Guidance for Industry 

 
Providing Regulatory 

Submissions in Electronic 

Format  Drug Establishment 

Registration and Drug Listing 

 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Office of the Commissioner 

  
May 2009 

Electronic Submission 

 
 
 
OMB Control No. 0910-0045 

Expiration Date: 3/31/2012 

See additional PRA statement in Section VII of this guidance
 
 
  Contains Nonbinding Recommendations 
 
Guidance for Industry 

Providing Regulatory 

Submissions in Electronic 

Format  Drug Establishment 

Registration and Drug Listing 

 
Additional copies are available from: 

Office of Training and Communication 

Division of  Drug Information, HFD-240
  
Center for Drug Evaluation  and Research 
 
Food and  Drug Administration 

5600 Fishers Lane 

Rockville, MD  20857 
 
(Tel) 301-827-4573
 
 http://www.fda.gov/cder/guidance/index.htm 

and/or 
 Office of Communication, Outreach  and  

Development, HFM-40 
 
Center for Biologics Evaluation and Research 

 Food and Drug  Administration 

1401 Rockville Pike, Rockville, MD  20852-1448  

 http://www.fda.gov/cber/guidelines.htm   

(Tel)  800-835-4709 or 301-827-1800 
 
and/or 
Communications Staff, HFV-12 

Center for Veterinary Medicine 

Food and  Drug Administration 

7500 Standish Place, 

Rockville, MD  20855 
 
(Tel) 240-276-9300 
 
http://www.fda.gov/cvm/guidance/guidance.htm 

 
U.S. Department of Health and Human Services 

Food and Drug Administration 

Office of the Commissioner 

 
May 2009 

Electronic Submission 

 
 
 
  Contains Nonbinding Recommendations 
 
 
 
TABLE OF CONTENTS 

 
 
I.   INTRODUCTION............................................................................................................. 1 
 
II.   BACKGROUND ............................................................................................................... 1 
 
III.   DRUG ESTABLISHMENT REGISTRATION AND DRUG LISTING 

INFORMATION FOR ELECTRONIC SUBMISSION ........................................................... 4 
 
A.   Drug Establishment Registration .................................................................................................4
  
1.  Who must register, when, and how?................................................................................................4
  
2.  What information is submitted for drug establishment registration?..............................................5 
 
B.   Drug Listing....................................................................................................................................6
  
1.  Who must list, when, and how?........................................................................................................6
  
2.  What information is submitted for drug listing?..............................................................................7 
 
IV.   CREATING THE DRUG ESTABLISHMENT REGISTRATION AND DRUG 

LISTING FILE FOR ELECTRONIC SUBMISSION .............................................................. 9 
 
A.   Structured Product Labeling ........................................................................................................9
  
B.   Code Sets and Codes....................................................................................................................10 
 
1.  Unique Ingredient Identifiers (UNII).............................................................................................10
  
2.  Data Universal Numbering System (D-U-N-S) Number.............................................................10 
 
3.  Other code sets...............................................................................................................................11 
 
C.   Submission and FDA Validation of Electronic Drug Establishment Registration and Drug 

Listing Information..............................................................................................................................11 
 
D.   Technical Assistance ....................................................................................................................12
  
V.   IMPLEMENTATION .................................................................................................... 12
  
VI.   WAIVER REQUEST...................................................................................................... 12 
 
VII.   PAPERWORK REDUCTION ACT OF 1995.............................................................. 13 
 
 
 
 
 
 
 
 
 
 
 
  Contains Nonbinding Recommendations 
 
1
 
Guidance for Industry  
Providing Regulatory Submissions in Electronic Format  

Drug Establishment Registration and Drug Listing 

 
This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic.  It 
does not create or confer any rights for or on any  person and does not operate to bind FDA or the public.  
You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
and regulations.  If you want to discuss an alternative approach, contact the FDA staff responsible for 
implementing this guidance.  If you cannot identify the appropriate FDA staff, call the appropriate 
number listed on the title page of this guidance.  
 
 
I.  INTRODUCTION  
 
This is one in a series of guidance documents intended to assist persons making regulatory 
submissions to FDA in electronic format.  This guidance is designed to assist manufacturers with 
electronic submissions of drug establishment registration and drug listing information. The 
guidance and accompanying technical documents explain (among other things): 
 	  The statutory requirement to submit electronically drug establishment registration and 
drug listing information;  
 	  How to create a Structured Product Labeling (SPL)2 file for submitting drug 
establishment registration and drug listing information to FDA through the Electronic 
Submissions Gateway (ESG) using defined code sets and codes, i.e., a language 
recognized by the computer system; and  
	   Beginning June 1, 2009, FDA intends to no longer accept drug establishment registration 
and drug listing information in paper format unless a waiver is granted. 
FDA intends to update these documents regularly to reflect the evolving technology and user 
experience. 
 
FDA's guidance documents, including this guidance, do not establish legally enforceable 
responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 
be viewed only as recommendations, unless specific regulatory or statutory requirements are 
cited. The use of the word should in Agency guidances means that something is suggested or 
recommended, but not required.  
 
 
II.  BACKGROUND 
 
                                                 
1 The Office of  Critical Path Programs, Office of the Commissioner, Food and  Drug  Administration prepared  this  
guidance document in cooperation with the Center for Drug Evaluation and Research, the Center for Biologics 
Evaluation and Research, and the Center for  Veterinary Medicine.  
  
2 SPL standard is a Health Level Seven, Inc. standard for the exchange of product information using extensible  
markup language (XML). 
  1
 
     Contains Nonbinding Recommendations 
 
Requirements for drug establishment registration and drug listing are set forth in section 510 of 
the Federal Food, Drug, and Cosmetic Act (the Act) and section 351 of the Public Health Service 
Act (the PHS Act), and 21 CFR Part 207.3  Fundamental to FDAs mission to protect the public 
health is the collection of this information, which is used for important activities such as 
postmarket surveillance for serious adverse drug reactions, inspection of drug manufacturing and 
processing facilities, and monitoring of drug products imported into the United States.  
Comprehensive, accurate, and up-to-date information is critical to conducting these activities 
with efficiency and effectiveness.   
 
Section 510 of the Act and 21 CFR part 207, subject to certain limited exceptions, require 
establishment owners and operators (registrants) upon first engaging in the manufacture, 
preparation, propagation, compounding, or processing of drugs, (including human drugs, 
veterinary drugs, and biological drug products4) to register their establishments and submit 
listing information for all drugs in commercial distribution.  Registrants are also required to 
submit registration information for their establishments on or before December 31 of each year.5   
At the time of registration, registrants must also submit required listing information.6  
Additionally, registrants are required to update listing information in June and December of each 
year to include information for drugs that have not been previously listed.7 Certain changes to 
information for previously listed drugs must also be submitted every June and December.8   
 
Changes in the Act, resulting from the Food and Drug Administration Amendments Act of 2007 
(Public Law 110-85) (FDAAA),9 require that drug establishment registration and drug listing 
information be submitted electronically unless a waiver is granted.  Before FDAAA was enacted, 
section 510(p) of the Act expressly provided that drug establishment registration information 
must be submitted electronically, based on a finding that electronic receipt was feasible, and 
section 510(j) of the Act stipulated that drug listing information must be submitted in the form  
and manner prescribed by FDA.  Section 224 of FDAAA, which amends section 510(p) of the 
Act, now expressly requires drug listing information to be submitted by electronic means in 
addition to requiring electronic drug establishment registration.   
 
                                                 
3 This guidance document does not apply to  establishment registration and product listing  information required 
solely under  21 CFR part 607  (Blood and Blood Products), 21 CFR part 807 (Devices), and 21 CFR part 1271  
(Human Cells, Tissues, and Cellular and Tissue-Based Products). 
 
4  Under section 351(j) of  the PHS Act, the Federal Food, Drug, and Cosmetic Act (and regulations promulgated  
thereunder) applies to  biological drug  products, except that New Drug Applications (NDAs) are not required for 
products licensed under section 351(a) of the PHS Act.  
 
5 Section 510(b)(1) of the Act.  
 
6 Section 510(j)(1)  of the Act. 
 
7 Section 510(j)(2)(A) of the Act.   
 
8 Section 510(j)(2)  of the Act. 
 
9 Signed into law on September 27, 2007.   
 
  2
 
     Contains Nonbinding Recommendations 
 
Drug establishment registration and drug listing information have, until now, been submitted 
using a paper-based format, i.e., Form FDA 2656 (Registration of Drug Establishment/Labeler 
Code Assignment), Form FDA 2657 (Drug Product Listing), and Form FDA 2658 (Registered 
Establishments Report of Private Label Distributors).10  Moving from a paper-based format to 
an electronic system will improve the timeliness and accuracy of the submissions.   
 
Prior to the amendment of the statute to require electronic submission of both drug listing and 
establishment registration information, FDA issued a proposed rule that would amend 21 CFR 
part 207 to require electronic submission of drug establishment registration and drug listing 
information, and that included proposals such as certain changes to the National Drug Code 
(NDC) system and requirements regarding placement of the appropriate NDC on the drug label 
(71 FR 51276, August 29, 2006). FDA is considering comments submitted on the proposed rule 
and intends to issue a final rule based on that proposal which will also serve to conform the 
regulations to the changes in section 510(p) mandating electronic submission.  FDA intends to 
revise, reissue, or revoke this guidance document as appropriate to make it consistent with the 
final rule, when the rule is issued. 
 
To facilitate the submission of drug establishment registration and drug listing information 
(including labeling as specified under 21 CFR 207.25), FDA is adopting the use of extensible 
markup language (XML) files in a standard SPL format. The automated submission process 
functions most efficiently and effectively when this information is provided in a standardized 
format with defined code sets and codes.  This guidance and accompanying technical documents 
describe how to make these submissions using the SPL format, which FDA can process, review, 
and archive.11  Information in a properly created and complete SPL file can facilitate processing 
and allows for greater precision and accuracy through the use of coded data fields rather than just 
electronic text. Receipt of timely and accurate information will enhance FDAs efforts to help 
ensure the integrity of the drug supply and protect public health. 
 
Technical specifications for creation of the electronic files are provided in the following 
technical documents, which can be found on the FDA Data Standards Council website, 
http://www.fda.gov/oc/datacouncil/spl.html: 
 	  Structured Product Labeling Implementation Guide for FDA Drug Establishment 

Registration and Drug Listing 

 	  Step-by-Step  Instructions for Creating Structured Product Labeling (SPL) Files for Drug 
Establishment Registration and Drug Listing 
 	  Structured Product Labeling Validation Procedures for Drug Establishment Registration 
and Drug Listing 
 
                                                 
10 These forms can be referenced at http://www.fda.gov/opacom/morechoices/fdaforms/default.html. 
 
11  When we are ready to receive a particular submission type in electronic format only, we generally identify the 
specific type of document that FDA can process,  review, and archive.  This  information can be found in  the public 
docket 92S-0251  at  regulations.gov.  See 21 CFR 11.2(b)(2);  see also  Guidance for Industry:  Part 11, Electronic 
Records; Electronic Signatures -- Scope and Application (August 2003).  
 
  3
 
     Contains Nonbinding Recommendations 
 
See also Section IV of this document for discussion of these specifications and other information 
on creating the drug establishment registration and drug listing file for electronic submission. 
 
SPL format is already used for submission of content of labeling in electronic format as required 
in New Drug Applications (NDAs), Abbreviated New Drug Applications (ANDAs), Biological 
License Applications (BLAs), and annual reports on approved drugs.12  See Providing 
Regulatory Submissions in Electronic Format  Content of Labeling (April 2005).13  Because the 
content of labeling required under those provisions can be duplicative in content and format 
(SPL) of the labeling required to be submitted electronically as part of listing information, FDA 
encourages applicants to submit this labeling material, and updates, primarily through the drug 
establishment registration and drug listing system.  Rather than make duplicate submissions, 
applicants are then encouraged to reference the SPL labeling file submitted through the 
electronic drug registration and listing system in making labeling updates to applications under 
the content of labeling requirements.  FDA intends to issue guidance that will address this issue 
in further detail. 
 
Beginning June 1, 2009, FDA intends to use the electronic drug establishment registration and 
listing system as the source of SPL to provide postapproval content of labeling for public access 
on the Web, making that system the key repository of this information.   
 
 
III.  D	 RUG ESTABLISHMENT REGISTRATION AND DRUG LISTING 
INFORMATION FOR ELECTRONIC SUBMISSION 
 
The following information should be submitted to FDA in the SPL file format described in the 
technical documents and the defined code sets and codes as described in section IV of this 
document. 
 
A. 	 Drug Establishment Registration 
 
1. 	 Who must register, when, and how? 
 
The owner or operator of an establishment entering into the manufacture, preparation, 
propagation, compounding, or processing (which includes, among other things, repackaging and 
relabeling) of a drug or drugs14 and not exempt under section 510(g) of the Act or subpart B of 
21 CFR part 207, must register the establishment with FDA within 5 days after beginning the 
operation (21 CFR 207.21(a) and 21 CFR 207.3(a)(8)).  Alternatively, if the establishment has 
not previously entered into such an operation, the owner or operator must register within 5 days 
after submitting (among other things) a drug application, biological license application, or 
                                                 
12 For regulations requiring submission of content of labeling in electronic format that FDA can process, review, and 
archive, see 21 CFR 314.50(l) (NDAs), 21 CFR 314.94(d)  (ANDAs), 21 CFR 601.14(b)  (BLAs), and 21 CFR 
314.81(b) (annual reports to  marketing applications). 
 
13  http://www.fda.gov/cder/guidance/6719fnl.htm 
 
14 Means both  human, including biological  drug products, and animal drugs. 
 
  4
 
     Contains Nonbinding Recommendations 
 
medicated feed mill license application. (21 CFR 207.21(a)).  Owners or operators must renew 
their registration information annually (Section 510(b)(1) of the Act; 21 CFR 207.21(a)). 
 
Establishments within any foreign country that engage in the manufacture, preparation, 
propagation, compounding, or processing (which includes, among other things, repackaging and 
relabeling) of a drug that is imported or offered for import into the United States (and that are not 
exempt) must upon first engaging in such activity immediately register and register annually 
thereafter (Section 510(i) of the Act; 21 CFR 207.40).   
Amendments to drug establishment registration must be submitted in accordance with 21 CFR 
207.26. 
 
Section 510(p) of the Act, as amended by FDAAA, now requires drug establishment 
registrations to be submitted electronically unless a waiver is granted.  Therefore, registration 
information should now be submitted electronically using SPL files with coded data fields.15  
 
Failure to register in accordance with section 510 of the Act is a prohibited act under section 
301(p) of the Act. Also, under section 502(o) of the Act, a drug is misbranded if it is 
manufactured in an establishment in any State not duly registered under section 510 of the Act.  
 
2.  What information is submitted for drug establishment registration? 
 
Section 510 of the Act and 21 CFR Part 207 set forth registration information required to be 
submitted by domestic and foreign drug establishments.  (See sections 510(b), (c), (d), and (i) of  
the Act and 21 CFR 207.25(a), 21 CFR 207.26, and 21 CFR 207.40).  Under these provisions, all 
registrants must provide the name and full address of each establishment, all trade names used by 
the establishment, the kind of ownership or operation (e.g., individually owned, partnership, or 
corporation), and the name of the owner or operator (including in the case of a partnership the 
name of each partner, and in the case of a corporation, the name and title of each corporate 
officer and director and the State of incorporation). 
 
In addition to the information required for all registered establishments, certain additional 
information must be provided to register a foreign establishment.  For example, a foreign 
registrant must submit:  
 
 	  the name, address, and phone number of the foreign registrants United States agent 
(Section 510(i)(1)(A) of the Act and 21 CFR 207.40)c)); 
 
 	  the name of each importer that is known to the establishment (Section 510(i)(1)(A) of the 
Act). (This means each U.S. company or individual in the United States that is an owner, 
consignee, or recipient of the foreign establishments drug that is imported into the 
United States.  An importer does not include the consumer or patient who ultimately 
                                                 
15 As explained in section IV.C., of this document, once the SPL file is created it can be submitted (uploaded)  by  
following the instructions for the FDA Electronic Submissions  Gateway (ESG).  There may be some delay in  
obtaining an ESG account;  review section IV.C. for further information. 
 
  5
 
     Contains Nonbinding Recommendations 
 
purchases, receives, or is administered the drug, unless the foreign establishment ships 
the drug directly to the consumer or patient.); and  
 
 	  the name of each person who imports or offers for import such drug (Section 510(i)(1)(A) 
of the Act). (This means the name of each agent, broker, or other entity, other than a 
carrier, that the foreign drug establishment uses to facilitate the import of their drug into 
the United States).   
 
To facilitate correspondence between registrants and FDA, foreign registrants should submit the 
email address for the U.S. agent, and the telephone number(s) and email address for the importer 
and person who imports or offers for import described in section III.A.2 of this document.   
 
Historically, registrants have also included additional drug establishment registration information 
when making submissions, using Form FDA 2656.16  Likewise, for electronic submission, 
registrants should submit the following additional information in their SPL file: 
 	  Official contacts name, mailing address, telephone number(s), and email address; and 
 	  The type of operation(s) performed at each establishment. 
 
Under section 510(e) of the Act, FDA may assign a registration number to any person or 
registered establishment.  FDA intends to use the Data Universal Numbering System (D-U-N
S) as the registration number for the electronic system.  Therefore, to facilitate and expedite 
processing of the SPL file, the registrant should submit their D-U-N-S Number with the 
registration information.  If the business entity does not submit a D-U-N-S Number with its 
submission, FDA intends to make arrangements for obtaining a D-U-N-S Number for that 
entity. An explanation of the D-U-N-S Number and how to obtain one is described in section 
IV.B of this document.   
 
B.  Drug Listing 
 
1.  Who must list, when, and how? 
 
Registrants not exempt under 21 CFR 207.10 must submit the initial listing information for all 
drugs17 in commercial distribution at the time of their initial registration of their establishment(s) 
(21 CFR 207.21(a)). 
 
Failure to provide any listing information required by section 510(j) of the Act is a prohibited act 
under section 301(p). Also, under section 502(o) of the Act, a drug is misbranded if it was not 
included in a list required by section 510(j) of the Act. 
                                                 
16  See 21 CFR 207.22(a) and  21 CFR 207.25(a).  As noted, with the amendment of section 510(p) of the Act in 
2007, registration information is required to  be submitted electronically. Therefore, submission of such information 
on a particular  paper form is no longer acceptable (absent grant of a waiver), and information should instead be 
submitted in accordance with  this guidance document.  FDA intends to amend the regulations to conform to the 
changes in the underlying statutory provision.   
 
17 Registration and listing  requirements for drugs should also  be met for combination products that include a drug as 
a constituent part, and for drugs intended as a constituent part of a combination  product, regardless of which  FDA 
center has the lead for review of  the combination product (See 21 U.S.C. 503(g); 21  CFR part 3). 
  6
 
     Contains Nonbinding Recommendations 
 
 
Although FDA does not accept drug establishment registration information from private label 
distributors (PLDs),18 PLDs may request their own NDC Labeler Code and elect to submit drug 
listing information to FDA.  (21 CFR 207.20(b)).  By submitting drug listing information, the 
PLD assumes full responsibility for compliance with the listing requirements. (21 CFR 
207.20(b)) In such instances, at the time of submitting or updating drug listing information, 
private label distributors must certify to the registered establishment(s) that manufactured, 
prepared, propagated, compounded or processed (which includes, among other things, 
repackaging and relabeling) the listed drug(s) that the drug listing submission was made (21 CFR 
207.20(b)). The certification to the registered establishment by the private label distributor may 
be satisfied using paper format.  If a drug product is listed by the PLD, it should not also be listed 
by the owner(s) of the registered establishment(s) that manufactured, prepared, propagated, 
compounded or processed (which includes, among other things, repackaging and relabeling) the 
listed drug(s). 
 
Registrants (and, if applicable, private label distributors) must update their drug listing 
information, and include drugs that have been introduced for commercial distribution and have 
not previously been listed (Section 510(j)(2) of the Act; 21 CFR 207.21(b); 21 CFR 20720(b)).  
Any updates must be submitted every June and December (Section 510(j)(2) of the Act; 21 CFR 
207.21(b)). However, registrants (and, if applicable, private label distributors) are encouraged to 
submit updates through the registration and listing system more frequently as changes occur, 
including labeling updates required to be submitted under listing requirements (21 CFR 
207.21(b); 21 CFR 207.22(b); 21 CFR 207.25; 21 CFR 207.30), or labeling submission needed 
to fulfill obligations for electronic submission of  content of labeling in connection with approval 
applications. (See section II of this document and footnote 12.)   As previously discussed in 
section II of this document, because the drug listing system is a key repository for labeling, it is 
particularly important to keep this information up to date. 
 
Section 510(p) of the Act, as amended by FDAAA, now requires drug listing, including updates, 
to be submitted electronically unless a waiver is granted.  Therefore, listing information should 
now be submitted electronically using SPL files with coded data fields. 
 
The electronic drug establishment registration and drug listing system will permit FDA to 
electronically populate the Agencys listing databases and the NDC Directory and will, therefore, 
improve the inclusiveness and accuracy of these databases.   
 
2.  What information is submitted for drug listing? 
 
Section 510 of the Act and 21 CFR Part 207 set forth the drug listing information required to be 
submitted by domestic and foreign drug establishments.   (Section 510(j) of the Act; 21 CFR 
207.25(b) and (c); 21 CFR 207.30; 21 CFR 207.31; 21 CFR 207.40).     For representative 
                                                 
18  Private label distributor or PLD means an owner or operator of an establishment not otherwise required to  
register under  section  510 of  the Act, but who distributes under its own label or trade name a drug manufactured or  
processed by a registered establishment.  (See 21 CFR  207.20(b))     
 
  7
 
     Contains Nonbinding Recommendations 
 
samples of advertising and labeling required under 21 CFR 207.25(b)(4) and (b)(5), only one 
need be submitted of each sample type, as described in 21 CFR 207.3(a)(9) and (a)(10).  
 
Historically, registrants have also submitted additional drug listing information on Form FDA 
2657 and Form FDA 2658.19  Likewise, for electronic submission, registrants should submit the 
following additional information in their SPL file: 
 	  Name of establishment(s) manufacturing or processing the listed drug and the type of  
operation(s) performed; 
 	  DEA schedule; 
 	  Route(s) of administration; 
 	  Inactive ingredients; 
 	  Marketing information (e.g., category, start/stop date)20; 
 	  Information related to the application (e.g., type and year of approval) or OTC 

monograph citation number; and 

 	  Package size and type. 
 
In addition to information that was previously submitted on Forms FDA 2657 and FDA 2658, 
the registrant should also submit:  
 
 	  NDC Product Code for a Source Drug Repacked or Relabeled 
 
Repackers and relabelers should submit the NDC Product Code for the source drug that is 
repacked or relabeled, in order to reference manufacturing establishment information submitted 
in the listing entry for the source drug. 
 
 	  Unique Ingredient Identifiers (UNII)  and other code sets 
 
An explanation of UNII codes and other code sets and where they may be found is described in 
section IV.B of this document.   
 
 	  Confidentiality Flag 
 
Registrants (and, if applicable, private label distributor) may identify an inactive ingredient or 
the registrants business relationship with an establishment that they view as confidential when 
submitting registration and listing information.  Pursuant to a Freedom of Information Act 
request or on our own initiative, FDA will ultimately make determinations as to whether drug 
establishment registration and drug listing information can be disclosed to the public pursuant to 
                                                 
19 See 21 CFR  207.22 and 21 CFR 207.25(b).  As noted, with  the amendment of section 510(p)  of the Act in  2007, 
listing information is  required to  be submitted electronically. Therefore, submission of such information on  
particular  paper forms is no longer acceptable (absent grant of a waiver), and information should instead be 
submitted in accordance with  this guidance document.  FDA intends to amend the regulations to conform to the 
changes in the underlying statutory provision.  
 
20 The expiration date of the last lot released  to  the marketplace is considered a stop-date.  
  8
 
     Contains Nonbinding Recommendations 
 
the Trade Secrets Act, the Freedom of Information Act, and other applicable law (e.g., section 
510(f) of the Act and 21 CFR 207.37).21  
 
   Distinctive Characteristics of Certain Listed Drugs 
 
Registrants (and, if applicable, private label distributors) should provide the following 
characteristics for the listed drug, when applicable.  Registrants (or private label distributors) 
have previously provided these characteristics voluntarily as helpful information for the safe and 
effective use of their products. 
 
o   Flavor 
 
When applicable, the registrant (and, if applicable, private label distributor) should provide the 
flavor as a unique distinguishing characteristic of the listed drug. (Registrants have previously 
provided this information on Form FDA 2657 as an ingredient.) 
 
o   Color 
 
For liquid dosage forms, the registrant (and, if applicable, private label distributor) should 
provide the color as a unique distinguishing characteristic.  This may be useful to assist in 
judging whether a change in color may indicate contamination or to avoid confusion of the 
intended color of a solution with contamination.  
 
o   Image 
 
For solid oral dosage forms, the registrant (and, if applicable, private label distributor) may 
submit an image of the actual dosage form.  This information is helpful in identifying the drug, 
for example in order to help determine that the correct drug has been dispensed.  The registrant 
can obtain instructions on obtaining the image and the proper format in the SPL file by following 
the instructions for technical assistance in section IV.D of this document.   
 
 
IV. 	 CREATING THE DRUG ESTABLISHMENT REGISTRATION AND DRUG 
LISTING FILE FOR ELECTRONIC SUBMISSION 
 
A. 	 Structured Product Labeling 
 
SPL is the standard that FDA intends to use for the exchange of drug establishment registration 
and drug listing information and is based on the Health Level Seven (HL7) version 3 Reference 
Information Model (RIM) and the Clinical Document Architecture (CDA). 
 
FDA uses SPL for electronic submissions of drug establishment registration and drug listing 
information.  The technical details on using SPL for registration and listing are available in the 
                                                 
21 Other elements of listing information, including the marketing date and application ,information described above,  
will help  FDA to determine the confidentiality of listing  information, including labeling, submitted for drugs still 
under premarket  review. 
  9
 
     Contains Nonbinding Recommendations 
 
document Structured Product Labeling Implementation Guide for FDA Drug Establishment 
Registration and Drug Listing (SPL Implementation Guide).  
 
FDA has been accepting SPL files for certain product information since 2004, and vendors have 
provided solutions for creating SPL files ranging from basic software tools to comprehensive 
information management systems.  Additionally, FDA has collaborated with GlobalSubmit on 
software to create SPL files based on XForms technology.  Information on using the XForms is 
available in the document Step-by-Step  Instructions for Creating Structured Product Labeling 
(SPL) Files for Drug Establishment Registration and Drug Listing. 
 
These documents are on the FDA Data Standards Council website, 
http://www.fda.gov/oc/datacouncil/spl.html.   
 
B.  Code Sets and Codes 
 
To facilitate FDAs ability to process, review, and archive electronic submissions, code sets and 
codes are used as a language that is recognized by a computer system.  FDA has been working 
with a number of organizations to develop and maintain such code sets and codes used for 
submitting drug establishment registration and drug listing information electronically.  Many 
code sets and codes are already available at the Data Standards Council website 
(http://www.fda.gov/oc/datacouncil/spl.html), and FDA is continuously updating these codes sets 
and adding codes.  Information on the organizations that maintain the code sets for submitting 
drug establishment registration and drug listing information electronically and how to obtain the 
code sets and codes used for electronic drug registration and listing follows. 
 
1.  Unique Ingredient Identifiers (UNII) 
 
UNII is the defined code FDA uses for ingredients/substances.  FDA along with United States 
Pharmacopeia (USP) maintains the UNII  using the FDA Substance Registration System. These 
names and identifiers are accessible through USP website at http://www.usp.org and 
publications, the Data Standards Council website (http://www.fda.gov/oc/datacouncil/spl.html) 
and the NCI Thesaurus website at http://evs.nci.nih.gov. Additional ingredient identifiers may be 
requested through FDA by sending a request to spl@fda.hhs.gov. 
 
2.  Data Universal Numbering System (D-U-N-S) Number22  
 
Dun & Bradstreet assigns and maintains a database of the D-U-N-S Numbers, which serve as 
unique identifiers (codes) of business entities.  Upon application, each business entity (e.g., 
registrant, establishment, importer, US agent) is assigned a distinct site-specific 9-digit D-U-N
S Number.  The site-specific D-U-N-S Number for an entity is a useful resource for FDA in 
identifying and verifying certain business information for that entity, e.g., trade names used by 
the entity, addresses, additional ownership information, such as the name of each partner or the 
                                                 
22 D-U-N-S Numbers are proprietary to and controlled by Dun & Bradstreet  (D&B).   Where practicable, the 
customer will refer to the number as a D-U-N-S Number and state that D-U-N-S is a registered trademark  of  
D&B. 
 
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name of each corporate officer and director, and the State of incorporation.  If the D-U-N-S 
Number for a location has not been assigned, a business may obtain one for no cost directly from  
Dun & Bradstreet (http://www.dnb.com). If the business entity does not submit a D-U-N-S 
Number with its submission, FDA intends to make arrangements for obtaining a D-U-N-S 
Number for that entity. 
 
3. 	 Other code sets 
 
FDA collaborates with the National Cancer Institute Enterprise Vocabulary Services (NCI EVS) 
to maintain code sets for dosage form, routes of administration, package types, DEA schedule, 
product color, product shape, flavors, business operations, marketing categories and equivalence 
codes. These code sets are located in the NCI Thesaurus and may be accessed through the NCI 
EVS website at http://evs.nci.nih.gov and the Data Standards Council website (see section II of 
this document).  Additional code sets and codes for use in registration and listing may be 
requested though FDA by sending a request to spl@fda.hhs.gov. 
 
The Regenstrief Institute23  maintains a number of different code sets used in electronic drug 
establishment registration and drug listing including: document types, section headings, and units 
of measure. These code sets are located in the Logical Observation Identifiers Names and Codes 
(LOINC) and Unified Codes for Units of Measure (UCUM) systems.  Both of these 
terminologies are available at http://www.regenstrief.org and at other locations.  Additional code 
sets and codes may be requested through FDA by sending a request to spl@fda.hhs.gov 
following the instructions in section IV.D of this document. 
 
C. 	 Submission and FDA Validation of Electronic Drug Establishment 
Registration and Drug Listing Information 
 
The SPL file should be created following the technical specifications in the SPL Implementation 
Guide and other information found in this document.  Other resources for creating the SPL file, 
including a link to a user-friendly software tool (XForms), are also available.24  Once the SPL 
file is created, it can then be submitted (uploaded) by following the instructions for the FDA 
Electronic Submissions Gateway (ESG), including digital certification.25    
 
The process for establishing an ESG account may involve a delay before drug registration and 
listing information can be received electronically by FDA.  FDA encourages owners and 
operators subject to registration and listing to establish their ESG accounts as soon as possible; 
establishing an ESG account 4-6 weeks in advance of the time when the owner or operator must 
register, list, or update a registration or listing will best ensure that electronic submissions are not 
delayed. 
                                                 
23 The Regenstrief Institute is an internationally recognized informatics and healthcare research organization.  
 
24 See http://www.fda.gov/oc/datacouncil/spl.html  for additional  resources, terminology, and data  standards 
regarding the SPL files.    See http://www.fda.gov/oc/datacouncil/xforms.html for information on the user-friendly  
software tool.  
 
25 See http://www.fda.gov/esg/default.htm for information on  other resources and using the FDA ESG.   
 
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FDA recognizes that there may be a delay between the time an owner or operator requests an 
ESG account and the time the account is established and can upload submissions.  Provided the 
owner or operator requests an ESG account before the due date of their first electronic 
submission, FDA intends to exercise enforcement discretion and does not intend to initiate action 
based on a first electronic submission that is late if the owner or operator also makes the required 
submission (e.g., registration, listing, or update) within 30 days following establishment of an 
ESG account. 
 
FDA uses a computer system for processing the SPL files using controlled code sets and codes. 
The computer system automatically checks the SPL files for certain errors, mistakes and 
omissions prior to entering the information into FDA systems.  FDA will work with companies 
to help correct identified problems in order to complete the registration and listing process.  
Information on the details used in checking SPL files for electronic drug establishment 
registration and drug listing are in the document FDAs Structured Product Labeling Validation 
Procedures for Electronic Drug Establishment Registration and Drug Listing.26 This document 
is on the Data Standards Council website (see section II of this document).    
 
D.  Technical Assistance 
 
For technical problems or assistance with creating SPL files, send an email to spl@fda.hhs.gov. 
 
 
V.  IMPLEMENTATION 
 
Beginning June 1, 2009, FDA intends to no longer accept drug establishment registration and 
drug listing information in paper format unless a waiver is granted. 
 
 
VI.  WAIVER REQUEST 
 
Under section 510(p) of the Act, registrations and listings (including the submission of updated 
information) must be submitted electronically unless FDA grants a waiver of such requirement 
because use of electronic means is not reasonable for the person requesting such waiver.  FDA 
does not anticipate many instances in which electronic submission of registration and listing 
information will not be reasonable for the person requesting the waiver.  However, if you are 
granted a waiver, you will be instructed as to how to submit the registration and listing 
information. 
 
To apply for a waiver from the requirement to electronically submit drug establishment 
registration and drug listing information, provide a written request with a complete explanation 
of why use of electronic means is not reasonable for you.  Submit the request to: 
 
                                                 
26 This  document is used  by FDA and describes FDAs computer instructions for automating the validation of  
submitted SPL files containing  registration and listing information.  
 
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SPL Coordinator 
U.S. Food and Drug Administration (HF-18) 
5600 Fishers Lane 
Rockville, MD 20857-0001 
 
Phone: 1-888-463-6332 
 
 
VII.  PAPERWORK REDUCTION ACT OF 1995 
 
This guidance contains information collection provisions that are subject to review by the Office 
of Management and Budget (OMB) under the paperwork Reduction Act of 1995 (44 U.S.C. 
3501-3520), 
 
The time required to complete this information collection is estimated to average 4.5 hours per 
response, including the time to review instructions, search existing data sources, gather the data 
needed, and complete and review the information collection.  Send comments regarding this 
burden estimate or suggestions for reducing this burden to spl@fda.hhs.gov.  
 
This guidance also refers to previously approved collections of information found in FDA 
regulations. The collections of information in Part 207 have been approved under OMB Control 
No. 0910-0045. 
   
 
An agency may not conduct or sponsor, and a person is not required to respond to, a collection of 
information unless it displays a currently valid OMB control number.  The OMB control number 
for this information collection is 0910-0045 (expires 3/31/2012). 
 
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