Guidance for Industry 
 
SPL Standard for Content of Labeling  
Technical Qs & As  
 
DRAFT GUIDANCE
 
 
   
This Guidance document is being distributed for comment purposes only. 
 
Comments and suggestions regarding this draft document should be submitted within 60 days of 
publication in the Federal Register of the notice announcing the availability of the draft 
guidance.  Submit comments to the Division of Dockets Management (HFA-305), Food and 
Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD  20852.  All comments 
should be identified with the docket number listed in the notice of availability that publishes in 
the Federal Register. 
 
For questions regarding this draft document contact Lonnie Smith 301-594-0011. 
 
 
 
 
 
 
 
 
 
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)  
 
October 2009 
Electronic Submissions 
Revision 1   Guidance for Industry  
SPL Standard for Content of Labeling  
Technical Qs & As 
 
 
 
 
 
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 
 
 
 
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 
Phone:  
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)  
 
October 2009 
Electronic Submissions 
 
Revision 1  Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
1 
Guidance for Industry
1   
SPL Standard for Content of Labeling  
2 
Technical Qs & As  
3 
4   
5   
6  This guidance represents the Food and Drug Administration's (FDA's) current thinking on this topic. It 
7  does not create or confer any rights for or on any person and does not operate to bind FDA or the public. 
8  You can use an alternative approach if the approach satisfies the requirements of the applicable statutes 
9  and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for 
10  implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number 
11  listed on the title page of this guidance.  
12   
13   
14   
15   
16  INTRODUCTION  
17   
18  This guidance is intended to assist applicants who submit content of labeling to FDA as part of 
19  a marketing application using the structured product labeling standard (SPL) in extensible 
20  markup language (XML). The guidance also provides information to FDA staff who review and 
21  manage product information using electronic systems. This is revision 1 of a guidance of the 
22  same name that was issued in December 2005. The guidance has been revised to reflect changes 
23  in the technology since 2005 and to harmonize the submission of SPL in the Center for 
24  Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research 
25  (CDER). We anticipate that additional guidance will be provided as new questions arise about 
26  the use of SPL in different contexts.2 
27   
28  FDA's guidance documents, including this guidance, do not establish legally enforceable 
29  responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should 
30  be viewed only as recommendations, unless specific regulatory or statutory requirements are 
31  cited. The use of the word should in Agency guidances means that something is suggested or 
32  recommended, but not required.  
33   
34  BACKGROUND  
35   
36  In the Federal Register of December 11, 2003 (68 FR 69009), FDA published final regulations 
37  requiring that the content of labeling be submitted to FDA electronically for new drug 
                                                 
1 This guidance has been prepared by Office of Critical Path Programs in the Office of the Commissioner at the 
Food and Drug Administration.  
 
2  See FDAs guidance Providing Regulatory Submissions in Electronic Format  Drug Establishment Registration 
and Drug Listing. 
  1 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
38  applications (NDAs), abbreviated new drug applications (ANDAs), certain biologics license 
39  applications (BLAs),3 and annual reports (see 21 CFR 314.50(l), 314.94(d), 601.14(b), and 
 
40  314.81(b), respectively). The regulations state that the content of labeling must be submitted to 
41  FDA electronically and "in a form that FDA can process, review, and archive.  
42   
43  Initially, CDER accepted electronic submissions of content of labeling in portable document 
44  format (PDF). Then, in September 2004, CDER announced that it would accept content of 
45  labeling in both PDF and SPL formats until the autumn of 2005, when PDF would be eliminated. 
46  On October 21, 2005, CDER announced in public docket number 92S-0251 that effective 
47  October 31, 2005, CDER would no longer accept content of labeling submissions in PDF format 
48  and that applicants should use the SPL standard when submitting content of labeling to FDA in 
49  XML with original submissions, supplements, and annual reports. CBER made a similar 
50  announcement on July 11, 2008, that went into effect on October 15, 2008.  In a Draft Guidance 
51  that published on July 10, 2008, CDER, CBER and the Center for Veterinary Medicine 
52  announced their intention to begin using the SPL standard for electronic drug establishment 
53  registration and drug product listing (a final version of that guidance was issued at the end of 
54  May 2009). 
55   
56  Since FDA began accepting content of labeling in SPL format for application submissions, we 
57  have received numerous questions about SPL submission requirements. Based on preliminary 
58  questions, and in an effort to provide easy access to the answers to frequently asked  questions, 
59  in December 2005, we published the first guidance for industry SPL Standard for Content of 
60  Labeling Technical Qs and As. In an effort to provide the most useful and up-to-date 
61  information on SPL submissions, FDA is revising the December 2005 guidance.  The revision 
62  provides both updated answers to questions previously addressed and information responsive to 
63  other questions related to submissions in SPL format. The Agency plans to continue updating 
64  this guidance with additional answers to questions as warranted.  
65  For definitions of SPL-related terms, please see FDAs Data Standards Council Web site at 
66  www.fda.gov/oc/datacouncil. If you have additional questions about SPL submissions, you 
67  should contact spl@fda.hhs.gov.  For questions on submissions to CDER or CBER, contact the 
68  appropriate electronic submission coordinator at esub@cder.fda.gov or esubprep@cber.fda.gov, 
69  respectively. Specific questions pertaining to content of labeling should be directed to the 
70  relevant review division or office in the appropriate center. 
                                                 
3 The final regulations do not apply to devices regulated under a BLA.  
  2 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
71   
72  TECHNICAL QUESTIONS AND ANSWERS 
73  1.  What was the implementation date for using the SPL for content of labeling in FDA 
74  application submissions?  
75  For CDER-regulated products, the implementation date was October 31, 2005. For CBER-
76  regulated products, the implementation date was October 15, 2008.  
77  2.  When do I need to include an SPL file in my submission?  
78  An SPL file must accompany all submissions that propose changes to the content of labeling, 
79  including certain amendments (e.g., an amendment to a changes being effected (CBE) 
80  supplement containing updated content of labeling), submissions of final approved content of 
81  labeling (regardless of marketing date), and annual reports  (see question 34 for more 
82  information on annual reports).4    
83  3.  What if I have already submitted SPL content of labeling during the registration 
84  and listing process? 
85   
86  This guidance only applies to SPL files submitted with applications. Additional guidance has 
87  been drafted that applies to the registration and listing process.5 If you have already submitted 
88  identical content of labeling in a SPL file during the registration and listing process, you need not 
89  include the SPL file in your application.  Instead, we recommend that you update your 
90  application by referencing the SPL file in the registration and listing system.  To do this, place a 
91  link in your application submission that directs FDA to your SPL file (e.g., We have submitted 
92  the SPL file with drug listing; it can be found at the following location 
93  http://www.accessdata.fda.gov/spl/data/ [insert your SPL document id root here/insert SPL 
94  document id root here].xml] (see also question 31)." 
95   
96  The SPL document ID has to be repeated in the URL for the users to be able to access the SPL 
97  files from the Web server location. 
98   
99  4.  Do other labeling documents need to be provided using the SPL standard? 
100   
101  No. Only electronic content of labeling is to be submitted using the SPL standard (including the 
102  XML document and all associated image files referenced in the XML document, such as 
103  chemical structures or graphs included in a clinical studies section). Other labeling documents 
104  (e.g., the annotated labeling, container labels, and carton labels) should not be submitted to the 
105  application using the SPL standard.  
                                                 
4 See 21 CFR 314.50(l) for NDAs, 314.94(d) for ANDAs, 601.14(b) for BLAs, and 314.81(b) for annual reports. 
 
5 See FDAs guidance Providing Regulatory Submissions in Electronic Format   
Drug Establishment Registration and Drug Listing. 
  3 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
106   
107  5.  Should an applicant still submit an annotated Word version of the content of 
108  labeling?  
109  Yes. We recommend that applicants continue to submit the annotated Word version of the label 
110  and all labeling for the product. SPL is the current standard for electronic content of labeling 
111  submissions and replaces proposed content of labeling submissions in PDF format.  
112  6.  How do I send my SPL file to FDA when making an electronic 
113  submission?  
114  The SPL file should be included in a folder marked spl within the labeling folder. Refer to 
115  guidance for industry Providing Regulatory Submissions in Electronic Format  Content of 
116  Labeling for more information on the SPL submission process.  
117   
118  Alternatively, you can provide the Uniform Resource Locater (URL) to the SPL file for CBEs, 
119  annual reports, and final approved labeling if the SPL labeling was already submitted during the 
120  electronic registration and listing process. 
121   
122  7.  How do I send my SPL file to FDA if my submission is in paper format?  
123  When accompanying a submission in paper format, the SPL file should be submitted using 
124  electronic media (e.g., CD-ROM). The SPL should be included in a folder marked spl (see 
125  guidance for industry Providing Regulatory Submissions in Electronic Format  Content of 
126  Labeling).  
127  8.  Where do I send my SPL submission?  
128  For products regulated by CDER, see http://www.fda.gov/cder/regulatory/ersr/default.htm, for 
129  the address to send electronic submissions.  For products regulated by CBER, see 
130  http://www.fda.gov/CBER/regsopp/8110.htm.  Consult www.fda.gov/esg for submissions via the 
131  Electronic Submissions Gateway for both CDER and CBER regulated products.  
132  9.  When did CDER and CBER begin accepting SPL for content of labeling?  
133  CDER began accepting content of labeling in SPL format in September 2004. At that time, 
134  CDER accepted content of labeling submissions in both SPL and PDF and announced that 
135  CDER would begin accepting only SPL beginning in the autumn of 2005. Since October 31, 
136  2005, CDER has been accepting content of labeling submissions only in SPL format. CBER 
137  began accepting content of labeling exclusively in SPL format on October 15, 2008, as noted 
138  in the memorandum to the electronic submissions docket, published on July 11, 2008. 
139  10.  Should ANDA applicants wait for submission of content of labeling for the 
140  reference listed drug (RLD) before they submit content of labeling in SPL format?  
141  No. If an ANDA applicant determines that content of labeling has not been submitted in SPL 
  4 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
142  format for the reference listed drug, the ANDA applicant should still submit its own content of 
143  labeling in SPL format.  
144  11.  Can the electronic labeling be submitted under separate cover and cross-
145  referenced to a paper submission for all types of submissions, including new ANDAs, 
146  supplements, and annual reports, or should the entire submission be done electronically?  
147  Yes, a combination of electronic labeling for the content of labeling and paper application 
148  submission would be appropriate.  
149  12.  Does the SPL content of labeling replace the 12 copies of paper labeling, 
150  also known as final printed labeling (FPL), that are normally submitted with an 
151  application? 
152  The requirement under 21 CFR 314.50 (l)(i) to provide content of labeling in electronic form 
153  is in addition to the obligation to submit copies of the label and all labeling, including 12 
154  paper copies of FPL, as required by section 314.50(e)(2)(ii) . See also 314.94(d)(i)(ii) 
155  (ANDAs) and 601.14(b)(2) (BLAs).  Applicants should submit either 12 paper copies or 1 
156  PDF copy of FPL carton and container labels, but should submit only SPL files for the 
157  content of labeling submitted with an application.   
158  13.  If the content of labeling is approved based on the draft SPL, when should the final 
159  SPL be submitted after approval? 
160   
161  The final SPL should be submitted preferably within 14 calendar days after approval or as soon 
162  as possible thereafter. 
163   
164  14.  Can we e-mail SPL to the Agency?  
165   
166  No. SPL should be submitted either to FDAs Electronic Document Room with documentation 
167  appropriate for the type of electronic submission or during the registration and listing process 
168  (see response to Question 7). 
169   
170  15.  Should I submit content of labeling in Word and/or PDF with the SPL?  
171   
172  You should no longer submit content of labeling in PDF.  However,  we recommend that you  
173  continue to submit content of labeling in Word.  The Word files facilitate the exchange of 
174  labeling comments and revisions between the applicant and FDA. 
175  16.  Where should I submit SPL files if the application contains both paper and 
176  electronic components? 
177  Both components of the application should be sent to the relevant centers central 
178  document room (just as before implementation of SPL). Similarly, as before 
179  implementation of SPL, the staff will upload the electronic component.  
  5 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
180  17.  Should companies resubmit labeling in SPL if it was submitted before October 
181  15, 2008, in another format and is currently under review in CBER? 
182  No, but we recommend that applicants work with the individual review division or divisions to 
183  ensure that SPL is available within a reasonable time frame for those products with submissions 
184  before October 15, 2008.  
185  18.  Can FDA refuse to file my submission if I do not provide SPL, given that I am 
186  required to do so?  
187  Yes, but we will work with you to help you submit the SPL.  
188  19.  What software do I use to create SPL files?  
189  An SPL file can be created using a variety of tools, ranging from a general-purpose word 
190  processor or XML editor to an SPL-specific editing tool. The type of tool suitable for a specific 
191  organization will vary depending on a wide variety of business and technical factors. Whatever 
192  tool is used, the final SPL document will be independent of the tool used for its creation. All 
193  tools should be able to create valid SPL files and to conform to the guidance for industry 
194  Providing Regulatory Submissions in Electronic Format  Content of Labeling. 
195  20.  What is the difference between XML and SPL? 
196  XML is a specification for creating custom markup languages for sharing structured data. SPL is 
197  a standard that uses XML. 
198   
199  21.  What version of the SPL schema is currently being used by FDA?  
200  The SPL schema currently being used is identified on the FDA Data Standards Council 
201  Web site located at www.fda.gov/oc/datacouncil.   
202  22.  What happens when a new release of the SPL standard is implemented? Should I 
203  resubmit current labels according to the schema in the new release? 
204  We have implemented SPL release 4 to be compatible with the drug registration and 
205  listing process. SPL files can be submitted using the schema in SPL release 4 or release 3 
206  until June 1, 2009, when only release 4 can be used. 
207  23.  Should I submit patient package inserts (PPIs) and Medication Guides (MGs) 
208  in SPL? 
209  Approved patient labeling documents should be included at the end of the SPL file. There are 
210  specific Logical Observation Identifiers Names and Codes (LOINC) codes for PPIs and MGs. 
211  Use the appropriate LOINC code for identifying this information. Each PPI or MG should have 
212  a separate LOINC code.   
  6 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
213  Patient information that is not approved labeling, such as patient information produced by 
214  third parties, should not be included in the SPL file.  
215  24.  Should my SPL file contain the entire content of labeling or just the portion of 
216  the content that has changed since my last application submission?  
217  All submissions should include the entire content of labeling in SPL. FDA cannot support partial 
218  submissions at this time.     
219  25.  The SPL standard provides tags to identify insertions and deletions of content in 
220  an SPL document. Should I submit a redlined or annotated version of the labeling, 
221  indicating version-to-version changes?  
222  No. You should not use the tags provided in the SPL standard to mark up the insertion and 
223  deletion of content.    
224   
225  26.  Should I include graphics for controlled substance symbols, the Rx symbol or 
226  corporate or product logos?  
227  No. These graphics should not be included in an SPL submission. Controlled substance symbols, 
228  and other symbols, should be included in the SPL as text (e.g., CII). 
229  27.  Can I retain hypertext links within a document if they were present in a Word or 
230  PDF file of content of labeling (e.g., clickable cross-references)? 
231  Yes. Hypertext links can be retained within the SPL document. However, these links should 
232  correspond only to other portions of the content of labeling, (e.g., see Dosage and 
233  Administration (2)). 
234  28.  Does the FDA distribute SPL documents to the Web with minor changes to the 
235  section identifiers submitted? 
236  Yes, at the moment, we correct certain coding omissions and errors. However, when applicants 
237  begin using SPL release 4, we will no longer make these corrections. 
238  29.  In preparing an SPL, should I update the section identifier when there is a change 
239  in a subsection?  
240  Yes.  
241  30.  If I relocate a section or subsection without changing its content, should its 
242  section identifier be changed?  
243  No. The identifier of a section that is relocated without content change remains unchanged, but 
244  the identifiers of any enclosing sections before and/or after the relocation should be changed, as 
245  should the document identifier.  
  7 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
246   
247  31.  How is labeling information transmitted to the Web?  
248  Beginning June 1, 2009, FDA will transmit postapproval SPL to the Web electronically from the 
249  electronic drug establishment registration and drug listing system, which will then be considered 
250  the key repository for postmarket SPL content of labeling. Labeling updates to applications can 
251  be made by referencing the SPL file submitted through the drug establishment registration and 
252  drug listing process (see question 3 for the Web address).  
253  32.  If an applicant identifies a problem with the SPL file posted on the Web site, 
254  what should he or she do? 
255  If an applicant notes an inconsistency, he or she should contact the SPL coordinator at 
256  spl@fda.hhs.gov and the relevant centers review division to make the necessary changes.  
257  33.  When is SPL transmitted to the Web and will FDA notify the applicant when SPL is 
258  posted? 
259  No. There is no notification to the applicant that labeling has been posted. Applicants are advised 
260  to check the Web site to ensure that their most recently submitted content of labeling is posted.  
261  34.  Should an applicant submit SPL with an annual report? 
262  Applicants should submit an SPL file of the content of labeling with an annual report if an SPL 
263  file has not previously been submitted for the application, or if there have been changes to the 
264  content of labeling since the last submission of final SPL.  If there have been no changes since 
265  the last submission of final SPL, then the annual report can include a reference to the electronic 
266  content of labeling previously submitted.6   
267   
268  35.  If the first SPL submission is a supplement, should both the current and proposed 
269  labeling be submitted in SPL, or is it sufficient to submit the proposed labeling in SPL? 
270  For supplements, only the proposed content of labeling should be submitted in SPL. In addition, 
271  annotated labeling should also be submitted for use in the application review process. (See 
272  response to Question 5).  
273  36.  Where do I find additional information and specifications on SPL?  
274  Additional information is available on the Internet at the FDA Data Standards Council Web 
275  site and http://www.hl7.org.  
                                                 
6 Final SPL is the submission of SPL that is in current use. This includes SPL with approved content of labeling 
submitted subsequent to the approval of an original BLA/NDA or prior approval supplement; SPL submitted to a 
CBE supplement (with the initial submission and any subsequent amendments); and SPL submitted to an annual 
report that contains annual reportable changes made since the last submission of final SPL. 
 
  8 Contains Nonbinding Recommendations 
Draft  Not for Implementation 
 
276  37.  Should content of labeling in a foreign language be submitted?  
277  Currently, foreign language content of labeling does not need to be submitted in SPL.  
  9