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DRAFT GUIDANCE

 

This Guidance document is being distributed for comment purposes only.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Draft — Not for Implementation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 

2 

3 

4 

Guidance for Industry

1

SPL Standard for Content of Labeling 

Technical Qs & As 

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 

17 

18 

19 

20 

21 

22 

23 

24 

25 

26 

27 

28 

29 

30 

31 

32 

33 

34 

35 

36 

37 

 

INTRODUCTION 

This guidance is intended to assist applicants who submit content of labeling to FDA as part of 

a marketing application using the structured product labeling standard (SPL) in extensible 

markup language (XML). The guidance also provides information to FDA staff who review and 

manage product information using electronic systems. This is revision 1 of a guidance of the 

same name that was issued in December 2005. The guidance has been revised to reflect changes 

in the technology since 2005 and to harmonize the submission of SPL in the Center for 

Biologics Evaluation and Research (CBER) and the Center for Drug Evaluation and Research 

(CDER). We anticipate that additional guidance will be provided as new questions arise about 

the use of SPL in different contexts.2

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. 

BACKGROUND 

In the Federal Register of December 11, 2003 (68 FR 69009), FDA published final regulations 

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 FDA’s guidance Providing Regulatory Submissions in Electronic Format – Drug Establishment Registration 

and Drug Listing.

1
Contains Nonbinding Recommendations 

Draft — Not for Implementation

38 

39 

40 

41 

42 

43 

44 

45 

46 

47 

48 

49 

50 

51 

52 

53 

54 

55 

56 

57 

58 

59 

60 

61 

62 

63 

64 

65 

applications (NDAs), abbreviated new drug applications (ANDAs), certain biologics license 

applications (BLAs),3

 and annual reports (see 21 CFR 314.50(l), 314.94(d), 601.14(b), and 

314.81(b), respectively). The regulations state that the content of labeling must be submitted to 

FDA electronically and "in a form that FDA can process, review, and archive.” 

Initially, CDER accepted electronic submissions of content of labeling in portable document 

format (PDF). Then, in September 2004, CDER announced that it would accept content of 

labeling in both PDF and SPL formats until the autumn of 2005, when PDF would be eliminated. 

On October 21, 2005, CDER announced in public docket number 92S-0251 that effective 

October 31, 2005, CDER would no longer accept content of labeling submissions in PDF format 

and that applicants should use the SPL standard when submitting content of labeling to FDA in 

XML with original submissions, supplements, and annual reports. CBER made a similar 

announcement on July 11, 2008, that went into effect on October 15, 2008. In a Draft Guidance 

that published on July 10, 2008, CDER, CBER and the Center for Veterinary Medicine 

announced their intention to begin using the SPL standard for electronic drug establishment 

registration and drug product listing (a final version of that guidance was issued at the end of 

May 2009). 

Since FDA began accepting content of labeling in SPL format for application submissions, we 

have received numerous questions about SPL submission requirements. Based on preliminary 

questions, and in an effort to provide easy access to the answers to frequently asked questions, 

in December 2005, we published the first guidance for industry SPL Standard for Content of 

Labeling Technical Qs and As. In an effort to provide the most useful and up-to-date 

information on SPL submissions, FDA is revising the December 2005 guidance. The revision 

provides both updated answers to questions previously addressed and information responsive to 

other questions related to submissions in SPL format. The Agency plans to continue updating 

this guidance with additional answers to questions as warranted. 

For definitions of SPL-related terms, please see FDA’s Data Standards Council Web site at 

www.fda.gov/oc/datacouncil. If you have additional questions about SPL submissions, you 

should contact spl@fda.hhs.gov. For questions on submissions to CDER or CBER, contact the 

appropriate electronic submission coordinator at 

66 

67 

esub@cder.fda.gov or esubprep@cber.fda.gov, 

respectively. Specific questions pertaining to content of labeling should be directed to the 

relevant review division or office in the appropriate center. 

68 

69 

70 

 

3

 The final regulations do not apply to devices regulated under a BLA. 

2
Contains Nonbinding Recommendations 

Draft — Not for Implementation

71 

72 

73 

74 

75 

76 

77 

78 

79 

80 

81 

82 

83 

84 

85 

86 

87 

88 

89 

90 

91 

92 

TECHNICAL QUESTIONS AND ANSWERS

1. What was the implementation date for using the SPL for content of labeling in FDA 

application submissions? 

For CDER-regulated products, the implementation date was October 31, 2005. For CBERregulated products, the implementation date was October 15, 2008. 

2. When do I need to include an SPL file in my submission? 

An SPL file must accompany all submissions that propose changes to the content of labeling, 

including certain amendments (e.g., an amendment to a “changes being effected” (CBE) 

supplement containing updated content of labeling), submissions of final approved content of 

labeling (regardless of marketing date), and annual reports (see question 34 for more 

information on annual reports).4 

3. What if I have already submitted SPL content of labeling during the registration 

and listing process? 

This guidance only applies to SPL files submitted with applications. Additional guidance has 

been drafted that applies to the registration and listing process.5

 If you have already submitted 

identical content of labeling in a SPL file during the registration and listing process, you need not 

include the SPL file in your application. Instead, we recommend that you update your 

application by referencing the SPL file in the registration and listing system. To do this, place a 

link in your application submission that directs FDA to your SPL file (e.g., “We have submitted 

the SPL file with drug listing; it can be found at the following location 

http://www.accessdata.fda.gov/spl/data/ [insert your SPL document id root here/insert SPL 

document id root here].xml”] (see also question 31)." 

93 

94 

95 

96 

97 

98 

99 

100 

101 

102 

103 

104 

105 

 

The SPL document ID has to be repeated in the URL for the users to be able to access the SPL 

files from the Web server location. 

4. Do other labeling documents need to be provided using the SPL standard?

No. Only electronic content of labeling is to be submitted using the SPL standard (including the 

XML document and all associated image files referenced in the XML document, such as 

chemical structures or graphs included in a clinical studies section). Other labeling documents 

(e.g., the annotated labeling, container labels, and carton labels) should not be submitted to the 

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 FDA’s guidance Providing Regulatory Submissions in Electronic Format – 

Drug Establishment Registration and Drug Listing. 

3
Contains Nonbinding Recommendations 

Draft — Not for Implementation

106 

107 

108 

109 

110 

111 

112 

113 

114 

115 

116 

117 

118 

119 

120 

121 

122 

123 

124 

125 

126 

127 

5. Should an applicant still submit an annotated Word version of the content of 

labeling? 

Yes. We recommend that applicants continue to submit the annotated Word version of the label 

and all labeling for the product. SPL is the current standard for electronic content of labeling 

submissions and replaces proposed content of labeling submissions in PDF format. 

6. How do I send my SPL file to FDA when making an electronic 

submission? 

The SPL file should be included in a folder marked spl within the labeling folder. Refer to 

guidance for industry Providing Regulatory Submissions in Electronic Format – Content of 

Labeling for more information on the SPL submission process. 

Alternatively, you can provide the Uniform Resource Locater (URL) to the SPL file for CBEs, 

annual reports, and final approved labeling if the SPL labeling was already submitted during the 

electronic registration and listing process. 

7. How do I send my SPL file to FDA if my submission is in paper format? 

When accompanying a submission in paper format, the SPL file should be submitted using 

electronic media (e.g., CD-ROM). The SPL should be included in a folder marked spl (see 

guidance for industry Providing Regulatory Submissions in Electronic Format – Content of 

Labeling). 

8. Where do I send my SPL submission? 

For products regulated by CDER, see http://www.fda.gov/cder/regulatory/ersr/default.htm, for 

the address to send electronic submissions. For products regulated by CBER, see 

128 

129 

http://www.fda.gov/CBER/regsopp/8110.htm. Consult www.fda.gov/esg for submissions via the 

Electronic Submissions Gateway for both CDER and CBER regulated products. 

130 

131 

132 

133 

134 

135 

136 

137 

138 

139 

140 

141 

9. When did CDER and CBER begin accepting SPL for content of labeling? 

CDER began accepting content of labeling in SPL format in September 2004. At that time, 

CDER accepted content of labeling submissions in both SPL and PDF and announced that 

CDER would begin accepting only SPL beginning in the autumn of 2005. Since October 31, 

2005, CDER has been accepting content of labeling submissions only in SPL format. CBER 

began accepting content of labeling exclusively in SPL format on October 15, 2008, as noted 

in the memorandum to the electronic submissions docket, published on July 11, 2008. 

10. Should ANDA applicants wait for submission of content of labeling for the 

reference listed drug (RLD) before they submit content of labeling in SPL format? 

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 

143 

144 

145 

146 

147 

148 

149 

150 

151 

152 

153 

154 

155 

156 

157 

158 

159 

160 

161 

162 

163 

164 

165 

166 

167 

168 

169 

170 

171 

172 

173 

174 

175 

176 

177 

178 

179 

format for the reference listed drug, the ANDA applicant should still submit its own content of 

labeling in SPL format. 

11. Can the electronic labeling be submitted under separate cover and crossreferenced to a paper submission for all types of submissions, including new ANDAs, 

supplements, and annual reports, or should the entire submission be done electronically? 

Yes, a combination of electronic labeling for the content of labeling and paper application 

submission would be appropriate. 

12. Does the SPL content of labeling replace the 12 copies of paper labeling, 

also known as final printed labeling (FPL), that are normally submitted with an 

application?

The requirement under 21 CFR 314.50 (l)(i) to provide content of labeling in electronic form 

is in addition to the obligation to submit copies of the label and all labeling, including 12 

paper copies of FPL, as required by section 314.50(e)(2)(ii) . See also 314.94(d)(i)(ii) 

(ANDAs) and 601.14(b)(2) (BLAs). Applicants should submit either 12 paper copies or 1 

PDF copy of FPL carton and container labels, but should submit only SPL files for the 

content of labeling submitted with an application. 

13. If the content of labeling is approved based on the draft SPL, when should the final 

SPL be submitted after approval? 

The final SPL should be submitted preferably within 14 calendar days after approval or as soon 

as possible thereafter.

14. Can we e-mail SPL to the Agency? 

No. SPL should be submitted either to FDA’s Electronic Document Room with documentation 

appropriate for the type of electronic submission or during the registration and listing process 

(see response to Question 7).

15. Should I submit content of labeling in Word and/or PDF with the SPL? 

You should no longer submit content of labeling in PDF. However, we recommend that you 

continue to submit content of labeling in Word. The Word files facilitate the exchange of 

labeling comments and revisions between the applicant and FDA. 

16. Where should I submit SPL files if the application contains both paper and 

electronic components?

Both components of the application should be sent to the relevant center’s central 

document room (just as before implementation of SPL). Similarly, as before 

implementation of SPL, the staff will upload the electronic component. 

5
Contains Nonbinding Recommendations 

Draft — Not for Implementation

180 

181 

182 

183 

184 

185 

186 

187 

188 

189 

190 

191 

192 

193 

194 

195 

196 

197 

198 

199 

200 

17. Should companies resubmit labeling in SPL if it was submitted before October 

15, 2008, in another format and is currently under review in CBER?

No, but we recommend that applicants work with the individual review division or divisions to 

ensure that SPL is available within a reasonable time frame for those products with submissions 

before October 15, 2008. 

18. Can FDA refuse to file my submission if I do not provide SPL, given that I am 

required to do so? 

Yes, but we will work with you to help you submit the SPL. 

19. What software do I use to create SPL files? 

An SPL file can be created using a variety of tools, ranging from a general-purpose word 

processor or XML editor to an SPL-specific editing tool. The type of tool suitable for a specific 

organization will vary depending on a wide variety of business and technical factors. Whatever 

tool is used, the final SPL document will be independent of the tool used for its creation. All 

tools should be able to create valid SPL files and to conform to the guidance for industry

Providing Regulatory Submissions in Electronic Format – Content of Labeling. 

20. What is the difference between XML and SPL? 

XML is a specification for creating custom markup languages for sharing structured data. SPL is 

a standard that uses XML.

21. What version of the SPL schema is currently being used by FDA? 

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 

203 

204 

205 

206 

207 

208 

209 

210 

211 

212 

22. What happens when a new release of the SPL standard is implemented? Should I 

resubmit current labels according to the schema in the new release?

We have implemented SPL release 4 to be compatible with the drug registration and 

listing process. SPL files can be submitted using the schema in SPL release 4 or release 3 

until June 1, 2009, when only release 4 can be used. 

23. Should I submit patient package inserts (PPIs) and Medication Guides (MGs) 

in SPL?

Approved patient labeling documents should be included at the end of the SPL file. There are 

specific Logical Observation Identifiers Names and Codes (LOINC) codes for PPIs and MGs. 

Use the appropriate LOINC code for identifying this information. Each PPI or MG should have 

a separate LOINC code. 

6
Contains Nonbinding Recommendations 

Draft — Not for Implementation

213 

214 

215 

216 

217 

218 

219 

220 

221 

222 

223 

224 

225 

226 

227 

228 

229 

230 

231 

232 

233 

234 

235 

236 

237 

238 

239 

240 

241 

242 

243 

244 

245 

Patient information that is not approved labeling, such as patient information produced by 

third parties, should not be included in the SPL file. 

24. Should my SPL file contain the entire content of labeling or just the portion of 

the content that has changed since my last application submission? 

All submissions should include the entire content of labeling in SPL. FDA cannot support partial 

submissions at this time. 

25. The SPL standard provides tags to identify insertions and deletions of content in 

an SPL document. Should I submit a redlined or annotated version of the labeling, 

indicating version-to-version changes? 

No. You should not use the tags provided in the SPL standard to mark up the insertion and 

deletion of content. 

26. Should I include graphics for controlled substance symbols, the Rx symbol or 

corporate or product logos? 

No. These graphics should not be included in an SPL submission. Controlled substance symbols, 

and other symbols, should be included in the SPL as text (e.g., CII).

27. Can I retain hypertext links within a document if they were present in a Word or 

PDF file of content of labeling (e.g., clickable cross-references)?

Yes. Hypertext links can be retained within the SPL document. However, these links should 

correspond only to other portions of the content of labeling, (e.g., see Dosage and 

Administration (2)). 

28. Does the FDA distribute SPL documents to the Web with minor changes to the 

section identifiers submitted?

Yes, at the moment, we correct certain coding omissions and errors. However, when applicants 

begin using SPL release 4, we will no longer make these corrections. 

29. In preparing an SPL, should I update the section identifier when there is a change 

in a subsection? 

Yes. 

30. If I relocate a section or subsection without changing its content, should its 

section identifier be changed? 

No. The identifier of a section that is relocated without content change remains unchanged, but 

the identifiers of any enclosing sections before and/or after the relocation should be changed, as 

should the document identifier. 

7
Contains Nonbinding Recommendations 

Draft — Not for Implementation

246 

247 

248 

249 

250 

251 

252 

253 

254 

255 

256 

257 

258 

259 

260 

261 

262 

263 

264 

265 

266 

267 

268 

269 

270 

271 

272 

273 

274 

31. How is labeling information transmitted to the Web? 

Beginning June 1, 2009, FDA will transmit postapproval SPL to the Web electronically from the 

electronic drug establishment registration and drug listing system, which will then be considered 

the key repository for postmarket SPL content of labeling. Labeling updates to applications can 

be made by referencing the SPL file submitted through the drug establishment registration and 

drug listing process (see question 3 for the Web address). 

32. If an applicant identifies a problem with the SPL file posted on the Web site, 

what should he or she do?

If an applicant notes an inconsistency, he or she should contact the SPL coordinator at 

spl@fda.hhs.gov and the relevant center’s review division to make the necessary changes. 

33. When is SPL transmitted to the Web and will FDA notify the applicant when SPL is 

posted?

No. There is no notification to the applicant that labeling has been posted. Applicants are advised 

to check the Web site to ensure that their most recently submitted content of labeling is posted. 

34. Should an applicant submit SPL with an annual report?

Applicants should submit an SPL file of the content of labeling with an annual report if an SPL 

file has not previously been submitted for the application, or if there have been changes to the 

content of labeling since the last submission of final SPL. If there have been no changes since 

the last submission of final SPL, then the annual report can include a reference to the electronic 

content of labeling previously submitted.6

 

35. If the first SPL submission is a supplement, should both the current and proposed 

labeling be submitted in SPL, or is it sufficient to submit the proposed labeling in SPL?

For supplements, only the proposed content of labeling should be submitted in SPL. In addition, 

annotated labeling should also be submitted for use in the application review process. (See 

response to Question 5). 

36. Where do I find additional information and specifications on SPL? 

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

9

276 

277 

37. Should content of labeling in a foreign language be submitted? 

Currently, foreign language content of labeling does not need to be submitted in SPL.