What Is SPL Format and How to Submit Drug Listings to FDA

What Is SPL Format?

Structured Product Labeling (SPL) is an XML standard adopted by FDA to receive and process drug product information electronically. Rather than submitting paper forms or free-text documents, manufacturers encode their drug listing data — including product names, active ingredients, dosage forms, routes of administration, labeling text, and National Drug Code (NDC) numbers — in a machine-readable XML schema defined by Health Level Seven (HL7).

FDA first mandated SPL for drug listing submissions in 2009 through the electronic Drug Registration and Listing System (eDRLS), and the requirement has been reinforced through successive guidance documents. Under the current regulations at 21 CFR §207.49 and §207.53, all drug listing information must be submitted electronically in SPL format unless a waiver is granted.

The SPL schema supports multiple document types, including:

• Human prescription drug labels — full prescribing information structured by section (Highlights, Full Prescribing Information, etc.)
• Human OTC drug labels — Drug Facts labeling in the standardized format
• Drug establishment registration data — facility information and business operations
• Homeopathic drug listings — product information for homeopathic products marketed without NDA/ANDA approval
• Bulk substance listings — active pharmaceutical ingredient (API) information

Each SPL submission is identified by a unique Set ID and version number, enabling FDA to track changes to a drug listing over time. When a manufacturer updates labeling or product information, they submit a new version of the same SPL document, which supersedes the prior version.

Drug Listing vs. Drug Registration: Key Differences

Drug listing and drug establishment registration are related but distinct FDA requirements, both governed by 21 CFR Part 207. Understanding the difference is critical because the SPL format is used for both processes, but they involve different data and serve different purposes.

Drug Establishment Registration (21 CFR §207.17–§207.29) identifies the physical facility and the business operations performed there (manufacturing, repacking, relabeling, testing, etc.). Every domestic and foreign establishment engaged in these activities must register with FDA annually. Registration is facility-level data.

Drug Listing (21 CFR §207.49–§207.57) identifies the specific drug products that each registered establishment manufactures, prepares, propagates, compounds, or processes. Listing includes the product name, active ingredients, dosage form, route of administration, NDC number, and labeling. Listing is product-level data.

Both must be submitted in SPL format. In practice, most establishments submit a combined SPL file that includes registration and listing data in a single XML document. The SPL schema accommodates this through different document types and sections.

Foreign establishments must additionally designate a U.S. Agent for drug establishments as part of the registration process. The U.S. Agent information is included in the registration SPL submission.

How to Create and Submit an SPL File

Creating an SPL file requires either specialized software or a thorough understanding of XML and the HL7 SPL schema. FDA provides several resources to assist:

Option 1: FDA's SPL Xforms Tool

FDA offers the SPL Xforms tool, a web-based form that generates valid SPL XML without requiring direct XML editing. This is the most common method for smaller establishments. The tool guides you through entering product information, generates the XML, and allows you to validate and submit directly through FDA's Electronic Submissions Gateway (ESG).

Option 2: WebSPL (DailyMed Submissions Portal)

The National Library of Medicine operates WebSPL, an online portal for creating, validating, and submitting SPL documents. WebSPL is particularly useful for OTC drug monograph products and for establishments that need a guided interface for complex SPL documents. The tool generates compliant XML and submits through the FDA ESG automatically.

Option 3: Commercial SPL Software

Larger pharmaceutical companies typically use commercial regulatory information management (RIM) platforms such as Veeva Vault RIM, IQVIA's SPL solutions, or other specialized tools that integrate SPL generation into their broader regulatory submission workflows. These tools offer template management, version control, and multi-product management capabilities.

Option 4: Manual XML Authoring

For technically skilled teams, SPL files can be authored directly in XML using the HL7 SPL schema. FDA publishes the schema files, implementation guides, and validation rules. However, this approach requires deep familiarity with the SPL standard and is error-prone for those without XML experience.

Regardless of the method used, all SPL files must pass FDA's automated validation before they are accepted. Common validation errors include malformed NDC numbers, missing required sections, schema violations, and inconsistent product information.

NDC Numbers and How They Connect to SPL

The National Drug Code (NDC) is a unique identifier for drug products in the United States. Every drug product listed with FDA is assigned an NDC number, which is a 10-digit, three-segment number in the format:

• Labeler Code (4 or 5 digits) — identifies the manufacturer, repacker, or distributor. Assigned by FDA.
• Product Code (3 or 4 digits) — identifies the specific drug product (strength, dosage form, formulation). Assigned by the labeler.
• Package Code (1 or 2 digits) — identifies the package size and type. Assigned by the labeler.

NDC numbers are embedded directly within the SPL XML document. When you submit a drug listing SPL, the NDC for each listed product is included in the structured data. FDA uses these NDC numbers to populate the NDC Directory, which is the public database of all registered drug products.

To obtain a labeler code, you must submit an initial establishment registration SPL. FDA assigns the labeler code, and you then use it to construct NDC numbers for your product listing SPL submissions. See our guide on how to get an FDA labeler code for the complete process.

DailyMed Publication and Public Access

Once FDA accepts an SPL submission, the labeling content is published on DailyMed (dailymed.nlm.nih.gov), a free, publicly accessible database operated by the National Library of Medicine (NLM). DailyMed renders the SPL XML into human-readable web pages, making drug labeling information available to healthcare providers, pharmacists, patients, and regulators.

DailyMed serves as the authoritative source for the most current FDA- approved drug labeling. Key features include:

• Full prescribing information for prescription drugs, organized by the Physician Labeling Rule (PLR) format
• Drug Facts labeling for OTC products in the standardized consumer format
• NDC number lookups and product identification
• Archived versions of drug labeling, enabling comparison of changes over time
• RSS feeds and API access for programmatic queries

For manufacturers, DailyMed publication is not optional — it is an automatic consequence of submitting a valid drug listing SPL to FDA. If your labeling information is incorrect on DailyMed, the fix is to submit an updated SPL version through FDA, which will be republished on DailyMed after processing.

SPL Update Requirements and Cadence

Drug listing is not a one-time obligation. Under 21 CFR §207.57, registrants must update their drug listing information when certain changes occur, and must also submit annual updates during the designated registration period (October 1 through December 31 each year).

Specific events requiring a listing update include:

• New drug marketed — submit listing SPL within 5 days of the drug being marketed or offered for import into the U.S.
• Drug discontinued — submit an updated SPL indicating the product has been discontinued, within 30 days
• Labeling changes — submit revised SPL when labeling is updated due to safety information, new indications, or other changes
• NDC changes — submit updated SPL if NDC format or package configurations change
• Annual registration — review and confirm or update all listing data during the October–December annual registration period

FDA monitors compliance with listing update requirements. Failure to maintain current listing information can result in Warning Letters, Import Alerts (for foreign manufacturers), or the product being flagged for detention at the border. Keeping your SPL submissions current is essential for uninterrupted U.S. market access.

For foreign manufacturers, working with a knowledgeable U.S. Agent like Assurentry ensures that registration and listing deadlines are tracked and that SPL submissions are prepared accurately and on time.