eCTD: EMEA Experiences

Strategic Management of CMC Dossiers in the eCTD Format: What CMC Professionals Need to

Know Now!

eCTD : EMEA Experiences

Evdokia Korakianiti Ph.DScientific Administrator

Quality sector Pre-Authorisation Human Medicines Unit

EMEA

10-11 March 2009 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


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.


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.


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.


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


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.


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


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


eCTD Statistics EMEA 988 eCTD submissions received since 1st 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


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 protected]

Specific practical guidance on using eCTD for PMF and ASMF submission currently being drafted


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


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.


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


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


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

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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


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


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.


Filenames

Q: Are ICH eCTD Appendix 4 filenames mandatory in Europe?

A: No, they are just highly recommended.


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


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


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


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).


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).


Validation

Q: Current validation rating is Category B (non serious) - will resubmissions be necessary for Category B validation rating?

A: No


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


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


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


Acknowledgements

Claire Holmes EMEA eCTD Business Team


Thank you for your attention !