Veterinary pre-submission Q&A: 21-40

Annex I to Directive 2001/82/EC describes the concept of an open and closed Active Substance Master File (ASMF) and specifies that:

“For a well-defined active substance, the active substance manufacturer or the applicant may arrange for the following information to be supplied in a separate document directly to the competent authorities by the manufacturer of the active substance as an Active Substance Master File:

(a) a detailed description of the manufacturing process;

(b) a description of the quality control during manufacture;

(c) a description of the process validation.

In this case, the manufacturer shall, however, provide the applicant with all of the data, which may be necessary for the latter to take the responsibility for the medicinal product…”

It should be emphasised that the concept of the ASMF shall only apply to a well-defined active substance and cannot be used for excipients, finished products and biological active substances. The information related to excipients, finished products and biological active substances shall be provided within the marketing authorisation application by the applicant and any post-authorisation changes as variations are to be submitted by the Marketing Authorisation Holder (MAH).

In case an application under the centralised procedure includes the submission of an Active Substance Master File (previously referred to as European Drug Master File (EDMF), applicants should be aware of the fact that, as mentioned in the guideline on the Active Substance Master File Procedure (EMEA/CVMP/134/02), an ASMF consists of 2 parts:

1. ASMF applicant’s part, also referred to as open part, which shall be at the disposal of the applicant.
2. ASMF restricted part, also referred to as closed part, which is a confidential document closed to the applicant.

Both parts need to be separated and follow the structure of Part 2 of the Notice to Applicants (NtA), or module 3.2.S of the common technical document (CTD), as applicable.

The content requirements as described in the above mentioned guideline should be followed.

Applicants should note that the ASMF constitutes an integral part of the dossier and therefore should always be made available to the EMA and CVMP Members. The applicant is responsible for the submission of all necessary documents.

The applicant or MAH should ensure that the ASMF dossier submitted by the ASMF holder is synchronized to arrive simultaneously with the marketing authorisation application or variation. Therefore, a close communication between the MAH or applicant and the ASMF holder is highly recommended.

Marketing authorisation applications or variations cannot be validated until all the necessary documents (medicinal product dossier and ASMF dossier) are received in a satisfactory form. This also applies to the ASMF-related responses during a procedure (e.g. responses to day 120 lists of questions and day 180 lists of outstanding issues). Applicants should be aware that a procedure cannot restart until the responses from the ASMF holder are received by the Agency.

The ASMF is developed to keep intellectual property (IP) confidential. However, it should be noted that the introduction of an ASMF is also possible in cases where the applicant is also the IP holder of the active substance.

ASMF holders are reminded of their responsibility to inform the MAHs of any changes to their ASMFs. Similarly, MAHs are reminded of their legal obligation to submit the applicable variation to their marketing authorisations when changes are proposed to the ASMF, i.e. when an updated version of the ASMF is submitted, the marketing authorisations linked to that ASMF will only integrate the ASMF update once the applicable variation is submitted and positively concluded.

Additional information on the ASMF procedure can be found in the in the Heads of Medicines Agencies website (Working Group on ASMF Procedures) and the Agency’s website (Guideline on Active substance Master File procedure).

Non-applicability of ASMF concept to biological active substances

Further to clarifications from the European Commission on the interpretation of Directive 2001/82/EC, and as explained in the guideline on ASMF, the ASMF concept is not acceptable for biological medicinal products.

The characterisation and determination of biological active substances requires not only a combination of physicochemical and biological testing, but also extensive knowledge of the production process and its control.

The MAH/applicant for a biological medicinal product could therefore not comply with the requirement to 'take responsibility for the medicinal product' without having full and transparent access, to these quality-related data. The use of an ASMF would prevent such access, and should therefore not be allowed for biological active substances.

In addition, active substances, which are present in certain medicinal products such as vaccines, do not fit with the concept of a 'well-defined' active substance.

References

• Annex I to Directive 2001/82/EC (Directive 2009/9/EC)
• Guideline on Active Substance Master File Procedure (EMEA/CVMP/134/02)
• HMA: CMD Working Group on ASMF Procedures

In the first submission of an ASMF to EMA, the ASMF holder is required to submit:

• ASMF dossier (applicant’s part, restricted part, quality overall Summary (if CTD format) or detailed and critical summary (if NtA format), and expert’s curriculum vitae);
• Letter of access (annex 2 of the ASMF guideline);
• Submission letter and administrative details (annex 3 of the ASMF guideline) duly filled in as detailed in the instructions provided in the additional guidance on documents relating to an active substance master file;
• A commitment to inform the applicant and the EMA of any change in the ASMF to be provided either as a separate letter or within the letter of access (annex 2 of the ASMF guideline).

In any later marketing authorisation application or variation submission referring to an ASMF already submitted to EMA, the ASMF holder is only required to submit:

• Letter of access (annex 2 of the ASMF guideline) if the ASMF is used in a new marketing authorisation application or variation for a veterinary medicinal product not supported by the ASMF. For variations for a veterinary medicinal product already supported by the ASMF, there is no need to re-submit the letter of access as the one already provided within previous procedure is valid throughout the product’s lifecycle;
• Submission letter and administrative details (annex 3 of the ASMF guideline) duly filled in as detailed in the instructions provided in the Additional guidance on documents relating to an active substance master file;
• The relevant revised sections of the ASMF dossier (applicant’s part and/or restricted part, as applicable) reflecting changes to the previously accepted version;
• A commitment to inform the applicant and the EMA of any change in the ASMF to be provided either as a separate letter or within the letter of access (annex 2 of the ASMF guideline) only if a letter of access is needed (see above).

The contact details of the ASMF holder contact person must be the same in the cover letter of the ASMF, in the letter of access and the application form submitted by the applicant or MAH.

The ASMF dossier and any subsequent updates should only be submitted once.

The ASMF holder may, at its discretion, contact vet.applications@ema.europa.eu directly for pre‑submission questions regarding classification of changes in the restricted part of the ASMF.

References:

• Guideline on Active Substance Master File Procedure, templates for annexes 2 and 3 of the ASMF guideline and additional guidance on documents related to an ASMF

Initial marketing authorisation applications

In the context of a marketing authorisation application the applicant should submit:

• application form stating, in section 2.5 “Manufacturers”, the correct EMEA/ASMF or EU/ASMF reference number;
• a copy of the letter of access (annex 2 of the ASMF guideline) in annex 5.10 of the dossier;
• a copy of the complete current version of the applicant’s part of the ASMF in the relevant part of the dossier;
• a copy of the commitment from the ASMF holder to inform the applicant and the EMA of any change in the ASMF to be provided either as a separate letter in annex 5.11 or within the letter of access (annex 2 of the ASMF guideline) in annex 5.10.

Variations to the terms of the marketing authorisation

In cases where the veterinary medicinal product is already supported by the ASMF in question, the MAH should submit:

• variation application form stating the correct EMEA/ASMF or EU/ASMF reference number in section 3 “Types of change(s)”;
• if applicable, copy of the revised sections of the applicant’s part of the ASMF which should be identical to the ones submitted by the ASMF holder.

In cases where a new ASMF is being introduced as part of a Type II variation (B.I.a.1.b – Introduction of a manufacturer supported by an ASMF), the MAH should submit:

• variation application form stating the correct EMEA/ASMF or EU/ASMF reference number in section 3 “Types of change(s)”;
• a copy of the letter of access (Annex 2 of the ASMF guideline);
• a copy of the complete current version of the applicant’s part of the ASMF in the relevant part of the dossier;
• a copy of the commitment from the ASMF holder to inform the applicant and the EMA of any change in the ASMF to be provided either as a separate letter or within the letter of access (annex 2 of the ASMF guideline).

The MAH or the applicant should ensure that the submission of the ASMF dossier by the ASMF holder is synchronized to arrive simultaneously with the planned variation or marketing authorisation application. Therefore, a close communication between the MAH or applicant and the ASMF holder is highly recommended.

Effective liaison between the MAH and the ASMF holder will promote the appropriate classification of the changes in accordance with the Commission’s variations guideline and for ensuring that the ASMF dossier or the relevant affect sections of the dossier have been submitted.

The latest version of the ASMF submitted in the context of a previous centralised procedure will be considered the current version of that ASMF. The current version of the ASMF should correspond to the version of the ASMF applicant’s part declared in a new marketing authorisation application or variation application form and included in the relevant part of the dossier. This will be subject to compliance checks during validation of the MAA and variation.

Example:

The version of EMEA/ASMF/12345 (EMEA/ASMF reference number) currently held at the Agency is: AP January 2012/RP April 2013.

If the version of the ASMF included in the dossier of the marketing authorisation application and referenced in the application form is AP November 2011, the applicant will be requested to update the dossier and the application form according to the current version of the EMEA/ASMF/12345.

Equally, if the version of the ASMF included in the dossier of the marketing authorisation application and referenced in the application form is AP December 2012, the ASMF holder will be requested to submit the latest version of the ASMF together with annex 3 of the ASMF guideline.

From 1 September 2013, ASMF holders submitting their ASMF dossiers relating to a centrally authorised product (CAP) are asked to send it to the Agency and Committee members only once.

According to the new ASMF submission rules the Agency will assign a reference number on request prior to submission of the ASMF that can cover multiple CAPs.

The ASMF reference number is an internal reference number sequentially assigned by the EMA to enable an appropriate data lifecycle management of ASMFs used in one or more centralised marketing authorisations.

The ASMF reference number does not replace the responsibility of the ASMF holders to version control their ASMF (in accordance with good manufacturing practice) nor replaces their own ASMF numbering system.

The ASMF reference number will follow one of these structures:

• EMEA/ASMF/XXXXX: this structure of ASMF reference number will be allocated when the ASMF is used in a marketing authorisation application in the centralised procedure and or in a variation for a centrally authorised product. The ASMF in this instance is not following the ASMF assessment worksharing procedure.
• EU/ASMF/XXXXX: this structure of ASMF reference number will be allocated when the ASMF follows the ASMF assessment worksharing procedure. This ASMF reference number can be allocated either by EMA (if the first submission of the ASMF is within a centralised marketing authorisation application or variation) or by the corresponding NCA (if the first submission of the ASMF is within a marketing authorisation application or variation in the decentralised procedure (DCP)).

References

• ASMF assessment worksharing procedure

The ASMF reference number should be requested by the ASMF holder for:

• new ASMFs submitted for marketing authorisation applications and variations as of 1 September 2013. From this date, reference to an ASMF reference number will be checked at validation,
• ASMFs submitted to the EMA before 1 September 2013 in cases where the ASMF is referenced in a new marketing authorisation application or variation. The request for the ASMF reference number should be made before submission of a new marketing authorisation application or variation to update the ASMF.

For previously submitted ASMFs, in cases where the ASMF is used in more than one marketing authorisation the ASMF holder should only request one ASMF reference number, when applicable¹. The allocated ASMF reference number should be communicated to the applicant or MAH, as they need to include the ASMF reference number in all future submissions.

¹Example: substantially different route of synthesis/manufacturing process which results in changes to important quality characteristics of the active substance, e.g. bioavailability of the active substance, may result in the allocation of two different EMEA/ASMF numbers.

Up to two weeks before submitting a complete new ASMF, or an update to an already submitted ASMF that has not been allocated yet an EMEA/ASMF or EU/ASMF reference number, the ASMF holder should request an ASMF reference number. To submit your request, raise a ticket via EMA Service Desk, using the Question option. The type of question to be selected is “Request for high-level procedure or ASMF number” followed by sub-option “ASMF number” and attaching the ASMF number request form . To raise a ticket via EMA Service Desk you need an EMA account. Should you not have one, you may create one via the EMA Account Management portal.

ASMF reference numbers are sequentially allocated. A request form is available.

The ASMF reference number allocated should be referenced in all subsequent communications (e.g. in response to validation issues, list of questions, list of outstanding issues, upcoming variation) and should always be included in the following documents:

• Marketing authorisation application (application form: in the field ‘National ASMF number’ if it is an EMEA/ASMF reference number or in the field ‘EU ASMF reference Number if available’ if it is an EU/ASMF reference number) or variation application form (in the field ‘Present and Proposed’);
• Letter of access (annex 2 of the ASMF guideline);
• Submission letter and administrative details (annex 3 of the ASMF guideline).

It is the responsibility of the ASMF holder to inform the applicant of the marketing authorisation application or the MAH in case of variations of the allocated ASMF reference number. Failure to state a valid ASMF reference number on the application form will trigger validation questions and may delay the start of procedure.

References

• Active substance master file procedure - Scientific guideline
• EMEA/ASMF reference number request form
• For EU/ASMF reference number request form visit: HMA: CMD Working Group on ASMF Procedures

ASMF holders should either have an EMEA/ASMF reference number or an EU/ASMF reference number before submitting an ASMF to EMA, but never both.

If an ASMF that is going to be submitted for the first time to EMA already has an EU/ASMF reference number previously allocated by an EU Competent Authority, the ASMF holder should not request to EMA either an EMEA/ASMF reference number or an EU/ASMF reference number. The EU/ASMF reference number allocated previously to that ASMF is the one to be used for the submission to EMA.

The EU/ASMF reference number allows for the identification by all Competent Authorities (National Competent Authorities and EMA) of ASMFs used in the ASMF assessment worksharing procedure. This procedure can be used for ASMFs that support marketing authorisations or variations in the centralised, decentralised and mutual recognition procedures.

ASMF holders are encouraged to request an EU/ASMF reference number if the ASMF is expected to be used in centralised and national applications (decentralised and mutual recognition procedures) and have not been used in any of these procedures previously.

For more information on the ASMF assessment worksharing procedure and the EU/ASMF reference number request template form please consult the Heads of Medicines Agencies website (Working Group on ASMF Procedures).

References

• EMEA/ASMF reference number request form
• HMA: CMD Working Group on ASMF Procedures

Currently the following formats are accepted for ASMF submissions for veterinary applications:

• Notice to Applicants: electronic (VNeeS).
• Common Technical Document (CTD): electronic (NeeS and eCTD).

Submissions of veterinary medicinal product dossiers in eCTD format cannot be accepted by regulatory authorities. However, a specific provision applies for ASMF dossiers. Please consult the document Exceptions to the VNeeS format for further details.

Guidance on the electronic formats can be found on the eSubmission website (VNeeS and NeeS).

References

• Veterinary e-submission website
• Exceptions to the VNeeS format

Submission to the EMA

As indicated above (see: When and how to request an ASMF reference number?), ASMF holders should request the ASMF reference number via  EMA Service Desk using the request form available. However, it is reminded that ASMFs submitted in support of marketing authorisation applications or variations for veterinary medicinal products should be submitted for the attention of Veterinary Applications (vet.applications@ema.europa.eu).

From 1 January 2017 all ASMF submissions to the Agency in respect of veterinary medicinal products must be made using the eSubmission Gateway / Web Client Portal. Further guidance is available on the Veterinary eSubmission website. 

Submission requirements for the rapporteurs and co-rapporteurs

For Centrally Authorised Products, the ASMF holders submit applications only once to the European Medicines Agency and there should be no further CDs/DVDs or CESP submissions to any individual Member States as distribution will take place electronically between the European Medicines Agency and the National Competent Authorities. Submissions sent to EMA via eSubmission Gateway/Web Client will be considered delivered to all CVMP members, alternates and National Competent Authorities.

The above also apply to the submission of responses to list of questions and list of outstanding issues.

References

• Veterinary eSubmission website
• eSubmission Registration
• eSubmission Gateway and Web Client online registration guidance
• eSubmission Web Client
• CAP dossier requirements for veterinary submissions

ASMF holders need to request the EMEA/ASMF reference number by filling in the request form. The EMA will provide the requestor with the number within 3 working days. Please note that this number is not equivalent to the EU/ASMF reference number and should never be inter-changed.

If the ASMF holder already has more than one lifecycle filed for the given substance, they will need to select one of these (informing the EMA in the cover letter which one it will be) and follow the lifecycle of the selected ‘product’ only. This selected lifecycle will then receive a new EMEA/ASMF/01xxx number covering all listed CAPs.

When the ASMF holder submits an update or new version to the ASMF, they have to do so with this new number. The ASMF holder will have to prepare a new package where they declare (in the cover letter) that the previously submitted ASMF version has not been modified since it was last submitted.

If there have been modifications (new version) since the last ASMF submission, the relevant parts of the ASMF dossier will have to be updated.

ASMF holders have to inform all MAH(s) about the new EMEA/ASMF/xxxxx number and if an update is submitted to an ASMF related to their centrally authorised product the MAH should then submit the relevant variation application.

References:

• Annex I to Directive 2001/82/EC (Directive 2009/9/EC, Title I, Part 2C)
• Guideline on Active Substance Master File Procedure, templates for annexes 2 and 3 of the ASMF guideline and additional guidance on documents related to an ASMF
• EMEA/ASMF reference number request form
• HMA: CMD Working Group on ASMF Procedures
• eSubmission website (VNeeS and NeeS)

With the letter of intention to submit an application for a marketing authorisation under the centralised procedure for a veterinary medicinal product containing or consisting of genetically modified organisms (GMOs) within the meaning of Article 2(2) of Directive 2001/18/EC, the applicant will be required to provide confirmation that all obligations under the Directive have been complied with.

In cases where there is a lack of clarity about whether the application falls within the meaning of Article 2(2) of Directive 2001/18/EC or whether the animals treated with the veterinary medicinal product would fall within this meaning it is important to contact the Agency as early as possible .

In the case of a medicinal product containing or consisting of GMOs within the meaning of Article 2(1) and 2(2) of Directive 2001/18/EC, the application must be accompanied by:

• a copy of any written consent or consents of the competent authorities to the deliberate release into the environment of the GMOs for research and development purposes where provided for by Part B of Directive 2001/18/EC.
• the complete technical dossier supplying the information requested in Annex III A to Directive 2001/18/EC and the environmental risk assessment resulting from this information.
• the results of any investigations performed for the purposes of research or development.

These particulars should be presented as follows:

• as an attachment to the relevant parts of the application dossier (Parts 1 and 3.E), and
• in a separate volume or electronic copy, which could stand alone and which could be handled separately from the remainder of the dossier.

Regulation (EC) No 726/2004 requires that the rapporteur hold necessary consultations with the competent national authorities under Directive 2001/18/EC, where the medicinal product contains or consists of a GMO.

Once the application has been validated, the EMA secretariat will send a copy of the timetable to the CVMP chairman and members, the applicant and the competent authorities under Directive 2001/18/EC. These competent authorities will be given the opportunity to request Part 3.E of the application dossier from the applicant. This request will be channelled via the EMA secretariat which will forward the requested information to the competent national authorities under Directive 2001/18/EC.

The risk assessment submitted with the application will be considered in conjunction with the assessment of quality, safety and efficacy according to the requirements laid down in Annex I to Directive 2001/82/EC, as amended, and will be assessed by the rapporteur, co-rapporteur or their experts.

The competent authorities under 2001/18/EC will be asked to provide any questions they may have on the dossier or assessment to the rapporteur or such person designated by the rapporteur, with a copy of any questions to the EMA secretariat.

The final conclusion, however, remains with the Committee, which, having assessed the quality, safety and efficacy data provided by the applicant in support of its product, shall discuss the risk versus the benefit of the use of the product and shall recommend or not the granting of a European Union marketing authorisation.

References:

• Regulation (EC) No 726/2004
• Annex I to Directive 2001/82/EC (Directive 2009/9/EC)
• Directive 2001/18/EC
• The Rules Governing Medicinal Products in the European Union, Volume 6C, Notice to Applicants
• SOP on GMOs

For each application the applicant must fulfil the requirements laid down in the Annex I to Directive 2001/82/EC, where demonstration of compliance is required with the Note for Guidance for minimising the risk of transmitting animal spongiform encephalopathy agents via human and veterinary medicinal products (EMEA/410/01 rev.3 or any future update) as well as with the corresponding monograph of the European Pharmacopoeia.

Demonstration of compliance with the note for guidance can be effected by submitting Certificates of Suitability from the European Directorate for the Quality of Medicines (EDQM), or by inclusion in the dossier (Part 2.D) of scientific data to substantiate this compliance.

For all applications, the table A on 'materials of animal origin covered by the Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products' should be completed.

For materials from animals not covered by the Note for guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products and the Annex I to Directive 2001/82/EC, applicants are requested to complete the table B on 'other materials of animal origin'.

Materials of human origin

If an application relates to medicinal product which contains or uses in the manufacture materials of human origin, applicants are requested to complete the table C on 'albumin and other human tissue derived products'.

References:

• Annex I to Directive 2001/82/EC (Directive 2009/9/EC)
• Note for Guidance on minimising the risk of transmitting animal spongiform encephalopathy agents via medicinal products (EMEA/410/01-rev.3 or any future update)

Some holders of European Union marketing authorisations have requested that a local contact point be identified in the package leaflet and on the outer carton. This would normally be the holder of the European Union marketing authorisation. However, where a marketing authorisation holder wishes to add the name of another (local) contact point in some or all EEA countries, the local representative may be indicated:

• in the package leaflet, under heading 15, by name, address, telephone number and e-mail address (as per the latest QRD template);
• in the blue box on the outer carton by name and, if space permits, by address, telephone number and e-mail address.

References to addresses on the internet are not allowed, neither for the marketing authorisation holder nor the local representatives.

Local Representative shall be taken to mean: any private or legal person established in the European Union charged, through a civil contract with the marketing authorisation holder, with representing him in a defined (geographical) area; this contract excludes any transfer of any responsibility imposed on the marketing authorisation holder by European Union law and by national law, regulation and administrative action implementing such European Union law.

There has been some confusion with regard to terms such as 'exploitant', 'technical director', 'distributor', etc. Since there is neither a commonly agreed understanding of these terms nor equivalent legal definitions of these terms amongst the EEA countries, and in the absence of any reference or definition in European Union law, reference to such terminology will not be accepted for a medicinal product authorised by the European Union.

It must be recalled that, under the case-law of the EC Court of Justice, EEA countries may not require that a local representative of the marketing authorisation holder be appointed for their territory. Therefore, the arrangements outlined above are purely optional for holders of European Union marketing authorisations.

Attention should be drawn to the fact that in cases where the manufacturer is different from the marketing authorisation holder, only the actual manufacturer responsible for batch release should be mentioned in the package leaflet in addition to the marketing authorisation holder.

References:

The Rules Governing Medicinal Products in the European Union, Volume 6, Notice to Applicants

In order to fulfil EU dossier requirements applicants must submit new marketing authorisation applications as follows:

Languages to be used:

All applications have to be submitted in English.

Format of submissions:

The e-dossier follows the structure of the Notice to Applicants, Volume 6B. Details on the structure are provided in the “Guideline on the specifications for provision of an electronic submission (e-submission) for a veterinary medicinal product”. CTD format is generally not appropriate for veterinary dossiers. However, exceptions might be possible for the chemical, pharmaceutical and biological/microbiological information for the finished product (Part 2), but need to be confirmed prior to submission of the dossier.

Guidance has been prepared by the Veterinary Harmonisation Group, made up of representatives from national competent authorities, the Agency and industry, to assist applicants in the preparation of their dossiers. EMA-specific guidance has been published by the Agency.

The use of the electronic Application Forms (eAFs) is mandatory for the Centralised Procedure. The Agency strongly recommends the use of a single electronic application form per submission, even if the submission concerns multiple target species / strengths / pharmaceutical forms.

Information on the electronic Application Form electronic application form can be found on the eSubmission eAF webpage.

Active Substance Master File (ASMF):

In cases where an Active Substance Master File (ASMF) exists, the applicant should ensure that the ASMF is submitted by the ASMF holder to the Agency at around the same time as the main application, in order to proceed with the validation of the dossier. See: Question “How shall I submit an Active Substance Master file (ASMF)?” and related questions to ASMF submissions.

Submission to the EMA:

The eSubmission Gateway / Web Client is the mandatory submission channel that should be used for submission of all veterinary applications.

More information on how to register and connect to the Gateway / Web Client as well as training materials on the use of the system can be found on the eSubmission website. An automated 'acknowledgement' email is sent from the system to the applicant.

Submission to the rapporteur and co-rapporteur:

Since 1 June 2018, the use of the Common Repository is mandatory for all CVMP members to retrieve submissions. Therefore, the applicant should submit their dossier only once, via the EMA eSubmission Gateway / Web Client. For further information, please consult “Dossier requirements for submission of marketing authorisation and maximum residue limit (MRL) applications to the European Medicines Agency (EMA) and to members of the Committee for Medicinal Products for Veterinary use (CVMP)”.

No parallel submissions to rapporteur, co-rapporteur or other committee members is required.

Validation of the application

In the event that the Agency requires additional data, information or clarification in order to complete its validation of the dossier, it will contact the applicant requesting to supply this information within a specific time limit. When supplying the Agency with this information, the applicant is not required to submit any additional copy of this information to the rapporteur and co-rapporteur as they would be able to retrieve this information via the Common Repository. In this case, the validation can only be completed after receipt and verification of the information submitted.

After validation of the application, the Agency will notify the applicant accordingly in writing. The same notification will also be sent to the rapporteur and co-rapporteur and all other CVMP members.

At that stage, the application will be considered to have been delivered to all national competent authorities (NCA) CVMP, alternates and scientific experts, so no additional copies of submissions on CD/DVD or via CESP should be submitted for centrally authorised products.

A full overview of the submission requirements is available on the Agency webpage.

The Agency is also publishing validation checklists for initial marketing authorisation applications for veterinary pharmaceutical and immunological products. These checklists are used by the Agency to validate initial marketing authorisation applications for pharmaceuticals and immunologicals and applicants are encouraged to use them as a means to review in advance of their submission that standard requirements are fulfilled.

References:

• eSubmission website
• EMA guidance on electronic submission
• The Rules Governing Medicinal Products in the European Union, Volume 6B, Notice to Applicants,
• Dossier requirements of the members of the CVMP
• Contact details of CVMP members
• Validation checklist for initial MAA – pharmaceuticals (applicable to submissions under Article 12(3) of Directive 2001/82)
• Validation checklist for initial MAA – pharmaceuticals (applicable to submissions under Article 12(3) of Directive 2001/82)

In the same way as it is important for applicants to plan their application strategies for an efficient use of their resources, it is important for the Agency, CVMP members and experts to be able to plan and allocate their workload efficiently. If the actual submission date is several months after the date originally indicated, the rapporteur and co-rapporteur may find it difficult to provide the necessary expertise and their re-appointment could be necessary.

The Agency advises applicants to consider the date of submission very carefully and to notify the Agency, rapporteur and co-rapporteur of a 'realistic' submission date. Furthermore applicants are requested to notify the Agency, rapporteur and co-rapporteur as soon as possible when the earlier notified submission date cannot be met. Real-time calculation of submission dates will be followed by real-time preparation of the review procedure.

Seven months before submission, applicants should notify the Agency of their intention to submit a marketing authorisation application (MAA) and provide the intended date of submission. This should be done by using the pre-submission request form, selecting 'Centralised procedure - Intent to submit a MAA' as the scope of the request. This should be sent to vet.applications@ema.europa.eu.

The appointment procedure for rapporteurs and co-rapporteurs will be initiated seven months prior to the MAA intended submission date. See: Question "What is the procedure for appointment of CVMP rapporteurs/co-rapporteurs and their assessment teams?”.

Furthermore, applicants are requested to notify the Agency, rapporteur and co-rapporteur as soon as possible when the previously notified submission date cannot be met, by re-sending an updated pre-submission request form, selecting 'notification of change - applicant /contact person details' as the scope of the request.

Applicants are finally requested, if they no longer wish to pursue the submission of their application, to notify the Agency of their intention to withdraw the request for submission of the MAA. This should be done by using the pre-submission request form, selecting 'withdrawal of request' as the scope of the request. This should be sent electronically vet.applications@ema.europa.eu.This will close the case procedure and the whole pre-submission history.

The submission deadlines and full procedural detailed timetables are published as a generic calendar on submission dates. The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates and milestones that occur during the procedure. Applicants should ensure that a technically valid submission is received by the Agency before the submission deadline. Any technically invalid applications will result in non-acceptance, which may cause a delay in the start of the procedure.

The date and time of delivery of the dossier to the Agency should be arranged between the applicant and the Agency. The applicant will be informed of recommended submission dates. The recommended dates for applications to be submitted to the Agency are also available on the Agency web site.

In order to accelerate and facilitate the procedure, applicants are invited to submit, in parallel to the Agency, copies of the dossier to both the rapporteur and the co-rapporteur. Otherwise there may be a delay in the start of the procedure because of the time lapse between the validation by the Agency and the confirmation from the rapporteur and the co-rapporteur that they have received the dossiers.

Soon after the notification of a valid application, the Agency will send an invoice to the applicant. The fees should be paid within 30 days of the receipt of this invoice. For more information regarding the applicable fee, see question “What fee do I have to pay and how is the appropriate fee for my application calculated?” .

For more information on the requirements for the submission and for the route for submission of the application, see question “How and to whom shall I submit my dossier?”

References:

• Guidance to applicants / marketing authorisation holders on oral explanations at CVMP
• Pre-submission request form
• Recommended submission dates for applications

Initial marketing authorisation applications (MAAs) submitted to the Agency as part of the centralised procedure are subject to a validation process. The objective is to make sure all essential regulatory elements required for scientific assessment are included in the MAA prior to the start of the procedure.

There are two elements to validation:

• technical validation, which takes place once an electronic application has been received by the Agency. This ensures that the structure of the submission is compliant with the EU specification for electronic dossiers for veterinary medicinal products;
• regulatory and administrative content validation, which can only commence once the application has successfully passed technical validation.

What to expect once an initial MAA has been submitted to the Agency

Once submitted to the Agency in the agreed standard format, the Agency performs in a first step a technical validation. If the submission is technically invalid the outcome of this technical validation is communicated to the applicant.

If the dossier is technically invalid and the replacement is not delivered by the intended submission deadline, the start of the procedure is automatically postponed to the next month, as only technically valid and complete applications can be subject to the validation process. This also applies to ASMF submissions.

If any issues are found during validation, the Agency will issue a request for additional information (validation-supplementary-information (VSI) request) to the applicant. Applicants will have to respond to this request in order to resolve any validation issues before the procedure can start.

Validation checklists are used by the Agency to validate initial marketing authorisation applications. Applicants should use them as a means to review in advance of their submission that standard requirements are fulfilled.

The Agency will communicate the outcome of the validation to the applicant. A positive outcome means that the scientific evaluation will start on the next available start date according to the Agency's timetables and the applicant will be invoiced the relevant fee. A negative outcome means that the applicant will have to submit a new application and will be invoiced a negative validation administrative fee.

References:

• Validation checklists for initial marketing authorisation applications

Once the application is validated, the Agency starts the procedure at the monthly starting date published on the EMA website.

The Agency shall ensure that the opinion of the CVMP is given within 210 days (less any clock-stops for the applicant to provide answers to question from the CVMP) in accordance with the following standard timetable, which can be shortened in exceptional cases. See: Question “Is my veterinary medicinal product eligible for an accelerated review?”

* Target dates for the submission of the responses are published on the Agency website (see recommended submission dates)

After receipt of the responses, the procedure is re-started. In general the following standard timetable will apply:

Upon adoption of the CVMP opinion, the Agency will inform the applicant within 15 days as to whether the opinion is favourable or unfavourable (including the grounds for the unfavourable outcome, if applicable).

Re-examination

In accordance with Article 34(2) of Regulation (EC) No 726/2004, an applicant may give written notice to the Agency that he/she wishes to request a re-examination within 15 days of receipt of the opinion. The grounds for the re-examination request must be forwarded to the Agency within 60 days of receipt of the opinion. Of note, the re-examination procedure may deal only with the points of the opinion initially identified by the applicant in the grounds for re-examination and may be based only on the scientific data available when the Committee adopted the initial opinion.

A positive opinion may be subject to re-examination as long as the request for re-examination relates to aspects of the opinion in relation to which there had been objections by the Committee, further to which the applicant opted to amend the application. In such case, the applicant, when submitting the amended documentation, (e.g. revised product information) prior to the opinion, will need to reserve the right to re-examination in the covering letter.

Applicants should refer to the Agency website for further specific Guidance on re-examination of CVMP opinions.

Linguistic review

After adoption of a positive CVMP opinion, the preparation of the annexes to the Commission Decision is carried out in accordance with the following timetable:

Further details on the post-opinion review of translations and forms to be used, are available on the Agency website (Guidance on the linguistic review process).

Once the veterinary medicinal product is authorised and in all cases before the product is placed on the market, mock-ups or specimens of the final outer and immediate packaging and the package leaflet must be submitted to the Agency. See: Question “When shall I submit mock-ups and/or specimens?”

References:

• Guidance to applicants / marketing authorisation holders on oral explanations at CVMP
• Regulation (EC) No 726/2004
• The Rules Governing Medicinal Products in the European Union, Volume 6A, Notice to Applicants
• Procedural advice to applicants/marketing authorisation holders on re-examination of CVMP opinions
• Product information linguistic review process for new applications in the centralised procedure
• Recommended submission dates for applications

Peer review is a process by which other members of the CVMP review the rapporteur's and co-rapporteur's scientific evaluation, as well as the validity of the scientific and regulatory conclusions reached. It applies to the assessment of new marketing authorisation applications, and also to other procedures: applications for line extensions and major identified type II variations of marketing authorisations, MRL applications and referrals.

Peer review is part of a quality assurance system established at CVMP level to enhance the scientific scrutiny of documents presented to the committee thereby enhancing their scientific quality and consistency. It consists of the review of the rapporteurs' assessment reports for the purpose of improving the quality of the day 120 list of questions and opinion by the CVMP members that are assigned by the committee as peer reviewers. It is also the particular task of those members assigned as peer reviewers to judge the quality of the assessment reports from the rapporteur and co-rapporteur especially in relation to potential divergences in scientific assessment made by the rapporteur and co-rapporteur.

A strengthened peer review system that can improve the consistency of scientific assessments is one of the objectives set out in the European Medicines Agency road map to 2015.

On appointment of the rapporteur and co-rapporteur during a CVMP meeting, the Committee also appoints peer reviewers. The Committee also decides on the number of peer reviewers to be assigned to this task.

Peer reviewers' comments are not made available to applicants. Moreover, it is not intended that applicants directly contact peer reviewers or other CVMP members in the context of an on-going CVMP assessment.

References:

• European Medicines Agency road map to 2015

The numbering system aims to allow for a clear identification of any application for the granting, extension, variation, transfer or renewal of a European Union marketing authorisation for any product and for any of its presentations throughout its life cycle.

The name and the active substance(s) of the product primarily identify applications for the granting of a European Union marketing authorisation for a medicinal product. However for administrative purposes, each application is also given a core number composed of four sections: EMA/V/C/…, where V stands for veterinary, C for centralised procedure and a unique number code for the product's identification is used.

In every case of an administrative procedure relating to the product, an additional marker denoting the nature of the procedure is appended to this core number, i.e. for the first application for the granting of the MA, any extension, variation, transfer or renewal of MA. A sequential number is added, too. The markers currently used are as follows:

These numbers are used as a reference by the EMA and should be used by the applicant in all correspondence relating to a certain procedure.

Presentations
In addition, the numbering system covers all presentations (pharmaceutical forms, strengths and pack sizes) of the product. This is mainly relevant during evaluation of the procedure and for the purpose of identifying single presentations in lists such as the Annex A to the opinion. (For correspondence, it is sufficient to indicate the procedural number as above.)
A sequential three digit number for each presentation is added to the procedural number (core number plus procedural marker). An example is given below for a product consisting of three different presentations, with two ensuing procedures creating new presentations:

NB: For all procedures creating new presentations, this numbering system is superseded after MA by the EU numbers, which would from then onwards appear in the Annex A to opinions. The EU number is allocated independently of the EMA number, but retains the principle of identifying each single presentation by ending in a three digit sequential number.

Legislative Basis

Directive 2001/82/EC states that manufacturing authorisation holders are obliged to comply with the good manufacturing practice (GMP) for medicinal products and to use as starting materials only active substances that have been manufactured in accordance with the detailed guidelines on good manufacturing practice for starting materials

The principles and guidelines for GMP for medicinal products for veterinary use are stated in Directive 91/412/EEC. Compliance with these principles and guidelines is mandatory within the European Economic Area (EEA), interpretation of these requirements is provided in part I of the Guide to Good Manufacturing Practice, published in Volume 4 of the rules governing medicinal products in the European Union. Part II of this guide provides for the detailed guidelines on good manufacturing practice for active substances used as starting materials.

The guide to Good Manufacturing Practice consists of detailed guidelines (part I and part II) which are supplemented by a series of annexes specific for certain types of product, or for a particular topic.

The ad hoc GMP Inspection Services Group within the Agency is in charge of publishing a "compilation of procedures" on behalf of the European Commission to gather all these guidelines, outlining the quality system requirements for national GMP pharmaceutical inspectorates. The compilation is published on the 'Inspections page' of this website.

Pre-submission notification

In their notification of intention to submit, applicants should mention the name and address of the proposed manufacturer(s) of the active substance(s) and finished product; and the name and address of the proposed site(s) in the EEA responsible for batch release of the medicinal product. If the medicinal product is imported from a third country, it should also include information on GMP inspections of the site(s) concerned carried out in the last 2-3 years by EEA competent authorities and/or by competent authorities of countries where a Mutual Recognition Agreement (MRA) is in operation, as applicable.

Final manufacturing and batch release arrangements will have to be provided when submitting the application.

A description of the sequence of all different sites involved should be added. The manufacturing sites mentioned should be in compliance with Good Manufacturing Practice (GMP) and hence be "inspection ready" at the time of submission of the application and throughout the assessment. Manufacturing sites in third countries should be aware of European Community GMP requirements as mentioned below.

Once the application is received, it is normally not permitted to add a new site or to change the steps of manufacture/release described in the dossier during the 210 day assessment procedure. Any additional site should be submitted as a variation after the granting of the marketing authorisation.

At receipt of the application, the Agency determines if satisfactory inspections information is available. If not, the Agency with the rapporteur and co-rapporteur asks the CVMP to make a request for inspection of the manufacturer of either the active substance or the medicinal product in order to complete the assessment.

The performance of these inspections by the EEA competent authorities will be co-ordinated by the Agency taking into account:

• Inspections carried out of the same manufacturers by the EEA Countries
• Inspections carried out of the same manufacturers by competent authorities of countries where a MRA is in operation, when applicable
• The advice of the rapporteur/co-rapporteur
• Specific issues and questions raised during the assessment of the application

Inspection team

The team required to perform the inspection will be proposed and co-ordinated by the Agency secretariat. The team will be drawn from the inspection services of the supervisory and other competent authorities of the EEA. On the advice of the rapporteur and/or co-rapporteur the inspection team may include scientific experts and/or a rapporteur for the inspection as referred to in the provisions of Article 33 of Regulation (EC) No 726/2004.

Type of inspection

Inspections may be carried out to verify compliance with Community good manufacturing practice principles and guidelines and/or to cover product or process related issues arising from the assessment of the application. Inspections may cover the following activities:

Manufacture of the Active Substance:

The detailed guidelines on good manufacturing practice adopted by the EEA for the manufacture of the active substance are contained in part II of the EU Guide to Good Manufacturing Practice (Good Manufacturing Practice for Active Pharmaceutical Ingredients) in "The Rules Governing Medicinal Products in the European Union - Volume 4". Inspectors of the competent authorities in the EEA will inspect against the requirements of this guideline.

Manufacture of the Finished Product:

The GMP principles and guidelines applying to the manufacture of medicinal products for veterinary use in the EU are laid down in Commission Directive 91/412/EEC, which are re-stated along with part I of the EU Guide to Good Manufacturing Practice in "The Rules Governing Medicinal Products in the European Union - Volume 4".

Where a manufacturing site is located in the EEA it is normally not necessary to request an inspection to confirm its GMP status as it is required by the above-mentioned Directive to be regularly inspected by the relevant authorities.

An inspection will normally be requested to confirm the GMP compliance status of manufacturing sites in third countries unless satisfactory information is available from an inspection of the same or similar category of product carried out during the last 2-3 years by an EEA competent authority or by the competent authority of a country where a MRA is in operation, as applicable.

In all cases (for sites in the EEA and third countries), an inspection may be requested to cover product or process related issues arising from the assessment of the application. In this case the rapporteur and/or co-rapporteur will provide the inspection team with a list of questions/issues, which should be addressed during the inspection.

Importing Site - Site located in the EEA:

Importing sites in the EEA are required by the provisions of Title III of Directive 2001/82/EC as amended, to hold a manufacturing authorisation. Inspections of importing sites to confirm their GMP compliance status are not normally requested in connection with applications for marketing authorisations. Inspections may however be requested to cover product or process related issues arising from the assessment of the application. In this case the rapporteur and/or co-rapporteur will provide the inspection team with a list of questions/issues, which should be addressed during the inspection.

Timetable for inspections

Inspection(s) requested in connection with an application for a marketing authorisation must be carried out and the final report(s) sent to the Agency and submitted to the CVMP in accordance with the 210 day time limit for the evaluation of the application by the CVMP.

Once an inspection request is adopted by the CVMP the Inspection sector of the Agency will write within 5 working days to:

• the applicant explaining that an inspection(s) will take place, giving details (target date for carrying out the inspection, inspection team, scope of the inspection, contact person in the relevant authority responsible for arranging the inspection)
• the rapporteur and co-rapporteur for information.

The inspection team will contact the company to agree inspection dates within the agreed target date. Inspections usually take place in parallel with the "clock stop" period and will approximately be conducted within two months from the adoption of the inspection request.

If the manufacture of the product is carried out infrequently or is not scheduled to take place during the period when the assessment of the application is to take place, the inspection team and the rapporteur/co-rapporteur may agree to inspect the manufacture of a similar product or process.

Inspection reports

Inspectors will send the draft inspection report to the manufacturer within fifteen days of the inspection for comments on major factual errors, any point(s) of disagreement or remedial actions. Where necessary, the manufacturer should respond within a further fifteen days to provide comments and, if necessary, an action plan with a timetable for implementation. This will be considered during the finalisation of the inspection report and, if necessary, attached to it.

The timing of any discussions, further actions and/or the provision of additional information arising from the inspection will be agreed with the inspectors and communicated by the inspectors to the rapporteur, the co-rapporteur and the Agency.

Inspectors finalise the report and send to the EMA inspections sector by day 180 at the latest, whichcirculate it to the rapporteur, co-rapporteur and CVMP. In case of an unsatisfactory inspection report, which cannot lead to a positive opinion, discussions between the Agency, the rapporteur, the co-rapporteur and the applicant should take place.

Documents for inspection

It is helpful to have a site/plant master file for use in preparing and carrying out the inspection. The preferred format is that recommended by the Pharmaceutical Inspection Co-operation Scheme (PIC/PICS). The applicant should supply this document directly to the inspection team as far in advance of the inspection as possible. The site/plant master file is however not required to be submitted to the Agency.

References:

• Regulation (EC) No 726/2004
• Council Directive 91/412/EEC
• Directive 2001/82/EC
• Good Manufacturing Practice for Active Pharmaceutical Ingredients", Volume 4 of the rules governing medicinal products in the European Union, Annex 18
• Inspections

The Agency relies for the scientific review of centralised applications for marketing authorisations for medicinal products on the expertise located in the member states.

The same approach exists in the area of inspections where inspections are conducted by member states' inspectorates on behalf of the European Community. These inspections, including the ones to evaluate compliance with GCP, are co-ordinated by the Agency if they pertain to centralised applications or referrals.

Clinical studies should be conducted in accordance with the Guideline on Good Clinical Practices (CVMP/VICH/595/98) and Annex I to Directive 2001/82/EC, as amended.

CVMP may request an inspection if significant concerns arise during the evaluation process that can only really be addressed by an inspection. It is most likely that an inspection request would be adopted at day 120 at the same time as the list of questions, and the inspection conducted in parallel to the clock stop period.

In the event that an inspection request is adopted, the applicant is notified within 5 working days following the CVMP meeting. This notification includes the sites and studies to be inspected. Fees and expenses are charged in accordance with the current regulations and guidelines.

References:

• VICH guideline on Good Clinical Practices (VICH GL09)
• Annex I to Directive 2001/82/EC (Directive 2009/9/EC)
• Fees payable to the European Medicines Agency

The Quality Review of Documents (QRD) group operates under the mandate adopted by the EMA Management Board and was initially created on the European Commission's proposal. The mandate states the group's objective as being "to facilitate the streamlining of the European decision-making process".

The QRD group is composed of one representative per member state with experience in regulatory affairs (designated by the national competent authority), and representatives of the Agency (which also provides secretariat facilities). The European Commission is invited to participate.

To date, the group has focussed on the creation of linguistic templates for EMA scientific opinions, and it will continue to work on the controlled upgrade of these. However, the mandate sets out a series of tasks, namely:

• verification of terminology used in translations of opinions and their consistency with the original version of documents,
• ensuring linguistic and other formal coherence and consistency between different terminology used in scientific opinions, and promotion of initiatives towards the standardisation of terminology,
• review and update of opinion templates,
• promotion of legibility of information and verification of specimens of sales presentations/mock-ups in all EU official languages,
• consideration of issues which could lead to delays in the Commission's decision-making process and possible development, on request, of advice (particularly with a view to contribute to the development of common understanding on the implementation of legislation and guidelines).

The mandate also provides that "the Group shall develop its own working methods" and will consider "how best it may be associated with the different stages of the evaluation and decision-making process".

A major task of the QRD group is to agree on standard templates for the different types of opinions that the CVMP adopts. This to ensure consistency and accuracy of translations of the product information (summary of product characteristics, labelling, package leaflet) attached to the scientific CVMP opinions.

The QRD's product information templates:

• Set out the standard headings and indicate the most commonly used standard phrases and terms in the official EU languages.
• Define the format and layout for summary of product characteristics (SPC); labelling and package leaflet (see also convention to be followed for QRD templates in order to ensure absolute consistency between all language versions).
• Provide useful guidance as to the content of the information to be supplied (see also QRD template with QRD group explanatory notes).

The templates are intended to provide applicants with practical advice on how to draw up the product literature, but without prejudice to any final position of the Agency, CVMP and European Institutions as to the contents of the document. Similarly, the templates and guidance are without prejudice to the binding nature of the relevant legislation, or as to any legal interpretation to be given by the European Commission or the Court of Justice of the European Communities.

QRD reference documents provide more detail guidance on various aspects concerning terminology and style.

Legal requirements: while the template and guidance notes aim to provide practical hints to the applicants, in particular in relation to how to address common problem areas, they are by no means a comprehensive guide to the information required to be included in the product literature. Thus applicants must also refer to the current Community legislation, CVMP guidelines, etc., when drawing up their drafts in order to be able to fully comply with the legal requirements with respect to product literature.

References:

• Product information pages
• Product information templates
• The new product information linguistic review process

References:

• Veterinary pre-submission Q&A

Incentives and assistance are available from the EMA for SMEs, which focus on reducing financial and administrative entry hurdles for SMEs in pre-marketing authorisation procedures such as scientific advice, the application for marketing authorisation and inspections.

These include:

• Administrative and procedural assistance from the SME Office at the Agency.
• Fee reductions for scientific advice, scientific services, inspections and MRL applications (90% fee reduction).
• Fee exemptions for certain administrative services (excluding parallel distribution).
• Deferral of the fee payable for an application for marketing authorisation or related inspection.
• Conditional fee exemption where scientific advice is followed and a marketing authorisation application is not successful.
• Assistance with translations of the product information documents submitted in a centralised application for marketing authorisation.

In determining which companies are eligible for SME incentives, the EMA applies the EU-definition of micro, small and medium-sized enterprises provided in Commission Recommendation 2003/361/EC.

Companies are classified according to their size (micro, small or medium):

• Micro enterprises employ less than 10 persons and have an annual turnover or balance sheet total not exceeding € 2 million;
• Small enterprises have fewer than 50 employees and an annual turnover or balance sheet total of not more than € 10 million;
• Medium enterprises have less than 250 employees and an annual turnover of not more than € 50 million or an annual balance sheet total of not more than € 43 million

and according to their category (autonomous, partner or linked).

Depending on the category in which the enterprise fits, some or all of the headcount and financial data from other partner or linked enterprises may need to be counted when calculating whether the SME criteria are met.

Further information on the definition of an SME is available in “The new SME definition - User guide and model declaration”, published by the European Commission (see link under References below).

A declaration of SME status (form available on EMA website on SMEs) should be submitted to the SME Office prior to requesting financial or administrative assistance from the Agency.

SME Office

The 'SME office' has been set up within the agency to address the particular needs of smaller companies. The office aims to facilitate communication with SMEs through dedicated personnel within the Agency who will respond to practical or procedural enquiries, monitor applications, and organise workshops and training sessions for SMEs.

Fee Reductions/Deferrals

SME applicants wishing to request a fee reduction and/or deferral should address a letter of intent to the SME Office (see below) of the EMA. It should be noted that fee reductions and deferrals can only be considered once the applicant has been assigned SME status by the EMA and are subject to the SME status remaining valid at the time that their application or request is validated by the Agency. Fee reductions and fee deferrals will not be granted retrospectively. Further information on fee reductions/deferrals is available here.

Translation assistance

Because translating product information into all EU languages represents a considerable financial and administrative burden to SMEs entering the EU market, the EMA will provide for translation of product information documents (summary of product characteristics, conditions of the marketing authorisation, label and package leaflet) required for the granting of an EU marketing authorisation. The applicant remains responsible for provision of the Norwegian and Icelandic translations according to the normal timelines and for the maintenance of all translations in the post-authorisation phase.

Due to the timelines required to translate the product information, the Agency will initiate translations through the Centre for Translation (CdT) in Luxembourg prior to the CVMP opinion (normally around day 180 of the procedure) and which will be finalised by CdT by day 215. These translations will then be checked through the national competent authorities in the member states (see also QRD product information - Tools used by the EMA to facilitate the streamlining of the European Decision Making process). To be eligible for translation assistance the applicant's SME status must be valid at the time the translations are initiated.

Companies wishing to benefit from SME incentives should visit the SME Office section of the EMA website first. This section provides useful information on how to request SME status, and provides a link to useful information sources (e.g. the User Guide for Micro, Small and Medium-sized Enterprises (SMEs) on the administrative and procedural aspects of the provisions, laid down in Regulation (EC) No 726/2004, that are of particular relevance to SMEs).

For further information or requests please contact:

SME Office

E-mail: sme@ema.europa.eu
Tel. +31 (0)88 781 8787

For further information please see the User guide for micro, small and medium-sized enterprises on the Agency website.

References:

• Commission Regulation (EC) No 2049/2005
• Commission Recommendation 2003/361/EC
• Fees payable to the European Medicines Agency
• QRD product information - Tools used by the EMA to facilitate the streamlining of the European Decision Making process
• SME register
• User guide for micro, small and medium-sized enterprises

In order to provide support to medicines innovation in EU, the EMA has established an internal multidisciplinary group including scientific, regulatory and legal competencies, the Innovation Task Force (ITF), creating a forum for early dialogue with applicants. ITF members are scientific and legal administrators appointed from different sectors of the Agency. To fulfil its task the ITF consults as appropriate EMA scientific Committees and Working Parties or individual experts.

The scope of the ITF activities encompasses emerging therapies (i.e. gene therapy, cell therapy and engineered tissues), emerging technologies (i.e. new development strategies, new manufacturing approaches) and borderline therapeutics (i.e. combination of pharmaceuticals and devices) for which there is no established EMA scientific, legal and regulatory experience.

Support available to applicants includes:

• General queries relating to emerging therapies and technologies
• Briefing meetings aiming to provide an early guidance and information, in liaison when needed with relevant EMA scientific committees or working parties. Additionally, the briefing meetings complement and reinforce existing formal regulatory procedures e.g. scientific advice.
• Requests for regulatory advice on the eligibility to EMA procedures e.g. marketing authorisation, scientific advice.

The scope of the ITF comprises support to veterinary medicines during the early stages of their development. For enquiries regarding suitability of the ITF in respect to their product or requests for ITF briefing meetings, applicants for innovative veterinary medicines are invited to send all potential applications to: vet.applications@ema.europa.eu.

For more information on Innovation Task Force and on how to request a briefing meeting or regulatory advice refer to the EMA Medicines and Emerging Science webpage.

References:

• Innovation Task Force (ITF)
• Mandate of the EMA Innovation Task Force (ITF)
• SOP/H/3044 on the organisation of Innovation Task Force briefing meetings (medicines for human or veterinary use)

The treaties on which the European Union and the European Communities are founded are available in the EUR-lex repository of European law. To exercise the Union's competences, the institutions may adopt regulations, directives, decisions, recommendations and opinions.

Information about the hierarchy of the European Union texts can be found in the Annex I to Chapter 1 of Volume 6 of the Notice to applicants and regulatory guidance for medicinal products for veterinary.

The rules governing medicinal products in the European Union concerning medicinal products for veterinary use is published on the European Commission website:

• Volume 4 – Good manufacturing practices for medicinal products for human and veterinary use;
• Volume 5 – EU pharmaceutical legislation for medicinal products for veterinary use, contains most of the relevant Directives, Regulations, decisions and communications;
• Volume 6 – Notice to applicants and regulatory guidance for medicinal products for veterinary use:
• Volume 6A - Procedures for marketing authorisation:
  • Introduction;
  • Chapter 1 – Marketing authorisation;
  • Chapter 2 – Mutual recognition;
  • Chapter 3 – Community referral;
  • Chapter 4 – Centralised procedure;
  • Chapter 5 – Variations;
  • Chapter 6 – Community marketing authorisation for veterinary medicinal products;
• Volume 6B - Presentation and content of the dossier: provides guidance for the compilation of dossiers for applications for marketing authorisation, and is applicable for the centralised procedure and national procedures, including mutual-recognition and decentralised procedures;
• Volume 6C - Regulatory guidelines: related to procedural and regulatory requirements, e.g. renewal procedures, variation procedures, summary of product characteristics (SPC), package information and classification for the supply, environmental risks of veterinary medicinal products, definition of potential serious risk;
• Volume 7 – Scientific guidelines for medicinal products for veterinary use (thisguidance is prepared by the CVMP, and are available on the EMA website (see below));
• Volume 8 - Maximum residue limits;
• Volume 9B – Pharmacovigilance for medicinal products for veterinary use.

The European Commission website offers the possibility to create a CD-ROM with the content of the rules governing medicinal products in the European Union, which can be used off-line with an integrated search engine.

Scientific guidelines related to quality, safety and efficacy are available on the Agency website, together with concept papers, draft guidelines and overviews of comments received during the consultation on draft versions.

The Agency also publishes procedural and technical guidance and document templates, which are intended to provide technical and procedural advice to applicants for marketing authorisations for medicinal products coming within the scope of the centralised procedure.

References

• Treaties in EUR-Lex database
• Eudralex – European Commission website on EU legislation (Vol. 1 to 10 of the The Rules Governing Medicinal Products in the European Union)
• EMA veterinary scientific guidelines
• Pre-submission, procedural guidance

It is acceptable to include the logo of the marketing authorisation holder, as this complements the name of the marketing authorisation holder already included on the outer packaging and can help the user to identify the legal entity responsible for the product. Similarly, if the name of a local representative is mentioned in the 'blue-box' then the logo of that local representative can also be included there (i.e. inside the 'blue-box' only, together with the name/contact details of that company, on the outer packaging only).

On the contrary, inclusion of an additional logo of a different company next to the logo of the marketing authorisation holder (or elsewhere on the packaging) could cause confusion among users and could also be considered as an element of promotional nature; therefore it cannot be accepted. This applies also to co-promotion and co-marketing partners (unless the second company is equally named in the role of a local representative, in which case its logo can be placed inside the 'blue-box' together with the name/contact details of the company).

Trademark statements cannot be considered as useful to the user, and could be regarded as an element of promotional nature. Therefore, in principle, such statements should not be included on the packaging, unless the non-inclusion of such trademark statement would constitute a breach of trademark law. Similarly, statements on licensing relationships between companies, and also copyright statements, cannot be considered as beneficial to the user, and consequently are not accepted on the packaging.

References:

• Directive 2001/82/EC
• See, question 24 - 'Where on my veterinary medicinal product information can I mention a local representative?' and question 15 'When shall I submit mock-ups and/or specimens?'

Changing the applicant for an ongoing MA application to a different entity is possible at certain procedural milestones in case the following requirement is met:

• The change of applicant will not create a ‘duplicate application’ to another pending application or authorised product, unless relevant authorisation from the European Commission is obtained (as per Article 82 of Regulation (EC) No 726/2004).

In order to request a change of the applicant, the following documents need to be submitted as part of responses to the Day 120 List of Questions or Day 180 List of Outstanding Issues:

• A  letter  requesting the change of applicant and signed by both the previous and the new applicant.
• Either a confirmation (as part of the cover letter) that this marketing authorisation application does not fall under the scope of a duplicate application as per Article 82 of the Regulation (EC) No 726/2004, or the relevant authorisation from the European Commission in case the application falls under the scope of a duplicate application as described above.
• A confirmation (as part of the cover letter) that the complete and up-to-date file concerning the medicinal product, or a copy of this file, has been made available to or has been transferred to the new applicant.
• If applicable, a confirmation (as part of the cover letter) that the minor use/minor species (MUMS)/limited market classification, if still valid, has already been transferred, or that notification of its transfer, has been submitted to VetMUMSapplications@ema.europa.eu.
• An updated application form and its affected annexes (includes proof of establishment of the new applicant within the Union (EEA) issued in accordance with national provisions and which should be no older than 6 months, and also includes updated mock-ups).
• Updated product information.
• Updated mock-ups.
• Any other documents of the marketing authorisation dossier affected by the change of applicant e.g. an updated Letter of Access for an application that includes an Active Substance Master File.

In order to facilitate the process for the change of applicant, applicants are advised to use the standard statements in this  template in order to cover all of the abovementioned, required confirmations.

The checkbox ‘contains request for change of applicant’ should be ticked in the eSubmission Gateway & eSubmission Web Client Delivery file user interface, as failure to do so may lead to significant delays in processing the change of applicant request. 

As a consequence of a change of applicant, any fee invoiced following the initial validation (i.e. fee for initial marketing authorisation and pre-authorisation inspection fee) will be credited to the original applicant and re-invoiced to the new applicant. This will include changes, if any, relating to micro, small or medium-sized enterprise.

Applicants are advised to contact vet.applications@ema.europa.eu as early as possible if a change of applicant is proposed.

References:

•  Change of applicant - cover letter standard text 
• Re-validation checklist for change of applicant for initial marketing authorisation applications

The Agency has a legal obligation to verify that manufacturers listed in the marketing authorisation applications comply with Good Manufacturing Practice (GMP). Applicants should provide relevant information concerning GMP in the application form and its annexes (5.6 and 5.9) so that pre-approval GMP inspections can be planned as required without causing delays to the assessment procedure.

Applicants are requested to provide the following declaration in the cover letter of their marketing authorisation applications:

“The undersigned, on behalf of the applicant, confirms the following:

The information in relation to the manufacturing sites contained in <Part 2> <Modules 3.2.S and 3.2.P> is correct in terms of names, addresses and manufacturing activities.

This information is consistent throughout the dossier, in particular with the corresponding information contained in Part 1 (electronic Application Form, flow-chart in Annex 5.8, QP declaration in Annex 5.19, GMP certificates in Annex 5.9, MIAs or MIAs equivalents in Annex 5.6).”

Should discrepancies be found after the start of procedure, the Agency will rely on the information in the electronic application form for registered manufacturing sites and applicants will have to take the next opportunity to bring Part 2 (if submission of the quality documentation is in NtA format) or Module 3 (if submission of the quality documentation is in CTD format) in line with the application form.

See Question “When can I expect a pre-approval GMP inspection and how are they conducted?” for more information on GMP inspections and the information to include in the application regarding GMP compliance.

References:

• Validation checklists for initial marketing authorisation applications