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  • could be misleading if the sequence is 0000, as this does not show that some regulatory activity occurred before

eCTD: EMEA Experiences eCTD: EMEA Experiences Presentation Transcript

  • eCTD : EMEA Experiences Evdokia Korakianiti Ph.D Scientific Administrator Quality sector Pre-Authorisation Human Medicines Unit EMEA Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Presentation overview
    • eCTD Implementation Strategy at EMEA-Key Milestones
    • Current Status EMEA
    • eCTD Statistics EMEA
    • Electronic Submission: Available Guidance
    • Frequently asked eCTD related questions
    • Key Messages for Industry
    • Conclusions
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • eCTD Implementation Strategy at EMEA- Key Milestones
    • From 1 July 2008:
    • The EMEA accepts electronic-only submissions , either in eCTD format or non-eCTD format (eCTD is the recommended electronic format), with no additional requirement for paper copies
      • This applies to all applications (new and existing) and all types of submissions to the EMEA in the context of the centralised procedure (e.g. new applications, supplementary information, variations, renewals).
      • Rapporteurs and CHMP members may, however, still have paper-copy requirements at this point.
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • eCTD Implementation Strategy at EMEA- Key Milestones
    • From 1 January 2009:
    • The EMEA strongly recommends electronic-only submissions , either in eCTD or non-eCTD format (eCTD is the recommended electronic format)
      • Paper will be an exception to the general e-format recommended for any application. This will apply to all applications (new and existing) and all submission types.
      • Rapporteurs and CHMP members will not receive paper copies from this date.
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • eCTD Implementation Strategy at EMEA - Key Milestones
    • From 1 July 2009:
    • The EMEA will strongly recommend eCTD-format electronic-only submissions.
      • Paper and other electronic formats will be an exception to the general e-CTD format recommended for any application.
      • This will apply to all applications (new and existing) and all submission types.
      • Rapporteurs and CHMP members will not receive paper copies or other electronic formats from this date.
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Mandatory eCTD for the Centralised Procedure
    • Although electronic-only submission for the Centralised Procedure cannot be mandated due to lack of legislative basis, it is possible to mandate the format of the electronic-only submission if received:
      • Hence new milestone in EMEA eCTD Implementation Strategy
      • Published December 2008
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Mandatory eCTD: New Milestone
    • From 1 January 2010:
    • The EMEA will mandate the use of the eCTD format for all electronic-only submissions for all applications (new and existing) and all submission types.
      • Rapporteurs and CHMP members will not receive paper copies or other electronic formats.
    • NEES:
      • In addition, until 1 January 2010, any non-eCTD electronic submission provided in the context of the Centralised Procedure must also comply with the EMEA’s new specific guidelines for non-eCTD electronic submissions . All other current guidance remains in force.
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Mandatory eCTD: Implications
    • Non-eCTD format electronic submissions will be rejected
    • Paper-only submissions would be accepted as an alternative, but:
      • Will lead to significant handling and review issues, as all EMEA processes will be engineered towards electronic submissions
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Current Status EMEA
    • Number of eCTDs are increasing exponentially at EMEA
    • European Review System for eCTDs (EURS) is used by the entire agency as the sole tool for the handling and review of eCTD and NEES submissions received by the Agency
    • Although still the majority of eCTDs are new applications, the last 6 months have seen an increase in the number of converted eCTD baselines received for authorised products with ongoing regulatory activity
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • eCTD Statistics EMEA
    • 988 eCTD submissions received since 1 st July 2008
    • 228 products currently managed in eCTD format (approximately half of all CP active products)
    • October 2008:
      • 573 electronic submissions received by EMEA
      • 112 of those eCTD
    • November 2008:
      • 561 electronic submissions received by EMEA
      • 63 of those eCTD
    • December 2008:
      • 787 electronic submissions received by EMEA
      • 204 of those eCTD (highest no. received in a month so far)
    • January 2009:
      • 485 electronic submissions received by EMEA
      • 162 of those eCTD
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Electronic Submission: Available Guidance
    • eCTD and electronic submission: Statement of Intent
    • Mandatory eCTD: Statement of Intent
    • NeeS Implementation: Statement of Intent
    • Q&A on eCTD/electronic-only Strategy
    • Practical/technical guidance on submitting eCTD to EMEA
    • Practical guidance on submitting NeeS to EMEA
    • All available at:
    • http://www.emea.europa.eu/htms/human/genguidance/genreg.htm
    • Or contact EMEA: [email_address]
    • Specific practical guidance on using eCTD for PMF and ASMF submission currently being drafted
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • 10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now! Frequently asked eCTD related questions (as received by the EMEA)
  • eCTD baseline content
    • Q: Should only the most current information be provided for each heading, or a cumulative & chronological presentation of the content over time in a single leaf element?
    • A: There is no need for a chronological cumulative presentation of the content of the dossier. The latest approved information should be included in an eCTD baseline submission.
    • Q: Is it acceptable to exclude information that is not current (e.g. for very old products)?
    • A: It is not acceptable to exclude any information from the original dossier unless it has been updated by a regulatory process, (e.g. variation, line extension etc).
      • The information included in 3.P.2 is not subject to variations, therefore all the original information should be included in the baseline plus any additional development studies that have been performed during the lifecycle of the product
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Sequence
    • Q: In the EU eCTD guidance, it is mentioned that the first sequence should be 0000. For the original MAA this is very clear, but what if an application is changed to eCTD after the MAA has been granted, e.g. for a type II variation?
    • A: The first eCTD sequence should always be 0000, regardless of whether it is an initial MAA, variation etc. or baseline.
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Blank folders
    • Q: For legacy products not all sections within the quality module might have content. Is this acceptable?
    • A: In principle all CTD sub headings should be addressed. Statements justifying absence of data for specific CTD sections should be provided in the relevant Quality overall summary (NTA, Vol.2 B). Placeholder documents highlighting 'no relevant content' should not be placed in the eCTD structure
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • eCTD structure- Multiple manufacturers
    • Q: In section 3.2.P.3 is a single file required with multiple bookmarks relating to each manufacturing site, or one file per manufacturing site?
    • A: There is no preference. In choosing either option the applicant should consider:
      • How different is the manufacturing process used in the sites
      • The ease of maintaining this information during the lifecycle of the product (e.g. deletion or replacement of sites)
    • Q: Is the optional XML attribute for finished product manufacturer useful for the Authorities?
    • A: Only, if it is manufacturer specific
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • eCTD structure – multiple strengths
    • Q: Do applications need to be structured per strength?
    • A: No. eCTD should be managed at INN level (EU harmonisation subgroup decision)
    • Q: Is it useful to include the strength in the XML Dosage Form attribute if most files are not written per strength?
    • A: Only for documents in the dossier that are specific to one strength. Metadata cannot be changed by the applicant during the product lifecycle the meta-data level should be future-proof
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • CMC XML attributes
    • Q: EU eCTD CMC guidance offers a range of options for CMC XML attributes - are some preferred over others? Is it accepted that 3.2 attributes are free-text fields that can be used as best decided by the applicant?
    • A: There are no preferred approaches , there is no guidance from any region. Attributes are free-text fields that can be used as best decided by the applicant . Over time when more experience is accumulated more guidance could be issued, at this point there is not enough experience
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • CMC XML attributes (cont’d)
    • Q: Is there a preference for the XML attribute entry of the Dosage form? e.g., EU standard term or a shorter term? How to handle discrepancies in the EU, e.g. 'prolonged release' vs. 'extended release'?
    • A: No preference as long as it is clear
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • CMC XML attributes (cont’d)
    • Q: Are CMC XML attributes used for other purposes other than providing separate sections?, e.g., referencing, cataloguing sources, database queries?
    • A: Not at the moment. It is intended that in the future CMC XML attributes will be used when the review tool is linked to the EMEA tracking databases but this is long way to go.
      • By that time the next version of the eCTD (RPS) might be issued, which will be more structured.
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Filenames
    • Q: Are ICH eCTD Appendix 4 filenames mandatory in Europe?
    • A: No, they are just highly recommended.
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • APPEND operation
    • Q: What is the EMEA’s view on the use of operation attribute APPEND in Module 3 and 2.3?
    • A: It’s best to avoid “APPEND”, because EMEA experience so far shows that it is the least understood operation by tool vendors and it is the most open to interpretation
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • ASMF in eCTD
    • How does the electronic Active Substance Master File fit into the eCTD or electronic-only submission structure? What if ASMF is in paper or NeeS and the product dossier is in eCTD?
    • TIGes Harmonisation Subgroup draft eCTD guidance (for all procedures) : The closed and open part of an ASMF should be submitted in the eCTD
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • CEPs- Tables A,B,C
    • Ph Eur Certificate(s) of Suitability also appear in Module 1.2
        • Drug Substance = Annex 5.10
        • TSE = Annex 5.12
      • These may be linked from Module 3.2.R
        • to point to the same file in the folder directory
    • Tables A,B,C need not appear in Module 1.2
      • For materials of animal origin
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Linking- Cross references to other sequences or eCTDs
    • Q: Hypertext linking - within the same application, how much is really needed in Module 3?
    • A: Keep it minimal
    • Q: Has linking of files across XML folders caused confusion for CMC reviewers? e.g., same P.4 file linked across 5 excipient folders but all pointing to the same file in the folder directory?
    • A: There is no confusion if a review tool is used. BUT some MS are not routinely using a review tool--> might be a problem
    • Q: Will EU accept cross-references to other eCTD applications? e.g., for Module 3 information?
    • A: Currently not, but might be possible with the next version of eCTD (still under discussion).
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Parallel variations
    • Q: How to handle parallel variations for Module 3?
    • A: If the same document is used to support two parallel variation, it is acceptable to include it only in one submission and the make a cross-reference in the other one (in this way the document lifecycle is maintained).
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Validation
    • Q: Current validation rating is Category B (non serious) - will resubmissions be necessary for Category B validation rating?
    • A: No
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Key Messages for Industry (1)
    • Concern at EMEA that the majority of electronic/eCTD applications are STILL accompanied by a paper copy – this is disposed of on receipt by EMEA
    • Many companies receiving requests for paper from NCAs – please do not provide paper but instead contact EMEA for guidance and resolution
    • Limit submissions to one per CD/DVD, clearly labelled
    • Send DVD in place of multiple CDs (multiple CDs lead to handling difficulties)
    • Companies should refer to the EMEA’s practical guidance for detailed information on presentation and structure of the eCTD
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Key Messages for Industry (2)
    • Not always sufficiently clear which regulatory activity a submission belongs to (correct use of application number in PA submissions, related sequence, submission description)
    • Information relating to multiple regulatory activities should not be combined within a single eCTD submission (applies particularly to FUMs/SOs/PSUR – we have seen several submissions that combine all these into one sequence)
    • EU M1 v1.3 must be used for all applications
    • List not exhaustive...if in doubt about any aspect of eCTD use, ask EMEA
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Conclusions
    • Implementation of eCTD at an Agency level has been successful so far
    • EMEA will comply with HMA statement by end 2009
    • Still work to do internally regarding deep understanding of the eCTD on an operational level
    • Work really only just beginning on lifecycle management requirements, integration with existing systems and further eCTD development
    • Learning process for all – applicants are encouraged to contact EMEA to discuss business and technical issues with eCTD – will lead to better understanding and guidance
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
  • Acknowledgements
    • Claire Holmes
    • EMEA eCTD Business Team
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!
    • Thank you for your attention !
    10-11 March 2009 Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to Know Now!