antiserum is contained within a product indicated against a disease where existing products are proven and recognised not to alleviate suffering from the said disease in the particular target species;
- the product consists of a substance which through immunological mechanisms affects the physiological function of an animal (e.g. one which causes immunocastration), either if the substance has a new efficacy claim or if a new active substance has a different mode of action;
- the product consists of a substance which modulates the function of the immune system either if the substance has a new efficacy claim or if a new active substance has a different mode of action.
(b) The veterinary medicinal product constitutes a significant therapeutic, scientific or technical innovation or the granting of the authorisation in accordance with Regulation (EC) No 726/2004 is in the interest of animal health at Union level.
For the purpose of determining whether a medicinal product for veterinary use constitutes a “significant therapeutic, scientific or technical innovation” the Agency will consider if:
- the veterinary medicinal product provides a new alternative in treating, preventing or diagnosing a disease, or,
- the veterinary medicinal product development is based on significant new scientific knowledge or on the application of new scientific knowledge, or
- a new technology or a new application of technology is used for the development or the manufacture of the product.
Generic/hybrid of centralised veterinary medicinal product applications (Article 3(3))
A generic or hybrid veterinary medicinal product of a reference veterinary medicinal product authorised via the centralised procedure has “automatic” access to the centralised procedure under Article 3(3).
Duplicate (sometimes also called “multiple”) or informed consent applications from the same or different marketing authorisation holder for a specific veterinary medicinal product already authorised via the centralised procedure, have “automatic” access to the centralised procedure.
In all cases listed above the eligibility of a veterinary medicinal product for evaluation via the centralised procedure must be requested by the applicant by submitting a Pre-submission request form (selecting the indent “Centralised procedure - Eligibility request”), together with appropriate attachments to: firstname.lastname@example.org (See: Question "How and when should the request for eligibility to the centralised procedure be sent to the European Medicines Agency?").
Regardless of whether the product falls into the mandatory or optional scope, or would have "automatic access”, an ‘eligibility request’ should always be submitted using the specific form (Pre-submission request form (selecting indent Eligibility request)) and accompanied by a justification of eligibility for evaluation under the centralised procedure and draft SPC. The applicant should clearly address the specific criterion fulfilled by the product to be eligible for the centralised procedure. See: Question "Is my veterinary medicinal product eligible for evaluation under the centralised procedure?"
Please note that:
- In the case where the product falls under the mandatory scope criterion (Art. 3(1) of Regulation (EC) No. 726/2004), the relevant justification should be provided.
- In the case where the product falls under one of the optional scope criteria (Art. 3(2) of Regulation (EC) No. 726/2004), the justification should consist of a concise summary document of preferably two pages stating why the product should qualify for evaluation through the centralised procedure. The applicant should clearly state in the request which criterion the appended justification concerns:
- Art. 3(2) a New active substance; or
- Art. 3(2) b Significant therapeutic innovation, or
- Art. 3(2) b Significant scientific innovation or
- Art. 3(2) b Significant technical innovation; or
- Art. 3(2) b Interest of animal health at Union level; or
- Art. 3(2) Immunological veterinary medicinal product for the treatment of animal diseases subject to Union prophylactic measures.
NB: Only one criterion can be chosen and must be adequately justified; e.g. eligibility in accordance with Art 3(2)b of Regulation (EC) No. 726/2004 – Significant therapeutic innovation
- In the following cases, where the medicinal product applied for may have "automatic access" to the centralised procedure, this should be the basis for the justification to be submitted.
This is the case when the veterinary medicinal product applied for, is either:
- a generic/hybrid (Art. 3(3) of Regulation (EC) No. 726/2004); or
- a duplicate/multiple; or
- an informed consent
to a centrally authorised medicinal product. Adequate and relevant information on the already centrally authorised medicinal product should be provided as background information (such as invented name/INN/ Commission Decision date/ type of application submitted and criteria/ indent under which the medicinal product was eligible to access the centralised procedure at the time).
The applicant should send the request electronically to email@example.com using the Pre-submission request form (selecting the indent “Centralised procedure - Eligibility request”), together with a separate Annex 1 (draft Summary of Product Characteristics) and Annex 2 (Justification for Eligibility).
The CVMP will discuss the request for eligibility to the centralised procedure at its meeting 7 months prior to the intended submission date. In order to allow this, applicants should submit their request and supporting documentation to the Agency at least 15 calendar days before the CVMP meeting at which eligibility is to be discussed (i.e. approximately 7.5 months prior to intended submission date). This will ensure inclusion of the request on the CVMP agenda. An earlier submission of a request for eligibility may be in particular useful for requests that fall under the “optional scope” above, in particular under Article 3(2)(b) or if scientific or other advice is sought early in the pre-submission phase.
Any eligibility request received after the deadline will be considered the following month.
The outcome of the CVMP discussions will be forwarded by the Agency to the applicant in the week following the CVMP meeting. If the supporting documentation is considered insufficient, further information and clarification from the applicant will be required. Upon receipt of such additional information the request will be re-discussed at the next CVMP meeting and the applicant will be informed accordingly.
Decisions on eligibility are not connected to the rapporteur/co-rapporteur assignment. The rapporteur/co‑rapporteur will be assigned at the CVMP meeting 4 months prior to the intended submission date. Eligibility requests can be submitted together with the notification of the intention to submit an application. (See: Question "What is the procedure for appointment of CVMP rapporteurs/co‑rapporteurs and their assessment teams?”).
For any scientific evaluation of a veterinary medicinal product in respect of a procedure, a rapporteur and, if relevant, a co-rapporteur shall be appointed from amongst the members of the Committee for Medicinal Products for Veterinary Use (CVMP) and their alternates. For initial applications (full applications and generic/hybrid products) for a marketing authorisation a rapporteur and a co-rapporteur are appointed.
The role of the rapporteur is to perform the scientific evaluation and to prepare an assessment report for the CVMP, according to the timetable agreed for the evaluation procedure. The co-rapporteur shall prepare a critique of the rapporteur's report.
INTENTION TO SUBMIT AN APPLICATION AND APPOINTMENT OF CVMP RAPPORTEUR/CO-RAPPORTEUR
The appointment of the rapporteur and co-rapporteur is made at the CVMP meeting 4 months prior to the intended submission date and is triggered by the receipt of the notification of the intention to submit an application. The rapporteur and co-rapporteur appointment will not take place prior to that date.
Applicants shall send their notification of the intention to submit an application by sending a completed Pre-submission request form (selecting the indent “Centralised procedure - Intent to submit MA”) to firstname.lastname@example.org together with the Draft Summary of Product Characteristics.
The CVMP will be informed of the intention to submit an application and appoint rapporteur and co‑rapporteur at its meeting 4 months prior to the intended submission date. In order to allow this, applicants should submit their notification and supporting documentation to the Agency at least 15 calendar days before the CVMP meeting at which rapporteurs are to be appointed (i.e. approximately 4.5 months prior to intended submission date). This will ensure inclusion of the notification on the CVMP agenda.
If the intended application is deemed to be admissible, and upon appointment by the CVMP of the rapporteur and co-rapporteur, the European Medicines Agency will notify the applicant after the CVMP meeting of the names of the rapporteur/co-rapporteur appointed.
The notification of the intention to submit an application can be submitted together with the eligibility request. In this case, applicants shall send their eligibility request/notification of the intention to submit an application by sending a completed Pre-submission request form (selecting the indent “Centralised procedure - Intent to submit MA”) together with the draft SPC and justification for eligibility to email@example.com. The timelines for submission are those applicable for eligibility requests, i.e. approximately 7.5 months before intended submission date (See: Question “How and when should the request for eligibility for the centralised procedure be sent to the European Medicines Agency?”)
Intended submission dates must be as realistic as possible. Such information is crucial to the Agency and to the rapporteur/co-rapporteur and their assessment teams for planning purposes. Any anticipated change to the submission date must be notified as soon as possible to the European Medicines Agency. Applicants should be aware that a re-appointment of the rapporteur or co‑rapporteur may become necessary due to other ongoing or planned assessments.
Withdrawal of requests: Should applicants no longer wish to pursue the submission of their application, they should notify the Agency of their intention to withdraw the request for submission of an MAA. This should be done by using the Pre-submission request form (selecting the indent “Withdrawal of request”). The notification should be sent electronically to firstname.lastname@example.org. The procedure will be closed accordingly.
The applicant should clearly indicate the legal basis for the submission of the application in the EU Application form, i.e. select one of the following articles of Directive 2001/82/EC:
- Article 12 (3) - Full or 'full-mixed' application
- Article 13 – Generic, hybrid or similar biological application
- Article 13a - Well established veterinary use application
- Article 13b - Fixed combination application (of known active substances)
- Article 13c - Informed consent application
The legal basis for a marketing authorisation application determines the data requirements. At pre‑submission meetings, it is strongly recommended to discuss the proposed legal basis in view of the available data with the Agency in order to prevent difficulties at validation.
Article 12 (3) - Full application:
For full applications according to Article 12(3) of Directive 2001/82/EC, the results of pharmaceutical tests (physico-chemical, biological or microbiological), safety and residue tests, pre-clinical and clinical trials and tests assessing the potential risks posed for the environment need to be submitted. Detailed data requirements are set-out in Annex I to Directive 2001/82/EC, as amended by Commission Directive 2009/9/EC.
Any deviations from these requirements, in particular, absence of a study/test report, requires a justification as to why the results are not provided and whether the requirements as set out in the Annex I to Directive 2001/82/EC, are considered fulfilled.
Article 12(3) - ‘Full-mixed’ application:
Where Part 3 and/or 4 consists of a combination of reports made up of limited safety, residues, pre‑clinical, clinical and/or environmental studies carried out by the applicant and of bibliographical references this kind of application has also to be submitted according to Article 12(3) of Directive 2001/82/EC (so‑called ‘full-mixed’ application - see also section on ‘mixed’ marketing authorisation application in Title III of Annex I of the Directive).
A justification for not having performed certain tests/trials and for providing literature references instead should be provided, explaining why the references provided by the applicant can replace the study reports and how the results presented fulfil the requirements as set out in the Annex I of the Directive 2001/82/EC.
Such literature references, when replacing required study reports, should be included in the relevant Part 3 or 4 sections and should be summarised in Part 1C (detailed and critical summaries) as required for any other study report. “Supportive-only” literature references (i.e. provided in addition to study reports), should be provided in the corresponding Part of the dossier as “references” but do not need to be summarised in Part 1C.
Justifications for absence of study reports in each of the sections can be based, for example, on the following principles:
- Specific derogations foreseen in Directive 2001/82/EC;
- Specific derogations foreseen in CVMP Guidelines;
- Animal welfare (Directive 2010/63/EU of the European Parliament and of the Council and the European Convention for the protection of vertebrate animals used for experimental and other scientific purposes);
- Expert assessment explaining why repetition of certain tests or trials is unlikely to extend scientific knowledge of the subject area (e.g., documented clinical experience with the active substance might override the need for certain non-clinical tests);
- Scientific argumentation regarding inapplicability of such tests and trials;
- Inability to provide comprehensive data in accordance with Article 39(7) of Regulation (EC) No 726/2004 and as outlined in general provisions of Section 6 of Title III of Annex I of the Directive 2001/82/EC (applications in exceptional circumstances);
Article 13(1) - Generic application:
According to Article 13(1) of Directive 2001/82/EC, the applicant is not required to provide the results of pre-clinical tests and clinical trials if he can demonstrate that the medicinal product is a generic medicinal product of a reference medicinal product which is or has been authorised under Article 5 of Directive 2001/82/EC for not less than 8 years in a member state or in the Union.
- the same qualitative and quantitative composition in active substances as the reference product,
- the same pharmaceutical form as the reference medicinal product,
- and whose bioequivalence with the reference medicinal product has been demonstrated by appropriate bioavailability studies.
This type of application refers to information that is contained in the dossier of the authorisation of the reference medicinal product, for which a marketing authorisation has been granted in the Community on the basis of a complete dossier in accordance with Article 12(3), 13a, 13b or 13c of Directive 2001/82/EC.
It should be noted that the period of 8 years from initial authorisation of the reference medicinal product, providing a period of so-called “data exclusivity”, only applies to those reference medicinal products for which the initial application for authorisation was submitted through the centralised procedure after 20 May 2004.
Article 13(3) - Hybrid application:
Hybrid applications under Article 13(3) of Directive 2001/82/EC differ from generic applications in that the results of appropriate safety and residue tests and pre-clinical tests or clinical trials will be necessary in the following three circumstances:
- where the strict definition of a 'generic medicinal product' is not met;
- where the bioavailability studies cannot be used to demonstrate bioequivalence;
- where there are changes in the active substance(s), therapeutic indications, strength, pharmaceutical form or route of administration of the generic product compared to the reference medicinal product.
In such cases the results of tests and trials must be consistent with the data content standards required in Annex I to Directive 2001/82/EC.
These applications will thus rely in part on the results of safety and residue tests and pre-clinical tests or clinical trials for a reference product and in part on new data. Some guidance on the appropriate additional studies required is indicated in Annex II of the Chapter 1 of the Notice to Applicants (Volume 6A).
Article 13(4) - Similar biological application:
In Article 13(4) of Directive 2001/82/EC it is stated that where a biological medicinal product which is similar to a reference biological product does not meet the conditions in the definition of generic medicinal products, owing to, in particular, differences relating to raw materials or differences in manufacturing processes of the similar biological medicinal product and the reference biological medicinal product, the results of appropriate pre-clinical tests or clinical trials relating to these conditions must be provided. The type and quantity of supplementary data to be provided must comply with the relevant criteria stated in Annex I to Directive 2001/82/EC and the related detailed guidelines. The results of other tests and trials from the reference medicinal product's dossier shall not be provided.
The chosen reference medicinal product must be a medicinal product authorised in the Union, on the basis of a complete dossier in accordance with the provisions of Article 12(3) of Directive 2001/82/EC.
Article 13a - Well established veterinary use application:
According to Article 13a of Directive 2001/82/EC it is possible to replace results of safety and residue tests or of pre-clinical tests or clinical trials by detailed references to published scientific literature (information available in the public domain) if it can be demonstrated that the active substances of a medicinal product have been in well-established veterinary use within the Union for at least 10 years, with recognised efficacy and an acceptable level of safety. In this regard, the provisions of Annex I to Directive 2001/82/EC shall apply.
It should be noted that, if well-known substances are used for entirely new therapeutic indications, it is not possible to solely refer to a well-established use and additional data on the new therapeutic indication together with appropriate safety and residues tests and pre-clinical and clinical data should be provided. In such case, Article 12(3) of Directive 2001/82/EC should be used as legal basis.
Article 13b - Fixed combination application:
According to Article 13b of Directive 2001/82/EC, in the case of medicinal products containing active substances used in the composition of authorised veterinary medicinal products but not hitherto used in combination for therapeutic purposes, the results of safety and residue tests, if necessary, and new pre-clinical tests or new clinical trials relating to that combination shall be provided in accordance with Article 12(3)(j) of the same Directive, but it shall not be necessary to provide scientific references relating to each individual active substance.
Applications for fixed combination veterinary medicinal products can be accepted and validated under Article 13b on condition that all the individual substances have been authorised as a veterinary medicinal product in the EEA via a Union or national procedure.
It follows from the wording of Article 13b as well as from Annex I to the Directive 2001/82/EC that a full dossier, comprising parts 1, 2, 3 and 4, has to be provided in relation to the fixed combination. Any absence of specific fixed combination data should be duly justified.
Although there is no requirement for the inclusion of data on the individual active substances, it is possible to include information on the individual substances (literature or actual data), especially in order to justify the absence of certain specific data on the combination.
Article 13c - Informed consent application:
According to Article 13c of Directive 2001/82/EC, following the granting of a marketing authorisation, the authorisation holder may allow use to be made of the pharmaceutical, safety and residues, pre-clinical and clinical documentation contained in the dossier for the veterinary medicinal product for the purpose of examining a subsequent application for a veterinary medicinal product having the same qualitative and quantitative composition in terms of active substances and the same pharmaceutical form.
It is a prerequisite for the use of Article 13c as the legal basis that consent has been obtained from the marketing authorisation holder of the reference product for all parts of the dossier containing the pharmaceutical, safety and residues, pre-clinical and clinical data, and the applicant of the informed consent application should have access permanently to this documentation or should be in possession of the information.
For such informed consent applications, only Part 1A and Part 1B should be submitted, including the Application Form with relevant Annexes (e.g. copy of correspondence with the European Commission for multiple applications, if applicable, and the letter of consent from the MAH of the authorised medicinal product allowing access to Parts 1C, 2, 3 and 4 of the initial dossier and any subsequent documentation submitted).
In accordance with Article 31 of Regulation (EC) No 726/2004, “each application for the authorisation of a medicinal product for veterinary use […], otherwise than in exceptional cases relating to the application of the law on trademarks, shall include the use of a single name for the medicinal product.” The centralised procedure therefore requires one single name for the medicinal product to be authorised.
According to Article 1(22) of Directive 2001/82/EC the name of the veterinary medicinal product may be “either an invented name not liable to confusion with the common name, or a common name or scientific name accompanied by a trademark or the name of the marketing authorisation holder.” According to Article 1(23) of the same Directive“The common name is the international non-proprietary name recommended by the World Health Organisation, or, if one does not exist, the usual common name.”
A veterinary medicinal product authorised under the centralised procedure must have the same name in all EU member states. Although it is not mandatory under Union legislation, in practice many companies submitting marketing authorisation applications under the centralised procedure wish to use invented names for their medicinal products.
If the name of the product is invented, it should be followed by the strength (if applicable) and the pharmaceutical form and, if necessary, the target species, in order to avoid any confusion over different presentations of the veterinary medicinal product (e.g. same active substance and invented name) in different formulations for different target species. (See: Product information templates - Quality review of documents veterinary product information annotated template)
As part of the Agency’s role in evaluating the safety of medicinal products in the authorisation procedure, it is obliged to consider whether the (invented) name proposed for a veterinary medicinal product could create an animal health concern or potential safety risks.
The EMA operates a procedure to ensure that objections raised by National Competent Authorities (NCAs) against the (invented) name of a medicinal product, due to potential safety risks or other criteria as defined in the CVMP guideline on acceptability of invented names, are identified at an early stage.
Provided that the medicinal product is eligible for evaluation under the centralised procedure, the applicant should inform the Agency of the proposed invented name(s) for their medicinal product as soon as eligibility to the centralised procedure has been granted and prior to the planned submission date of the marketing authorisation application. (See: Question "How and when should the request for eligibility to the centralised procedure be sent to the European Medicines Agency?").
To allow for review of proposed invented names, the applicant(s)/marketing authorisation holder(s) are requested to send to the Agency (VMPname@ema.europa.eu) their proposed invented name(s) and the draft summary of product characteristics (SPC) or product profile and any information justifying the acceptability of the name(s). The 'Proposed Invented Name Request form' and further details of timing and content of an invented name application are available on the Agency website.
- The rules governing medicinal products in the European Union, Volume 6A, Notice to Applicants
- Guideline on the acceptability of names for veterinary medicinal products processed through the centralised procedure
- European Pharmacopoeia (Ph. Eur.) standard terms
- Product information requirements (Quality review of documents – QRD)
- Proposed invented name request form
In accordance with Article 34(4)c and 35 of Regulation (EC) No 726/2004, the CVMP opinion and subsequent Commission Decision on the marketing authorisation must include details of any conditions or restrictions which could be imposed on the supply or the use of the medicinal product concerned, including the conditions under which the medicinal product may be made available to users, in accordance with the criteria laid down in Article 67 of Directive 2001/82/EC and Directive 2006/130/EC.
The expression of the legal status in the label text (Annex IIIA of the CVMP opinion) is limited to the main classification, which is common to all member states:
- subject to medical prescription, or
- not subject to medical prescription.
As regards mock-ups and specimens, the use of any subcategory at national level (e.g. renewable/non-renewable) and the information required to express this should be addressed in the “Blue Box”. A member state may ask for additional information to appear on the outer packaging (in a “Blue Box” concerning identification and authenticity of the product, the legal category for supply, etc.
Once the veterinary medicinal product has received a marketing authorisation, it is possible for the MAH to apply to change the legal status by means of a variation, subject to the necessary data being presented.
According to Articles 31(3) and 32d of Regulation (EC) No 726/2004 the maximum timeframe for the evaluation of a marketing authorisation application under the centralised procedure is 210 active days, which exclude clock stops, when additional written or oral information is to be provided by the applicant in response to questions asked by the CVMP.
In accordance with Article 39(8) of Regulation (EC) No 726/2004, when an application is submitted for a veterinary medicinal product of major interest, particularly from the point of view of animal health and from the viewpoint of therapeutic innovation, an accelerated assessment may be requested.
The request for an accelerated assessment must be duly substantiated.
Any request for accelerated review needs to be sent to the European Medicines Agency accompanied by the appropriate justification and presented in accordance with the Guideline on the procedure for accelerated assessment pursuant to Article 39(8) of Regulation (EC) No 726/2004. Such a request should be sent at the latest one month before the anticipated date of submission of the application, and preferably at the time of notification of the intention to submit an application.
Applicants shall send their accelerated assessment request by sending a completed Pre-submission request form (selecting the indent “Centralised procedure - Accelerated review of MAA”) and applicant's justification to email@example.com.
Upon receipt of a request for accelerated review, the CVMP will consider whether the product meets the criteria and take a decision at their next meeting.
If the CVMP supports the request, the time limit of 210 days to give an opinion will be reduced to 150 days.
The applicant will be informed after the CVMP meeting.
The European Medicines Agency is regularly approached by applicants wishing to obtain, either simultaneously or successively, more than one marketing authorisation for the "same" product, under different (invented) names. The applicants' motivation may be based on business agreements governing joint research efforts and investment (e.g. co-development, co-marketing, co-licensing).
In the framework of Article 82(1) of Regulation (EC) No 726/2004, a specific procedure has been agreed between the Agency and the European Commission. Under this procedure applicants should, approximately four months prior to the anticipated date of submission, notify the Commission of their motives for submitting duplicate applications and provide the necessary explanation and justification addressing Article 82(1) of Regulation (EC) No 726/2004 criteria, with a copy to the Agency, addressing either public health reasons or co-marketing reasons.
Such notification should be sent to the following address:
DG Health and Food Safety
B5: Medicines: policy, authorisation and monitoring
Rue Breydel 4
The Commission will consider the situation, liaise with the applicant(s) where appropriate, and inform the applicant(s) as to whether it would have specific objections to the granting of duplicate marketing authorisations or not. The applicant always needs to include this Commission response as an annex to the application form, otherwise the Agency cannot validate such applications.
Duplicate applications for a specific medicinal product already under assessment via the centralised procedure have automatic access to the centralised procedure. Nevertheless, in all cases the eligibility of a medicinal product for evaluation via the centralised procedure needs to be requested by the applicant by submitting an eligibility request to the European Medicines Agency.
For the assessment procedure, the objective is to ensure the adoption of a CVMP opinion for a duplicate application at the same time as the CVMP opinion for the initial application. Therefore, for practical reasons, the Agency strongly recommends the following time points for submission of any duplicate application(s):
- in parallel with the initial application submission (day 0);
- before the adoption of the list of questions (before day 120) for the initial application;
- at the time of the responses to the list of questions (day 121) for the initial application.
It should be noted that duplicate applications are subject to a full validation as they are stand-alone applications. Therefore, the validation outcome may differ from that for the original application. If the above timeframes have been duly observed by the applicant, following the positive outcome of the validation, the evaluation of the duplicate applications will be aligned with that of the ongoing initial application. The submission of any duplicate applications should therefore be made in advance, to allow sufficient time for their validation to be completed by day 120 or day 121 of the ongoing initial application.
Duplicate applications can also be submitted after the Commission Decision on the initial application, but in this case as stand-alone applications or informed consent applications. The same requirements for eligibility and rapporteur assignment remain. However, as a rule, an abridged timetable for their assessment will be adopted in line with a 60 day procedure. Submission of such application(s) should therefore be made in advance to allow the completion of their validation before the intended start date of the procedure.
- Guidance on fees payable to the European Medicines Agency
- The rules governing medicinal products in the European Union, Volume 6A, Notice to Applicants
- Handling of duplicate applications (information from the European Commission; updated October 2011)
Fees for obtaining and maintaining a centralised authorisation to market medicinal products for veterinary use in the European Union are levied in accordance with Regulation (EC) No 297/95.
The Agency will issue an invoice to the applicant following the notification of the administrative validation and fees will be payable in Euro within 45 calendar days of the date of the said notification. The invoice is sent to the billing address indicated by the applicant, and will contain clear details of the product and procedures involved, the type of fee, the amount of the fee, the bank account to where the fee should be paid and the due date for payment.
If the application cannot be validated, the Agency will issue an invoice to the applicant for an administrative charge following the notification of the administrative non-validation to cover administrative costs.
For applicants, who have been registered as micro, small and medium-sized enterprise (SME), fee payment may be deferred by up to 45 days after the date of notification of the centralised marketing authorisation, or, in the event of withdrawal of the application, within 45 days of the date of notification of withdrawal. In the event of a negative outcome, where scientific advice has previously been sought from the EMA and taken it into account in the development of the medicinal product, the fee for the application for marketing authorisation will be fully waived by the Agency.
Further details on application fees and how they are calculated can be obtained in the “Explanatory Note on fees payable to the European Medicines Agency”.
Where an applicant disagrees with the classification by the Agency of an application under one of the fee categories described in the “Fee Regulation”, the following procedure may apply:
- Any disagreement should be sent to the Executive Director accompanied by the appropriate justification, at the latest two weeks after receipt of the invoice indicating the fees payable to the European Medicines Agency.
- The Executive Director will take a decision following consultation with the CVMP.
The guideline on the categorisation of new applications versus variation applications describes the agreement reached as to the use of the same definition of strength for applications submitted through the centralised procedure or the mutual recognition/decentralised procedure.
This definition will be taken into account for the calculation of fees, as well as for the allocation of EU numbers for presentations used by both the European Medicines Agency and the Commission (see "Explanatory Note on fees payable to the European Medicines Agency").
The following definitions apply:
- For single-dose preparations, total use, the strength is defined as the amount of active substance per unit dose.
- For single-dose preparations, partial use, the strength is defined as the concentration expressed as the amount of active substance per ml, per puff, per drop, per kg, per m2, or in percentage, as appropriate.
- For multi-dose preparations, the strength is defined as the concentration expressed as the amount of active substance per ml, per puff, per drop, per kg, or per m2, as appropriate.
- For powders for reconstitution (powders for oral solution or suspension, powders for solution for injection, etc.) the strength is defined as the concentration after dissolution or suspension (reconstitution) to the volume specified, with the liquid recommended.
- For concentrates for solution (for injection or for infusion) the strength is defined as the concentration of the concentrate before dilution.
For all inspections requested by the CVMP in respect of an application under the centralised procedure fees are payable by the applicant in accordance with Regulation (EC) 297/95, as amended, on fees payable to the European Medicines Agency.
Invoices are issued within 20 days of the confirmation of the inspection dates by the relevant inspectors and are sent by registered post to the applicant. Applicants for marketing authorisations under the centralised procedure are required to pay the total fee charged within 45 days from the date on which the inspection is carried out. (Important: The invoice reference number must be mentioned with each payment).
For inspections outside the EEA/European Union the applicant is also required to pay the travel and accommodation expenses of the inspector(s) and any experts or rapporteur involved in carrying out the inspection(s). These expenses are to be paid directly by the applicant to the inspector's authority.
In the case of multiple applications for the same medicinal product, the applicants may agree between themselves that one of them will be regarded as the “lead” applicant for the purpose of inspections. The identity of the “lead” applicant must be notified in writing to the Agency at the pre-submission stage. In such a case, the multiple applications will be treated as a single one and the total fee(s) will be charged to the “lead” applicant.
Where an inspection that has been formally notified to the applicant (and an invoice has been issued) is cancelled due to the withdrawal of or change to an application at any stage in the processing of the application, the applicant will be liable for 50% payment of inspection fee(s) as follows:
- Applicant decides to withdraw the application.
- In the context of GMP inspection, change to manufacturing arrangements by the manufacturer necessitating cancellation of the inspection, agreed at any time before the inspection is carried out.
- In the context of GCP inspection, change to the scope of the application or submitted data, or access to, ownership of, or location of facilities or data necessitating cancellation of the inspection, agreed at any time before the inspection is carried out.
Where the cancelled inspection was to take place outside the EEA/European Union, the applicant will be liable for any travel expenses already incurred by the inspectors at the date of cancellation for which they are not able to obtain reimbursement.
Applicants may benefit from fee incentives if at the time of the administrative validation the application or the applicant itself meets the criteria for a fee reduction or deferral. Any changes which may take place after validation would not retrospectively affect the levied fee.
Article 79 of Regulation (EC) No 726/2004 requires the Agency to introduce measures to assist applicants at the time of submitting applications for products for limited markets. The Agency developed a policy on Minor Use and Minor Species (MUMS)/limited market, which came into effect in September 2009. The measures made available range from administrative assistance, through to fee reductions and cover all aspects of applications from scientific advice, through maximum residue limits (MRLs), to marketing authorisation applications.
It should be noted that fee reductions can only be considered once a decision on the MUMS/limited market designation has been granted, and the product has been considered eligible for fee incentives.
Applicants which meet the definition of a micro, small or medium-sized enterprise (SME) as set out in Regulation (EC) 2049/2005, are eligible for certain fee reductions from the Agency. This includes fee reductions for scientific advice, pre- and post-authorisation inspections, scientific services and MRL applications, and a full fee waiver for administrative services (with the exception of parallel distribution).
SMEs may also request deferral of the fee payable for the application for marketing authorisation and/or related inspection.
It should be noted that fee reductions and deferrals can only be considered once the applicant has been assigned SME status by the Agency. SME applicants wishing to receive written confirmation of fee reduction and/or deferral should address an email to the Agency's SME Office (firstname.lastname@example.org). See: Question “Do I qualify as a small or medium-sized enterprise (SME)?”
Further information on the level of fee reductions/deferrals available to SME applicants and how to request them is available on the designated SME website.
Requests for fee reductions may be granted by the Executive Director in exceptional circumstances and for imperative reasons of public or animal health under the terms of paragraph 1 of Article 9 of Regulation (EC) No 297/95 on fees payable to the European Medicines Agency. Duly substantiated requests should be submitted by the applicant. A formal request for fee reduction addressed to the Executive Director citing Article 9 paragraph 1 is required, providing details of the product, procedure type and applicable fee, and the reason(s) for the request that justify exceptional circumstances and imperative reasons of public or animal health. Applicants should address their enquiry to email@example.com.
It is strongly recommended that a request be sent at least 3 months before the date of submission of the relevant application. Fee waivers or fee reductions are granted after consultation of the CVMP on the basis of the above criteria and only when funds are available.
- (Revised) Policy for classification and incentives for veterinary medicinal products indicated for minor use minor species (MUMS)/limited market
- Guidance for companies requesting classification as MUMS/limited markets
- Supporting SMEs
- Fees payable to the European Medicines Agency
- Regulation (EC) No 2049/2005, Volume 1, Notice to Applicants
Directive 2001/82/EC requires that all pharmacologically active substances contained in a veterinary medicinal product for food producing species need to be included in Table 1 of the Annex to Commission Regulation (EC) No 37/2010. Article 6 of Directive 2001/82/EC, as amended, states that:
"A member state shall not authorise the placing on the market of a veterinary medicinal product intended for administration to food producing animals whose flesh or products are intended for human consumption unless:
- the active substance or substances capable of pharmacological action is/are mentioned in Annex I, II or III to Council Regulation (EEC) No 2377/90."
Regulation (EEC) No 2377/90 was repealed by Regulation (EC) No 470/2009 and the substances previously included in Annex I, II or III of the Regulation are now listed in alphabetical order in table 1 of the Annex to Commission Regulation (EU) No 37/2010.
Prior to initiating a procedure for a marketing authorisation for a veterinary medicinal product, applicants should establish whether the product in question, if intended for use in food producing animals, complies with Article 6 of the aforementioned Directive, i.e. has an MRL been established for the relevant ingredients of the product.
Useful information on the establishment of MRLs can also be obtained from the European Medicines Agency website on Maximum Residue Limits.
Many excipients and adjuvants have been included in Table 1 of the Annex to Commission Regulation (EC) No 37/2010 with a “No MRL required” status, and others have been entered into the list of Substances not falling within the scope of the Regulation (EC) No 470/2009, with regard to residues of veterinary medicinal products in foodstuffs of animal origin, often called the “out-of-scope” list.
An excipient for a new product that is not listed in either Table 1 of the Annex to Commission Regulation (EC) No 37/2010 or the out-of-scope list can only be used if it has been demonstrated that the substance is not expected to show pharmacological activity or, after an evaluation for the establishment of MRLs, is included in Table 1 of the Annex to Regulation (EU) No 37/2010.
Guidance on the information required for inclusion of an excipient in the out-of-scope list is provided in the Guideline on the data to be provided in support of a request to include a substance in the list of substances considered as not falling within the scope of Regulation (EC) No 470/2009.
- Directive 2001/82/EC
- Regulation (EC) No. 470/2009
- Annex to Commission Regulation (EU) No. 37/2010
- Maximum residue limits (MRL)
- Guideline on the data to be provided in support of a request to include a substance in the list of substances considered as not falling within the scope of Regulation (EC) No 470/2009
Where the product in question is intended for food producing species and relevant MRLs have not been established, the following procedure should be followed:
Applicants should notify the European Medicines Agency of the intention to submit an MRL application. A letter of intent indicating the name of the substance, intended use, target species and intended submission date should be submitted to the Agency at least 6 months before the intended submission of the application for the establishment of MRLs. If the applicant has a valid micro, small and medium-sized enterprise (SME) status or a minor-use-minor-species and limited-markets classification, this information should also be included. The MRL application should be made at least 6 months before the application for the marketing authorisation application procedure.
Once the applicant has notified his intention to submit an application, the CVMP appoints a rapporteur and, if appropriate, a co-rapporteur. The applicant is notified of the appointment of the rapporteur (and co-rapporteur if appropriate), as well as the preferred submission date (closest to the submission date identified by the applicant). For applications for extensions or modifications of MRLs, usually no co-rapporteur is appointed.
For an MRL application for a new substance a full dossier should be submitted respecting the requirements of Commission Regulation (EU) 2017/12 and following the methodological principles outlined in Commission Regulation 2018/782. Applicants need to submit their application through the eSubmission Gateway / Web Client portal and should follow the Guideline on eSubmissions for a veterinary medicinal products.
For enquiries in respect of a product for which an MRL is required, applicants are invited to seek the advice of the Agency.
Applicants should address their enquiry or request for a pre-submission meeting regarding an intended MRL application to firstname.lastname@example.org.
- Questions and answers on maximum residue limits
- Regulation (EC) No. 470/2009
- Commission Implementing Regulation (EU) 2017/12
- Guidance documents
- Procedure for appointment and responsibilities of rapporteur and co-rapporteur
- Fees payable to the European Medicines Agency
- Guideline on the specifications for provision of an electronic submission (e-submission) for a veterinary medicinal product
A "mock-up" is a copy of the flat artwork design in full colour, presented so that, following cutting and folding where necessary, it provides a replica of both the outer and immediate packaging so that the three dimensional presentation of the label text is clear. It is generally referred to as a "paper copy" or "computer generated version". Mock-ups should be submitted in full size hard copy and in colour or electronically.
At submission of the Initial marketing authorisation application:
For validation purpose the Agency requests that all applications for a Marketing Authorisation should include the labelling texts in English, together with one English mock-up and one multi-lingual mock-up ('worst case') of the outer and small immediate packaging for each pharmaceutical form in the smallest pack size.
Mock-ups must be included in Part 1 of the application dossier.
The proposed outer and immediate labelling and package leaflet should be in compliance with the requirements outlined in Directive 2001/82/EC. Detailed reviews of the content of the labelling and package leaflet proposals and their translations, i.e. Annexes I and III, will take place during the scientific assessment and linguistic review of the application.
MAHs are responsible for the correct implementation of the agreed product information texts in their printed packaging materials, in line with the Commission Decision and relevant EU legislation;
The Agency can, at any time, request specific specimens from the applicant / MAH for review (e.g. further to a safety-related or product defect issue).
When required by the Agency, mock-ups or specimens should be submitted using the “Mock-Ups/Specimens Submission Form” (Annex 2 of the Revised checking process of mock-ups and specimens of outer/immediate labelling and package leaflets in the centralised procedure for veterinary medicinal products).
In some cases, the rapporteurs or the agency may ask for a sample to be submitted as an aid in better understanding e.g. the shape of a novel type of container or applicator, or in order to get a clearer understanding of space limitations in regard to labelling issues.
- Directive 2001/82/EC
- Revised checking process of mock-ups and specimens of outer/immediate labelling and package leaflets in the centralised procedure for veterinary medicinal products (updated March 2014)
- Commission “Guideline on the Packaging Informationof Veterinary Medicinal Products authorised by the Community”, Volume 6C, Notice to Applicants
- The Rules Governing Medicinal Products in the European Union, Volume 6A, Notice to Applicants
- Product information linguistic review process for new applications in the centralised procedure
The CVMP may however request the testing of samples of the medicinal product and/or its ingredients during the assessment of the application in accordance with the provisions of Article 32(1)b of Regulation (EC) No 726/2004.
In this case the rapporteur and/or co-rapporteur will specify a test protocol (type of samples, number of samples, number of batches, testing to be performed and methods and specifications to be used) and agree with the Agency which Official Medicines Control Laboratory (OMCL) will carry out the required testing.
Sampling and testing will be co-ordinated by the Agency in collaboration with the European Directorate for the Quality of Medicines and Healthcare (EDQM).
The marketing authorisation holder (MAH) is the person who holds the authorisation to place a medicinal product on the market and is legally responsible for marketing the medicinal product. The granting of a marketing authorisation by a competent authority does not discharge the holder from civil and criminal liability as provided for by the European Union law.
The MAH may be a natural or legal person.
The MAH of a centralised marketing authorisation must be established within the European Economic Area (EEA: member states of the European Union, Norway, Iceland and Liechtenstein).
In order to fulfil this requirement the MAH must have a permanent legal structure which is formed in accordance with the law of an EEA member state and which allows the concerned holder to assume the duties and responsibilities as well as to perform the tasks laid down by European Union law.
Companies or firms formed in accordance with the law of a member state and having their registered office, central administration or principal place of business within the EEA shall be treated in the same way as natural persons who are nationals of member states. An applicant should demonstrate that they are duly established in the EEA. A proof of establishment from the applicant company is required by the Agency in order for an application to be validated (e.g. in the United Kingdom, a certificate of incorporation issued by the Registrar of Companies, and in France an extrait du registre du commerce et des sociétés). This proof of establishment should be included in Annex 5.3 of the application form.
It should be emphasised that while the MAH may delegate certain activities to third parties, the MAH remains responsible for assuring all the obligations imposed on MAHs by the European legislation and by national law, as applicable.
In Volume 9B of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Veterinary Use published by the European Commission, clarification is given in a number of places on the level of detail expected in the DDPS.
The DDPS should explain how the pharmacovigilance system described applies to the proposed marketing authorisation holder (MAH), particularly if the pharmacovigilance system spans a number of differently named subsidiaries and their parent company, and any one of those companies may be the MAH for a particular marketing authorisation application (MAA). MAHs should provide a brief description of the organisation of the companies/subsidiaries/affiliates that may fulfil the role of MAH and are directed by the pharmacovigilance system described. It should be clear that the MAH named in the MAA is governed by the pharmacovigilance system. The description should be written so that it can be applied to any MAA, whatever the authorisation procedure or whichever of multiple MAHs is the MAH for a particular MAA.
Where aspects of the system such as the organisational arrangements are particular to the product rather than the main system of the MAH/company this should be indicated in a product specific addendum. The DDPS should be supported by documentation maintained by the company. However, written procedures, such as standard operating procedures, for example, should not be included in the DDPS.
It is important that applicants take account of this in order to avoid providing an unnecessary level of detail, with the consequences this has in relation to future variations when such detail changes. Further information is available in the pre-submission instruction for MAHs listed below. In addition the checklist on elements to be provided by MAHs in their DDPSs for competent authorities' assessment (link below) may also be useful for potential MAHs.
- Pre-submission instruction on the detailed description of the pharmacovigilance system of a marketing authorisation holder; to be submitted with a marketing authorisation application for a veterinary medicinal product
- Checklist on information/elements that should be provided by marketing authorisation holders in their detailed descriptions of the pharmacovigilance system for competent authorities' assessment
- Volume 9B of The Rules Governing Medicinal Products in the European Union – Guidelines on Pharmacovigilance for Medicinal Products for Veterinary Use
The Agency requires the applicant to provide background information in support of the application relating to the manufacture (including packaging), batch testing and final batch release by the qualified person in the EEA. This should be sent to the Agency along with the application dossier. The EEA includes European Union (EU) member states plus Iceland, Liechtenstein and Norway. Switzerland is not part of the EEA.
Once validated, it is normally not permitted to add a new site or to change the steps of manufacture/ batch release described under Part 1A of the application during the 210-day review period. Any additional site or change in the manufacturing or batch release arrangements should be submitted as a variation after the granting of the marketing authorisation.
The information on manufacturing and batch-release sites submitted in Part 1A of the application must be consistent with Part 2. All the manufacturing and batch-release sites mentioned in Part 2 must be listed in Part 1A and the activities carried out at each site must be described in part 1A consistently with the information provided in Part 2.
All sites involved in the production of both the active substance(s) and the finished medicinal product must be described (name and detailed address, including building reference) in Part 1A of the application for a marketing authorisation together with a description of the steps performed. This should include:
- active substance manufacture and packaging
- any contract laboratories used for testing the active substance (incl. ongoing stability monitoring)
- bulk medicinal product manufacture
- diluent/solvent manufacture (if any)
- manufacture of any other associated medicinal product (if any)
- finished product manufacture and packaging
- batch release
- any contract manufacturing sites
- any contract laboratories used for testing the finished product
- Official Medicines Control Laboratory (OMCL) for vaccines if 'official batch release' is a requirement for the product in question.
For third country manufacturers, information about any previous EU/EEA inspection in the last 2-3 years (with, if possible, a copy of the inspection report) and any planned EU/EEA inspections should be provided. This should include details of the inspection dates, product categories inspected and the name of the inspecting competent authority.
Documents to be attached to Part 1A of the application:
The following documents should be attached to Part 1A of the application:
- Copies of the manufacturing authorisation authorising the sites involved in the manufacture, importation, control and testing and qualified-person release of batches of the medicinal product for all sites in the EEA, other than active substance manufacturers. Alternatively, a reference can be made to the appropriate entry in the EudraGMP database.
For sites in the EEA, good-manufacturing-practice (GMP) certificates are not an acceptable alternative to a manufacturing authorisation. However, GMP certificates can be useful additional information. Also, particular attention should be paid that the scope of the manufacturing authorisation for a given manufacturer covers the activities proposed as part of the marketing authorisation application.
- A mutual-recognition-agreement (MRA) certificate for all sites other than active substance manufacturers located in third countries where an MRA or other relevant agreement is in place. This certificate must not be older than three years, and must come from the local competent authority that carried out the inspection. Alternatively, a GMP certificate from the EEA inspecting competent authority should be provided if the site has been inspected by an EEA competent authority in the last two or three years. Where the MRA partner has placed the certificate in EudraGMDP, a reference to the entry will suffice. For a list of the countries which have operational MRAs with the EU, please consult the website on MRAs.
- For all sites other than active substance manufacturers located in third countries with no MRA with the EU, a GMP certificate from the EEA inspecting competent authority if the site has been inspected by an EEA competent authority in the last two or three years. Alternatively, a reference can be made to the appropriate entry in the EudraGMDP database.
- In addition to the above, a copy of the registration or other document analogous to a manufacturing authorisation from the local competent authority demonstrating that the site is authorised for manufacture of the product or pharmaceutical form and details of any inspections performed other than by EEA authorities (e.g. GMP certificates or similar statements from the competent authority that carried out the inspection).
- A flowchart describing all the main steps involved in the manufacture of the active substance and finished product.
- For each active substance, a declaration from the qualified persons of all the finished product manufacturers located in the EEA listed in Part 1A where the active substance is used as a starting material and from the qualified persons of the batch release sites in the EEA stating that the active substance manufacturers listed in Part 1A operate in compliance with the detailed guidelines on GMP.
Contact person in the EU/EEA for product defects/recalls:
A proposed contact point/person in the EEA for quality problems and defective batches of product must also be provided in Part 1A of the application (name, full address, 24 hour emergency phone and fax numbers, e-mail address and mobile phone number, if available).
Importing site / supervisory authority
According to Article 55(1)(b) of Directive 2001/82/EC, each batch of a veterinary medicinal product must be certified by a qualified person prior to release onto the market in the EEA.
In the case of products imported from a third country, and for the purpose of Article 55(1)(b) of Directive 2001/82/EC, the site where the certification of batches by the qualified person occurs is considered to be the importing site in the EEA, and not necessarily the site through which the batch first physically enters the EEA. The EEA includes EU member states plus Iceland, Liechtenstein and Norway. Switzerland is not part of the EEA.
In accordance with the provisions of Article 43 of Regulation (EC) No. 726/2004, the supervisory authority is the competent authority of the member state that granted the manufacturing authorisation provided for in Article 44(1) of Directive 2001/82/EC in respect of the manufacture of the medicinal product concerned. In the case of products imported from third countries, the supervisory authority is the competent authority of the member state that granted the manufacturing authorisation provided in 44(3) of Directive 2001/82/EC to the importer, unless a mutual recognition agreement (MRA) covering GMP for the product under consideration is operating with the country where the medicinal product is manufactured.
In the exceptional circumstances where a valid manufacturing authorisation is not in place at the time of the marketing authorisation submission for any finished product manufacturer, importer or batch-release site located in the EEA, the Agency will consult the supervisory authority and a request for inspection may be triggered. The marketing authorisation procedure will require the inspection outcome before opinion and, in particular, confirmation of the granting of the manufacturing authorisation.
For any finished product manufacturer located in third countries with no MRA that is not in possession of a GMP certificate at the time of the marketing authorisation submission, a request for inspection will normally be triggered. The marketing authorisation procedure will require the inspection outcome before opinion.
Batch testing upon importation:
For medicinal products imported from third countries, retesting of each batch within the EEA upon importation is required unless a mutual recognition agreement (MRA) or other relevant agreement covering GMP for the product under consideration is operating with the country where the medicinal product is manufactured. If such an MRA is in operation, batch controls and tests carried out in the country where the product is manufactured are acceptable.
It should be noted that MRAs cover batch control and testing and do not cover batch release. Batch release must take place in the EEA territory for every production batch released to market in the EEA, regardless of whether an MRA with the exporting country is in place or not.
For the countries that have operational MRAs with the EU, see website on MRAs. Batch release of an imported medicinal product from a third country without retesting is a serious failure of a Qualified Person's legal obligations. According to Article 56 of Directive 2001/82/EC, it is expected that member states' supervisory authorities launch appropriate administrative measures and may withdraw the product concerned from the market (Article 84(1)(e) of Directive 2001/82/EC).
Contracting out of certain controls:
The provisions of Article 24(b) of Directive 2001/82/EC allows certain of the controls required under the provisions of Article 55 of Directive 2001/82/EC to be contracted out to third parties, if justified, and provided that the laboratories have been verified by the relevant competent authorities. Laboratories used for contract testing upon importation of medicinal products manufactured in third countries may be located in any EEA country.
The qualified person of the manufacturing authorisation holder named in the application is however responsible for ensuring that any contract laboratory used carries out the controls in accordance with GMP, as applicable and with the requirements of the marketing authorisation, once granted.