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 EEA? - Rev. Feb 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 the Union law.
The MAH may be a natural or legal person.
The MAH of a centralised marketing authorisation must be established within the 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 which is formed in accordance with the law of an EEA Member State and which allows the concerned holder to assume the duties and responsibilities as well as to perform the tasks laid down by Union law.
Companies or firms formed in accordance with the law of a Member State and having their registered office, central administration or principal place of business within the EEA shall be treated in the same way as natural persons who are nationals of Member States.An applicant should demonstrate that it is duly established in the EEA.. A proof of establishment from the applicant company is required by the EMA in order for an application to be validated (e.g. UK: Certificate of incorporation issued by the Registrar of Companies, FR: Extrait du registre du commerce et des sociétés). This proof of establishment should be included in Annex 5.3 of the Application Form (Available in the Notice to Applicants (NTA) Volume 2B - Application Form: Module 1.2).
It should be emphasised that while the Marketing Authorisation Holder may delegate certain activities to third parties, the MAH remains responsible for assuring all the obligations imposed on Marketing Authorisation Holders by the European legislation and by national law, as applicable.
- 22. What information relating to the manufacture and batch release should be provided as part of my application? - Rev. Feb 2012
The EMA 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 European Economic Area (EEA). This should be sent to the EMA along with the application dossier.
The EEA includes European Union 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/batch release described under Module 1.2 (i.e. Application Form) of the application during the 210-day review period. Any additional site or change in the manufacturing or batch release arrangements should be submitted as a variation after the granting of the Marketing Authorisation.
The information on manufacturing/batch release sites submitted in Module 1.2 of the application must be consistent with module 3. All the manufacturing/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.
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 product (if any)
- finished product manufacture and packaging
- batch release
- any contract manufacturing sites
- any contract laboratories used for testing the finished product
- Official Medicines Control Laboratory (OMCL) for blood products/vaccines if “Official Batch Release” is a requirement for the product in question.
For third country manufacturers, information about any previous EEA inspection in the last 2-3 years and/or any planned EEA inspection(s) should be provided and should include details of the inspection dates, product category 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:
- For all sites in the EEA, other than active substance manufacturers, copies of the "Manufacturing Authorisation" authorising the sites involved in the manufacture, importation, control and /or testing and Qualified Person release of batches of the medicinal product. Alternatively, a reference can be made to the appropriate entry in the EudraGMDP database.
(Note: for sites in the EEA, 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).
- For all sites other than active substance manufacturers, located in third countries where a Mutual Recognition Agreement or other relevant agreement is in place, MRA certificate, not older that 3 years, from the local competent authority that carried out the inspection and/ or GMP certificate from the EEA inspecting competent authority if the site has been inspected by an EEA competent authority in the last 2/3 years. Where the MRA partner has placed the certificate in the EudraGMDP a reference to the entry will suffice. For the countries which have operational Mutual Recognition Agreements (MRA) with the EU, please consult the EMA website on Mutual Recognition Agreements.
- For all sites other than active substance manufacturers, located in third countries with no Mutual Recognition Agreement, GMP certificate from the EEA inspecting competent authority if the site has been inspected by an EEA competent authority in the last 2/3 years. Alternatively, a reference can be made to the appropriate entry in the EudraGMDP database.
- In addition to the above, 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/pharmaceutical form and details of any inspection performed other than by EEA authorities (e.g. GMP certificate or similar statement from the competent authority which carried out the inspection).
- A flow-chart 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 Person(s) of all the finished product manufacturer(s) located in the EEA listed in Module 1.2 where the active substance is used as a starting material and from the Qualified Person(s) of the batch release site(s) in the EEA that the active substance manufacturer(s) listed in Module 1.2 operate in compliance with the detailed guidelines on Good Manufacturing Practice.
Contact person in the EU/EEA for product defects/recalls:
A proposed contact point/person in the EEA for Quality problems and defective batches of product must also be provided in Module 1.2 of the application (name, full address, 24 hour emergency phone and fax numbers + e-mail address, and mobile phone number if available).
- 23. What batch release arrangements in the EEA are required for my medicinal product? - Rev. Feb 2012
Importing site/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 to 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 European Union 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(ies) shall be the competent authorities of the Member State or Member States which 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(ies) shall be the competent authority(ies) of the Member State(s) which granted the manufacturing authorisation provided in Article 40(3) of Directive 2001/83/EC to the importer, unless a Mutual Recognition Agreement (MRA) or other relevant agreement covering GMP for the product under consideration is operating with the country where the medicinal product is manufactured.
In the exceptional circumstances where a valid manufacturing authorisation is not in place at the time of the marketing authorisation submission for any finished product manufacturer/importer/batch release site located in the EEA, EMA 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 grant 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 Mutual Recognisition Agreement, a request for inspection will normally be triggered. The marketing authorisation procedure will require the inspection outcome before opinion.
Batch testing upon importation:
For medicinal products imported from third countries, retesting of each batch within the EEA upon importation is required unless a Mutual Recognition Agreement (MRA) or other relevant agreement covering GMP for the product under consideration is operating with the country where the medicinal product is manufactured. If such MRA is in operation, batch controls/tests carried-out in the country where the product is manufactured are acceptable.
It should be noted that MRAs cover batch control/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 if a MRA with the exporting country is in place or not.
For the countries which have operational Mutual Recognition Agreements (MRA) with the EU, please consult the EMA website on Mutual Recognition Agreements.
Batch release of an imported medicinal product from a third country without re-testing 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 certain 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 Good Manufacturing Practice, as applicable and with the requirements of the Marketing Authorisation, once granted.
- Directive 2001/83/EC
- Regulation (EC) No 726/2004
- Annex 16 to GMP Certification by a Qualified person and Batch Release (July 2001), Volume 4 of the rules governing medicinal products in the European Union
- 24. How shall I submit an Active Substance Master File (ASMF)? - Rev. Feb 2012
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, 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. A table of content and a separate Quality Overall Summary for each part must also be provided as part of the ASMF.
The content requirements, as described in the above mentioned Guideline should be followed.
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 submit both the Applicant’s Part (which should be identical to the one provided by the applicant) and the Restricted Part. 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 submitted as part of a new MAA.
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.
The ASMF holder should submit the full ASMF to the EMA accompanied by the following documents:
- A cover letter, in accordance with the template provided in Annex 3 of the above mentioned Guideline.
- A "Letter of Access", to be included in Annex 5.10 of the application form, Module 1.2. According to the template provided in Annex 2 of the above mentioned Guideline, the letter must contains:
- The number, version and issue date of the ASMF, when possible. This number is internally assigned by the ASMF holder.
- The name and address of the manufacturing site
- The name and address of the ASMF holder
- The name of the applicant
- The name of product and Marketing Authorisation (MAA) number.
- The planned date of submission of the Marketing Authorisation Application
- A statement that the ASMF holder gives permission to the EMA including all CHMP Members and their experts to refer to and review the ASMF
- A commitment to inform the applicant and the EMA of any change in the ASMF to be provided either as a separate letter included in Annex 5.11 or within the letter of access provided in Annex 5.10 to the application form.
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 AP 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 must be the same in the Cover Letter of the ASMF, in the Letter of Access and the Application Form (Module 1.2).
It is necessary for the applicant and the ASMF holder to liaise to ensure that the ASMF including these 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.
At Day 120 of the scientific assessment timetable of the application, a list of questions is sent to the applicant. It is to be noted that the Rapporteur, the Co-Rapporteur and the CHMP will define those questions which refer to the closed part of the ASMF, and therefore in order to respect the confidentiality of the information included in this part, the scientific assessment of the restricted part and its questions will only be sent to the ASMF holder. The applicant will receive the scientific assessment and questions concerning the applicant’s part of the ASMF.
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.
- Annex I to the Directive 2001/83/EC, as amended
- Guideline on Active Substance Master File Procedure
- Procedural announcement CHMP Monthly report October 2004
- Guideline on requirements for Vaccine Antigen Master File (VAMF) certification
- Guideline on requirements for Plasma Master File (PMF) certification
- 25. What shall I submit if my medicinal product contains or consists of genetically modified organisms (GMOs)?
Potential applicants are advised to discuss their future applications which consists or contains of GMOs well in advance (6 months – 1 year) of their submission with the European Medicines 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 the Environmental Risk Assessment (ERA), the necessary consultations will be held with the designated GMO Competent Authorities (CAs).
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 Genetically Modified Organisms (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 on the markets of GMOs as or in products authorised under part C (article 12) of the above-mentioned Directive.
Article 6 of Regulation (EEC) No 2309/93 specifies the documents to be presented in Module 1.6.2 for a Marketing Authorisation Application (MAA) for a medicinal product consisting of or containing GMO(s):
- A copy of the CA’s written consent to the deliberate release into the environment of the GMOs for research and development purposes. Although already appearing in Modules 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 and/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 M1.6.2 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 CA 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 MA application 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 the 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 CAs to act as lead consulted CA. This lead consulted CA will liaise with its fellow GMO CAs 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 CA and including any comments received from the fellow CAs, 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, an SOP will be prepared by the European Medicines Agency for discussion and adoption by the CHMP.
- Council Regulation (EEC) No 2309/93, as amended (OJ L 214/1 of 24 August 1993 and OJ L 88/7 of 24 March 1998)
- Council Directive 2001/18/EC (OJ L 106/1 of 17 April 2001)
- Commission Decision 2002/623/EC of 24 July 2002 establishing guidance notes supplementing Annex II to Directive 2001/18/EC of the European Parliament and of the Council of 12 March 2001 on the deliberate release into the environment of genetically modified organisms and repealing Council Directive 90/220/EC
- The Rules governing Medicinal Products in the European Community, Notice to Applicants, Volume 2B, Presentation and content of the dossier
- Guideline on environmental risk assessments for medicinal products containing, or consisting of, genetically modified organisms (GMOs)
- 26. What information shall I provide if my medicinal product contains or uses in the manufacturing process materials of animal and/or human origin? - Rev. Jul 2006
The applicant must comply with the Part I Module 3.2 (9) "Content: basis and principle" of the 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 (EDQM) (in Annex 6.12 of the Application form), or by inclusion in module 3.2 of the dossier of scientific data to substantiate this compliance. In the latter situation, this data should be reviewed in Module 2.3 (expert reports).
For all applications, the 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 the 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, 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 materials' and include it in Module 3.2.R.
- 27. Where on my medicinal product information can I mention a local representative? - Rev. Jan 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, a Marketing Authorisation Holder may wish to add the name of another (local) contact point, the "local representative".
"Local representative" shall be taken to mean: any private or legal person established in the Community charged, through a civil contract with the Marketing Authorisation Holder, with representing him in a defined (geographical) area; this contract excluding any transfer of any responsibility imposed on the Marketing Authorisation Holder 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 QRD Product information Template , by name, telephone number and electronic 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 interfering 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 which is not accessible from abroad, an alternative international number may have to be added).
Reference to website addresses or to e-mails linking to websites are not allowed, neither for the marketing authorisation holder nor 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, all of the 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 States or EEA country and may be also the Marketing Authorisation Holder when no other local representative is indicated. Moreover it is reminded that, 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(s) of the country for which he or she is designated.
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 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 Marketing Authorisation Holder be appointed for their territory. Therefore, the arrangements outlined above are purely optional for Holders of the Community Marketing Authorisations.
- Guideline on the packaging information of medicinal products for human use authorised by the Community the Rules governing Medicinal Products in the European Community, Notice to Applicants, Volume 2C
- QRD Templates with Explanatory Notes
- In the Package Leaflet, under heading 6 as detailed in the QRD Product information Template , by name, telephone number and electronic e-mail address (optional) only. Postal address may be added space permitting,
- 28. How and to whom shall I submit my dossier? - Rev. March 2013
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 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 and CD/DVDs, 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 and eSubmission Web Client package or CD-ROM or DVD 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 submitted by the ASMF holder to the Agency, at around the same time as the main application (see also question "Submission of a ASMF”), in order to proceed with the validation of the dossier.
Submission to the EMA:
The EMA strongly recommends using the eSubmission Gateway or the eSubmission Web Client as the preferred submission methods of all eCTD submissions. 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 the Gateway Q&A and the Web Client Q&A. Applicants must not send duplicate submissions electronically or via CD-ROM or DVD as this might lead to delays in the handling of applications.
Applications that are sent using the eSubmission Gateway and eSubmission Web Client will receive an automated ‘acknowledgement’, confirming whether their submission has passed the applicable technical validation criteria and has been uploaded to the agency’s review tool. There is no need to send any separate paper cover letters for these submissions, as the cover letter will be in the relevant part of eCTD module 1 in PDF format.
MAHs not yet using the eSubmission Gateway or the Web Client solution should send applications as CD-ROM or DVD for the attention of the Product and Application Business Support (PA-BUS):
Product and Application Business Support (PA-BUS)
European Medicines Agency
London E14 4HB
Only one CD-ROM or DVD of the Marketing Authorisation Application (MAA), including the applicant’s part of the active Substance Master File, where applicable should be submitted to the Agency, together with one original, signed cover letter when using this format of submission.
Submission requirements for the different Committee (Co-)Rapporteurs:
After receiving the confirmation of technically valid submission through the Gateway or the Web Client from the Agency, the applicants 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. In case of a CD-ROM or DVD submission to the EMA, the submission to the (Co-)Rapporteurs should be sent at the same time as the submission is sent to the Agency.
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. In this case, the validation can only be completed after receipt and verification of the information submitted. The submission of responses to validation additional information (VSI) should be sent in accordance with eCTD requirements as specified in the previous paragraph, including validation additional 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 additional validation information on the day where 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 MAH should forthwith send the application to the other Committee Members, including any additional data or information supplied during the validation phase as appropriate.
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.
For a full overview of the submission requirements for (all Committee members please see:Dossier requirements for Centrally Authorised Products (CAPs).
- “Centralised Procedure”, the Rules governing Medicinal Products in the European Community, Notice to Applicants, Volume 2A, Chapter 4
- The Rules governing Medicinal Products in the European Community, Notice to Applicants, Volume 2B, Electronic Technical Document (eCTD)
- Official Website for ICH
- eSubmission Website
- eSubmission Gateway and the Web Client
- Electronic Application Form
- 29. How and to whom shall I submit my dossier and how many copies? - Rev. Feb 2012
Answer integrated in Q&A 28 “How and to whom shall I submit my dossier”.
- 29a. What are the names and addresses of the CHMP members? - Rev. Jun 2007
Please use this list of CHMP members wishing to receive partial or complete copies of the dossier as the address might be different to the address in the CHMP members list.
- 30. When to submit the Marketing Authorisation Application? - Rev. March 2013
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-)Rapporteur 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-)Rapporteur 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 email@example.com. 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 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 Pre-submission request form, selecting as a scope of request: Withdrawal of request; this should be sent electronically to firstname.lastname@example.org. 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, applicants must submit, in parallel to the European Medicines Agency, the required copies of the dossier to both the all (Co-)Rapporteurs, as stated in 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. Alternatively, one CD/DVD and one signed paper cover letter can be sent.
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 complete set of documents that need to be submitted and for the addresses of CHMP members for submission of the application, see question "How and to whom shall I submit my dossier and how many copies?"
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