Notes on the Enforcement of the AMG-EV, Version 5.0, of 1 Juli 2007

Transcription

1 Contents Explanatory Notes on the Enforcement of the Ordinance on the Submission of Documents within Licensing and Renewal Procedures for Medicinal Products (AMG-Submission Ordinance, AMG-Einreichungsverordnung, AMG-EV) of 21 December Version 5.0 of 1 July Explanatory Notes on the Enforcement of the Ordinance on the Submission of Documents within Licensing and Renewal Procedures for Medicinal Products (AMG-Submission Ordinance, AMG- Einreichungsverordnung, AMG-EV) of 21 December Version 5.0 of 1 July General remarks address for the electronic submission Information Hotline contact for electronic submissions in accordance with AMG-EV as well as explanatory notes on the on-line procedure electronic notification of variation Contact person for procedural and scientific questions Contact person ectd Modalities of electronic submission General Documents to be submitted... 6 Table 1 CTD-Module according to NTA Vol 2 B Supplementsl and additions New applications for marketing authorisation in accordance with Section 21ff. AMG / Request for ENR Technical specifications concerning s subject content attachments and file formats Problems with the MS-TNEF format in Outlook Zip containers Files with documents to be submitted Files with metadata Table 2 Construction of attribut.txt for procedure types Search for ENR / PNR Encryption of the container Version 5.0 of 1 July 2007 Page 1 / 38

2 5.3.7 Encryption software Encryption with the BfArM key Downloading of the BfArM key, encryption of the zip container File name convention Elements of file names for electronic submission to BfArM Table 3 Types of Document, set file names File name convention in accordance with ICH ectd Specification Checklist to monitor whether all conditions have been fulfilled Table 4 Checklist Item Verification and confirmation of s Confirmation of receipt and confirmation as to the coherence of the formal/technical properties Confirmation as to the intellectual verification of content Possible error messages regarding electronic verification of coherence of formal/technical characteristics Table 5 Error message Possible error messages regarding intellectual verification of submitted s Table 6 Error message System response What to do in the case of false-positive system responses Submission under a wrong ENR Submission of partly wrong data Important information concerning permission of exclusive submission of paper documents in accordance with Section 3 AMG-EV List of changes Table of figures: 1. Fig 1 Dialogue for download of BfArM public key Fig 2 Download subdirectory Fig 3 Import of key into key manager / Schlüsselverwaltung Fig 4 Selection and iimport of BfArM public key Fig 5 Schlüsselimport / key import dialogue Fig 6 Status message Schlüsselimport Fig 7 Display of imported key Fig 8 Fingerprint degree of trust Fig 9 Fingerprint check Fig 10 Ownertrust Fig 11 Encryption of zip container Version 5.0 of 1 July 2007 Page 2 / 38

3 12. Fig 12 Selection of BfArM key Fig 13 with attached zip container Figure 14 Cancellation of a false-positive system response Version 5.0 of 1 July 2007 Page 3 / 38

4 1 General remarks The AMG-Submission Ordinance (AMG-Einreichungsverordnung, called AMG-EV in the following) regulates the electronic submission of documents for applications for authorisation, variation or renewals in Module 1 and Module 2 of the Common Technical Documents (CTD, Within this purview, the AMG-EV as well as these Explanatory Notes override earlier regulations on the submission of documents. Divergent requirements in previous notifications are replaced by these Explanatory Notes. Aside from this, unless otherwise specified by the AMG-EV, the currently existing regulations on the submission of documents apply. This means, e.g., that if documents can or must be submitted on paper according to Sections 3 and 4 of the AMG-EV, the existing requirements for such submissions must still be observed. These Explanatory Notes override the previous explanatory notes of version 4.09 dated 01 August. 2 address for the electronic submission [email protected] Attention: For test purposes, documents can be sent to the following address: [email protected] Electronic submissions to the test address exclusively serve for testing for possibly existing formal errors and are not further processed by BfArM. In no case do positive test messages replace the actual submission. 3 Information 3.1 Hotline contact for electronic submissions in accordance with AMG-EV as well as explanatory notes on the on-line procedure electronic notification of variation Request for advice as to problems with electronic submission in accordance with AMG-EV should be addressed to the hotline account [email protected]. Contact person: Ms. Dudszus-Hentschel The hotline can be contacted by phone: / or / Attention: For enquiries about submitted documents refer to the serial number of the day (Tagesnummer) of the BfArM response mail. This number is found in the subject line (Betreffzeile) of the positive or negative response message. For further details see 6.5 System response. Questions about the application for a PNR or ENR or other frequently asked general and technical questions including system response are answered under FAQ on BfArM homepage. Version 5.0 of 1 July 2007 Page 4 / 38

5 Questions about the use or functionality of compression tools are principally not answered by BfArM. Information about the on-line procedure electronic notification of variation : Submissions via the procedure electronic notification of variation need not be additionally made to the a.m. address. However, the AMG-EV conventions, especially for the file format (rtf for SPC and PIL/Fach- and Gebrauchsinformation), remain valid unchanged. You will find further information on "Electronic notification of variation" on the BfArM homepage or PharmNet homepage: Contact person for procedural and scientific questions Procedural and scientific questions concerning ongoing procedures are answered by the responsible project management. Please contact the address [email protected]. 3.3 Contact person ectd The AMG-EV for electronic submission does not interfere with the ectd submission procedure. Web addresses of ectd specifications are: ectd contact persons are General questions: Dr. Menges, phone: oder 0228/ , [email protected] Technical questions: Mr. Kunz, phone: or 0228/ , [email protected] 4 Modalities of electronic submission 4.1 General Electronic submission of documents is to be made to the address < [email protected] >. At the same time the written version (paper) is to be sent to the regular mailing addresses depending on which procedure is used. For electronic submission of documents in accordance with Section 1 sub-section 2 of the AMG- EV only the web-technology is to be used. Thus, transfer of data via disk or CD is impossible. For more information please refer to the reasoning of the Federal Council of Germany (Bundesrat) on the AMG-EV of 10 November 2000 (BR-Drs/resolution 745/2000). The same applies to supplements, insofar as they are included in Section 2 sub-section 1 of the AMG-EV. Version 5.0 of 1 July 2007 Page 5 / 38

6 4.2 Documents to be submitted All documents listed in Section 2 sub-section 1 AMG-EV are to be submitted electronically, i.e. drafts for Labelling in accordance with Section 10 AMG Patient information in accordance with Section 11 AMG Expert information ("Fachinformation") in accordance with Section 11a AMG Expert Reports in accordance with Section 24 sub-section 1 numbers 1-3 AMG. In accordance with Commission Directive 2003/63/EC of 26 June 2003 and the "Hinweise zum Einreichen von Zulassungsanträgen im CTD-Format beim Bundesinstitut für Arzneimittel und Medizinprodukte" (Instructions on Submitting Applications for Marketing Authorisation in CTD Format to the Federal Institute for Drugs and Medical Devices) of 2 July 2003, use of the CTD format is mandatory as of 1 November 2003 (apart from the exceptions permitted in the a.m. instructions). Therefore, as of 1 November 2003 the term "Expert Report in accordance with Section 24 sub-section 1 numbers 1-3 AMG" is considered to mean the corresponding documents according to the Notice to Applicants, Vol 2 B, edition July 2003 as presented in the following comparison: Table 1 CTD-Module according to NTA Vol 2 B NTA NTA Vol 2 B, edition 1998 EU CTD (NTA Vol 2 B, edition 2005) CTD IC Expert Reports IC1 rsp. Section 24 (1) Expert Report on the chemical, pharmaceutical and biological documentation no. 1 AMG IC1 Product profile Introduction 2.2 IC1 Critical Assessment Quality Overall Summary Quality Expert Statement 2.3 IC1* Signature, Information on the expert* Information about the experts* 1.4* IC1 Appendix 1: Tabular Formats - - IC1 Appendix 2: Written Summary - - IC 2 rsp. Section 24 (1) no. 2 AMG Expert Report on the toxico-pharmacological documentation IC2 Product profile Introduction 2.2 IC2 Critical Assessment Nonclinical Overview 2.4 Nonclinical Expert Statement IC2* Signature, Information on the expert* Information about the experts* 1.4* IC2 Appendix 1: Tabular Formats Nonclinical Summary Pharmacology Tabulated Summary Pharmacokinetics Tabulated Summary Toxicology Tabulated Summary IC2 Appendix 2: Written Summary (Pharmacology) Nonclinical Summary Pharmacology Written Summary Pharmacokinetics Written Summary IC3 rsp. Expert Report on the clinical documentation Section 24 (1) no. 3 AMG IC3 Product profile Introduction 2.2 IC3 Critical Assessment Clinical Overview Clinical Expert Statement Version 5.0 of 1 July 2007 Page 6 / 38

7 NTA NTA Vol 2 B, edition 1998 EU CTD (NTA Vol 2 B, edition 2005) CTD IC3* Signature, Information on the expert1 * Information about the experts* 1.4* IC3 Appendix 1: Tabular Formats Synopsis of individual studies IC3 Appendix 2: Written Summary Clinical Summary Notice to Applicants Vol. 2A, 2B and 2 C is found on the EUDRALEX website: Notice to Applicants, Vol. 2B - Common Technical Document (CTD), June 2006, on: Notice to Applicants, Vol. 2B Electronic Common Technical Document (ectd), December 2006, on: The complete list of types of document to be submitted (cf. Point Elements of file names) applies to all applications for marketing authorisation, renewals of marketing authorisation in accordance with Section 31 and/or 105 AMG, and variations in accordance with Section 29 AMG. In order to accelerate all mutual recognition and decentralised procedures (RMS and CMS procedures) it is recommended to submit all informative texts during the procedure in coordination with the responsible project management. On completion of a procedure, the final version of the product information texts are to be submitted in accordance with the regulations of the AMG-EV and these Explanatory Notes. Registration procedures in accordance with Section 38 AMG and centralised European Procedures are not subject to the purview of Section 1 AMG-EV. Electronic submission for registration and/ or re-registration of homeopathic medicines 2 are not prescribed by law, however, in the interest of accelerating the procedure it is urgently recommended. The documentation according to Sections 10, 11, 11a as well as the Expert Reports according to Section 24 AMG must be submitted electronically as separate files (i.e. no summary of drafts of labelling and wording in accordance with Sections 10, 11 and 11a in one file). Furthermore, all links to other files in the respective file must be removed prior to saving. Any type of document must only be saved in one single file. Aside from this, splitting the types of documents (cf. Point Elements of file names) into individual files in the style of the ectd is only permissible in the following exceptions. Exception: In the case of Modules 2.3, 2.6 and 2.7 a splitting as in the ectd is possible. When doing this, the type of document is always to be provided with a 3-digit sequential number (cf Elements of file names). This sequential number is also to be assigned if only one file is submitted. * Until introduction of the electronic signature, these documents must be submitted on paper. However, in addition, they can also be submitted electronically (e.g. as a.pdf file). 2 Homeopathic medicines without specified indications are covered by the procedural type of registration or post-marketing registration. Version 5.0 of 1 July 2007 Page 7 / 38

8 Example: qos-001.rtf For a transitional period, submission of the documents CTD 2.2, 2.3, 2.4, 2.5, 2.6 and 2.7, instead of the Expert Report in accordance with Section 24 AMG, is considered to be sufficient to fulfil the AMG-EV. For each application (= processing number of the medicinal product = ENR hier ergänzen, s. folg. Hinweis ) a separate is to be sent to BfArM. Attention: If, for one ENR, one and the same type of document occurs repeatedly within an , this is rejected; exception cf. 5.4 File name convention. 4.3 Supplementsl and additions After 1 January 2001, electronic submission is required also for supplements or additional documents concerning drafts for Labelling (Section 10 AMG) Patient information leaflet (Section 11 AMG) Expert information ("Fachinformation") (Section 11a AMG) Expert Reports (Section 24 AMG sub-section 1, numbers 1-3, corresponding to Section 2 subsection 1 AMG-EV). This also applies to applications filed prior to 1 January Attention: With supplements take care that the dates stated in attribut.txt are identical with the date of application in the paper version, otherwise the reference might get lost. 4.4 New applications for marketing authorisation in accordance with Section 21ff. AMG / Request for ENR If the pharmaceutical company intends a new authorisation procedure, the BfArM is first to be informed of this in writing under the mailing address: Bundesinstitut für Arzneimittel und Medizinprodukte Z Antragseingang / Fachregistratur Kurt-Georg-Kiesinger-Allee Bonn, preferably via telefax no.:+49 (0)228/ , stating the name of the medicinal product and the pharmaceutical form. As a response to this informal letter, the applicant will receive a processing number (ENR) reserved for this procedure. In the case that the pharmaceutical company, as the applicant, has commissioned a consultant to apply for the ENR on the applicant s behalf, the PNR of the pharmaceutical company (applicant) must always be stated. Enclose a power of attorney unless already available at BfArM. Once received, the processing number should always be stated throughout the documents for application as well as in the dossier (e.g. in the corresponding field of the application forms). Version 5.0 of 1 July 2007 Page 8 / 38

9 Attention: Please do not reserve processing numbers as so-called "variables". The application should be submitted within four weeks after reservation of a processing number. As before, only actual submission of the application is relevant for the date of receipt of the application and not the advance assignment of the processing number. 5 Technical specifications concerning s More than one electronic submissions for one and the same ENR are possible. Since the system allocates serial number of the day, previous submissions do not get overwritten. The files to be sent with the submitted document should be compressed with the help of a compression program (e.g. zip or tar-formats) (cf Zip container). Attention: The following examples use zip containers, but they also apply to tar containers subject Only the 7-digit processing number (ENR) which is intended for the submission is to be stated in the subject line of the . The validation program checks whether the subject line exclusively states the processing number (ENR), if not, the is rejected. The is likewise rejected if the subject line is empty. The sender is not informed of this fact as the is considered spam mail content The text ( content ) of the is optional and is not evaluated by BfArM but is returned as an attachment to the confirmation of receipt. Therefore, the text can be used for in-company purposes attachments and file formats Every contains a zip container attachment with the files of the documents to be submitted including the attribut.txt with its metadata. If necessary, the zip container can be encrypted (cf Checklist) Problems with the MS-TNEF format in Outlook The use of MS outlook (MS-TNEF format) may cause problems because MS-TNEF chabges the file name: it packs the zip container in a winmail.dat thus blocking the electronic submission; the sender will wait in vain for a system response. For this reason, deactivate MS-TNEF in Outlook. Deactivation of MS-TNEF-formats: Select format in the index card/in der Registerkarte -Format auswählen Change to text only in format selection/formateinstellung auf Nur Text ändern Save the changes and re-write the . Version 5.0 of 1 July 2007 Page 9 / 38

10 5.3.2 Zip containers Exactly one zip container shall be provided with every . The name of the zip container shall be as follows: <7-digit ENR>. zip Example: zip Websites for information about data compression (Freeware-Download-Portal) &modus=suche&such=winzip&dtt_filter= Files with documents to be submitted Currently, the only file format readable by the BfArM with a justifiable effort in accordance with Section 1 sub-section 2 AMG-EV is the Rich Text Format (*.rtf) (cf. BR-Drs./resolution 745/00, p. 5). Use of the.pdf format (*.pdf) is permissible for complete documents if the text contained therein is additionally submitted separately as an.rtf file with identical name (cf. 5.4 File name convention). Furthermore, it is allowed to submit Module 2.3 Quality Overall Summary (also for Quality Expert Statement) exclusively as a.pdf file. However, the.pdf files must not contain any restricted or scanned documents. Modules ixq = Information about the Expert - Quality Expert; ixn = Information about the Expert -Non-Clinical Expert; ixc = Information about the Expert -Clinical Expert) are currently not part of the electronic submission. In any case they are to be submitted in paper and can additionally be submitted as.pdf files. Due to the possibility of transmitting macro viruses, files in MS Word format are excluded from processing. Furthermore, the use of text fields in the actual text is not permitted for safety reasons (with the exception of headers and footers). Attention: The files must be saved with MS Word as.rtf files. It is not sufficient to change the file extension to ".rtf". Version 5.0 of 1 July 2007 Page 10 / 38

11 5.3.4 Files with metadata Each zip container (attached to each submission mail) includes a file with metadata (attribut.txt), as already stated in 5.3 attachments and file formats. The file format is text (.txt), the standard file name is: attribut.txt The file contains the following describing attributes: Table 2 Construction of attribut.txt for procedure types authorisation: renewal: post-approval: zulassung verlaengerung nachzulassung Note: a. m. types of procedure apply likewise to the authorisation of homeopathic medicines with specified indication/s. Content of attribut.txt for the authorisation procedure for homeopathic medicines without specified indication/s: Registration registrierung Post-registration nachregistrierung Variation: aenderung pnr = pharmaceutical manufacturer number enr = entry number verf = type of procedure edat = dd.mm.yyyy (date of submission identical with the date of cover letter of paper version submission) Example attribut.txt: pnr = enr = verf = authorisation edat = pnr = pharmaceutical manufacturer number enr = entry number verf = variation aend = dd.mm.yyyy (date of submission identical with the date of cover letter of paper version submission) Example attribut.txt: pnr = enr = verf = variation aend = Attention: As in the above examples the following notation is preferred: lower case letters for the field names, blanks before and after the equals signs, lower case letters for the value list date format (dd.mm.yyyy). pnr (number for pharmaceutical company) always 7-digit, if necessary, leading zeros. enr (processing number) always 7-digit. Version 5.0 of 1 July 2007 Page 11 / 38

12 5.3.5 Search for ENR / PNR ENR and PNR can be searched for at in AMIS Public Section (chargeable part of the DIMDI database offer) Encryption of the container Optionally, the zip container can be encrypted. The encryption software will automatically add to the file name of the container.pgp or.gpg, depending on the software used, so the file name is either <7-digit ENR>. zip.pgp or <7-digit ENR>. zip.gpg Only entire zip or tar containers should be encrypted. Individual files of a zip container shall not be encrypted Encryption software Exclusively the PGP (Pretty Good Privacy) program or a product compatible with OpenPGP are to be used for encryption. Other encryption methods cannot be processed or used without an unjustifiable effort. The free program GnuPG and information on its use can be found on the internet under or The product is called, e.g., Windows Privacy Tray (WinPT Tray released). Depending on the version of the program, German is not used continuously. Example: Windows Privacy Tray, Version 07.96rc1 ( ). The following is a description of the necessary steps for downloading the encryption software: 1. Download of "gnupp-1.1-de-installer.exe" to a specified directory (e.g. C:\Programs\GnuPP) and installation of the program. 2. The programme Windows Privacy Tray is started from the start menu (Start -> Programs -> GnuPP -> Windows Privacy Tray); it is then constantly available in the taskbar Encryption with the BfArM key You will find the respective valid public key of the BfArM in the file: nnn=true. You can download the key (file BfArM-OpenPGP-AS-Key.asc) for encryption in the course of submissions in accordance with the AMG-EV and save as BfArM-OpenPGP-AS-Key-asc.txt in your computer. The public key is replaced by a new one every six months on 2 January and 1 July. This serves to increase the safety of both parties. Use of an expired key generates an error message Downloading of the BfArM key, encryption of the zip container The following is a description (Figures 1 to 11) of the necessary steps for downloading the public BfArM key and encrypting the zip container (Fig. 13 shows an prepared for an electronic submission plus attachment with encrypted zip container): Version 5.0 of 1 July 2007 Page 12 / 38

13 1. Fig 1 Dialogue for download of BfArM public key 2. Fig 2 Download subdirectory The file with the key is stored in your system in a download subdirectory you create yourself. Version 5.0 of 1 July 2007 Page 13 / 38

14 3. Fig 3 Import of key into key manager / Schlüsselverwaltung The BfArM public key is integrated via the menu option "Schlüsselverwaltung"/ key manager of the Windows Privacy Tray. Click on "Import" in the "Schlüssel"/ key menu. 4. Fig 4 Selection and iimport of BfArM public key The downloaded BfArM key file is selected and then imported. Version 5.0 of 1 July 2007 Page 14 / 38

15 5. Fig 5 Schlüsselimport / key import dialogue Click on "Öffnen" to open the "Schlüsselimport" dialogue. Click on "Import" to receive status message as in Fig Fig 6 Status message Schlüsselimport 7. Fig 7 Display of imported key Click on "OK" as in Fig. 6 to display the imported key in Schlüsselverwaltung / key manager. If the key is not displayed immediately close the Schlüsselverwaltung / key manager and reopen. Version 5.0 of 1 July 2007 Page 15 / 38

16 8. Fig 8 Fingerprint degree of trust In the "Schlüssel" menu option "Eigenschaften" you can check the fingerprint and adjust the degree of trust. 9. Fig 9 Fingerprint check For verification of key identity compare the fingerprint of the imported key with the published fingerprint. Version 5.0 of 1 July 2007 Page 16 / 38

17 10. Fig 10 Ownertrust 11. Fig 11 Encryption of zip container Open the file to be encrypted. Open Datei /file in the Dateimanager /file manager and click on Verschlüsseln to encrypt the.zip-file. Version 5.0 of 1 July 2007 Page 17 / 38

18 12. Fig 12 Selection of BfArM key Select the BfArM key in the "Datei verschlüsseln"/encrypt file dialogue. The status in the file manager states that the file has been encrypted. This is also apparent from the automatically added extension ".gpg". The file with the double extension "~.zip.gpg" is the encrypted zip file to be sent to the BfArM. 13. Fig 13 with attached zip container Now the mail is ready for electronic submission and can be sent. The encrypted zip container, e.g zip.gpg, is attached. Version 5.0 of 1 July 2007 Page 18 / 38

19 5.4 File name convention In accordance with the AMG-EV, the applicant must name the files in a zip container of an electronic submission pursuant to a harmonised file name convention: The minimum designation for the BfArM (cf Elements of file name, Table 3 - type of document, file name requirements) shall precede any company term. Attention: The following types of document have been newly adopted: palen for patient information leaflets in English (while document type pal has ceased to exist) palde for patient information leaflets in German (while document type pal has ceased to exist) phvsis for parmacovigilance system and qualified person riskmp for risk management action plan. Type of document (possibly with a respective sequential number which is added after a hyphen) and company term are separated by a hyphen. The hyphen after type of document is only necessary if a company term is added. Further hyphens can be included within this designation. The file name convention of the ICH ectd Specification V 3.0 of 8 October 2002 shall be observed (cf file name convention). As a rule, only one file of one type of document may be sent per mail. For several types of document, submission of multiple files per type is permitted. In this case the files are to be named with the corresponding type of document and a sequential 3-digit number. The numbering is an inherent part of the file name and must also be assigned if only a single file is submitted. Thus, the following file name would result, e.g., for "labelling (inner pack)": labip-001.rtf labip-002.rtf etc It is permitted and even encouraged that the files be submitted, possibly with the text corrections automatically made by MS Word highlighted. However, the identification of such files in the name of the file is not required. Further versions of this file (e.g. without the markings (clean version)) shall not be submitted. If a document contains diagrams or pictures, handling can be simplified as follows: a) in the.rtf format, diagrams and pictures are omitted b) in addition to the.rtf file, a.pdf file shall be submitted with the same file name which contains the complete text including diagrams and pictures. Example: labip-001.rtf and labip-001.pdf Version 5.0 of 1 July 2007 Page 19 / 38

20 Attention: The pdf file must not contain any restrictions. The submission is also rejected if only the pdf file is submitted without the corresponding rtf file. The sole exception is the type of document Quality Overall Summary, which can be submitted either as.rtf file or as pdf file (cf , Table 3 under qos-001). The types of document ixq, ixn and ixc are to be submitted in paper and can additionally be submitted as.pdf files. Hyperlinks are not permissible Elements of file names for electronic submission to BfArM Only those types of document stated in the list below shall be submitted electronically. The required file names are arranged in column 1 (left). See also our example zip container zip published on our homepage. Example: palde.rtf qos-001.rtf In accordance with the file name convention (cf ), you can make optional name extensions by hyphens. Example: qos-001-optional-extension.rtf It is recommended that the file name be structured: <document-><enr>-<procedure>-<yyyy-mm-dd> (yyyy-mm-dd is identical with the date of application in paper) Example: palen verl rtf Please remember that in additional submissions of pdf-documents, rtf file name and pdf file name are identical. Example: palen verl rtf palen verl pdf For files with diagrams and pictures: <Type of document according to the list below>[-<optional>].extension. Attention: The brackets are not part of the file name. They specify the part that can be inserted optionally. Of course, the limitations stated in Point with regard to use of upper and lower case and characters are also to be observed for this part. Example: labbl verl rtf Observe the notes following Table 3. Version 5.0 of 1 July 2007 Page 20 / 38

21 Table 3 Types of Document, set file names Type of Document (always first component of file name) spcde spcen spcpal labbl labip-001 (cf. notes at end of Table) labop-001 (see notes at end of Table) labpal-001 (see notes at end of Table) palde palen ixq-001 (see notes at end of table) German Term / designation in accordance with 11a AMG: Fachinformation Summary of Product characteristics (the English version to be harmonised) Section 11a paragraph 4 AMG Kombinierte Fach- und Gebrauchsinformation Section 10 AMG: Beschriftung der Durchdruckfolie (for tablets) Section 10 AMG: Beschriftung des Packungsinhalts (z.b.tablettenröhrchen,tropffläschchen) Section 10 AMG: Beschriftung der Packungsumhüllungen (z.b. Faltschachteln) Section 10 AMG: (z.b. Etikettaufkleber auf Mineralwasserflaschen) Section 11 AMG: German product information, (Beipackzettel, Patienteninformation) Section 11 AMG: English product information, (Beipackzettel, Patienteninformation) Lebenslauf / Veröffentlichungen des Sachverständigen zum analytischen Gutachten English Term (NTA, Vol 2 B) Summary of Product Characteristics (Part IB) Summary of Product Characteristics Term according to NTA (CTD, NTA, Vol 2 B) (CTD 1.3.1) Summary of Product Characteristics (CTD 1.3.1) Summary of Product Characteristics Labelling (Blister) (CTD 1.3.1) Labelling Blister Labelling (inner pack) (CTD 1.3.1) Labelling inner pack Labelling (outer pack) (CTD 1.3.1) Labelling outer pack package leaflet Package Leaflet (CTD 1.3.1) Package Leaflet Package Leaflet (CTD 1.3.1) Package Leaflet (EU Module 1; 1.4.1) Information about the Expert Quality Expert Permissible File Formats.pdf (if in paper (always) Version 5.0 of 1 July 2007 Page 21 / 38

22 Type of Document (always first component of file name) ixn-001 (see notes at end of table) ixc-001 (see notes at end of table) era German Term / designation in accordance with Lebenslauf / Veröffentlichungen des Sachverständigen zum Pharmakologischtoxikologischen Gutachten Lebenslauf / Veröffentlichungen des Sachverständigen zum klinischen Gutachten English Term (NTA, Vol 2 B) Umweltrisikobewertung Environmental Risk Assessment (IIIR / II H) phvsys Section paragraph 6 AMG Pharmakovigilanzsystem und qualifizierte Person riskmp Maßnahmenplan zur Risikoüberwachung Pharmacovigilance system and qualified Person Term according to NTA (CTD, NTA, Vol 2 B) (EU Module 1; 1.4.2) Information about the Expert - Non-Clinical Expert (EU Module 1; 1.4.3) Information about the Expert - Clinical Expert (CTD 1.6) Environmental Risk Assessment (CTD Annex) (EU Module 1;1.8.1) Pharmacovigilance- System Risk Management Plan (EU Module 1; 1.8.2) Risk-Management- System intro Produktprofil Product Profile (CTD 2.2) Introduction qos-001 (see notes at end of Table) Analytisches Sachverständigengutachten qts Anhang 1: Tabellarische Aufstellung zum Sachverständigengutachten qws Anhang 2: Schriftliche Zusammenfassung des Sachverständigengutachtens qoses Erklärung des Sachverständigen gemäß BfArM- Quality Expert Report (I.C.1) Appendix 1: Tabular Formats Appendix 2: Written Summary Expert Statements (CTD 2.3) Quality Overall Summary and Quality Expert Statement Safety Update Report Licensing Status Safety Update Report Sales Volume Permissible File Formats in paper (always) in paper (always) optional:.rtf.pdf optional:.rtf.pdf optional:.rtf.pdf Version 5.0 of 1 July 2007 Page 22 / 38

23 Type of Document (always first component of file name) nco co ncs German Term / designation in accordance with Bekanntmachung vom (Punkt 7) Section 24 sub-section 1 Nr. 1 AMG Pharmakologischtoxikologisches Sachverständigengutachten Section 24 sub-section 1 Nr. 3 AMG Klinisches Sachverständigengutachten Zusamenfassung des Pharmakologisch-toxikologischen Sachverständigengutachtens English Term (NTA, Vol 2 B) Preclinical Expert Report (I.C.2) Clinical Expert Report (I.C.3) Term according to NTA (CTD, NTA, Vol 2 B) (CTD 2.4) Nonclinical Overview (CTD 2.5) Clinical Overview and Clinical Expert Statement (CTD 2.6) Nonclinical Summary, possibly separated into: ncsi Einführung (CTD 2.6.1) Nonclinical Summary Introduction plws plts pkws pkts tows tots Zusammenfassung des pharmakologischen Gutachtens Tabellarische Aufstellung zum pharmakologischen Gutachen Zusammenfassung des pharmakokinetischen Gutachtens Tabellarische Aufstellung zum pharmakokinetischen Gutachten Zusammenfassung des toxikologischen Gutachtens Tabellarische Aufstellung zum toxikologischen Sachverständigengutachten Written Summary (I.C.2) Tabular Formats (I.C.2) Written Summary (I.C.2) Written Summary (I.C.2) Tabular Formats (I.C.2) (CTD 2.6.2) Pharmacology Written Summary (CTD 2.6.3) Pharmacology Tabulated Summary (CTD 2.6.4) Pharmacokinetics Written Summary (CTD 2.6.5) Pharmacokinetics Tabulated Summary (CTD 2.6.6) Toxycology Written Summary (CTD 2.6.7) Toxicology Tabulated Summary Permissible File Formats Version 5.0 of 1 July 2007 Page 23 / 38

24 Type of Document (always first component of file name) German Term / designation in accordance with English Term (NTA, Vol 2 B) Term according to NTA (CTD, NTA, Vol 2 B) Permissible File Formats cs Klinische Zusammenfassungen (CTD 2.7) Clinical Summary, possibly separated into: sbpm Bekanntgabe der biopharmazeutisch-analytischen Methoden Written Summary (I.C.3) (CTD 2.7.1) Summary of Biopharmaceutics and Associated Analytical Methods scps Bekanntgabe der klinischpharmakologischen Studien Written Summary (I.C.3) (CTD2.7.2) Summary of Clinical Pharmacology Studies sce Erklärung zur klinischen Wirksamkeit Written Summary (I.C.3) (CTD 2.7.3) Summary of Clinical Efficacy scs Erklärung zur klinischen Sicherheit/Unbedenklic hkeit Written Summary (I.C.3) (CTD 2.7.4) Summary of Clinical Safety syis Section 24 sub-section 1 Nr. 3 AMG Inhaltsangabe/Gegenüberstellung zum klinischen Sachverständigengutachten Tabular Formats (I.C.3) (CTD 2.7.6) Synopsis of Individual Studies Notes: The set file names (column 1 left) for types of document characterised by sequential 3-digit numbers (e. g. qos-001) are inherent parts of the file names. The sequential number must also be assigned if only one sinlge file is submitted electronically: For submission of different drafts of labelling in accordance with Section 10 AMG regarding various package sizes, beginning with the smallest size For diverse information on the expert in an structured according to the order of the EU Modules: EU Module 1.4 "Information about the Expert" is divided into two documents illustration of the scientific and occupational development of the expert - declaration by the expert concerning the delivered Expert Report. Both documents must be signed by hand. Therefore, they currently need not be part of the electronic submission; however, they can be submitted electronically (e.g. also as a.pdf file) and must be submitted on paper in any case. Version 5.0 of 1 July 2007 Page 24 / 38

25 The analytical Expert Report shall be submitted preferably in a single file in.rtf format or in.pdf format. However, since some companies already use a structure in accordance with the ectd, the individual submodule can alternatively be numbered serially beginning at File name convention in accordance with ICH ectd Specification File extension: All files must have only one file extension (i.e. only 1 dot!), e.g. nnnnn.pdf nnnnn.rtf Name: The file name must have no more than 64 characters. Only lower case letters are allowed this also applies to the extension. The following characters are admissible: - letters from "a" to "z" [U+0061 to U+007A] - numbers "0 to "9" [U+0030 to U+0039] - special characters "-" [HYPHEN, U+002D] The notation "U" refers to Unicode. Note: incorrect file names without extension are e.g.: part a (' '; blank is not permissible) myfile.xml hello:pdf part_a änd ('.'; dot is not permissible) (':'; colon is not permissible) ('_': underscore is not permissible) ('ä' or 'ö' or 'ü' umlauts are not permissible). Version 5.0 of 1 July 2007 Page 25 / 38

26 5.4.3 Checklist to monitor whether all conditions have been fulfilled Table 4 Checklist Item Item Entry Example Create.txt file with metadata with the standard name "attribut.txt" (cf. Point File with metadata) File name convention for text files (cf Elements of file names File name convention) Treatment of documents that contain diagrams and pictures: create.rtf file with text and enter wildcards [<Type of Document- ENR-pdf>] for the pictures. Additionally submit complete document as.pdf file (must not contain any restrictions). Except for the extension, both files must be given the same file name Elements of file names File name convention pnr = number for pharmaceutical company enr = processing number verf = value list: aenderung nachzulassung registrierung nachregistrierung verlaengerung zulassung Type of date either edat = date of submission dd.mm.yyyy or aend = date of variation (only in case of notifications of variation) dd.mm.yyyy 64 characters no special characters only lower case letters term for type of document comes first separated from company file name by a hyphen.rtf is the only file format permissible term for type of document hyphen company file name.rtf (for the text file) term for type of document hyphen company file name.pdf (for the complete document (text with diagrams and pictures) pnr = enr = verf = zulassung edat = spcde-optional dkl.rtf spcde-optional.rtf spcde-blabla.pdf Version 5.0 of 1 July 2007 Page 26 / 38

27 Item Entry Example Expert Report File name (cf. Point Elements of file names) Compress files: make containers (cf Zip container) Encryption of containers (cf ) Sending of attachments (cf. Point 5.3) Expert Reports must likewise be renamed in accordance with the file name convention. The analytical Expert Report (qos = Quality Overall Summary) can alternatively be submitted as an.rtf file or as a.pdf file Put the file "attribut.txt" and the files with the documentation to be submitted into a container by way of a compression program (.zip format or.tar format). The container receives the ENR as file name. Encryption of containers is optional The container is attached to the qos001-optional.rtf Example: zip Example: zip.pgp Example: zip or zip.pgp subject (cf. Point 5.1) Processing number (ENR) Example: content (cf. Point 5.2) optional The following files have been submitted for procedure xyz, application date??.??.200x 6 Verification and confirmation of s The submitter receives several confirmations by , depending on the status of the verification. All response mails contain unique numbers in the subject-line (e.g. positive response 1 (P _000039) for ENR ). This number is to be quoted in case of queries. 6.1 Confirmation of receipt and confirmation as to the coherence of the formal/technical properties After receipt of the at the DIMDI's server designated for submissions in accordance with the AMG-EV, it is verified according to the following purely formal criteria: Does the contain the required attachments (zip container) with the required extensions? Are file names in accordance with the file name convention? Is the name of the zip container in accordance with the name convention? Are the characteristics of the "attribut.txt" file as required? Does the subject line exclusively contain the 7-digit processing number (ENR) Has the zip container been encrypted exclusively with the mandatory encryption? Are the files in the zip container unencrypted? Version 5.0 of 1 July 2007 Page 27 / 38

28 Was the BfArM key used to encrypt the file container? Was the required compression program (.zip or.tar) used? If no mistakes are found, the submitter receives a confirmation of receipt in the subject line "Positivmeldung <sequential number>"; however, this merely refers to the formal accuracy of the e- mail. There are no further positive notices. Incorrect s are rejected promptly with a confirmation of receipt in the subject line: "Negativmeldung <sequential number>". s with no or faulty subject lines are discarded as spam without notification of the sender. 6.2 Confirmation as to the intellectual verification of content Further formal mistakes can only be determined intellectually, e.g. Processing number and content do not correspond. The file cannot be opened. The file cannot be read. The file is not in the correct format. The submitter is informed of these mistakes via . The intellectual verification of the submission content can result in different confirmations (notice of marketing authorisation etc.). Should further mistakes be observed during the course of this, they will be communicated via individual correspondence. Should one of the formal/technical errors be recognised in the course of processing, further validation is discontinued and a mail with the corresponding error message (cf. 6.3 Possible error messages) is returned to the sender's address. We kindly ask that such error messages be first analysed by the sender before BfArM is contacted with possible queries. If a submission is correct as to formal/technical aspects, receipt is confirmed in an (subject line: "Positivmeldung"). Version 5.0 of 1 July 2007 Page 28 / 38

29 6.3 Possible error messages regarding electronic verification of coherence of formal/technical characteristics Note: This list of errors is dynamic and will be updated on an ongoing basis as new errors emerge. Table 5 Error message Error Message Possible Cause Proposed Solution Die Maildatei ist fehlerhaft. Der Mailanhang konnte nicht entschlüsselt werden. Die Mail enthält mehr als eine GPG/PGP-Datei. Es darf nur eine verschlüsselte Datei im Mailanhang vorhanden sein. Fehler beim Entpacken der Zip-Datei. Die Zip-Datei ist wahrscheinlich beschädigt. Die Anzahl oder der Typ der Mailanhänge entspricht nicht den formalen Vorgaben. Fehler beim Extrahieren der tar-datei. Die tar-datei ist wahrscheinlich beschädigt. Der Mailanhang enhält nicht zulässige Dateitypen. Die Datei <DATEI> entspricht nicht den formalen Vorgaben. Der Name der Datei <DATEI> enthält nicht zulässige Zeichen. Die Mail enthält keine Attributdatei im Anhang. Die Mail enthält mehr als eine Attributdatei im Anhang. Die Angaben in der Attributdatei sind nicht vollständig. Das Format der ENR <ENR> in der Attributdatei ist nicht korrekt. Die ENR muss immer siebenstellig The structure of the mail is incorrect and it can therefore not be processed. The structure of the encrypted file is presumably defective. Only one encrypted container per mail is permitted. The archiving format employed (*.zip) is faulty (the check sum is incorrect, data is incomplete, etc.) Only the container and its separate signature may be attached. The archiving format employed (*.tar) is faulty (the check sum is incorrect, data is incomplete, etc.) Only files with the extensions.rtf,.pdf, and the "attribut.txt" file are permissible. Permissible characters are: lower case letters [a-z], numbers [0-9], and hyphens. The "attribut" file is necessary for validation and processing of the submission Only one "attribut.txt" is permitted. Syntax error in the file "attribut.txt". Syntax error in the file "attribut.txt". The ENR must always consist of 7 digits. Check type, version, or settings of own mail client. Check type, version, or settings of own encryption software. Send a separate mail per container. Check the archiving program employed and settings. Create a new mail with archive file and send. Create a new mail with archive and signature file and send. Check the archiving program employed and settings. Create a new mail with archive file and send. Correct types of file and create new container. The container shall be named "<ENR>.zip" or "<ENR.tar". Cf. Explanatory notes in File with metadata Delete redundant files and create new container. Cf. Explanatory notes in File with metadata Cf. Explanatory notes in File with metadata The correct ENR can be found in "AMIS Public Section". Version 5.0 of 1 July 2007 Page 29 / 38

30 Error Message Possible Cause Proposed Solution angegeben werden. Das Format der PNR <PNR> in der Attributdatei ist nicht korrekt. Das Format des Feldes EDAT in der Attributdatei ist nicht korrekt. Der Name einer Datei (<DATEI>) im Mailanhang entspricht nicht den formalen Vorgaben. Der Mailanhang enthält nicht zulässige Dokumenttypen. Die Datei ERRVAO> enspricht nicht den formalen Vorgaben Der Mailanhang enthält nicht zulässige Dokumenttype. Die Datei <ERRVA> entspricht nicht den formalen Vorgaben Die ENR (<ENR>) in der Attributdatei ist unbekannt. Es sind mehrere Dateiarchive (zip oder tar) im Mailanhang vorhanden. Es ist kein Dateiarchiv (zip oder tar) im Mailanhang vorhanden. Die ENR (<ENR>) aus Mail- Betreff, Containernamen und Attributdatei stimmen nicht überein. Die ENR im Betreff-Feld der Mail ist unbekannt. Der Name der Archivdatei in der Mail ist nicht korrekt. Die ENR (<ENR>) im Namen der Archivdatei der Mail ist unbekannt. Die Bezeichnung des Verfahrens (<VERF>) in der Datei "attribut.txt" ist nicht korrekt. Syntax error in the file "attribut.txt". The PNR must always consist of 7 digits. Syntax error in the file "attribut.txt". The format is "dd.mm.yyyy". Permissible characters are: lower case letters [a-z], numbers [0-9], and hyphens. The file name convention was disregarded. The file name convention of the palde and/or palen type of document was disregarded. pal has been replaced by palde for the German language and by palen for the English language patient information leaflet The ENR is possibly incorrect. Exactly one archive file must be attached Exactly one archive file must be attached Only the 7-digit ENR is to be stated in the subject line. The ENR is possibly incorrect. The name must read <ENR>.zip or <ENR>.tar. Cf. Explanatory notes in Zip container The ENR is possibly incorrect. Syntax error in the file "attribut.txt". Your correct PNR can be found in "AMIS Public Section". Check spelling, observe date format, cf. Point File with metadata Cf. Explanatory notes in Elements of file names and File name convention Cf. with the list of types of document in Elements of file names, and change accordingly. Compare with the list of types of document Elements of file names and change accordingly Your correct ENR can be found in "AMIS Public Section". Create a new mail with archive file and send. Create a new mail with archive file and send. Cf. Explanatory notes in 5.2 subject Your correct ENR can be found in "AMIS Public Section". Give archive file correct name, create a new mail with archive file and send. Your correct ENR can be found in "AMIS Public Section". Check spelling, observe date format, cf. also File with metadata Version 5.0 of 1 July 2007 Page 30 / 38

31 Error Message Possible Cause Proposed Solution Der Datencontainer im Mailanhang enhält verschlüsselte Dateien. Das Format des Feldes "AEND" (<ERRVARO>) in der Attributdatei ist nicht korrekt Die Datei <ERRVARO> enthält nicht das angegebene Dateiformat Der Datencontainer im Mailanhang enthält Unterverzeichnisse Das Einreichungsdatum ist ungültig Das Änderungsdatum ist ungültig Die PNR (<ERRVARO>) in der Attributdatei ist unbekannt Mehrere Dokumente eines Dokumenttyps (<DOCTYPE<) sind nicht zulässig Das Änderungsdatum ist in der Attributdatei nicht vorhanden Die Angabe eines Einreichungsdatums in der Attributdatei im Verfahren "aenderung" ist nicht zulässig Das Einreichungsdatum ist in der Attributdatei nicht vorhanden Die Angabe eines Änderungsdatums in der Attributdatei im Verfahren "<ERRVARO>" ist nicht zulässig Im Dokumentnamen "<ERRVARO>" fehlt ein Bindestrich nach dem Dokumenttyp. Das Format der ENR im Betreff-Feld der Mail ist nicht korrekt. Die ENR muss immer siebenstellig angegeben werden Files in a container must not be encrypted. Typing error The extension of a doc-file was changed to.rtf Result of copying. Typing error, invalid date such as Typing error, invalid date such as Typing error. Several files were created for one type of document. The declaration verf = aenderung lacks the respective date. Typing error. The following is not stated under "procedure": verf = aenderung. Make new container with unencrypted files. Send mail again. Date = dd.mm.yyyy cf File with metadata.doc files must be saved as.rtf files. Delete subdirectories. Date = dd.mm.yyyy cf File with metadata Date = dd.mm.yyyy cf File with metadata 7-digit number Your correct ENR can be found in "AMIS Public Section". Exception cf. 5.4 File name convention Otherwise merge all files to a type of document. Date = dd.mm.yyyy cf File with metadata State the date of the variation in the "attribut" file cf File with metadata State the date of submission in the "attribut" file cf File with metadata Check which procedure is meant cf File with metadata cf File name convention Send the mail again with the corrected subject line. Version 5.0 of 1 July 2007 Page 31 / 38

32 6.4 Possible error messages regarding intellectual verification of submitted s Attention: This list of errors is dynamic and will be updated on an ongoing basis as new errors emerge. The following error messages are intellectually marked in the document management system docubridge and are generated within the program: Table 6 Error message Error Message Possible Cause Proposed Solution Datei enthält fehlerhafte Daten Datei kann nicht gelesen werden Datei kann nicht geöffnet werden Falsches Dateiformat For instance, submitted texts for medicinal product and processing number (ENR) do not match. Incorrect character set, wrong format, even though extension is permissible. Wrong format, even though extension is permissible. Format is neither.rtf nor.pdf; the extension is permissible but is not suitable for the format. Check allocation of ENR and file Check character set and format Check format For details cf File name convention 6.5 System response You will receive an automatic system response (positive or negative response), at the earliest, half an hour after your electronic submission was sent. Should you not receive a system response within one day, contact the hotline per <[email protected]>. If you have problems with your electronic submission, if you do not receive a system response or a negative response and if you do not understand what the error is, please do not make further attempts of submission; instead, contact the hotline immediately via [email protected]. In such cases you are advised to provide the original submission to the hotline for analysis of the problem. 6.6 What to do in the case of false-positive system responses Submission under a wrong ENR If an electronic submission was made under a wrong ENR by mistake, contact the hotline [email protected] for cancellation (cf. Example in Fig. 14). Then repeat the electronic submission under the correct ENR. Version 5.0 of 1 July 2007 Page 32 / 38

33 14. Figure 14 Cancellation of a false-positive system response Submission of partly wrong data No cancellation is made if some of the data in the zip container are wrong (among correct ones). In this case inform the hotline [email protected] only about the false-positive system response (e. g. positive response 1 (P _00003) for ENR ) and the invalid files contained in it. Then send another electronic submission with the correct data. In both cases the hotline will inform those in charge. Version 5.0 of 1 July 2007 Page 33 / 38

34 7 Important information concerning permission of exclusive submission of paper documents in accordance with Section 3 AMG-EV We advise you that applications for exceptional permissions in accordance with Section 3 number 1 AMGEV can only be made related to the procedure, i.e. with reference to the individual medicinal product. As a rule, an exception can only be granted without further inquiry, if the reasoning of the application shows comprehensibly and conclusively that the applicant fulfils all prerequisites of an "undue hardship". Global statements without further explanation necessarily lead to procedural delays and/or to rejection of the application. In this context please also observe the following: If an undue financial burden is claimed, more details are necessary especially as to the expected costs of compilation and electronic submission of the required documents as well as a comparison of these costs with the presumed turnover from the medicinal product concerned. In the case of technical reasons these are to be explained in detail and justified. Where it should be stated why electronic submission of the documents is impossible also if the help of others is enlisted. Exceptional permissions in accordance with Section 3 number 1 AMG-EV are generally only granted temporarily. This means that the documents must be supplemented electronically in the procedure after termination of the exemption. In order to ensure that an adequate time limit is fixed, applicants are requested to declare, upon submitting the application, when the obstacles asserted will presumably be removed. Version 5.0 of 1 July 2007 Page 34 / 38

35 8 List of changes Date Version Chapter/Paragraph Reason for change 16 May May May May May The Explanatory Notes have been revised resulting in changed numbers for headings. Links to websites have been added. We have no influence, though, on possible changes of web addresses General remarks Category remarks deleted addresses Revised Information Shifted forward to become Chapter 3. Information plus subchapters 3.1 Contact for electronic submissions/amg-ev-hotline/ online variation procedures 3.2 Contact for procedural and scientific questions 3.3 Contact ectd 16 May May May May May May Modalities / Procedures for electronic submission Documents to be submitted New applications for marketing authorisation in accordance with Section 21 ff AMG Technical specifications concerning s 4.09 Punkte 4.1 subject 4.2 content 4.3 attachments and file formats Current number: 4. Modalities / Procedures Current number: 4.2 Documents to be submitted Reference to the Notice to Applicants was updated (October 2005). Current number: 4.4. New applications for marketing authorisation in accordance with Section 21 ff AMG. Additions to PNR for pharmaceutical company (applicant) and commissioned consultant for the procedure (application for ENR, electronic submissions). Current number 5. Technical specifications concerning s. Current numbers: 5.1 subject 5.2 content 5.3 attachments and file formats 4.09 Addition of new sub-item: Problems with the MS-TNEF format in Outlook 16 May Current numbers: Partly revised, especially for: date format edat or aend (cf. attribut.txt). Choice of type of procedure registrierung (authorisation of homeopathic medicines without specification of indication) for Version 5.0 of 1 July 2007 Page 35 / 38

36 Date Version Chapter/Paragraph Reason for change 16 May May May May May May August 04 authorisations from abroad Addition of a new sub-item: Search for ENR- / PNR Downloading of the BfArM key File name convention Elements of file names for the electronic to BfArM Elements of file names for the electronic to BfArM, Table, type of document, footnote Verification and confirmation of e- mails listing Current number: Downloading of the BfArM key Fig with encrypted zip container updated. Current numbers: 5.4. File nameconvention Elements of file name for the electronic File name convention in accordance with ICH ectd specification Checklist to monitor whether all conditions In Elements of the file names Information on additional new types of document palen for English language patient information palde for German language patient information (cancellation of pal document type) phvsis for parmacovigilance system and qualified person riskmp for risk management plan. Corresponding supplementation of Table 3. New examples of file names Revision of the entire table structure and supplements, especially: Column Deutsche Bezeichnung Column Bezeichnung gemäß NTA for CTD 2.3 sowie Quality Expert Statement CTD 2.5 sowie Clinical Expert Statement Former footnote under table in has become text in Element of file names., stating that file name in document type -001* must be strictly adhered to. Omission of footnote ** If the dossier was submitted in the course of an MR procedure prior to July 2003, it is possible to submit under these types of document in the old EU format until the end of Current numbers: 6. Verification and confirmation of s Insertion of new sub-items: Confirmation of receipt and confirmation as to the coherence of the formal/technical properties. 6.2 Confirmation as to the intellectual verification 6.3 Possible error messages regarding electronic. 6.4 Possible error messages regarding intellectual 6.5 System response 6.6 What to do in the case of false-positive system responses The types of document ixq, ixn and ixc are to be submitted in paper and can additionally be submitted as.pdf file. 01 August New column in the list of types of document with the permissible Version 5.0 of 1 July 2007 Page 36 / 38

37 Date Version Chapter/Paragraph Reason for change 04 file formats for each type of document 15 March March March March March March March March th paragraph from the bottom rd paragraph from the bottom last paragraph Based on many comments it has been registered that the type of document "qos" (Quality Overall Summary) is already separated into individual documents in accordance with ectd by numerous companies. Therefore, multiple submission of this type of document is possible now by appending a 3-digit sequential number. The reference to.rtf-file was deleted from this paragraph as Module 2.3 (qos = Quality Overall Summary) can now alternatively be submitted as a.pdf file. Deleted as the transmission of electronic signatures is technically not yet possible. Information on sending duplicates has been clarified due to inquiries Receipt of an is not confirmed if either the subject line is empty or contains something other than the 7-digit ENR alone. It is assumed to be a spam mail which is immediately discarded new last paragraph st paragraph Assessment of the most frequently occurring errors showed that apparently merely by renaming the extension (e.g., from.doc to.rtf) would-be.rtf files are created. However, this is not the case: they still are.doc files that can be opened, but they are not encouraged due to the danger of macroviruses or such. The desired format is only achieved by saving a file as an.rtf file. Module 2.3 (qos = Quality Overall Summary) can now alternatively be submitted as an.rtf file or as a.pdf file as this document is frequently only available to industry in.pdf format. However, the.pdf file must neither contain restrictions nor scanned documents The file "attribut.txt" shall preferably be filled with lower case letters, however, the validation program also permits upper and lower case. Furthermore, with consideration to submissions from abroad, the German umlauts were broken down ("aenderung" instead of "Änderung"). In this case the validation program is tolerant and allows both spellings. Furthermore, it is planned that after translation of these notes into English the English terms for the procedures are also permitted nd paragraph from the top Use of the hyphen within the file name was construed differently. Therefore, it was made clear that the hyphen is a fixed component of the name of the type of document, if this type of document can be submitted in multiple by adding a sequential number. If the type of document is extended by a company term, the hyphen serves as separation. Within the company term, as many further hyphens as desired can be used. Examples for possible alternatives: spcde.rtf spcde-internal.rtf spcde-internal-term-blabla.rtf qos-001.rtf qos-001-internal.rtf qos-001-internal-term-blabla.rtf Version 5.0 of 1 July 2007 Page 37 / 38

38 Date Version Chapter/Paragraph Reason for change 15 March March March March March March March March March th paragraph from the top th paragraph from the top new 1st paragraph after the 2nd paragraph list of types of documents Some types of document can now be submitted repeatedly with a sequential numbering following a hyphen. The numbering is a fixed component of the name of the type of document and must also be assigned if only one file is submitted (cf. above, comment on Item 3.2, 4th paragraph from the bottom). Based on several inquiries, the handling of files with diagrams and pictures has been facilitated. Now, text files without diagrams and pictures can be submitted in.rtf format and at the same time the complete file with text and pictures can be submitted additionally in.pdf format. An exception to this rule is the type of document "qos" (Quality Overall Summary), which can either be submitted as an.rtf file or as a.pdf file. Again and again it is attempted to submit "other" documents (e.g. cover letters); therefore, it is again expressly pointed out that only the documents stated in the types of document list are to be submitted electronically. Adaptation of description and examples to the altered conventions for submission of documents that contain diagrams and pictures (cf. above, comment on 4.4, 6th paragraph from the top). In the case of the type of document "labbl" (Labelling (Blister)) there is no longer the possibility of multiple submission with sequential numbers. In the case of the type of document "qos" (Quality Overall Summary), multiple submission is possible now (cf. above, comment on Item 3.2, 4th paragraph from the bottom) footnote It is pointed out that the numbering of a type of document is a fixed component that must always be included. In point c) it is pointed out that the type of document qos (Quality Overall Summary) can either be submitted as an.rtf file or as a.pdf file Checklist adapted according to the a.m. changes new paragraph after the 6th paragraph List of error messages The absence of a confirmation of receipt within an appropriate period of time indicates that the subject line of the was missing or not in accordance with the conventions. Such s are discarded as spam and are not answered. Updated. Version 5.0 of 1 July 2007 Page 38 / 38