Explanatory Notes on the Enforcement - BfArM

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

Version 5.0 of 1 July 2007 / 38

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 2000 - Version 5.0 of 1 July 2007-

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 2000 - Version 5.0 of 1 July 2007- .............. 1 1 General remarks ........................................................................................................................ 4 2 E-mail address for the electronic submission ............................................................................ 4 3 Information................................................................................................................................. 4

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“ .............. 4 3.2 Contact person for procedural and scientific questions..................................................... 5 3.3 Contact person eCTD........................................................................................................ 5

4 Modalities of electronic submission ........................................................................................... 5 4.1 General.............................................................................................................................. 5 4.2 Documents to be submitted............................................................................................... 6

Table 1 – CTD-Module according to NTA Vol 2 B ..................................................................... 6 4.3 Supplementsl and additions .............................................................................................. 8 4.4 New applications for marketing authorisation in accordance with Section 21ff. AMG / Request for ENR ............................................................................................................... 8

5 Technical specifications concerning e-mails.............................................................................. 9 5.1 E-mail subject.................................................................................................................... 9 5.2 E-mail content ................................................................................................................... 9 5.3 E-mail attachments and file formats .................................................................................. 9

5.3.1 Problems with the MS-TNEF format in Outlook ............................................................ 9 5.3.2 Zip containers.............................................................................................................. 10 5.3.3 Files with documents to be submitted ......................................................................... 10 5.3.4 Files with metadata ..................................................................................................... 11 Table 2 – Construction of attribut.txt for procedure types........................................................ 11 5.3.5 Search for ENR / PNR................................................................................................. 12 5.3.6 Encryption of the container.......................................................................................... 12



5.3.7 Encryption software..................................................................................................... 12 5.3.8 Encryption with the BfArM key .................................................................................... 12 5.3.9 Downloading of the BfArM key, encryption of the zip container .................................. 12

5.4 File name convention ...................................................................................................... 19 5.4.1 Elements of file names for electronic submission to BfArM ........................................ 20 Table 3 – Types of Document, set file names ......................................................................... 21 5.4.2 File name convention in accordance with ICH eCTD Specification ............................ 25 5.4.3 Checklist to monitor whether all conditions have been fulfilled ................................... 26 Table 4 – Checklist Item .......................................................................................................... 26

6 Verification and confirmation of e-mails................................................................................... 27 6.1 Confirmation of receipt and confirmation as to the coherence of the formal/technical properties .............................................................................................. 27 6.2 Confirmation as to the intellectual verification of content ................................................ 28 6.3 Possible error messages regarding electronic verification of coherence of formal/technical characteristics ....................................................................................... 29

Table 5 – Error message ......................................................................................................... 29 6.4 Possible error messages regarding intellectual verification of submitted e-mails ........... 32

Table 6 – Error message ......................................................................................................... 32 6.5 System response............................................................................................................. 32 6.6 What to do in the case of false-positive system responses............................................. 32

6.6.1 Submission under a wrong ENR ................................................................................. 32 6.6.2 Submission of partly wrong data ................................................................................. 33

7 Important information concerning permission of exclusive submission of paper documents in accordance with Section 3 AMG-EV.................................................................................... 34 8 List of changes......................................................................................................................... 35 Table of figures: 1. Fig 1 Dialogue for download of BfArM public key .................................................................... 13 2. Fig 2 Download subdirectory ................................................................................................... 13 3. Fig 3 Import of key into key manager / „Schlüsselverwaltung“ ................................................ 14 4. Fig 4 Selection and iImport of BfArM public key ...................................................................... 14 5. Fig 5 „Schlüsselimport“/”key import” dialogue ......................................................................... 15 6. Fig 6 Status message „Schlüsselimport“ ................................................................................. 15 7. Fig 7 Display of imported key .................................................................................................. 15 8. Fig 8 Fingerprint – degree of trust ........................................................................................... 16 9. Fig 9 Fingerprint check ............................................................................................................ 16 10. Fig 10 Ownertrust .................................................................................................................... 17 11. Fig 11 Encryption of zip container ........................................................................................... 17



12. Fig 12 Selection of BfArM key ................................................................................................. 18 13. Fig 13 Email with attached zip container ................................................................................. 18 14. Figure 14 Cancellation of a false-positive system response.................................................... 33



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, http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/b/ctd_06-2006.pdf). 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 E-mail 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:

01888 307-3700 / -4319 or 0228 207-3700 / -4319

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 e-mail 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.

http://www.bfarm.de/de/Arzneimittel/amg_ev/VO_AMG-EV.pdf

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/b/ctd_06-2006.pdf

mailto:zulassung@amg-zulassung-de

mailto:[email protected]



http://www.bfarm.de/cln_042/nn_424576/DE/Arzneimittel/amgEv/faq/faqamgev-node.html__nnn=true



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. e-mail 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 www.bfarm.de or PharmNet homepage: http://www.pharmnet-bund.de/dynamic/en/index.html

3.2 Contact person for procedural and scientific questions

Procedural and scientific questions concerning ongoing procedures are answered by the responsible project management. Please contact the e-mail 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:

http://www.ich.org/cache/compo/276-254-1.html

http://www.emea.eu.int/

eCTD contact persons are

General questions: Dr. Menges, phone: 01888-307-3458 oder 0228/207-3458, e-mail: [email protected]

Technical questions: Mr. Kunz, phone: 01888-307-5948 or 0228/207-5948, e-mail: [email protected]

4 Modalities of electronic submission

4.1 General

Electronic submission of documents is to be made to the e-mail 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 e-mail 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.

www.bfarm.de

http://www.pharmnet-bund.de/dynamic/en/index.html

http://www.ich.org/cache/compo/276-254-1.html

http://www.emea.eu.int/



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) no. 1 AMG

Expert Report on the chemical, pharmaceutical and biological documentation

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

Nonclinical Expert Statement 2.4

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

2.6 2.6.3 2.6.5 2.6.7

IC2 Appendix 2: Written Summary (Pharmacology)

Nonclinical Summary Pharmacology Written Summary Pharmacokinetics Written Summary

2.6 2.6.2 2.6.4

IC3 rsp. Section 24 (1) no. 3 AMG

Expert Report on the clinical documentation

IC3 Product profile Introduction 2.2

IC3 Critical Assessment Clinical Overview Clinical Expert Statement 2.5



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 2.7.5 IC3 Appendix 2: Written Summary Clinical Summary 2.7

1

Notice to Applicants Vol. 2A, 2B and 2 C is found on the EUDRALEX website:

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.htm

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:

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/b/update_2007-03/eum1-v1.2.1.zip

The complete list of types of document to be submitted (cf. Point 5.4.1 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 medicines2 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 5.4.1 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. 5.4.1 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.

http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/homev2.htm


http://ec.europa.eu/enterprise/pharmaceuticals/eudralex/vol-2/b/update_2007-03/eum1-v1.2.1.zip



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 e-mail is to be sent to BfArM.

Attention: If, for one ENR, one and the same type of document occurs repeatedly within an e-mail, this e-mail 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 2001. 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 Z14.1.01 – Antragseingang / Fachregistratur Kurt-Georg-Kiesinger-Allee 3 53175 Bonn,

preferably via telefax no.:+49 (0)228/207-3681, 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).



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 e-mails 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. 5.3.1 Zip container).

Attention: The following examples use zip containers, but they also apply to tar containers.

5.1 E-mail subject

Only the 7-digit processing number (ENR) which is intended for the submission is to be stated in the subject line of the e-mail. The validation program checks whether the subject line exclusively states the processing number (ENR), if not, the e-mail is rejected. The e-mail is likewise rejected if the subject line is empty. The sender is not informed of this fact as the e-mail is considered spam mail.

5.2 E-mail content

The text (“content”) of the e-mail 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.

5.3 E-mail attachments and file formats

Every e-mail 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. 5.3.4. Checklist).

5.3.1 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 ”e-mail format“ in the index card/in der Registerkarte „E-Mail-Format“ auswählen

Change to “text only“ in format selection/Formateinstellung auf „Nur Text“ ändern

Save the changes and re-write the e-mail.



5.3.2 Zip containers Exactly one zip container shall be provided with every e-mail. The name of the zip container shall be as follows: <7-digit ENR>. zip

Example: 1999023.zip Websites for information about data compression

http://www.tu-chemnitz.de/ods/waldenburg/linux/packen/zusammenfassung.htm

http://www.linux-forum.biz/tutorial_tar.php

www.zdnet.de (Freeware-Download-Portal)

http://www.pc-magazin.de/datatip/common/dtt/file.php?areaid=56&orderby=lastModified&dsp_start=0&fileid=772&modus=suche&such=winzip&DTT_filter=

5.3.3 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 1.4.1 - 1.4.3

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".

http://www.tu-chemnitz.de/ods/waldenburg/linux/packen/zusammenfassung.htm

http://www.linux-forum.biz/tutorial_tar.php

http://www.zdnet.de/






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 E-mail 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: zulassung renewal: verlaengerung post-approval: nachzulassung Note: a. m. types of procedure apply likewise to the authorisation of homeopathic medicines with specified indication/s.

Variation: aenderung

Content of attribut.txt for the authorisation procedure for homeopathic medicines without specified indication/s: Registration registrierung Post-registration nachregistrierung

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)

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 = 0000000 enr = 1999023 verf = authorisation edat = 24.12.2006

Example attribut.txt: pnr = 0000000 enr = 1999023 verf = variation aend = 24.12.2006

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.



5.3.5 Search for ENR / PNR ENR and PNR can be searched for at www.dimdi.de in AMIS Public Section (chargeable part of the DIMDI database offer).

5.3.6 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.

5.3.7 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 www.winpt.org or www.gnupg.de. 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 (2003-04-26).

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.

5.3.8 Encryption with the BfArM key You will find the respective valid public key of the BfArM in the file: http://www.bfarm.de/cln_042/nn_424576/DE/Arzneimittel/amgEv/umsetzung/umsetzung-node.html__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.

5.3.9 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 e-mail prepared for an electronic submission plus attachment with encrypted zip container):

www.dimdi.de

http://www.winpt.org/

http://www.gnupg.de/

http://www.bfarm.de/cln_042/nn_424576/DE/Arzneimittel/amgEv/umsetzung/umsetzung-node.html__nnn=true

http://www.bfarm.de/cln_042/nn_424576/DE/Arzneimittel/amgEv/umsetzung/umsetzung-node.html__nnn=true

http://www.bfarm.de/cln_042/nn_424576/SharedDocs/Publikationen/DE/Arzneimittel/amg-ev/BfArM-OpenPGP-AS-Key-asc,templateId=raw,property=publicationFile.txt/BfArM-OpenPGP-AS-Key-asc.txt



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.



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.



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. 6. 6. 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.



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.



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.



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 Email with attached zip container

Now the mail is ready for electronic submission and can be sent. The encrypted zip container, e.g. 1234567.zip.gpg, is attached.



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. 5.4.1 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. 5.4.2 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



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. 5.4.1, 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.

5.4.1 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 1999023.zip published on our homepage.

Example:

palde.rtf

qos-001.rtf

In accordance with the file name convention (cf. 5.4.2.), 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-1999023-verl-2005-09-29.rtf

Please remember that in additional submissions of pdf-documents, rtf file name and pdf file name are identical.

Example:

palen-1999023-verl-2005-09-29.rtf palen-1999023-verl-2005-09-29.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 5.4.2 with regard to use of upper and lower case and characters are also to be observed for this part. Example: labbl-1999023-verl-2005-09-29.rtf

Observe the notes following Table 3.

http://www.bfarm.de/nn_424576/DE/Arzneimittel/amgEv/umsetzung/umsetzung-node.html__nnn=true



Table 3 – Types of Document, set file names 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

spcde § 11a AMG: Fachinformation

Summary of Product Characteristics (Part IB)

(CTD 1.3.1) Summary of Product Characteristics

.rtf (always)

.pdf (if applicable, additionally)

spcen Summary of Product characteristics (the English version to be harmonised)

Summary of Product Characteristics

(CTD 1.3.1) Summary of Product Characteristics

.rtf (always)


spcpal Section 11a paragraph 4 AMG Kombinierte Fach- und Gebrauchsinformation

.rtf (always) .pdf (if applicable, additionally)

labbl Section 10 AMG: Beschriftung der Durchdruckfolie (for tablets)

Labelling (Blister) (CTD 1.3.1) Labelling Blister

.rtf (always)


labip-001 (cf. notes at end of Table)

Section 10 AMG: Beschriftung des Packungsinhalts (z.B.Tabletten-röhrchen,Tropf-fläschchen)

Labelling (inner pack) (CTD 1.3.1) Labelling inner pack

.rtf (always)


labop-001 (see notes at end of Table)

Section 10 AMG: Beschriftung der Packungsumhüllungen (z.B. Faltschachteln)

Labelling (outer pack) (CTD 1.3.1) Labelling outer pack

.rtf (always)


labpal-001 (see notes at end of Table)

Section 10 AMG: (z.B. Etikettaufkleber auf Mineralwasserflaschen)

package leaflet .rtf (always) .pdf (if applicable, additionally)

palde Section 11 AMG: German product information, (Beipackzettel, Patienteninformation)

Package Leaflet (CTD 1.3.1) Package Leaflet

.rtf (always)


palen Section 11 AMG: English product information, (Beipackzettel, Patienteninformation)

Package Leaflet (CTD 1.3.1) Package Leaflet

.rtf (always)


ixq-001 (see notes at end of table)

Lebenslauf / Veröffentlichungen des Sachverständigen zum analytischen Gutachten

(EU Module 1; 1.4.1) Information about the Expert Quality Expert

in paper (always) .pdf (if applicable, additionally)



Type of Document (always first component of file name)





ixn-001 (see notes at end of table)

Lebenslauf / Veröffentlichungen des Sachverständigen zum Pharmakologisch-toxikologischen Gutachten

(EU Module 1; 1.4.2) Information about the Expert - Non-Clinical Expert


ixc-001 (see notes at end of table)

Lebenslauf / Veröffentlichungen des Sachverständigen zum klinischen Gutachten

(EU Module 1; 1.4.3) Information about the Expert - Clinical Expert


era Umweltrisikobewertung Environmental Risk Assessment (IIIR / II H)

(CTD 1.6) Environmental Risk Assessment (CTD Annex)

.rtf (always)


phvsys Section 22 2. paragraph 6 AMG Pharmakovigilanz-system und qualifizierte Person

Pharmacovigilance system and qualified Person

(EU Module 1;1.8.1) Pharmacovigilance-System

optional: .rtf .pdf

riskmp Maßnahmenplan zur Risikoüberwachung

Risk Management Plan (EU Module 1; 1.8.2) Risk-Management-System

optional: .rtf .pdf

intro Produktprofil Product Profile (CTD 2.2) Introduction

.rtf (always)


qos-001 (see notes at end of Table)

Analytisches Sachverständigen-gutachten

Quality Expert Report (I.C.1)

(CTD 2.3) Quality Overall Summary and Quality Expert Statement

optional: .rtf .pdf

qts Anhang 1: Tabellarische Aufstellung zum Sachverständigen-gutachten

Appendix 1: Tabular Formats

Safety Update Report Licensing Status

.rtf (always)


qws Anhang 2: Schriftliche Zusammenfassung des Sachverständigengut-achtens

Appendix 2: Written Summary

Safety Update Report Sales Volume

.rtf (always)


qoses Erklärung des Sachver-ständigen gemäß BfArM-

Expert Statements .rtf (always) .pdf (if applicable,








Bekanntmachung vom 27.11.2000 (Punkt 7)

additionally)

nco Section 24 sub-section 1 Nr. 1 AMG Pharmakologisch-toxikologisches Sachverständi-gengutachten

Preclinical Expert Report (I.C.2)

(CTD 2.4) Nonclinical Overview

.rtf (always)


co Section 24 sub-section 1 Nr. 3 AMG Klinisches Sachver-ständigengutachten

Clinical Expert Report (I.C.3)

(CTD 2.5) Clinical Overview and Clinical Expert Statement

.rtf (always)


ncs Zusamenfassung des Pharmakologisch-toxi-kologischen Sachver-ständigengutachtens

(CTD 2.6) Nonclinical Summary, possibly separated into:

.rtf (always)


ncsi Einführung (CTD 2.6.1) Nonclinical Summary Introduction

.rtf (always)


plws Zusammenfassung des pharmakologischen Gutachtens

Written Summary (I.C.2)

(CTD 2.6.2) Pharmacology Written Summary

.rtf (always)


plts Tabellarische Aufstellung zum pharmakologischen Gutachen

Tabular Formats (I.C.2)

(CTD 2.6.3) Pharmacology Tabulated Summary

.rtf (always)


pkws Zusammenfassung des pharmakokinetischen Gutachtens


(CTD 2.6.4) Pharmacokinetics Written Summary

.rtf (always)


pkts Tabellarische Aufstellung zum pharmakokinetischen Gutachten


(CTD 2.6.5) Pharmacokinetics Tabulated Summary

.rtf (always)


tows Zusammenfassung des toxikologischen Gutachtens

(CTD 2.6.6) Toxycology Written Summary

.rtf (always)


tots Tabellarische Aufstellung zum toxikologischen Sachverständigengut-achten


(CTD 2.6.7) Toxicology Tabulated Summary

.rtf (always)









cs Klinische Zusammenfassungen

(CTD 2.7) Clinical Summary, possibly separated into:

.rtf (always)


sbpm Bekanntgabe der bio-pharmazeutisch-analyti-schen Methoden


(CTD 2.7.1) Summary of Biopharmaceutics and Associated Analytical Methods

.rtf (always)


scps Bekanntgabe der klinisch-pharmakologischen Studien


(CTD2.7.2) Summary of Clinical Pharmacology Studies

.rtf (always)


sce Erklärung zur klinischen Wirksamkeit


(CTD 2.7.3) Summary of Clinical Efficacy

.rtf (always)


scs Erklärung zur klinischen Sicherheit/Unbedenklichkeit


(CTD 2.7.4) Summary of Clinical Safety

.rtf (always)


syis Section 24 sub-section 1 Nr. 3 AMG Inhaltsangabe/Gegen-überstellung zum klini-schen Sachverstän-digengutachten


(CTD 2.7.6) Synopsis of Individual Studies

.rtf (always)


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 e-mail 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.



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 001.

5.4.2 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 ('.'; dot is not permissible)

hello:pdf (':'; colon is not permissible)

part_a ('_': underscore is not permissible)

änd ('ä' or 'ö' or 'ü' umlauts are not permissible).



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 5.3.3 File with metadata)

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

pnr = 7654321 enr = 1234567 verf = zulassung edat = 12.12.2002

File name convention for text files (cf. 5.4.1 Elements of file names 5.4.1 File name convention)

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

spcde-optional-20030303-dkl.rtf

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 5.4.1 Elements of file names 5.4.2 File name convention…

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)

spcde-optional.rtf spcde-blabla.pdf



Item Entry Example

Expert Report File name (cf. Point 5.4.1 Elements of file names)

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

qos001-optional.rtf

Compress files: make containers (cf. 5.3.1 Zip container)

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.

Example: 1999023.zip

Encryption of containers (cf. 5.3.5)

Encryption of containers is optional

Example: 1999023.zip.pgp

Sending of e-mail attachments (cf. Point 5.3)

The container is attached to the e-mail

Example:1999023.zip or 1999023.zip.pgp

E-mail subject (cf. Point 5.1) Processing number (ENR) Example: 1999023

E-mail content (cf. Point 5.2) optional The following files have been submitted for procedure xyz, application date ??.??.200x

6 Verification and confirmation of e-mails The submitter receives several confirmations by e-mail, depending on the status of the verification. All response mails contain unique numbers in the subject-line (e.g. positive response 1 (P-20060317_000039) for ENR 1999023). 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 e-mail 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 e-mail 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 e-mail 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?



• 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 e-mails are rejected promptly with a confirmation of receipt in the subject line: "Negativmeldung <sequential number>".

E-mails 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 e-mail.

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 e-mail (subject line: "Positivmeldung").



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. The structure of the mail is incorrect and it

can therefore not be processed. Check type, version, or settings of own mail client.

Der Mailanhang konnte nicht entschlüsselt werden.

The structure of the encrypted file is presumably defective.

Check type, version, or settings of own encryption software.

Die Mail enthält mehr als eine GPG/PGP-Datei. Es darf nur eine verschlüsselte Datei im Mailanhang vorhanden sein.

Only one encrypted container per mail is permitted.

Send a separate mail per container.

Fehler beim Entpacken der Zip-Datei. Die Zip-Datei ist wahrscheinlich beschädigt.

The archiving format employed (*.zip) is faulty (the check sum is incorrect, data is incomplete, etc.)

Check the archiving program employed and settings. Create a new mail with archive file and send.

Die Anzahl oder der Typ der Mailanhänge entspricht nicht den formalen Vorgaben.

Only the container and its separate signature may be attached.

Create a new mail with archive and signature file and send.

Fehler beim Extrahieren der tar-Datei. Die tar-Datei ist wahrscheinlich beschädigt.

The archiving format employed (*.tar) is faulty (the check sum is incorrect, data is incomplete, etc.)

Check the archiving program employed and settings. Create a new mail with archive file and send.

Der Mailanhang enhält nicht zulässige Dateitypen. Die Datei <DATEI> entspricht nicht den formalen Vorgaben.

Only files with the extensions .rtf, .pdf, and the "attribut.txt" file are permissible.

Correct types of file and create new container.

Der Name der Datei <DATEI> enthält nicht zulässige Zeichen.

Permissible characters are: lower case letters [a-z], numbers [0-9], and hyphens.

The container shall be named "<ENR>.zip" or "<ENR.tar".

Die Mail enthält keine Attributdatei im Anhang.

The "attribut" file is necessary for validation and processing of the submission

Cf. Explanatory notes in 5.4.3 File with metadata

Die Mail enthält mehr als eine Attributdatei im Anhang.

Only one "attribut.txt" is permitted. Delete redundant files and create new container.

Die Angaben in der Attributdatei sind nicht vollständig.

Syntax error in the file "attribut.txt". Cf. Explanatory notes in 5.4.3 File with metadata

Das Format der ENR <ENR> in der Attributdatei ist nicht korrekt. Die ENR muss immer siebenstellig

Syntax error in the file "attribut.txt". The ENR must always consist of 7 digits.

Cf. Explanatory notes in 5.4.3 File with metadata The correct ENR can be found in "AMIS Public Section".



Error Message Possible Cause Proposed Solution angegeben werden.

Das Format der PNR <PNR> in der Attributdatei ist nicht korrekt.

Syntax error in the file "attribut.txt". The PNR must always consist of 7 digits.

Your correct PNR can be found in "AMIS Public Section".

Das Format des Feldes EDAT in der Attributdatei ist nicht korrekt.

Syntax error in the file "attribut.txt". The format is "dd.mm.yyyy".

Check spelling, observe date format, cf. Point 5.4.3 File with metadata

Der Name einer Datei (<DATEI>) im Mailanhang entspricht nicht den formalen Vorgaben.

Permissible characters are: lower case letters [a-z], numbers [0-9], and hyphens.

Cf. Explanatory notes in 5.4.1 Elements of file names … and 5.4.2 File name convention

Der Mailanhang enthält nicht zulässige Dokumenttypen. Die Datei ERRVAO> enspricht nicht den formalen Vorgaben

The file name convention was disregarded. Cf. with the list of types of document in 5.4.1 Elements of file names, and change accordingly.

Der Mailanhang enthält nicht zulässige Dokumenttype. Die Datei <ERRVA> entspricht nicht den formalen Vorgaben

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

Compare with the list of types of document 5.4.1 Elements of file names and change accordingly

Die ENR (<ENR>) in der Attributdatei ist unbekannt.

The ENR is possibly incorrect. Your correct ENR can be found in "AMIS Public Section".

Es sind mehrere Dateiarchive (zip oder tar) im Mailanhang vorhanden.

Exactly one archive file must be attached Create a new mail with archive file and send.

Es ist kein Dateiarchiv (zip oder tar) im Mailanhang vorhanden.

Exactly one archive file must be attached Create a new mail with archive file and send.

Die ENR (<ENR>) aus Mail-Betreff, Containernamen und Attributdatei stimmen nicht überein.

Only the 7-digit ENR is to be stated in the subject line.

Cf. Explanatory notes in 5.2 E-mail subject

Die ENR im Betreff-Feld der Mail ist unbekannt.


Der Name der Archivdatei in der Mail ist nicht korrekt.

The name must read <ENR>.zip or <ENR>.tar. Cf. Explanatory notes in 5.3.2 Zip container

Give archive file correct name, create a new mail with archive file and send.

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". Check spelling, observe date format, cf. also 5.4.3 File with metadata



Error Message Possible Cause Proposed Solution Der Datencontainer im Mailanhang enhält verschlüsselte Dateien.

Files in a container must not be encrypted. Make new container with unencrypted files. Send mail again.

Das Format des Feldes "AEND" (<ERRVARO>) in der Attributdatei ist nicht korrekt

Typing error Date = dd.mm.yyyy cf. 5.4.3 File with metadata

Die Datei <ERRVARO> enthält nicht das angegebene Dateiformat

The extension of a doc-file was changed to .rtf

.doc files must be saved as

.rtf files.

Der Datencontainer im Mailanhang enthält Unterverzeichnisse

Result of copying. Delete subdirectories.

Das Einreichungsdatum ist ungültig

Typing error, invalid date such as 30.2.2004.

Date = dd.mm.yyyy cf. 5.4.3 File with metadata

Das Änderungsdatum ist ungültig

Typing error, invalid date such as 30.2.2004.

Date = dd.mm.yyyy cf. 5.4.3 File with metadata

Die PNR (<ERRVARO>) in der Attributdatei ist unbekannt

Typing error. 7-digit number Your correct ENR can be found in "AMIS Public Section".

Mehrere Dokumente eines Dokumenttyps (<DOCTYPE<) sind nicht zulässig

Several files were created for one type of document.

Exception cf. 5.4 File name convention Otherwise merge all files to a type of document.

Das Änderungsdatum ist in der Attributdatei nicht vorhanden

The declaration verf = aenderung lacks the respective date.

Date = dd.mm.yyyy cf. 5.3.3. File with metadata

Die Angabe eines Einreichungsdatums in der Attributdatei im Verfahren "aenderung" ist nicht zulässig

Typing error. State the date of the variation in the "attribut" file cf. 5.3.3 File with metadata

Das Einreichungsdatum ist in der Attributdatei nicht vorhanden

State the date of submission in the "attribut" file cf. 5.3.3 File with metadata

Die Angabe eines Änderungsdatums in der Attributdatei im Verfahren "<ERRVARO>" ist nicht zulässig

The following is not stated under "procedure": verf = aenderung.

Check which procedure is meant cf. 5.3.3 File with metadata

Im Dokumentnamen "<ERRVARO>" fehlt ein Bindestrich nach dem Dokumenttyp.

cf. 5.4.2 File name convention

Das Format der ENR im Betreff-Feld der Mail ist nicht korrekt. Die ENR muss immer siebenstellig angegeben werden

Send the mail again with the corrected subject line.



6.4 Possible error messages regarding intellectual verification of submitted e-mails

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

For instance, submitted texts for medicinal product and processing number (ENR) do not match.

Check allocation of ENR and file

Datei kann nicht gelesen werden

Incorrect character set, wrong format, even though extension is permissible.

Check character set and format

Datei kann nicht geöffnet werden

Wrong format, even though extension is permissible.

Check format

Falsches Dateiformat Format is neither .rtf nor .pdf; the extension is permissible but is not suitable for the format.

For details cf. 5.4.2 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 <[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 e-mail: [email protected]. In such cases you are advised to provide the original submission e-mail to the hotline for analysis of the problem.

6.6 What to do in the case of false-positive system responses

6.6.1 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.





14. Figure 14 Cancellation of a false-positive system response

6.6.2 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-20060317_00003) for ENR 1999023) 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.



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 applicable, 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.



8 List of changes

Date Version Chapter/Paragraph Reason for change 16 May 06

4.09 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.

16 May 06

4.09 1. General remarks Category “remarks“ deleted.

16 May 06

4.09 2. E-mail addresses Revised.

25 May 07 16 May 06

4.09 6. Information Shifted forward to become Chapter 3. Information plus sub-chapters 3.1 Contact for electronic submissions/AMG-EV-Hotline/ on-line variation procedures 3.2 Contact for procedural and scientific questions 3.3 Contact eCTD

16 May 06

4.09 3 Modalities / Procedures for electronic submission

Current number: 4. Modalities / Procedures……

16 May 06

4.09 3.2 Documents to be submitted

Current number: 4.2 Documents to be submitted Reference to the Notice to Applicants was updated (October 2005).

16 May 06

4.09 3.4 New applications for marketing authorisation in accordance with Section 21 ff AMG

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).

16 May 06

4.09 4. Technical specifications concerning e-mails

Current number 5. Technical specifications concerning e-mails.

16 May 06

4.09 Punkte 4.1 E-mail subject 4.2 E-mail content 4.3 E-mail attachments and file formats

Current numbers: 5.1 E-mail subject 5.2 E-mail content 5.3 E-mail attachments and file formats

16 May 06

4.09 Addition of new sub-item: 5.3.0 Problems with the MS-TNEF format in Outlook

16 May 06

4.09 4.3.1 – 4.3.7 Current numbers: 5.3.1 – 5.3.8 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



Date Version Chapter/Paragraph Reason for change authorisations from abroad.

16 May 06

4.09 Addition of a new sub-item: 5.3.4 Search for ENR- / PNR

16 May 06

4.09 4.3.7 Downloading of the BfArM key

Current number: 5.3.8 Downloading of the BfArM key Fig. 12. E-mail with encrypted zip container updated.

16 May 06

4.09 4.4. File name convention 4.4.1 4.4.2 4.4.3

Current numbers: 5.4. File nameconvention 5.4.1 Elements of file name for the electronic… 5.4.2 File name convention in accordance with ICH eCTD specification 5.4.3 Checklist to monitor whether all conditions In 5.4.1 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.

16 May 06

4.09 4.4.1 Elements of file names for the electronic…to BfArM

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“

16 May 06

4.09 4.4.1 Elements of file names for the electronic…to BfArM, Table, type of document, footnote

Former footnote under table in 4.4.1 has become text in 5.4.1 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 2004.“

16 May 06

4.09 5. Verification and confirmation of e-mails 5.1 5.2

Current numbers: 6. Verification and confirmation of e-mails Insertion of new sub-items: 6.1 – 6.6 6.1 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

01 August 04

4.08 4.3.2 4.4 5. • listing

The types of document ixq, ixn and ixc are to be submitted in paper and can additionally be submitted as .pdf file.

01 August 4.08 4.4.1 New column in the list of types of document with the permissible



Date Version Chapter/Paragraph Reason for change 04 file formats for each type of document 15 March 2004

4.07 3.2 4th paragraph from the bottom

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.

15 March 2004

4.07 3.2 3rd paragraph from the bottom

Deleted as the transmission of electronic signatures is technically not yet possible.

15 March 2004

4.07 3.2 last paragraph

Information on sending duplicates has been clarified due to inquiries.

15 March 2004

4.07 4.1 Receipt of an e-mail 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.

15 March 2004

4.07 4.3.1.1 new last 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.

15 March 2004

4.07 4.3.2 1st paragraph

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.

15 March 2004

4.07 4.3.3 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.

15 March 2004

4.07 4.4 2nd 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



Date Version Chapter/Paragraph Reason for change 15 March 2004

4.07 4.4 4th paragraph from the top

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).

15 March 2004

4.07 4.4 6th paragraph from the top

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.

15 March 2004

4.07 4.4.1 new 1st paragraph

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.

15 March 2004

4.07 4.4.1 after the 2nd paragraph

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).

15 March 2004

4.07 4.4.1 list of types of documents

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).

15 March 2004

4.07 4.4.1 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.

15 March 2004

4.07 4.4.3 Checklist adapted according to the a.m. changes

15 March 2004

4.07 5. new paragraph after the 6th paragraph

The absence of a confirmation of receipt within an appropriate period of time indicates that the subject line of the e-mail was missing or not in accordance with the conventions. Such e-mails are discarded as spam and are not answered.

15 March 2004

4.07 5.1 List of error messages

Updated.

Explanatory Notes on the Enforcement - BfArM

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Transcript of Explanatory Notes on the Enforcement - BfArM