1. DRAFT Guidance for Industry: Providing Regulatory Submissions in Electronic Format – Drug Establishment Registration and Drug Listing Denise Sánchez, J.D., M.S., M.A. Regulations and Policy Staff Office of the Director Center for Biologics Evaluation and Research

2. 2 Registration and Listing Framework Section 510 of the Federal Food, Drug, and Cosmetic Act ( “ the Act ” ) and 21 Code of Federal Regulations (CFR) part 207 set forth requirements for drug establishment registration and drug listing for allergenic products. Section 510 of the Federal Food, Drug, and Cosmetic Act ( “ the Act ” ) and 21 Code of Federal Regulations (CFR) part 207 set forth requirements for drug establishment registration and drug listing for allergenic products. Drug establishments must register annually with FDA. [21 CFR 207.20] Drug establishments must register annually with FDA. [21 CFR 207.20] Drug establishments must list with FDA all drug products in commercial distribution and update listing every June and December. [21 CFR 207.20, 21 CFR 207.21] Drug establishments must list with FDA all drug products in commercial distribution and update listing every June and December. [21 CFR 207.20, 21 CFR 207.21] The Food and Drug Administration Amendments Act of 2007 (“FDAAA”) established the requirement that drug establishment registration and drug product listing information (which includes labeling) be submitted electronically unless a waiver is granted (FDAAA, Section 224, which amends Section 510(p) of the Act) The Food and Drug Administration Amendments Act of 2007 (“FDAAA”) established the requirement that drug establishment registration and drug product listing information (which includes labeling) be submitted electronically unless a waiver is granted (FDAAA, Section 224, which amends Section 510(p) of the Act)

3. 3 Electronic Registration and Listing Pilot FDA published Draft Guidance on 7/11/2008 to initiate pilot program FDA published Draft Guidance on 7/11/2008 to initiate pilot program Federal Register Notice [73 FR 39964, July 11, 2008]: Federal Register Notice [73 FR 39964, July 11, 2008]: http://www.regulations.gov Draft Guidance and Technical Documents: http://www.fda.gov/oc/datacouncil/spl.html Draft Guidance and Technical Documents: http://www.fda.gov/oc/datacouncil/spl.html http://www.fda.gov/oc/datacouncil/spl.html Proposed Rule on Electronic Registration and Listing [71 FR 51276, August 29, 2006]. Proposed Rule on Electronic Registration and Listing [71 FR 51276, August 29, 2006]. FDA is still considering comments and is in the process of finalizing the rule.

4. 4 Electronic Registration and Listing Pilot is a Transitioning Effort Objectives of Pilot Program: Assist manufacturers in transition from current paper- based system to the electronic submissions mandated by FDAAA. Assist manufacturers in transition from current paper- based system to the electronic submissions mandated by FDAAA. Assist FDA in testing performance of its systems for electronic submissions. Assist FDA in testing performance of its systems for electronic submissions. Important piece in transition as FDA intends to only accept electronic drug establishment registration and drug listing information beginning June 1, 2009 (unless a waiver is granted). Important piece in transition as FDA intends to only accept electronic drug establishment registration and drug listing information beginning June 1, 2009 (unless a waiver is granted).

5. 5 Electronic Registration & Listing: Structured Product Labeling (SPL) Format FDA has adopted extensible mark-up language (XML) files in SPL format as the means of electronic submission of registration and listing information to the Agency. FDA has adopted extensible mark-up language (XML) files in SPL format as the means of electronic submission of registration and listing information to the Agency. FDA ’ s new electronic listing system allows FDA to process SPL files submitted by industry through the FDA Gateway. FDA ’ s new electronic listing system allows FDA to process SPL files submitted by industry through the FDA Gateway. SPL(r4) can handle labeler code request, registration, and listing information. SPL includes coded drug listing data elements (DLDE) for drug product listing information. SPL(r4) can handle labeler code request, registration, and listing information. SPL includes coded drug listing data elements (DLDE) for drug product listing information. FDA systems extract the coded data from the SPL file to accomplish drug product listing and drug establishment registration. FDA systems extract the coded data from the SPL file to accomplish drug product listing and drug establishment registration. Technical specifications on how to create SPL files are provided in detail in the technical documents that accompany the Guidance. http://www.fda.gov/oc/datacouncil/spl.html Technical specifications on how to create SPL files are provided in detail in the technical documents that accompany the Guidance. http://www.fda.gov/oc/datacouncil/spl.html http://www.fda.gov/oc/datacouncil/spl.html

6. 6 Drug Establishment Registration – Current Requirements Who must register and when? Who must register and when? 21 CFR 207.21(a) 21 CFR 207.21(a) Owners/operators of establishments entering into the manufacture, preparation, propagation, compounding or processing (including repackaging and relabeling) of drugs, within 5 days after beginning the operation. If establishment has not previously entered into such an operation, owner/operator must register within 5 days after submitting an application, e.g., BLA. Owners/operators must renew their registration information annually.

7. 7 Drug Establishment Registration – Current Requirements Who must register and when? Who must register and when? 21 CFR 207.26 21 CFR 207.26 Changes in individual ownership, corporate, or partnership structure location or drug-handling activity must be submitted as amendments to registration within 5 days of such changes. 21 CFR 207.40 [Foreign Establishments] 21 CFR 207.40 [Foreign Establishments] Foreign drug establishments whose drugs are imported or offered for import into the United States must register with FDA and renew registration annually thereafter.

8. 8 Drug Establishment Registration – Current Requirements What information is required? What information is required? 21 CFR 207.25(a) 21 CFR 207.25(a) Name and full address of each drug establishment Name and full address of each drug establishment All trade names used by the establishment All trade names used by the establishment Type of ownership and operation Type of ownership and operation Name of owner or operator Name of owner or operator 21 CFR 207.40 [Foreign Establishments] 21 CFR 207.40 [Foreign Establishments] Name, address, phone number of US agent Name, address, phone number of US agent Each importer known to establishment [510(i)(1)(A) of the Act] Each importer known to establishment [510(i)(1)(A) of the Act] Each person who imports/offers for import [510(i)(1)(A) of the Act] Each person who imports/offers for import [510(i)(1)(A) of the Act]

9. 9 Drug Establishment Registration - Recommendations What additional information is FDA recommending that you submit? What additional information is FDA recommending that you submit? For All Establishments Official contact’s name, mailing address, telephone numbers, and email address Official contact’s name, mailing address, telephone numbers, and email address Each registered establishment’s telephone number Each registered establishment’s telephone number Type of operations performed at each establishment Type of operations performed at each establishment Site Specific D-U-N-S® number for each site specific entity Site Specific D-U-N-S® number for each site specific entity Foreign Establishment Additional Information U.S. agent email address U.S. agent email address Telephone numbers for importers and persons who import/offer for import known to the establishment Telephone numbers for importers and persons who import/offer for import known to the establishment

10. 10 Drug Product Listing – Current Requirements Who must list and when? Who must list and when? 21 CFR 207.21(a) 21 CFR 207.21(a) Registrants submit initial drug listing information for all drugs in commercial distribution at time of initial registration of their establishments. 21 CFR 207.20(b) 21 CFR 207.20(b) Private label distributors may request own NDC labeler code and elect to submit drug listing information to FDA. 21 CFR 207.21(b) 21 CFR 207.21(b) Updates to listing information must be submitted every June and December.

11. 11 Drug Product Listing – Current Requirements What information is required? What information is required? 21 CFR 207.25(b) and (c) 21 CFR 207.25(b) and (c) Listed drug’s established and proprietary name Listed drug’s established and proprietary name Application number Application number NDC number NDC number Copy of all current labeling Copy of all current labeling 21 CFR 207.30: JUNE and DECEMBER UPDATES 21 CFR 207.30: JUNE and DECEMBER UPDATES List of drugs submitted for commercial distribution since last update List of drugs submitted for commercial distribution since last update List of drugs for which commercial distribution has been discontinued since last update List of drugs for which commercial distribution has been discontinued since last update List of drugs for which notice of discontinuance was submitted and for which commercial distribution has been resumed. List of drugs for which notice of discontinuance was submitted and for which commercial distribution has been resumed.

12. 12 Drug Product Listing – Current Requirements What information is required? What information is required? 21 CFR 207.31 21 CFR 207.31 FDA may require additional listing information through notification by letter or FR notice FDA may require additional listing information through notification by letter or FR notice 21 CFR 207.40 [Foreign Establishments] 21 CFR 207.40 [Foreign Establishments] Listing of all drugs imported or offered for import into United States by a registered foreign establishment is required. Listing of all drugs imported or offered for import into United States by a registered foreign establishment is required.

13. 13 Drug Product Listing - Recommendations What additional information is FDA recommending that you submit? What additional information is FDA recommending that you submit? Name of establishment(s) manufacturing or processing the listed drug and type(s) of operations performed. Name of establishment(s) manufacturing or processing the listed drug and type(s) of operations performed. DEA schedule DEA schedule Route(s) of administration Route(s) of administration Inactive ingredients and strength or amount Inactive ingredients and strength or amount Marketing information Marketing information Information related to the application number Information related to the application number Package size and type Package size and type

14. 14 Drug Listing Data Elements (DLDE) in SPL Examples of DLDE in a firm’s SPL file Examples of DLDE in a firm’s SPL file Substance names, UNII (SRS) Substance names, UNII (SRS) Strength Strength Route of Administration Route of Administration Dosage Form Dosage Form Appearance Appearance Package Size and Type Package Size and Type DEA Schedule DEA Schedule NDC number NDC number

15. 15 Terminology Used for DLDE In SPL Unique Ingredient Identifiers (UNIIs) Unique Ingredient Identifiers (UNIIs) Defined terminology used to identify substances in drugs/biologics Defined terminology used to identify substances in drugs/biologics Maintained by FDA and the US Pharmacopeia (USP) through the FDA Substance Registration System (SRS) Maintained by FDA and the US Pharmacopeia (USP) through the FDA Substance Registration System (SRS) UNII codes needed in order to list products electronically through SPL UNII codes needed in order to list products electronically through SPL UNII codes are assigned by FDA UNII codes are assigned by FDA FDA/CBER in the process of creating allergenic products hierarchy for assignment of UNII codes FDA/CBER in the process of creating allergenic products hierarchy for assignment of UNII codes FDA/CBER to notify industry through formal regulatory correspondence of their UNII codes FDA/CBER to notify industry through formal regulatory correspondence of their UNII codes

16. 16 Terminology Used for DLDE In SPL NCI Enterprise Vocabulary Services [http://www.evs.nci.nih.gov] NCI Enterprise Vocabulary Services [http://www.evs.nci.nih.gov]http://www.evs.nci.nih.gov Maintains defined terminology for other DLDE such as: Maintains defined terminology for other DLDE such as: Dosage form Dosage form Routes of Administration Routes of Administration Package Type Package Type DEA schedule DEA schedule Product color Product color Product shape Product shape Flavors Flavors Marketing Codes Marketing Codes Request for any additional terms and codes: Request for any additional terms and codes: Email: spl@fda.hhs.gov Email: spl@fda.hhs.govspl@fda.hhs.gov Identify Center for Biologics in email subject line Identify Center for Biologics in email subject line

17. 17 Creation of SPL File Review of Technical Documents Are Essential! Review of Technical Documents Are Essential! Structured Product Labeling Implementation Guide for FDA Drug Establishment Registration and Drug Listing Structured Product Labeling Implementation Guide for FDA Drug Establishment Registration and Drug Listing Technical Criteria for SPL files Technical Criteria for SPL files Structured Product Labeling Validation Procedures for Drug Establishment Registration and Drug Listing Structured Product Labeling Validation Procedures for Drug Establishment Registration and Drug Listing Provides computer instructions for automating the validation of SPL files for the drug establishment registration and drug listing process at FDA Instructions for using Electronic Drug Establishment Registration and Drug Listing XForms Instructions for using Electronic Drug Establishment Registration and Drug Listing XForms Provides step by step instructions for creating SPL using drug establishment registration and drug listing XForms.

18. 18 Projected Implementation Projected Implementation Date for FDA to receive all registration and listing information only electronically and only through SPL format is June 1, 2009, except where a waiver is granted. Projected Implementation Date for FDA to receive all registration and listing information only electronically and only through SPL format is June 1, 2009, except where a waiver is granted. Because of this transition period to facilitate bringing industry into compliance with FDAAA’s mandate for electronic registration and listing, FDA expects to grant few waivers. Because of this transition period to facilitate bringing industry into compliance with FDAAA’s mandate for electronic registration and listing, FDA expects to grant few waivers.

19. 19 November 17 th SPL Public Workshop Notice Published: [73 FR 54405, Sep. 19, 2008] REGISTER TODAY! REGISTRATION IS FIRST COME FIRST SERVE AND CLOSES OCTOBER 30, 2008. TOPICS: DRAFT Guidance on Electronic Registration and Listing DRAFT Guidance on Electronic Registration and Listing SPL Registration and Listing: Technical Perspective SPL Registration and Listing: Technical Perspective FDA Gateway FDA Gateway Q & A Panel on SPL Q & A Panel on SPL SPL Vendor Exhibition SPL Vendor Exhibition

20. 20 Post Meeting Follow-Up: Key Points Review the DRAFT Guidance with an eye towards current requirements and FDA ’ s recommendations. Review the DRAFT Guidance with an eye towards current requirements and FDA ’ s recommendations. Review SPL Technical Guides for creation of registration and listing SPL Review SPL Technical Guides for creation of registration and listing SPL FDA encourages submission of comments on the Draft Guidance and Technical Guides to the Docket [FDA-2005-N-0464]. FDA encourages submission of comments on the Draft Guidance and Technical Guides to the Docket [FDA-2005-N-0464]. Register for November 17 th public workshop on SPL registration and listing. Register for November 17 th public workshop on SPL registration and listing. Contact In Federal Register Notice: Contact In Federal Register Notice: Donna Lipscomb, CBER Phone: 301–827–2000 Fax: 301–827–3079 Email: spl@fda.hhs.gov Subject line: CBER SPL Public Workshop