Structured product labeling FDA rules, SPL files and DailyMed

Structured product labeling at the FDA

Structured Product Labeling (SPL) is the HL7 XML format the FDA uses for drug labels, drug listings and establishment registrations. It exchanges product and facility information electronically (FDA SPL resources). FDA sends drug-label SPL files to the National Library of Medicine (NLM) for publication on DailyMed (NLM).

What is structured product labeling?

SPL is an HL7 standard accredited by ANSI (FDA SPL Implementation Guide). HL7 lists Release 5 as its current normative version (HL7). For FDA submissions, use the schema and validation files FDA publishes.

FDA uses SPL beyond drug labeling. Its uses include (FDA SPL resources):

• drug establishment registration, drug listing and content of labeling for human drugs
• 503B outsourcing facility product reports
• animal drug registration and listing
• cosmetic facility registration and product listing under MoCRA
• blood and tissue establishment registration and listing
• REMS documents and electronic lot distribution reports

Which rules require SPL

Registration and listing information must go through FDA's electronic system (21 CFR 207.61(a)). FDA requires those drug submissions in SPL format (FDA eDRLS). An NDA must include the content of labeling, "commonly referred to as the package insert or professional labeling," with all text, tables and figures, in electronic format (21 CFR 314.50(l)). BLAs have the same requirement (21 CFR 601.14(b)). FDA uses SPL for that content of labeling as well (FDA SPL resources).

Since June 1, 2009, FDA has only accepted electronic registration and listing submissions unless a waiver is granted (74 FR 26248). Submit updated drug listing information twice each year, in June and December, notifying FDA if the information has changed (FDA eDRLS).

One change to plan for: under the NDC final rule published March 5, 2026, all NDCs move to a uniform 12-digit 6-4-2 format, effective March 7, 2033. That change will affect NDCs carried in SPL listings (91 FR 10749).

What the SPL format contains

An SPL file is an XML document in the HL7 v3 namespace. It must validate against FDA's hosted schema, spl.xsd (FDA SPL Implementation Guide). Each document has a header and a body. The header carries a set ID, a GUID that stays the same across versions. Each new version gets a higher version number (Implementation Guide).

Codes make SPL data machine-readable. Ingredients use UNII codes from FDA's Substance Registration System. Dosage forms and routes use NCI Thesaurus terms. Label sections use LOINC codes, such as 42231-1 for a Medication Guide (Implementation Guide). FDA asks application holders to pick "the most specific, appropriate" LOINC codes for prescribing information, patient labeling, and carton and container labeling sections (FDA). Every SPL also has a document type with its own LOINC code, such as Human Prescription Drug Label (34391-3), Human OTC Drug Label (34390-5) or Establishment Registration (51725-0) (FDA document types).

For a drug listing, FDA says the SPL must include the items below. One listing SPL can cover several NDCs that share the same labeling (FDA, how to list a drug):

• the full proposed NDC, plus proprietary and non-proprietary names
• dosage form and route of administration
• each active ingredient with its UNII and strength, and each inactive ingredient with its UNII
• a copy of current labeling, including a .jpg of the package and label
• the name and DUNS number of every establishment involved in manufacturing

SPL vs PLR

The Physician Labeling Rule (PLR) sets prescribing information content and layout under 21 CFR 201.56 and 201.57. PLR format applies to new human prescription drugs approved since June 2001 (FDA prescribing information resources). PLR-format labeling includes Highlights, a table of contents and numbered Full Prescribing Information sections. SPL is the XML file that carries that content. A PLR-format label still goes to FDA as SPL, and the Implementation Guide has validation rules written for PLR sections (FDA SPL Implementation Guide).

Structured product labeling software and submissions

Drug registration and listing submissions use SPL and must pass FDA validation. FDA names three ways to build the file: FDA Direct, SPL Xforms, or commercial or in-house software (FDA registration and listing instructions).

FDA Direct (direct.fda.gov) is FDA's free authoring and submission portal, with two modules: CDER Direct for drugs and Cosmetics Direct (FDA). SPL Xforms are web forms that need no download, and FDA says the built-in validator catches about 95% of possible technical errors (FDA SPL Xforms). FDA also lists resources for commercial SPL software, conversion vendors and self-generated SPL (FDA).

For drug registration and listing, submissions outside FDA Direct and Xforms go through the Electronic Submissions Gateway Next Generation (ESG NextGen) (FDA submission instructions). Its Unified Submission Portal replaced the legacy WebTrader interface on April 14, 2025 (FDA ESG NextGen). An ESG NextGen account is free, but setup can take about 1 to 3 weeks (FDA), so don't leave it to the week of a deadline. Before you build, download the current schema, Implementation Guide and validation files from the SPL resources page.

How SPL feeds DailyMed

Manufacturers submit drug-label SPL to FDA, which sends it to NLM. DailyMed presents the labeling in a readable format, searchable by NDC, set ID or drug class (NLM).

DailyMed calls itself "the official provider of FDA drug label information (package inserts)." But it shows the latest labeling submitted and in use, which "may not have been verified by FDA," and "NLM does not review any SPL content prior to publication" (DailyMed). Drugs marked "unapproved" are not FDA-approved (DailyMed). A DailyMed label is not proof of FDA approval.

DailyMed has a REST API and bulk zip downloads split into Rx, OTC, homeopathic, animal and remainder (DailyMed web services, bulk downloads). The openFDA drug label API is built from submitted SPL and updated weekly, and it warns that most OTC drugs are not reviewed and approved by FDA (openFDA). FDA's daily NSDE file is built from submitted SPLs and includes NDC11, marketing category, application number and billing unit (FDA NSDE).

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