Presubmission guidance: questions 21 to 30

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This page lists questions 21 to 30 of the European Medicines Agency's questions and answers on presubmission guidance.

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. Revised topics are marked 'New' or 'Rev.' on publication.

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21. Am I, as applicant, duly established in the European Economic Area? Rev. February 2012

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 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; Norway, Iceland, Liechtenstein and the Member States of the European Union).

In order to fulfil this requirement, the MAH must have a permanent legal structure that is formed in accordance with the law of an EEA Member State and allows the concerned holder to assume the duties and responsibilities as well as to perform the tasks laid down by 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 will be treated in the same way as natural persons who are nationals of Member States. An applicant should demonstrate that it is 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.

References

22. What information relating to the manufacture and batch release should be provided as part of my application? Rev. February 2012

The Agency requires the applicant to provide background information in support of the application relating to the manufacture (including packaging), batch testing and batch certification (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, Norway and Liechtenstein. 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 or batch release described under module 1.2 (i.e. the application form) of the application during the 210-day review period. Any additional sites or changes 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 module 1.2 of the application must be consistent with module 3. All the manufacturing and batch-release sites mentioned in module 3 must be listed in module 1.2 and the activities carried out at each site must be described in module 1.2 consistently with the information provided in module 3. 

Manufacturing sites

All sites involved in the production of the finished medicinal product and of the active substance must be described (name and detailed address, including building reference) in module 1.2 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 (including ongoing stability monitoring);
  • bulk medicinal-product manufacture;
  • diluent / solvent manufacture (if any);
  • manufacture of any other associated medicinal products (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 blood products and vaccines if official batch release is a requirement for the product in question.

For third-country manufacturers, information about any previous EEA inspections in the last two to three years and any planned 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 module 1.2 of the application

The following documents should be attached to module 1.2 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 EudraGMDP 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 that have operational MRAs with the EU, please consult MRAs;
  • for all sites other than active-substance manufacturers located in third countries with no MRA, 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 for all of the finished product manufacturers located in the EEA listed in module 1.2 where the active substance is used as a starting material and from the qualified persons for the batch release sites in the EEA, sttaing that the active substance manufacturers listed in module 1.2 operate in compliance with the detailed guidelines on GMP.

Contact person in the EEA for product defects and recalls

A proposed contact point or person in the EEA for quality problems and defective batches of product must also be provided in module 1.2 of the application (name, full address, 24-hour emergency telephone and fax numbers, e-mail address, and mobile telephone number, if available).

References

23. What batch-release arrangements in the EEA are required for my medicinal product? Rev. February 2012

Importing site and supervisory authority

According to Article 51(1) of Directive 2001/83/EC, each batch of a 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 51(1)(b) of Directive 2001/83/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, Norway and Liechtenstein. Switzerland is not part of the EEA.

In accordance with the provisions of Article 18 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 40(1) of Directive 2001/83/EC in respect of the manufacture of the medicinal product. 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 Article 40(3) of Directive 2001/83/EC to the importer, unless an MRA or other relevant agreement covering GMP for the product under consideration is operating with the country where the medicinal product is manufactured.

In the exceptional cases 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 that is not in possession of a GMP certificate at the time of the marketing-authorisation submission located in third countries with no MRA, 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 an 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 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 52 of Directive 2001/83/EC, it is expected that Member States’ supervisory authorities will launch appropriate administrative measures and may withdraw the product concerned from the market (Article 117(1)(e) of Directive 2001/83/EC).

Contracting out of certain controls

The provisions of Article 20(b) of Directive 2001/83/EC allows some of the controls required under the provisions of Article 51(1) of Directive 2001/83/EC to be contracted out to third parties, if justified, and provided that the laboratories have been verified by the 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 certifying 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.

References

24. How should I submit an active-substance master file (ASMF)? Rev. August 2014

Annex I to Directive 2001/83/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:

i)          Detailed description of the manufacturing process

ii)         Quality control during the manufacture, and

iii)         Process validation

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.

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 emphasized 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 (MAA) by the applicant.

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 Active Substance Master File Procedure (CPMP/QWP/227/02), an ASMF consists of 2 parts:

  • An ASMF Applicant’s Part, also referred to as Open Part, which shall be at the disposal of the applicant.
  • An 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 the Module 3.2.S of the CTD.

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

It is necessary for the applicant and the ASMF holder to liaise to ensure that the ASMF including all necessary documents are synchronized to arrive at ideally the same time as the planned MAA to be submitted by the applicant, although an interval of some days may be allowed.Note that the marketing authorisation application cannot be validated until all the necessary documents are received in a satisfactory form. This also applies to the ASMF-related responses to Day 120 LoQ and Day 180 LoOI. Applicants should be aware that the procedure cannot re-start until the responses from the ASMF holder are received by the Agency.

Non applicability of ASMF concept to biological active substances

Further to clarifications from the European Commission on the interpretation of Directive 2001/83/EC as amended, and the subsequent announcement in the October 2004 CHMP Monthly report, the ASMF concept is not acceptable for biological medicinal products.

The characterisation and determination of biological active substances requires not only a combination of physico-chemical 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 or cell therapy medicinal products, do not fit with the concept of a ‘well-defined’ active substance.

Non applicability of ASMF concept of open and closed parts to Vaccine Antigen Master File (VAMF) and Plasma Master File (PMF)

The concept of the ASMF does not apply to blood derived medicinal products and vaccine antigens. In this context, the manufacturer can submit a PMF or a VAMF.

Regarding the VAMF, the legislation specifies that the VAMF holder cannot differ from the MAH/applicant for the concerned medicinal product: there is hence no rationale for an open /closed parts system.

For VAMF linked MAs, if a particular MAH name and address are not identical to the name and address of the proposed VAMF certificate holder, a relevant declaration should be provided attached to the application form, stating that the MA applicant and the MAH belong to the same mother group of companies, which share the same data package.

For the PMF the legislation specifies that where the MAH/applicant differs from the holder of the PMF, the PMF shall be made available to the MAH/applicant for submission to the competent authority.

References

What data should be submitted by the ASMF holder? Rev. Dec 2013

In the first submission of an ASMF with an allocated EMEA ASMF reference number, the ASMF holder is required to submit:

In later marketing authorisation application or variations submissions referencing to an already submitted ASMF with an allocated EMEA/ASMF number, the ASMF holder is only required to submit:

The Letter of Access and the Letter of Commitment to inform the applicant about any changes in the ASMF should be included both in the application form submitted by the applicant (Annexes 5.10 and 5.11) and also in the ASMF submitted by the ASMF holder.

The contact details of the ASMF holder contact person (including contact email address) must be the same in the Cover Letter of the ASMF, in the Letter of Access and the Application Form (Module 1.2 of the eCTD or NeeS submission).

ASMF holders are reminded that any initial submission and update to an ASMF should be accompanied by the Submission Letter and Administrative Details (Annex 3 of the ASMF Guideline) dully filled as detailed in the instructions provided in the Additional guidance on documents relating to an active substance master file. Either an EMEA/ASMF/xxxxx number or EU/ASMF/xxxxx number has to be entered.

New MAA or MAV should always reference the last version of the ASMF submitted. This will be subject to compliance checks during validation of the MAA and MAV.

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

What data should be submitted by the applicant or MAH? Rev. Dec 2013

In all cases, the applicant (in the context of a MAA) or MAH (in the context of a MAV) should submit:

  • MAA and MAV application form stating the correct EMEA ASMF reference number;
  • Copy of the Letter of Access (Annex 2 of the ASMF Guideline), as applicable;
  • Copy of the complete current version of the Applicant’s part of the ASMF in Module 3 or its revised sections, as applicable;
  • 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 Letter of Access and the Letter of Commitment to inform the applicant about any changes in the ASMF should be included both in the application form submitted by the applicant (Annexes 5.10 and 5.11) and also in the ASMF submitted by the ASMF holder.

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 MAA or MAV form and included in Module 3. This will be subject to compliance checks during validation of the MAA and MAV.

Example:

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

If the version of the ASMF included in the Module 3 of the MAA and referenced in the application form is AP November 2011, the applicant will be requested to update Module 3 and the application form according to the current version of the EMEA/ASMF/12345.

Equally, if the version of the ASMF included in the Module 3 of the MAA 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 the Annex 3 of the ASMF Guideline.

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 MAs when changes are proposed to the ASMF, i.e. when an updated version of the ASMF is submitted, the MA(s) linked to that ASMF will only integrate the ASMF update once the applicable variation is submitted and positively concluded.

The applicant should submit the Applicant’s Part of the ASMF. It should be included in their application within Module 3.2.S of the dossier. The ASMF holder should only submit updates to the Applicant’s Part (which should be identical to the one provided by the applicant) and/or Restricted Part, as applicable, in the context of a MAA or MAV. Both parts should be the latest versions available of the ASMF. It is recommended to include a table summarising those changes made to the ASMF compared to the previous version.

Applicants should note that the ASMF constitutes an integral part of the dossier and therefore it should be always made available to the EMA and CHMP Members.

The applicant is responsible for the submission of all necessary documents to the EMA.

It should be noted that although the ASMF procedure is developed to keep intellectual property confidential, it is also permitted to use the procedure when the applicant is also the manufacturer of the active substance.

Additional information on the ASMF procedure can be found in the ASMF WG webpage.

What is the EMEA/ASMF reference number? Rev. Dec 2013

From 1 September 2013, ASMF holders submitting their ASMF dossiers relating to a Centrally Authorised Product 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 EMEA/ASMF/XXXXX 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 Authorisation.

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

Who should request an EMEA ASMF reference number? Rev. Dec 2013

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

  • new ASMFs submitted for MAAs and MAVs as of 1 September 2013. From this date, reference to an EMEA ASMF number will be checked at validation,
  • ASMFs previously submitted to the EMA when referenced in a new MAA or MAV. The request for the EMEA ASMF reference number should be made before submission of a new MAA or MAV to update the ASMF.
  • ASMFs submitted in relation to a variation application.

For previously submitted ASMFs, in cases where the ASMF is used in more than one MA the ASMF Holder should only request one EMEA ASMF reference number, when applicable[1]. The allocated EMEA ASMF reference number should be communicated to the applicant or MAH, so that reference to the EMEA/ASMF/XXXXX number is made in all future submissions.

When and how to request an EMEA ASMF reference number?

Up to two weeks before submitting a complete ASMF, or an update to an already submitted ASMF, the ASMF holder should request the EMEA ASMF reference number. The request should be sent to PA-BUS@ema.europa.eu.

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

The EMEA ASMF reference number allocated by the Agency should be referenced in all subsequent communications (e.g. in response to a validation issue, List of Questions, List of Outstanding Issues, upcoming variation) and should always be included in the following documents:

It is the responsibility of the ASMF holder to inform the applicant of a MAA or MAV of the allocated EMEA ASMF reference number. Failure to state a valid EMEA ASMF reference number on the MAA or MAV form will trigger validation questions and may delay the start of procedure.

EMEA ASMF or EU ASMF reference number? Rev. Dec 2013

The EU/ASMF reference number allows for the identification by all Competent Authorities(National Competent Authorities and EMA) of ASMFs used in centralised and national (Decentralised and Mutual Recognition) MAAs or MAVs, and therefore enabling the ASMF Assessment Report Work Sharing (ASMF AR WS) procedure.
More information on the ASMF AR WS will be made available closer to the start of the pilot phase (1 December 2013) in the dedicated ASMF WG webpage.

ASMF holders should either have an EMEA/ASMF/ reference number or an EU/ASMF/ reference number before submitting an ASMF. Both numbering systems will run in parallel as of the start of the pilot phase of the ASMF AR WS. ASMF holders are encouraged to request an EU/ASMF/reference number if the ASMF is expected to be used in centralised and national applications.

Which format and submission channel should be used for submitting ASMFs? Rev. Aug 2014

Under the new ASMF submission requirements, the following formats are accepted for ASMF submissions:

  • Electronic Common Technical Document (eCTD);
  • Non-eCTD electronic submission (NeeS).

Guidance on the above formats can be found on the eSubmission website. Additional, please take a note of the EMA’s statement of intent of the mandatory use of eSubmission Gateway and WebClient.

Submission requirements for the different Committee (Co-) Rapporteurs

ASMF holders must submit the application to all (Co-) Rapporteurs, otherwise there may be a delay in the start of the procedure due to the time lapse between the validation by the Agency and the confirmation from the (Co-) Rapporteurs that they have received the dossier. For a full overview of the submission requirements for the different Committee (Co‑) Rapporteurs see:Dossier requirements for Centrally Authorised Products (CAPs).

The above method and requirements also apply to the submission of responses to List of Questions / List of Outstanding Issues. 

How to proceed if the ASMF was previously submitted in paper format? Rev. Dec 2013

The ASMF holder of ASMFs previously submitted in paper format should request an EMEA ASMF reference number as indicated above.

After the reference number is allocated the ASMF holder should submit the ASMF in an accepted electronic format (Electronic Common Technical Document (eCTD) or Non-eCTD electronic submission (NeeS).

How to proceed if there is an existing eCTD life-cycle for the ASMF? NEW Dec 2013

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

If the ASMF holder already has more than one eCTD life-cycle 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 eCTD life-cycle of the selected ‘product’ only. This, selected life-cycle will, then receive a new EMEA/ASMF/01xxx number covering all listed CAPs.

Once the ASMF holder is submitting an update or new version to the ASMF, they have to do so with thisnew number. The ASMF holder will have to prepare a new sequence (increasing by one) in which (module 1, cover letter) they declare 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, additonally the relevantmodules within this new eCTD sequence 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)

25. What should I submit if my medicinal product contains or consists of genetically modified organisms (GMOs)?

Potential applicants are advised to discuss their future applications that consist of or contain GMOs well in advance (six months to a year) of their submission to the Agency.

Applicants may also find it useful to apply for scientific advice during the development of their medicinal product. For any scientific-advice questions relating to environmental risk assessment (ERA), the necessary consultations will be held with the designated GMO competent authorities.

With the letter of intent to submit an application for a marketing authorisation under the centralised procedure for a medicinal product containing or consisting of GMOs within the meaning of Article 2 of Directive 2001/18/EC, the applicant will be required to provide a confirmation that all obligations have been complied with. It is necessary to ensure the traceability at all stages of the placing onto the market of GMOs as or in products authorised under part C (Article 12) of the abovementioned Directive.

Article 6 of Regulation (EEC) No 2309/93 specifies the documents to be presented in module 1.6.2 for an MAA for a medicinal product consisting of or containing GMOs:

  • a copy of the competent authority’s written consent to the deliberate release into the environment of the GMOs for research and development purposes. Although already appearing in module 1 (annex to the application form), this information should be repeated in module 1.6.2;
  • the technical and scientific information on the GMO specified in annexes III and IV to Directive 2001/18/EC. As the Directive qualifies this point with a statement to the effect that not all listed points may be applicable to particular GMOs or GMO categories, the list in these annexes should be understood to be a compilation of points to consider, which is subject to justified deletions or additions, depending on the nature of the medicinal product. The information also needs to take into account, inter alia, the diversity of sites of use of the GMO and the results of research and trials already completed on the GMO;
  • the ERA dossier. The content of this dossier should follow the order of headings and requirements specified within annex II to Directive 2001/18/EC and expanded upon in Commission Decision 2002/623/EC;
  • the results of any investigations performed for the purposes of research or development.

In addition and in analogy with the requirements of Article 6 of Regulation (EEC) 2309/93, it is recommended to complete module 1.6.2 with the following:

  • information on the proposed product information (including proposed conditions of use and handling) and on the packaging of the product. Although already appearing elsewhere in the MAA, this information should be repeated in module 1.6.2 for the benefit of the lead consulted competent authority, which will not receive the full MAA dossier;
  • a plan for monitoring, in accordance with Council Decision 2002/811/EC, during the period of use and beyond, of the product, or a justification for the omission of such a plan;
  • a summary following the summary information format set out in the Annex to Council Decision 2002/812/EC;
  • bibliographical references.

The module section 1.6.2, presenting all these particulars, should be bound separately from the remainder of the dossier. Moreover, there is no provision for a summary to be included in module 2 of the dossier.

The fundamental dossier requirements for ERAs for GMOs proposed to be placed on the market as or in products are included in Directive 2001/18/EC and in Commission Decision 2002/623/EC.

Technical and scientific information presented in the ERA will overlap with items of information presented in other sections of module 1, and other modules of the MAA dossier. Applicants are reminded to ensure full consistency of all data throughout the dossier, bearing in mind that variability, reflecting different origins (medicinal product regulatory versus environmental regulatory texts) may occasionally be encountered in the official terminology describing GMO attributes.

This Directive 2001/18/EC shall not apply to GMOs as or in products as far as they are authorised by Council Regulation (EEC) No 2309/93 provided a specific environmental risk assessment is carried out in accordance with the principles set out in Annex II to this Directive and on the basis of the type of information specified in Annex III to this Directive.

Council Regulation (EEC) 2309/93, as amended, 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 GMOs.

To accelerate the consultation process, the CHMP rapporteur may appoint one of the national GMO competent authorities to act as lead consulted competent authority. This lead consulted competent authority will liaise with its fellow GMO competent authorities on the review of the documentation forwarded to it by the applicant.

The assessment report on the module 1.6.2 data, prepared by the lead consulted competent authority and including any comments received from the fellow competent authorities, will be sent to the rapporteur for CHMP consideration. The CHMP members will subsequently have the opportunity to comment on all aspects of the scientific assessment. The environmental assessment is an integral part of the assessment report, and is done accordingly to the same timelines.

It should be highlighted that current experience under the centralised procedure with medicinal products containing or consisting of GMOs is rather limited. Once more experience is accumulated, a standard operating procedure will be prepared by the Agency for discussion and adoption by the CHMP.

References

26. What information should I provide if my medicinal product contains or uses materials of animal or human origin in the manufacturing process? Rev. July 2006

The applicant must comply with the part I module 3.2 (9) 'content: basis and principle' of annex I to Directive 2001/83/EC, as amended, which requires that:

The applicant must demonstrate that the medicinal product is manufactured in accordance with the note for guidance on minimising the risk of transmitting-animal-spongiform-encephalopathy agents via medicinal products...

and its updates.

Demonstration of compliance with the note for guidance on minimising the risk of transmitting-animal-spongiform-encephalopathy agents via medicinal products can be done by submitting certificates of suitability from the European Directorate for the Quality of Medicines and Healthcare (EDQM) (in annex 6.12 of the application form) or by inclusion of the dossier of scientific data in module 3.2 to substantiate this compliance. In the latter situation, this data should be reviewed in module 2.3 (expert reports).

For all applications, table A on materials of animal origin covered by the notice for guidance on minimising the risk of transmitting-animal-spongiform-encephalopathy agents via medicinal products should be completed and included in module 3.2.R.

For materials from animals not covered by the notice for guidance on minimising the risk of transmitting-animal-spongiform-encephalopathy agents via medicinal products and annex I to Directive 2001/83/EC as amended, applicants are requested to complete the table B on 'other materials of animal origin', and include it in module 3.2.R.

Materials of human origin

If an application relates to a medicinal product that contains or uses materials of human origin in its manufacture, applicants are requested to complete the table C on albumin and other human-tissue-derived materials and include it in module 3.2.R.

References

27. Where in my medicinal product information can I mention a local representative? Rev. January 2006

Some holders of Community marketing authorisations have requested that there be a contact point identified in the package leaflet and on the label. This would normally be the holder of the Community marketing authorisation. However, an MAH may wish to add the name of another (local) contact point, the 'local representative'.

'Local representatives' shall be taken to mean any private or legal person established in the Community charged, through a civil contract with the MAH, with representing it in a defined (geographical) area, this contract excluding any transfer of any responsibility imposed on the MAH by Community law and by national law, regulation and administrative action implementing such Community law.

The local representative may be indicated:

  • in the package leaflet, under heading 6 as detailed in the product-information templates, by name, telephone number and e-mail address (optional) only. Postal address may be added space permitting;
  • by name in the blue box on the label, as long as not it does not interfere with the legibility of the EU text on the outer packaging, and if mentioned, in the leaflet.

All telephone numbers should be accessible when dialled from abroad (e.g. when a toll-free number is given that is not accessible from abroad, an alternative international number has to be added).

Reference to website addresses or to e-mails linking to websites are not allowed, either for the marketing authorisation holder or for the local representative.

Designation of a local representative cannot be a requirement but, when the holder of a Community marketing authorisation wishes to identify a local representative in the leaflet, the whole Community must be covered so that the consumer in each Member State and EEA country has equivalent access to a local representative. A local representative may be designated for more than one Member State or EEA country and may also be the MAH when no other local representatives are indicated. Moreover, in principle, only one local representative should be indicated per Member State or EEA country. Local representatives should be able to address queries in the local official EEA language of the country for which he or she is designated.

There has been some confusion with regard to terms such as ‘exploitant’, ‘technical director’ and 'distributor'. Since there is neither a commonly agreed understanding of these terms nor an equivalent legal definition of them amongst the Member States, and in the absence of any reference or definition in Community law, reference to such terminology will not be accepted for a medicinal product authorised by the Community.

It must be recalled that Member States may not require that a local representative of the MAH be appointed for their territory. Therefore, the arrangements outlined above are purely optional for holders of Community marketing authorisations.

References

28. How and to whom should I submit my dossier? Rev. August 2014

In order to fulfil EU dossier requirements applicants must submit new Marketing Authorisation Applications (MAA) as follows:

Languages to be used

All applications have to be submitted in English.

Format of submission

From 1 January 2010, eCTD is the only acceptable electronic format for all applications and all submission types in the context of the centralised procedure (e.g. new applications, variations, renewals). Any other electronic format, including NeeS, will be automatically rejected and the submission receipt will not be acknowledged. Additionally, if the eCTD submission results in an invalid Technical Validation the submission will not be accepted.

The latest version of the ICH M2 eCTD specification can be found at http://www.ich.org/products/electronic-standards.html, and the current version of the eCTD EU Module 1 specification can be found in the Rules governing Medicinal Products in the European Community, Notice to Applicants, Volume 2B or the eSubmission website with related documents.

Where applications are amended during the agency’s review, such as e.g. responses to the lists of questions or a withdrawal, a new or consolidated eCTD sequence should be provided in order to maintain the eCTD life-cycle. Replacement sequences of a previously submitted eCTD application (e.g. following corrections) are not acceptable. Any modification of an eCTD application must be reflected in a new eCTD sequence.

For further information regarding the e-submission requirements in the context of the Centralised Procedure, please refer to the TIGes Harmonised Guidance for eCTD submissions.

The use of the electronic Application Forms (eAFs) is strongly recommended for Centralised Procedure. Information on the electronic Application Form electronic application form can be found on the eSubmission eSubmission eAF webpage.

Cover letter

The European Medicines Agency is standardising the administrative information required in cover letters for any submission concerning centralised procedures. This is in line with changes to the internal financial system and quality improvements to distribution workflows. The Summary Table should be incorporated in the cover letter of each submission in the Centralised Procedure (see explanatory notes in the template).

Please refrain from sending additional and separate copies of cover letters, as they will create delays in processing.

Product Information (PI)

As per eCTD requirement, the Product Information (SmPC, PIL and labelling) has to be submitted within the module 1 of the eCTD structure in PDF format. Additionally, this information should also be submitted in Word format outside the eCTD structure but in the same eSubmission Gateway /eSubmission Web Client package within a folder called “xxxx­_working documents”, where the number (xxxx) equals the sequence number

Active Substance Master File (ASMF)

In cases where an Active Substance Master file (ASMF) exists, the applicant should ensure that the Active Substance Master File is or has been submitted by the ASMF holder to the Agency (see also question "How should I submit an active-substance master file (ASMF)?”), in order to proceed with the validation of the dossier.

Submission to the EMA

From 1 March 2014 the use of the eSubmission Gateway or Web client is mandatory for all electronic Common Technical Document (eCTD) submissions through the centralised procedure. The European Medicines Agency (EMA) no longer accepts submissions on CD or DVD. This applies to all applications for human medicines.

More information on how to register and connect to the Gateway / Web Client can be found in the eSubmission website and detailed information on the required naming conventions and file formats can be found in European Medicines Agency eSubmission Gateway: Questions and answers relating to practical and technical aspects of the implementation and the eSubmission Gateway web client: Guidance for applicants. Applicants must not send duplicate submissions electronically or via CD-ROM or DVD as this might lead to delays in the handling of applications.

An automated ‘acknowledgement’ email is sent from the system confirming whether their submission has passed the relevant technical validation criteria and has been uploaded to the agency’s review tool and made available via the Common Repository. There is no need to send any accompanying hard media or separate paper cover letters for these submissions, as the cover letter will be in the relevant part of eCTD module 1 in PDF format.

Submission requirements for the different Committee (Co-) Rapporteurs

One electronic copy should be submitted to the (Co-) Rapporteurs after the eSubmission Gateway/ Web Client confirmation of a technically valid submission to the EMA if the relevant NCA is not using the Common Repository. Otherwise there may be a delay in the start of the procedure due to the time lapse between the validation by the Agency and the confirmation from the (Co-) Rapporteurs that they have received the dossier.

For a full overview of the submission requirements for the different Committee (Co‑) Rapporteurs see:Dossier requirements for Centrally Authorised Products (CAPs).

The above method and requirements also apply to the submission of responses to List of Questions / List of Outstanding Issues. 

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 should also send a copy of this information to the (Co-) Rapporteurs, if necessary in accordance with the published document “Dossier requirements for Centrally Authorised Products (CAPs)”. In this case, the validation can only be completed after receipt and verification of the information submitted. The submission of responses to validation supplementary information (VSI) should be sent in accordance with eCTD requirements, including validation supplementary information (VSI) related to the ASMF part of the dossier, when applicable.

In order to start the procedure by the targeted start date, the applicant is required to provide the information requested within a given deadline. If the applicant is unable to respond within the deadline, the Agency is able to accept the responses up to 2 months from the VSI letter. The published submission timetable applies. If no response is received within 2 months the validation outcome will be considered negative and the application closed. An invoice for the relevant administrative fee will follow.

If the (Co-) Rapporteurs have not received their copy of the dossier and/or supplementary validation information on the day the dossier is validated by the Agency, the start of the procedure may be delayed until the procedural starting date of the next month.

Submission requirements for the other Committee members

After validation of the application, the Agency will notify the applicant accordingly in writing. The same notification will also be sent to the (Co-) Rapporteurs.

Upon receipt of this notification, the applicant should forthwith send one electronic copy of the application to the other Committee Members who are not using the Common Repository, including any additional data or information supplied during the validation phase as appropriate.

There is number of NCAs that have access to centrally authorised product submissions directly via the Common Repository after submission to the Agency. Please note that these NCAs do not need additional submissions. Please refer to the “Dossier requirements for Centrally Authorised Products (CAPs)” document to see if an electronic copy should also be sent to the other Committee members after the validation phase for evaluation, to maintain the life cycle of the eCTD dossier.

It is essential that identical eCTD sequences are circulated to Committee Members. Any minor changes that affect the ‘md5 checksum’ will lead to inconsistency and possibly result in future technical invalidity.

References

28a. What are the names and addresses of the CHMP members? Rev. June 2007

See CHMP members.

29. How are initial Initial Marketing Authorisation Applications validated at the EMA? Rev. August 2014

Initial marketing authorisation (MA) applications submitted to the European Medicines Agency (EMA) 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 MA application prior to the start of the procedure. Initial MA validation has been centralised and is now being performed by a dedicated service within the Agency.

There are two elements to validation:

  • The first is 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 Module 1 Specification.
  • The second element is regulatory and administrative content validation, which can only commence once the application has successfully passed technical validation.

What to expect once an Initial Marketing Authorisation Application has been submitted to the EMA?

Once submitted to the European Medicines Agency in the agreed standard format, the Agency performs a technical validation. The outcome of this technical validation is immediatelynotified to the applicant when the application is received via eSubmission Gateway / Web client.

If the dossier is technically invalid and the replacement sequence 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 the Active Substance Master File (ASMF) submissions (see - How to avoid most common Quality validation issues - Active Substance Master File (ASMF)).

The Agency will inform the applicant of the start of the regulatory and administrative content validation.

If any issues are found during validation then the Agency will issue a 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. Any response to this VSI request has to be sent as a new sequence.

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

What are the potential scenarios when validating an Initial Marketing Authorisation Application?

There are four potential scenarios:

Scenario one (valid first time, no supplementary information requested)

  • The applicant submits a complete application according to the Agency’s guidance (see below: What are the main principles that my application should follow in order to pass validation successfully?)
  • The Agency does not require any additional information.
  • The Agency will confirm the positive validation to the applicant via a positive validation letter.
  • The scientific evaluation will start on the next available start date according to the EMA timetables.

Scenario two (validation supplementary information requested)

  • The applicant submits an application that is not in accordance with the Agency’s guidance (see below: What are the main principles that my application should follow in order to pass validation successfully?).
  • The Agency will ask the applicant via a request for Validation Supplementary Information (VSI) to submit the additional information, clarifications or corrections.
  • The applicant provides the above additional information within the validation timeline. If the additional information submitted is as requested, the Agency will confirm the positive validation to the applicant.
  • The scientific evaluation will start on the next available start date according to the Agency timetables.

Scenario three (suspension of validation)

  • The applicant submits an application that is not in accordance with the Agency’s guidance. (see below: What are the main principles that my application should follow in order to pass validation successfully?).
  • The Agency will ask the applicant via a request for Validation Supplementary Information (VSI) to submit the additional information, clarifications or corrections.
  • However, if the additional information is not provided as requested and within the validation timeline, the validation will be suspended and the applicant informed accordingly. The applicant will have up to two months from the date of the initial Validation Supplementary Information (VSI) request to provide the additional information, clarifications or corrections.
  • Within the two month period and according to the EMA timetables, the Agency will confirm the positive validation if all pending issues have been addressed otherwise a negative validation will be generated.

Scenario four (negative validation)

  • In the case of non-compliance with applicable legal and regulatory requirements within the above mentioned 2 months, the Agency will issue a negative validation.
  • In that case, the Agency will confirm the negative validation to the applicant via a negative validation letter and invoice the administrative fee.

What are the timelines of initial Marketing authorisation validation?

Validation takes place according to the Agency procedural timetable. Applications received on or before a quoted submission date will undergo validation by the Agency. The application must receive a positive validation outcome in order for a procedure to start on the next available start date.

What are the main principles that my application should follow in order to pass validation successfully?

The agreed standard format should be used. An eCTD structure according to the TIGes Harmonised Guidance for eCTD Submission should be sent and the format should strictly follow Volume 2B of the Notice to Applicants.

The use of the Electronic Application Form is also highly recommended.

The application form and the different parts / modules of the dossier should be consistent (e.g. the composition is the same in the application form and in module 3 and SmPC).

How to avoid common validation issues?

The following sub-paragraphs provide guidance on how to avoid common issues found during validation that will help to submit an application valid first time.

How to avoid most common Good Manufacturing Practice (GMP) validation issues

Manufacturing authorisations or equivalent for MRA partners (GMP certificates)

  • Please make sure that the scope covers the activities that a given applicant is seeking registration for in the marketing authorisation application.

QP declaration(s)

  • Please make sure that the Qualified Person (QP) declaration (annex 5.22) is in accordance with NTA requirements. For human medicinal products, please make sure the date of the last audit of the active substance manufacturer(s) is included.

Consistency / missing information

  • Please make sure that the following sections are consistent:
    • Sections 2.5.1, 2.5.2 and 2.5.1.2 of the application form versus section 3.2.P.3.1 of module 3;
    • Section 2.5.3 of the application form versus section 3.2.S.2.1 of module 3;
    • Flow-chart indicating all manufacturing and control sites involved in the manufacturing process of the medicinal product and the active substance (annex 5.8) versus the application form.
  • Please make sure that the following documents are not missing:
    • Documents equivalent to manufacturing authorisation (Article 8.3(k) Dir. 2001/83) for non-EU/EEA manufacturers. While not explicitly a validation issue, applicants should bear in mind that active substance manufacturers located in third countries should be registered with their local authorities in order to facilitate the import of active substances, in accordance with the Falsified Medicines Directive (Directive 2011/62/EU).

How to avoid most common Good Clinical Practice (GCP) validation issues

  • The pivotal studies to support the application in module 2.5 must be identified as such.
  • Please make sure that a list of inspection(s) conducted or planned by other regulatory authorities, related to the product and trial sites involved, is provided, preferably attached to the application cover letter. Alternatively provide confirmation that no inspections have taken place nor are planned.
  • Ensure the list of investigators (name, address, country), preferably in a tabular form, showing the number of patients enrolled by each site, and the total number of sites is included.
  • Please make sure that a table with the number of patients enrolled per country is included. These should be identified in the clinical study report of each study, for instance in section 10.1 or appendix 16.1.4.
  • Please make sure that a clear description of the study administrative structure (clear identification of the sponsor and of the parties who have performed the monitoring, data management, statistics, laboratory assessments, randomization, site(s) of manufacture, other applicable activities and the location of the trial master file) preferably in a tabular form and indicating name and address of the site where each activity was performed, responsibilities and scope of each activity is included. These should be identified in the clinical study report of each study, for instance in section 6, or appendix 16.1.4.

How to avoid most common Paediatrics validation issues

  • When applicable, please make sure that the full Paediatric Investigation Plan (PIP) decision (with all annexes) is submitted and not the Opinion. Please make sure that the compliance letter is not missing (sometimes applicant submits only the Compliance report).
  • In the application form, please make sure that the decision number (P/0xxx/YY) is submitted and not the PIP procedure number (EMEA-000xxx-PIPxx-YY). In case of class waiver, please make sure that not only the applicability letter is submitted, but also the last class waiver decision (currently CW/1/2011).

How to avoid most common Quality validation issues

  • Where permitted, valid justifications for the absence of documents in Module 3 must be provided in module 2.3, e.g. for novel excipients or material of human and animal origin.
  • Latest versions of Certificates of Suitability (CEP) for the active substance (chemical) or TSE must be provided.
  • Please make sure that the following sections are consistent with one another:
    • Section 2.6.1, of the application form versus section 3.2.P.1 of module 3 versus Product Information (composition)
    • Section 2.6.2 of the application form versus module 3.2.A.2 versus module 3.2.R (materials of human or animal origin)
    • Section 2.2.3.2 of the application form versus module 3.2.P.8.1 versus Product Information (shelf-life)
  • Please make sure that the following information is included:
    • Composition of coating mixtures, printing inks and gelatine capsules (both in application form section 2.6.1 and module 3.2.P.1)
    • Description of analytical methods/validation – information for all methods should be present in 3.2.S.4 and/or 3.2.P.5

Active Substance Master Files (ASMF):

  • Active Substance Master Files are often submitted to the EMA in a non-compliant and incomplete format. Applicants should provide the ASMF Holder with the requested information in advance of their submission and ensure that the EMA ASMF Submission Rules are always followed. Non-compliant or incomplete submissions will result in failed technical validation.
  • An ASMF is an integral part of the MAA dossier. If the ASMF procedure is used by the applicant as indicated in section 2.5.3 of the application form, the ASMF should be delivered to the Agency well before the submission deadline, in coordination with the related dossier. If the ASMF is technically invalid or arrives to the Agency after the submission deadline for the given month, the dossier is considered incomplete. In this case, the applicant will be informed of this fact and the validation process would be suspended until a complete dossier is presented. The applicant should liaise with the ASMF holder in order to provide a valid ASMF as soon as possible.
  • The validation will be resumed upon receipt of the valid ASMF. Once the validation is finalised, the options are:
    • No validation issues. The procedure starts at the next available date
    • Validation issues identified. A VSI letter will be issued and deadline for responses identified. The following steps are as above (scenario 2, 3 or 4)
  • Check there are no missing expert statements in the Active Substance Master File (ASMF)
  • The ASMF holders are encouraged to use the eSubmission tool, i.e. Gateway/Web Client portal. This prevents delays related to courier services, holidays and technical validation.

Other frequently encountered issues:

  • Application for the new active substance status should be presented as annex 5.23 to the Application Form (required as of 3 June 2013).
  • Name of the active substance in the application form:
    • Title page, section 2.2.1, section 2.6.1 – active substance including salt/hydrate
    • 2.1.2 – INN
  • Strength of the dosage form in the dossier and Product Information should be expressed per active moiety (i.e. base), corresponding to the actual salt – e.g. exemplain 120 mg (corresponding to 135 mg exemplain hydrochloride); see also here.
  • Section 2.6.2 of the application form and modules 3.2.A.2. and 3.2.R should contain ALL materials of human and animal origin, including those used during manufacture of the active substance (e.g. components of fermentation media), while module 3.2.P.4.5 relates only to excipients.
  • Where applicable, justification for not using a standard term for pharmaceutical form should be placed in module 1.3.
  • Excipients should be tested according to Ph. Eur. monograph where available. Where no Ph. Eur. monograph exists, other pharmacopoeias may be used as supportive but description and validation of the methods used should be provided. Detailed requirements can found on the Guideline on excipients in the dossier for application for marketing authorisation of a medicinal product.
  • Ph. Eur. analytical methods should be used whenever possible (e.g. for heavy metals, loss on drying)

How to avoid most common Non-clinical and Clinical validation issues

  • When documents in Modules 4 or 5 are absent, a valid justification must be provided:
    • The non-clinical overview and summaries should be structured following the indents of module 4.
    • The clinical overview and summaries do not mandate explicitly addressing some indents of module 5 (most commonly: 5.3.1.2. Comparative Bioavailability (BA) and Bioequivalence (BE), 5.3.1.3 In vitro - In vivo Correlation, 5.3.5.1 Study Reports of Controlled Clinical Studies and 5.3.5.2 Study Reports of Uncontrolled Clinical Studies). Justifications for the absence of studies in any indent of module 5, even when it is considered self-explanatory, should be included in the clinical overview.
  • Please make sure that a valid justification for empty eCTD modules/indents is provided, i.e. a statement that relevant studies have not been conducted or are not available is not considered a valid justification. Even if it is straightforward or a matter of development strategy (e.g. reliance of outstanding results from uncontrolled studies to support marketing authorisation application in the absence of controlled data), the reason for ultimately not submitting certain studies should be explained.
  • Please make sure that justifications are easy to locate/identify: Validation does not entail extensive review of submitted materials, but only identification of legally required elements. Providing a necessary justification for empty eCTD modules/indents within a discussion may prevent the validation officer from identifying it. One may want to place such justifications under relevant subsections of the (Non-) Clinical Overview or provide them as an Annex at the end of the (Non-) Clinical Overview making sure of the use of the correct terminology of the indent.

How to avoid most common pharmacovigilance validation issues

  • Please make sure that a statement indicating that “the applicant has the necessary means to fulfil the tasks and responsibilities listed in Title IX of Directive 2001/83/EC” is included.
  • Please make sure there is a reference to the location where the pharmacovigilance system masterfile for the medicinal product is kept.
30. When should I submit my Marketing Authorisation Application? Rev. August 2014

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 European Medicines Agency, Committee 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, (Co-) Rapporteurs may find it difficult to provide the necessary expertise and re-appointment could be necessary.

The European Medicines Agency advises applicants to consider the date of submission very carefully and to notify the Agency and (Co-)Rapporteurs of a 'real' submission date.

At least seven months before submission, applicants should notify the European Medicines Agency of their intention to submit a MAA and provide the intended date of submission. This should be done by using the Pre-submission request form Pre-submission request form (Intent to submit MA), selecting as a scope of request: Centralised Procedure-Intent to submit a MAA; this should be sent electronically to pa-bus@ema.europa.eu. The appointment procedure for (Co-)Rapporteurs will be initiated 7 months prior to the Marketing Authorisation Application intended submission date (see question "What is the procedure for appointment of CHMP Rapporteur/Co-Rapporteur and their assessment teams?").

Furthermore applicants are requested to notify the European Medicines Agency and (Co-) Rapporteurs as soon as possible when the previously notified submission date cannot be met, by re-sending an updated Pre-submission request form, selecting as a scope of request: Notification of change-applicant/contact person details.

Applicants are finally requested, if they no longer wish to pursue the submission of their application, to notify the European Medicines Agency of their intention to withdraw the request for submission of a MAA. This should be done by using the Pre-submission request form, selecting as a scope of request: Withdrawal of request; this should be sent electronically to pa-bus@ema.europa.eu. Please note that 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 (see submission deadlines and full procedural timetables). The published timetables identify the submission, start and finish dates of the procedures as well as other interim dates/milestones that occur during the procedure. Applicants should ensure that a technically valid eCTD submission is received by the EMA before the submission deadline. Any technically invalid sequence will result in non-acceptance that may cause a delay in the start of the procedure.

In order to accelerate and facilitate the procedure, one electronic copy should be submitted to the (Co-) Rapporteurs after the eSubmission Gateway/Web Client confirmation of a technically valid submission to the EMA if the relevant NCA is not using the Common Repository (refer to the published Dossier requirements for Centrally Authorised Products (CAPs)). Please note that the EMA requires only one eSubmission Gateway/ Web Client submission without any paper cover letter.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 complete set of documents that need to be submitted and for the addresses of Committee members for submission of the application, see question "How and to whom shall I submit my dossier?"

References: