Generic / hybrid applications: questions 23 to 34

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This page lists questions 23 to 34 of the European Medicines Agency's questions and answers on generic and hybrid applications.

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

See EMA pre-submission guidance for users of the centralised procedure.

24. How shall I submit an Active Substance Master File (ASMF)?

See EMA pre-submission guidance for users of the centralised procedure.

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

See EMA pre-submission guidance for users of the centralised procedure.

26. What information shall I provide if my medicinal product contains or uses in the manufacturing process materials of animal and/or human origin? When should I submit TSE tables A, B and C?

See EMA pre-submission guidance for users of the centralised procedure.

27. Where on my medicinal product information can I mention a local representative?

See EMA pre-submission guidance for users of the centralised procedure.

28. How, to whom and in how many copies shall I submit my dossier?

See EMA pre-submission guidance for users of the centralised procedure.

29. When shall I submit my application?

See EMA pre-submission guidance for users of the centralised procedure.

See submission dates for full applications

30. How shall my generic or hybrid application be evaluated (timetable)? Rev. March 2013

Upon receipt of the application, the Agency will start the validation on the next submission deadline stated on its website (see question 24). Validation has to be completed by the corresponding starting date of the procedure; applicants need to be ready to answer within few days to any issues raised at this stage. 

At the end of the validation process and provided the Rapporteur and Co-Rapporteur have received the dossier, the EMA starts the procedure at the monthly starting date published on the EMA website. For generics of Centrally authorised medicinal products, provided successful validation, the procedure starts the same month. Where the application concerns a generic/hybrid of a medicinal product authorised through a national/MRP/DCP procedure, the EMA will request from the Member state where the reference product received a marketing authorisation to transmit within a period of one month, a confirmation that the reference medicinal product is or has been authorised together with the information on the full composition of the reference product and if necessary other relevant information. Therefore the evaluation process will only start once all relevant information has been received.

If, within a month from the start of the procedure, any other member of the CHMP has not received the requested parts of the dossier from the applicant, the EMA will stop the clock until the problem is resolved. A timetable is prepared by the Agency and presented to the CHMP for information.

Applicants are advised to submit the MAA according to the published EMA calendar (See submission timelines).

Generic applications under Article 10(1) of Directive 2001/83/EC

The Agency shall ensure that the opinion of the CHMP is given in accordance with the standard Timetable for the evaluation of ‘generic applications’ under Article 10(1) of Directive 2001/83/EC.

DAY

ACTION

1*

Start of the procedure

80

Receipt of the Assessment Reports from CHMP Rapporteur by CHMP members and EMA. EMA sends CHMP Rapporteur Assessment Reports to the applicant making it clear that it only sets out their preliminary conclusions. The so-called Day-80 assessment reports in no ways bind the CHMP and are sent to the applicant for information only.

87

PRAC Rapporteur circulates the RMP assessment report and proposed RMP LoQ

90

Adoption of GxP Inspection Request

100

(Co-)Rapporteurs, other Committee members and EMA receive comments

101-104

PRAC adopts PRAC RMP Assessment Overview and Advice for D120 LOQ

115

Receipt of draft list of questions (LoQ) from CHMP Rapporteur, including the CHMP recommendation and scientific discussions, together with the PRAC RMP Assessment Overview and Advice by CHMP members and EMA (If applicable)

120

Adoption CHMP Opinion + CHMP Assessment Report unless “major” objections, GxP Inspection issues or questions on the restricted part of the ASMF are identified. Adoption of a timetable for the provision of translations.

 

DAYACTION

121*

Submission of the responses, including revised SmPC, labelling and package leaflet texts in English.

 

Restart of the clock

150

PRAC Rapporteur circulates the RMP assessment report and proposed LoOI

157

Circulation of the CHMP Rapporteur (Joint) Response Assessment Report (so-called Day-150 Assessment Report). EMA sends this (joint) Assessment Report to the applicant making clear that it is sent for information only and does not yet represent the position of the CHMP

167

PRAC adopts PRAC RMP Assessment Overview and Advice for D180 LoOI

170

Comments from CHMP Members to Rapporteur, the EMA and other CHMP members

180

Adoption CHMP Opinion + CHMP Assessment Report unless “major” objections are identified to be addressed in writing or during an Oral explanation and/or outstanding GxP issues.

Adoption of a timetable for the provision of translations

 

Clock stop in case of Oral Explanation

181

Restart of the clock. Oral explanation and circulation of the final GxP Inspection Report

183

PRAC Rapporteur circulates the RMP assessment report

197

PRAC adopts the final PRAC RMP Assessment Overview and Advice

By day 210

Adoption of CHMP Opinion + CHMP Assessment Report

Adoption of a timetable for the provision of translations

* According to the published EMA calendar (See Dates for CHMP meetings dates), after receipt of the responses, the EMA will prepare a timetable for the evaluation of the responses. In general the following timetable will apply:

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

DAY

ACTION

+ 5 Days after adoption of Opinion

Applicant provides the EMA with SPC, Annex II, labelling, package leaflet and Annex A in all EU languages (including Icelandic and Norwegian). EMA circulates draft translations to Member States for review

+ 22 Days after adoption of Opinion

Applicant provides EMA with final translations of SPC, Annex II, labelling and package leaflet in all EU languages (including Icelandic and Norwegian), taking account comments received from Member States by +19 Days after adoption of the Opinion

+ 27 Days after adoption of Opinion

Transmission of Opinion and Annexes in all EU languages to applicant, Commission, and Members of the Standing Committee, and Norway and Iceland

Further details on the post-opinion review of translations and forms to be used, are available in the "New linguistic review process of product information in the centralised procedure" guideline as published on the EMA website.

Mock-ups and specimens of the outer and immediate packaging together with the package leaflet must be submitted by the applicant to the EMA for review, before commercialisation of the medicinal product. Further details on the mock-ups and specimens requirements are available on the EMA website.

Hybrid applications under Article 10(3) of Directive 2001/83/EC

For hybrid applications under Article 10(3), the timetable for a new full application applies for the first evaluation phase. For the second evaluation phase, a shortened timetable could be agreed upon on a case-by-case basis.

References

31. How is an EMA Application Number attributed?

See EMA pre-submission guidance for users of the centralised procedure.

32. Which information do I need to provide in my marketing authorisation application regarding GCP Inspections and GLP Compliance? Rev. September 2015

For the non-clinical studies and clinical studies submitted as part of the application, applicants are requested to provide the following information as annexes to the Cover Letter in their marketing authorisation applications:

Regarding GCP Inspections

A list of GCP inspection(s) conducted or planned by any regulatory authority at clinical trial sites for all clinical trials included in the dossier. In case of BE trials a list of the inspections conducted at the clinical and analytical facility were the study was conducted. 

Alternatively, a confirmation that no inspections had been requested nor taken place and that no inspection are planned.

Please also refer to Question 35 “When can I expect a pre-approval GCP inspection and how are they conducted?” for more information on GCP Inspections and the information to include in the application regarding GCP compliance.

Regarding GLP Compliance

A summary table, listing the non-clinical studies claimed to be GLP compliant and indicating for each study:

  • study title,
  • study code (Unique identifier assigned to the study),
  • date the Final Report was completed,
  • test facility and test sites in which the study was conducted,
  • complete address of the test facility (and test sites were applicable),
  • period in which the test facility(ies) and/or test site(s) was(were) used indicating if in that period they were part of an European Union (EU) or an Organisation for Economic Co-operation and Development (OECD) Mutual Acceptance of Data (MAD) accepted GLP monitoring programme.

Regarding GLP compliance, as per Notice to Applicant, Volume 2B, there should be comment on the GLP status of the studies submitted in Module 2.4 Nonclinical Overview and Module 2.6 Nonclinical Summary.

References

33. When can I expect a pre-authorisation GCP inspection and how are they conducted? Rev. December 2015

The GCP standards applied to clinical trials carried out for generic medicinal products are the same as those applied to any other medicinal product. In addition it should be noted that the Guideline on the investigation of bioequivalence states in the “Chemical analysis” section that the analytical part of bioequivalence trials should be conducted in accordance with the applicable principles of Good Laboratory Practice.

Timetable for GCP inspections for generic application

In accordance with the legislation, any pre-approval inspection in the centralised procedure is requested by CHMP. The Timetable for Generic Applications states that the inspection request is usually adopted by CHMP by day 90 of the centralised procedure. If a GCP inspection is deemed necessary to complete the assessment of a centralised application for a generic medicinal product, a 120-day procedure is not possible and a clock-stop during the procedure is necessary.

GCP inspections are usually requested by CHMP when the Assessment Report is available, therefore by day 90. The inspection is announced to the applicant within 5 days from the adoption of the inspection request and it is coordinated by the EMA Inspection Sector to take place as soon as possible thereafter. The inspection is carried out by the relevant inspectorate usually in parallel with the clock stop period and the inspection results are generally reported by day 150.

Regarding the importance of GCP compliance for marketing authorisation applications, applicants/marketing authorisation holders are invited to refer to the EMA Position paper on the non-acceptability of replacement of pivotal clinical trials in cases of GCP non-compliance in the context of marketing authorisation applications in the centralised procedure.

References

34. When can I expect a pre-authorisation GMP inspection and how are they conducted?

The level of GMP supervision and the GMP standards applied to generic medicinal products are the same as any other medicinal product. The only difference relating to pre-authorisation GMP inspections between generics and other products assessed through the centralised procedure is that, for the former, a shorter timeline is possible (see Timetable for Generic Applications).

This means that all the information included in the document: GMP inspections during the assessment of the application, published on the EMA website as part of the pre-submission guidance, is applicable with the exception of the section: Timetable for Inspections.

Timetable for GMP inspections for generic applications

According to the legislation, any pre-authorisation inspection for medicinal products for human use in the centralised procedure is requested by the CHMP and, according to the Timetable for Generic Applications, the inspection request is adopted for generics by day 90 of the centralised procedure and the inspection results are reported by day 150.

As for any other centralised application, two types of pre-authorisation GMP inspections are possible: to verify compliance with European Community Good Manufacturing Practice Principles and Guidelines and/or to verify specific manufacturing and control activities related to the assessment of an application.

The first type of inspection is normally carried out when a manufacturing site located outside the European Economic Area (EEA) and in a country where no operational Mutual Recognition Agreement with the EU is in place, has not been inspected for GMP compliance in the last 3 years by an EEA competent authority.

The need for this type of inspection is identified in the early stages of the procedure and an early inspection request can be adopted by the committee (e.g. at day 30), so that unnecessary delays are avoided.

As assessment-related inspections can not be foreseen until the Assessment Report is available, inspections are usually requested at day 90 of the centralised procedure. In this case a clock-stop might be necessary. The inspection is organised without delay by the EMA secretariat and is usually carried out by the responsible inspectorate within 3 months of the adoption of the inspection request by the committee.

References

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