ectd and CTD update SARI 2014 Pharmaceutical Science, Medicine Registration and Control A scientific approach

Transcription

1 ectd and CTD update SARI 2014 Pharmaceutical Science, Medicine Registration and Control A scientific approach Estelle Taute, MCC 1

2 Overview Specifications, Guidelines Guidance and Technical requirements How to find documents in CTD and ectd Requirement vs actual CTD Technical validation failure Business validation failure Evaluation phase Do s and don ts 2

3 Guidelines & Specifications Everything required for paper CTDs PLUS ectd specific documents CTD e.g.: ZA CTD Module General Information 2.05 Stability 2.06 Biostudies 2.07 Dissolution Guidance General Module P&A CTD 6.15 Screening template for new applications for registration Plus 2.21 South African Specification for ectd Regional & Module South African ectd Validation Criteria 2.23 Guidance for the Submission of Regulatory Information in ectd format 2.27 ectd Checksums 2.28 Q&A Implementation of ectd in South Africa Electronic Common Technical Document Specification V3.2.2 (

4 Why do we need specifications? 4

5 ectd requirements 2.21 Specification 1.3 Technical requirements The specification is designed to support high-level functional requirement such as Copying and pasting Viewing and printing of documents Annotation of documentation Facilitating the exporting of information to databases Searching within and across applications Navigating throughout the ectd and its subsequent amendments/variations 5

6 ectd requirements cont Guidance 3 Structure and content e.g. ectd identifier, envelope, folders, Module 3.2.R, letter of application 4.1 Submission media Hard media e.g. CD / DVD - no laptops or other hardware Large application single DVD rather than multiple CDs Individual modules not split over multiple CDs Adequately packed and labelled 4.3 PDF files Version 1.4, 1.5, 1.6 or 1.7 Maximum individual acceptable file size is approximately 100 MB. File size should ensure clarity, speed of download and ease of review. 4.5 Hyperlinks 4.7 Additional files in Word format Appendix 2: List of documents in paper format 6

7 ectd requirements cont Specification 7

8 ectd requirements cont Guidance 3.5 Letter of Application folder 1.0 of Module 1 Accompany all submissions - in both paper and portable document format (PDF). The PDF should be a scan of the originally signed document and must be searchable (OCR scanned). State the context of the submission, e.g. the submission type and the application or registration number. The paper and PDF letters must have the same content. Document operation attribute should always be new. The printout of the checksum file (index-md5.txt) should be attached as an annex to the letter (paper version). The annex must be dated and signed. 8

9 Letter of application cont. The following statement must be included: - We confirm that the CD/DVD-burning session is closed and the submission is checked with an up-to-date and state-of-the art virus checker: [name of the antivirus software and version of the virus checker] Tabular format of tracking (history) of the submitted sequences (or in annex) The letter (paper version) must be signed Include / annex ectd Reviewer s Guide or similar document for reviewers if there are specificities concerning the ectd submission, e.g. Hyperlink appearance and strategy Bookmarks 9

10 3.2.R structure 10

11 3.2.R Granularity 3.2.R 3.2.R R.1.1 Overview 3.2.R.1.2 Reference product (identification/docs) 3.2.R.1.3 Certificates of Analysis 3.2.R R Dissolution 3.2.R Exemptions and Other 3.2.R R.2.1 API parent manufacturer and sites 3.2.R.2.2 CoAs 3.2.R.3 CEPs 3.2.R R.4.1 Comparison of API synthesis routes 3.2.R.4.2 Tabulated comp results >1 API manufacturers 3.2.R.4.3 Confirmation of compliance with guidelines 3.2.R.4.4 Certificates of Analysis each batch in 3.2.R R.4 Declaration - similarity of FPP process 3.2.R.5 Medical device 3.2.R.6 Materials of animal / human origin 3.2.R.7 Batch records of sample confirm availability 3.2.R.8 Other Documents rolled up to this level are not considered appropriate One document may be submitted at this level 11

12 How do we find documents? CTD 2.24 Guidance General Module 1.1 Comprehensive table of contents Module 1 should include a comprehensive table of contents for the entire application. The comprehensive table of contents should include a complete list of all documents provided in the application by module. In the table of contents, the location of each document should be identified by referring to the volume numbers that contain the relevant documents and any tab identifiers. In general, the name for the tab identifier should be the name of the document (section heading according to the CTD format e.g. 3.2.P.4.2). If the full name of the document is too long for the tab identifiers, an alternative name that adequately identifies the document should be substituted. Page numbers should not be used in the table of contents to refer to documents, rather, tab identifiers as described above should be used. 12

13 CTD cont Guidance General 3 Organising documents Documents can be combined in volumes as long as they are separated by appropriately named tab identifiers. 5 Pagination A document is a set of pages, numbered sequentially and divided from other documents by a tab. Page numbering should be at the document level and not at the volume or module level. (The entire submission should never be numbered consecutively by page.) In general, all documents should have page numbers. Since the page numbering is at the document level, there should only be one set of page numbers for each document. Cross-referencing to documents should be made by referring to the CTD module, volume, tab identifier, and page number (for example: see Module 3, Vol. 6, P.4.3 Method validation, p 23 ) General Information 4.3 The application for registration of a dossier should have clearly labelled tabs to indicate each PART and sub-part or appendices/documents/reports of the dossier. Responses to recommendations should comply with the format and requirements of the Amendments guideline. Each part / section of the response should be indicated by clearly labelled tabs. 13

14 How to find documents in ectd Hypertext linking and Bookmarks ICH ectd Specification v3.2.2 Appendix 3 General Considerations for the CTD Modules (page 3-1) Appendix 7 Specification for Submission Formats (page 7-3 to 7-4) Submission in ectd format 4.5 Hyperlinks References in documents (e.g. tables, figures, images, sections, inter-document links) ToCs hyperlinked to the corresponding sections in the document 3.5 Letter of Application 14

15 Bookmarks Provide bookmarks for documents exceeding 5 pages that contain multiple headings/sections, tables, figures Provide enough bookmarks for easy navigation in the document Use meaningful names 15

16 Leaf titles Each document in the ectd has both a file name and a leaf title. File name is the actual name of the file the evaluator doesn t see this e.g. application-letter-10mg.pdf and label-10mg.pdf are the file names Leaf title is displayed when the evaluator views the submission 16

17 Leaf titles cont.

18 Requirement vs Actual What have we have found to date 18

19 Presentation 19

20 CTD ToC not comprehensive refers to main modules only Tabs are not included Tabs are not sequential documents in incorrect sequence Tabs do not reflect section number Tabs fall off during handling Tabs are illegible handwritten or names too long Coloured pages included as dividers but no tabs Module numbered instead of at document level 3.2.R not completed e.g. for NCEs Post-screening sets in sequence of MRF1 and not CTD Amendment schedule not used correctly reply to Committee recommendations and post-reg amendments Hybrid submissions (only allowed for post-reg amendments) 20

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22 Examples of what reviewer sees Submission Explorer Document Explorer 22

23 What does reviewer see EURS is Yours colour code identifies changes by the applicant Modifications to former submission Modifications in documents 23

24 ectd pilot Validation & other errors Only 2 submissions passed technical & business validation upon first submission 4 submissions failed technical validation 12 submissions passed technical but failed business validation Up to 4 sequences before complying New sequence 0000 instead of 0003 to minimise confusion in first review Because of invalid sequence 0000, non-compliance in business validation only detected in sequence 0001 Errors corrected in 0001 only to find new errors, e.g. letter OCR scanned in 0000 but not in 0001 Application forms of different strengths identified in 0000 but not in 0001 (leaf titles) PIL no longer hyperlinked 24

25 Technical Validation Failure cont. 25

26 Technical Validation Failure All showed own validation = valid Validation carried out on the submission e.g. on desktop and not on medium submitted Files in Module 3 found to be missing Export path too long Checksum not valid PDF protected by security settings or a password (rule no. 18) File or folder name contains invalid characters 26

27 Technical Validation Failure cont. Unable to make ISO copy DVD-RW or CD-RW used Multisession DVD suggesting that it may not have been properly closed Zipped file submitted 27

28 Technical Validation Failure cont. Unreferenced files 28

29 Technical Validation Failure cont. The thumbs.db files resulting in the error can be prevented. Link to the Microsoft webpage in this regard: ows/en-us/fbc b a- 5b74dcf59c20/how-to-disable-thumbsdb-filesgeneration-on-network-folders Won t see thumbs.db files unless you ve checked Show Hidden Files and Folders in the Folder Option panel and are using the icon mode in Explorer 29

30 Technical Validation Failure cont. To disable thumbs.db for Windows XP Open My Computer Click on Tools Click Folder Options Click the View tab Put a check in the box next to Do not cache thumbnails Click OK 30

31 Best Practice Warnings File size exceeds 100 MB (rule no. 28) 31

32 Best Practice Warnings cont. Broken bookmarks Broken hyperlinks PDF does not open in Most recent view 32

33 Business Validation issues Incorrect information in envelope Data in support of efficacy Biostudy + Other Clinical + Non-clinical Related sequence Information in envelope Letter not OCR scanned Application Form not OCR scanned 33

34 Business Validation cont. PI / PIL / Labels not hyperlinked Screening template not hyperlinked for ease of technical verification by reviewer Module 2 not hyperlinked to 3 / 4 / 5 CDs not correctly labelled not signed Confusion of dates in follow up sequences 34

35 Business Validation cont. Official document name in footer of and 1.8 changed 35

36 Business Validation cont. Application number not included in R Regional Information Node extensions not used Section numbers not included 3.2 Body of Data Sections included that are not applicable o This affects life cycle management of these sections 36

37 Evaluation phase 37

38 Bookmarks & Hyperlinks How should the reviewer find the Annexures? 38

39 Bookmarks & Hyperlinks cont. Appendices not hyperlinked. Documents that follow this list of Appendices are not the Appendices numbered, also not in the same order as the list of Appendices 39

40 Bookmarks & Hyperlinks cont. Clinical report bookmark leads to a Statement 40

41 Other Not possible to copy text as documents are not OCR scanned Whole module numbered, instead of per document Module 3.2.R not completed As for CTD 41

42 Do s and Don ts Granularity Planning is important! How does ectd structure apply to product and submission, especially with Multiple manufacturers API and/or product Dosage strengths Level of granularity Only entire documents can be replaced in ectd, not sections or pages within a document Initial granularity choices affect future updates and / or amendments (Refer to the ICH Granularity Document, Annex to M4: Organisation of the CTD) Once granularity and structure have been decided, they generally can t be changed during the life cycle 42

43 Module 1 mandatory documents The following documents are mandatory for all application types: Letter of application (1.0) Application form (1.2.1) Also for PI amendments Screening template (1.8), Section A.3 43

44 Hyperlinks Important to the evaluation process Evaluators save time following hyperlinks instead of searching for a reference (table, figure, document, etc) Hyperlinks that are not functioning properly can erode the evaluator s confidence in the submission 44

45 Hyperlinks cont. Include at least the following hyperlinks: Cross-references in the package insert ( ) to the actual references Cross-references in the Patient Information Leaflet (1.3.2) to the package insert ( ) References in Sections B to D of the Screening template (1.8) to the documents in the ectd Summaries in Module 2 to the relevant documents in Modules 3 to 5 Document Table of Contents (ToC) to the corresponding section in the document 45

46 Hyperlinks cont. Check the hyperlinks before submitting: Are there any broken hyperlinks? Do all hyperlinks go to correct destinations? Are all external hyperlinks removed? (e.g. web links, links) Do hyperlinks appear as blue text or blue box links if blue text isn t possible? Are hyperlinks set to Inherit Zoom? 46

47 Bookmarks Check the bookmarks before submitting Does the bookmark name indicate the bookmark s destination/content? Is the bookmark too long? Are bookmarks provided for the ToC items? Does the bookmark match the description/title showing on the ToC? Will someone who is unfamiliar with the application know what content they ll see before they click on the bookmark? Are bookmarks set to Inherit Zoom? 47

48 Quality control In ectd format, QC includes Check all hyperlinks and bookmarks Check lifecycle functions (new, append, delete, replace) Technical validation Ensure no file names are truncated Typically occurs when the path exceeds limits Check leaf titles short, indicative of document content Correct validation errors before submission Ensure media contains the submission and doesn t have defects Ensure submission is virus free 48

49 Electronic is not as patient as paper Paper is forgiving can slot in extra pages or replace documents just before submission ectd is not forgiving last minute changes will lead to checking of hyperlinks, re-validation, re-export 49

50 Before you submit, ask... If I was an evaluator, could I.? Easily locate the information/document Easily copy and paste from the document Easily differentiate between same type documents displayed in the ectd Easily navigate and access references in documents via bookmarks, links and the Table of Contents The ultimate goal is to provide an evaluatorfriendly ectd so that the focus of evaluation is on content, not format. 50

51 Conclusion Presentation and content issues in CTD manifest in ectd Read the guidelines Follow the guidelines Check the submission Check the submission Think like an evaluator 51

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53 Acknowledgements Anita Smal Abex Pharmaceutica, local Extedo partner Reviewers 53