Guidance for Industry 
 
 
Providing Regulatory Submissions in 

Electronic Format  Content of 

Labeling 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
 
Food and Drug Administration 
 
Center for Drug Evaluation and Research (CDER) 
 
Center for Biologics Evaluation and Research (CBER) 
 
 
April 2005  

Electronic Submissions 
 
   
 
Guidance for Industry
 
 
 
Providing Regulatory Submissions in 

Electronic Format  Content of 

Labeling 
 
 
 
 
 
 
 
Additional copies are available from: 
 
 
Office of Training and Communications  

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  

 
or
 
 
 Office of Communication, Training and  

Manufacturers Assistance, 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  

Phone: the Voice Information System at 800-835-4709 or 301-827-1800 
 
 
 
 
 
 
U.S. Department of Health and Human Services 
 
Food and Drug Administration 
 
Center for Drug Evaluation and Research (CDER) 
 
Center for Biologics Evaluation and Research (CBER) 
 
 
April  2005  

Electronic Submissions 

   
Table of Contents  
 
I.   INTRODUCTION.....................................................................................................................................................1
  
II.   BACKGROUND .......................................................................................................................................................2
  
A.   THE ELECTRONIC LABELING RULE........................................................................................................................2
  
B.   NEW TECHNOLOGY FOR PROCESSING LABELING..................................................................................................2
  
AND LABELING CHANGES.................................................................................................................................................2
  
III.   GENERAL ISSUES.............................................................................................................................................4
  
A.   FILE FORMATS FOR PROVIDING CONTENT OF LABELING .....................................................................................4
  
B.   CREATING THE CONTENT OF LABELING FILE........................................................................................................4
  
C.   PROCEDURES FOR SENDING THE CONTENT OF LABELING....................................................................................5
  
D.   TECHNICAL PROBLEMS OR QUESTIONS.................................................................................................................5
  
IV.   ORGANIZING THE MAIN SUBMISSION FOLDER.................................................................................5
  
 
  i  Contains Nonbinding Recommendations  
 
 
 
1 
Guidance for Industry  
 
Providing Regulatory Submissions in Electronic Format  
   
Content of Labeling  

 
 
 
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 applicants making regulatory 
submissions to FDA in electronic format. Agency guidance documents on electronic submissions 
will be updated regularly to reflect the evolving nature of the technology and the experience of 
those using this technology.   
 
The Agency is adopting new technology for processing and managing labeling and labeling 
changes, including the content of labeling submitted electronically.  This guidance describes how 
to submit the content of labeling using the Structured Product Labeling (SPL) standard, which is 
based on extensible markup language (XML).  
 
This guidance discusses issues related to the submission of the content of labeling in electronic 
format for marketing applications for human drug and biologic products, including new drug 
applications (NDAs), abbreviated new drug applications (ANDAs), and biological license 
applications (BLAs) for biological products that meet the definition of drug in the Federal Food, 
Drug, and Cosmetic Act.  The content of labeling is the labeling required under 21 CFR 
201.100(d)(3) including all text, tables, and figures (commonly referred to as the package insert 
or professional labeling). This guidance applies to the content of labeling provided with original 
submissions, supplements, and annual reports.  Copies of the formatted label and labeling and 
                                                 
1 This guidance has been prepared by the Information Management Program in the Center for Drug Evaluation and 
Research (CDER).  
 
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 collections of information in this guidance have been approved under OMB Control No. 0910
0530.  
  1
  Contains Nonbinding Recommendations  
 
 
specimens of enclosures required elsewhere in the regulations (e.g., 21 CFR 314.50(e)(2)(ii)), 
including carton and container labels, must still be submitted either electronically in Portable 
Document Format (PDF) or on paper.  
 
For a list of guidances that are under development on electronic submissions, see the guidance 
Regulatory Submissions in Electronic Format  General Considerations.2 The general 
considerations guidance also addresses issues (e.g., appropriate file formats, media, and 
submission procedures) that are common to all submission types.  
 
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  
 
A.  	 The Electronic Labeling Rule  
 
On December 11, 2003, FDA published final regulations (the electronic labeling rule) requiring 
the submission of the content of labeling in electronic format for marketing applications (68 FR 
69009).  The requirements of the electronic labeling rule can be found in   314.50(l) for NDAs, 
  314.94(d) for ANDAs,  601.14(b) for BLAs, and  314.81(b) for annual reports to marketing 
applications. The effective date of the rule was June 8, 2004.  The regulations specify that the 
content of labeling must be submitted electronically in a form that FDA can process, review, and 
archive.  The regulations also state that FDA will periodically issue guidance on how to provide 
the electronic submission.  This guidance provides information on how to submit the content of 
labeling in electronic format.  
 
B.  	 New Technology for Processing Labeling 
 
and Labeling Changes  

 
The regulations require that the content of labeling be submitted in a form that we (FDA) can 
process, review, and archive.  Since 1999, FDA has been receiving the electronic content of 
labeling in Portable Document Format (PDF), and this format has allowed us to process, review 
and archive the content of labeling.  Recently, however, recommendations from the Institute of 
Medicine and the National Committee on Vital and Health Statistics and mandates in the 
Medicare Prescription Drug, Improvement, and Modernization Act of 2003 (Public Law 108
173) have created a new role for electronic labeling information. Electronically formatted 
content of labeling will be used to support health information management technologies such as 
electronic prescribing; the electronic health record (EHR), which will provide health care 
                                                 
2 We update guidances periodically. To make sure you have the most recent version of a guidance, check the 
CDER guidance page at http://www.fda.gov/cder/guidance/index.htm and the CBER guidance page at 
http://www.fda.gov/cber/guidelines.htm.  
 
  2
  Contains Nonbinding Recommendations  
 
 
providers, patients, and other authorized users access to patient information in electronic format; 
and the DailyMed, a new way to distribute up-to-date and comprehensive medication 
information in a computerized format for use in health care information systems.  
 
We have determined that our current procedures using PDF are not adequate to support these 
electronic initiatives. To support the new programs, the Agency is changing the way it processes, 
reviews, and archives the content of labeling.  The Agency is adopting a new technology for 
exchanging information between computer systems based on Clinical Document Architecture 
(CDA).  CDA was developed by Health Level Seven (HL7), a standards development 
organization accredited by the American National Standards Institute (ANSI). CDA allows 
information to be exchanged in extensible markup language (XML) and is the standard being 
investigated for the EHR.   
 
FDA, working with other parties in HL7 (experts from HL7, industry, and technology solution 
providers), has adapted CDA for labeling in an HL7 standard called Structured Product Labeling 
(SPL). When compared with PDF, SPL exhibits the following advantages.  
 
	   SPL allows the exchange of information between computer systems in a way that cannot 
be accomplished with PDF. For example, the information in SPL can be used to support 
health information technology initiatives for improving patient care.   
	   The exchange of labeling changes with SPL can be easier and more efficient for both 
FDA and manufacturers when compared with PDF. For example, with SPL, only those 
sections or data elements of the labeling that are changed would need to be checked 
rather than the entire labeling.  
	   SPL allows automation of comparison of text by section and comparison of specific drug 
information data elements.  
	   SPL can also be used to exchange information needed for other submissions, such as drug 
listing, thus eliminating redundant data collection and improving efficiency.  
 
The Agency is developing an automated system using SPL for processing and managing labeling 
and labeling changes. The Center for Drug Evaluation and Research has identified SPL in public 
docket number 92S-0251 as a format that FDA can use to process, review, and archive the 
content of labeling.  During our transition to the automated system, the Agency is able to accept 
the content of labeling in either PDF or SPL file format.  After the automated system is 
implemented, PDF will no longer be a format that we can use to process, review, and archive the 
content of labeling. The change to SPL will apply only to those submissions with content of 
labeling files that are provided after the impleme ntation of the automated system.  At this time, it 
is our goal to complete the transition to SPL format for content of labeling submissions for 
approved prescription drugs by fall 2005.  
 
The Agency is changing to SPL format so the content of labeling can be used in a variety of 
ways  searched, moved between systems, combined with other data sources  to support 
electronic health initiatives.  At this time, the Agency will continue to receive other parts of 
electronic applications in the formats described in applicable Agency guidance on electronic 
submissions.  
  3
  Contains Nonbinding Recommendations  
 
 
III.   GENERAL ISSUES  

 
This guidance applies to the content of labeling for any marketing application (ANDAs, BLAs, 
NDAs) submission required to be submitted in electronic format under  314.50(l) 
314.81(b)(2), 314.94(d),  and 601.14(b).  
 
A.   File Formats for Providing Content of Labeling  
 
Prior to the implementation of the automated system, we will be able to receive content of 
labeling in PDF or SPL file format. After implementation of the automated system, we will only 
be able to receive content of labeling in SPL format.   
 
This guidance describes how to submit the content of labeling using XML based on the HL7 SPL 
specifications.  
 
For information on how to submit the content of labeling using PDF based on the Adobe 
Systems Incorporated specifications, see the current Agency guidance on providing regulatory 
submissions in electronic format.3    
 
B.   Creating the Content of Labeling File  
 
Please refer to the HL7 published specifications for Structured Product Labeling (SPL) for 
details on how to create the content of labeling file for submission to FDA.  The SPL 
specifications can be obtained from HL7 (www.hl7.org). Additional details on creating SPL for 
submission to FDA can be found in the HL7 document SPL Implementation Guide for FDA 
Content of Labeling Submissions. The implementation guide may be found on the HL7 web site 
at http://www.hl7.org.  Links to SPL-related documents located on the HL7 Web site and 
additional SPL-related resources (including the most recent updates, stylesheet files for viewing 
SPL files, and example labels) can be found at the FDA Web site at 
www.fda.gov/oc/datacouncil/spl.html.  
 
Bookmarks commonly included in the PDF content of labeling files to sections within the 
labeling are not needed because the tags in the SPL file provide this functionality. SPL does not 
replace various methods used for negotiating labeling changes (e.g., FAX, Word files). Prior to 
the implementation of the automated system, FDA can accept content of labeling submitted in 
SPL file format only in a complete SPL file.  Submission of multiple versions of the labeling 
(e.g., proposed or current) and submission of the history.pdf file can be eliminated only after 
the implementation of the automated system.  
 
                                                 
3 See the guidances for industry entitled Providing Regulatory Submissions in Electronic Format  NDAs and 
Providing Regulatory Submissions to the Center for Biologics Evaluation and Research (CBER) in Electronic 
Format  Biologics Marketing Applications. To make sure you have the most recent version of a guidance, check 
the CDER guidance page at http://www.fda.gov/cder/guidance/index.htm or the CBER guidance page at 
http://www.fda.gov/cber/guidelines.htm.  
 
  4
  Contains Nonbinding Recommendations  
 
 
C.   Procedures for Sending the Content of Labeling  
 
Content of labeling must be provided in electronic format ( 314.50(l), 314.94(d), 601.14(b), 
and 314.81(b)), even when it is part of a paper submission.   Before implementation of the 
automated system, you should follow the procedures in either this guidance or Agency guidance 
on submitting electronic NDAs or BLAs4 for information on how to submit the content of 
labeling electronically.  After implementation of the automated system, you should follow the 
procedures in this guidance for submission of the content of labeling electronically.   
 
Note: In order for FDA to process, review, and archive electronic content of labeling,  all 
submissions, including annual reports, must be made in accordance with certain provisions of 21 
CFR part 11 specified in the electronic labeling rule ( 314.50(l), 314.94(d)(1), 601.14(b), and 
314.81(b)) and sent to the appropriate central document room facilities specified in public docket 
number 92S-0251.  Electronic documents that are sent directly to division document rooms or to 
reviewers bypass the controls established for the receipt and archiving of documents and, 
therefore, are not considered official documents for review.  
 
D.   Technical Problems or Questions  
 
If you have any questions on technical issues related to providing the content of labeling in 
submissions according to the recommendations in this guidance, please contact the appropriate 
electronic submission coordinator at esub@cder.fda.gov or esubprep@cber.fda.gov.  Specific 
questions pertaining to content should be directed to the appropriate review division or office.  
 
 
IV.   ORGANIZING THE MAIN SUBMISSION FOLDER  
 
The content of labeling  SPL files should be placed in a single folder titled spl. The spl folder is 
used for all submissions in SPL whether they are part of an electronic submission or a paper 
submission.  
 
If the content of labeling in  SPL is provided with an electronic submission, you should place the 
spl folder in the appropriate folders for labeling. For additional information on organizing the 
submission folder in an electronic submission, see current Agency guidance on providing 
regulatory submissions in electronic format.5  
 
                                                 
4 For content of labeling submitted as part of a paper submission, see the guidances for industry entitled Providing 
Regulatory Submissions in Electronic Format  NDAs and Providing Regulatory Submissions to the Center for 
Biologics Evaluation and Research (CBER) in Electronic Format  Biologics Marketing Applications.  
 
5 See footnote 3.  
  5