Structured Product Labeling (SPL): Document Types, Data Elements, and the Validation Rules That Cause Rejection

Structured Product Labeling (SPL) is the HL7-approved XML document format FDA requires for drug establishment registration, drug listing, labeler code requests and content of labeling. Knowing what SPL is takes one sentence. Getting a file accepted takes knowing the numbered validation procedures that reject it — and most rejections are not schema errors. They are cross-document rules: an establishment whose registration lapsed, an NDC whose active ingredient you changed, a No Change Notification that is not allowed to be a No Change Notification this year.

This page is written against the SPL Implementation Guide with Validation Procedures, Version 1, Revision 202312080859 (December 2023), issued jointly by CBER, CDER, CVM and the Office of the Chief Scientist. That document is actively revised and the revision string is how you tell which one you have — always check the revision on the copy you are validating against before treating any rule below as current. Registration and listing procedure details are taken from FDA’s Drug Registration and Listing Instructions pages, content current as of 3 August 2026.

The three submissions, and the order they have to happen in

FDA describes registration and listing as three separate SPL submissions, each with an initial filing and ongoing maintenance. They are not interchangeable and they are order-dependent:

1. Labeler code request — assigns the NDC labeler code that identifies the company marketing the drug. Required before any drug listing or NDC reservation. One labeler code covers all establishments of a manufacturer; a separate code per establishment is not required.
2. Establishment registration — registers each physical establishment that manufactures, repacks, relabels or salvages drugs for U.S. distribution.
3. Drug listing — lists every drug an establishment produces for U.S. commercial distribution under its own labeler code.

Applicants may additionally reserve an NDC up to two years before launching a drug. Reservations are tracked: validation procedure 3.1.1.7 requires that a product item code has not been previously submitted in an NDC reservation under a different document set ID with marketing status new. A code reserved under one document family cannot be quietly listed under another.

The dependency that trips first-time filers: after FDA reviews an initial labeler code request and assigns the code, you must submit an updated labeler code SPL carrying the newly assigned number. Until that second submission lands, no drugs can be listed under that labeler code, even though the code exists.

Picking the document type

Every SPL carries a LOINC document type code in <code codeSystem="2.16.840.1.113883.6.1">, and a large share of the validation rules are conditioned on it — the same XML that passes as one document type fails as another. Codes confirmed in the implementation guide’s own procedure text include:

LOINC code	Document type	Used for
51725-0	Establishment Registration	Initial and full-update registration of an establishment
53410-7	No Change Notification	Annual renewal where nothing about the registration changed
70097-1	Establishment De-Registration	Removing one establishment
53411-5	Out of Business Notification	De-listing all establishments of an organisation
51726-8	NDC/NHRIC Labeler Code Request	Requesting or updating a human-drug labeler code
72871-7	NDC Labeler Code Request – Animal Drug	Animal-drug labeler code
69968-6	NDC Labeler Code Inactivation	Retiring a labeler code
34391-3	Human Prescription Drug Label	Rx drug listing and content of labeling
34390-5	Human OTC Drug Label	OTC / nonprescription drug listing
53409-9	Bulk Ingredient	Bulk substance listing
78744-0	Drug for Further Processing	Intermediate not in final dosage form
75031-5	Human Compounded Drug Label	503B outsourcing facility products
53404-0	Vaccine Label	Vaccines (CBER)
82351-8	REMS Document	Risk Evaluation and Mitigation Strategy content
75030-7	Wholesale Drug Distributor / 3PL Facility Report	DSCSA annual reporting

The full list is longer and spans CBER, CDER, CDRH, CVM and CFSAN products. Take it from FDA’s published Document Type terminology file, not from memory or a vendor template — the codes are periodically added and retired, and the guide encodes real transitions between them (for example, Recombinant Deoxyribonucleic Acid Construct Label, 78745-7, is validated as having been superseded by Intentional Animal Genomic Alteration Label, 101437-2).

Two document-type rules cause avoidable rejections:

• A document with an existing set ID must keep the same document type as its predecessor — the one carved-out exception being Bulk Ingredient (53409-9) or Bulk Ingredient – Animal Drug (81203-2) moving to Drug for Further Processing (78744-0).
• If a product moves from Human Prescription Drug Label to Human OTC Drug Label, you do not re-type the existing file. You submit a new listing with new NDC product codes for the OTC drug.

Header data elements every SPL carries

Four identifiers in the header do the versioning work, and confusing them is the single most common structural error:

• <id root> — the document ID. A GUID, new for every version, lower-case letters, no extension, and unique against every other ID anywhere in the document.
• <setId root> — the set ID. A GUID that stays constant across all versions of the same document. Every update carries the original set ID; generating a fresh one starts a new, unrelated document family.
• <versionNumber> — a whole number greater than zero, and greater than any version previously submitted for that set ID. Generally one higher than the last accepted submission.
• <effectiveTime> — day precision, YYYYMMDD.

A less obvious header rule: the preceding version of a set ID must not already have been replaced by a document with a different set ID — that is, the set ID must not have been referenced as a related document of type RPLC from elsewhere. Once a set ID has been superseded that way, further versions under it are rejected.

Establishment registration: required elements and timing

An establishment registration SPL is header-only: one registrant organisation and one or more registered establishments. FDA’s instructions call for:

• The name and DUNS number of the establishment itself — explicitly not the DUNS linked to corporate headquarters. In the XML the DUNS carries root 1.3.6.1.4.1.519.1.
• Contact information for a person responsible for receiving FDA communications about that establishment.
• All applicable business operations the establishment performs — at least one is required, the code must come from FDA’s business operations list, and the display name must match the code.
• For foreign establishments, the name and DUNS of a U.S. agent and of all importers.

Each establishment’s DUNS must be unique within the file, and the establishment element carries nothing besides its ID and name.

Timing. U.S. establishments register within five days of introducing drugs into commercial distribution. Foreign establishments must complete registration before the drug is offered for import. Everyone renews between 1 October and 31 December each year. Registration status is visible on the Drug Establishments Current Registration Site (DECRS) by the end of the next business day, showing an expiration of 31 December of the following year. An establishment registration SPL is also validated for effective time year matching the current year and for having no title.

When a No Change Notification is not allowed

This is where a routine annual renewal quietly fails. A No Change Notification (53410-7) must be submitted between 1 October and 31 December, and it must reference the set ID of a previously submitted Establishment Registration, No Change Notification or De-Registration. Beyond that, the implementation guide forces a full Establishment Registration file instead in three specific situations:

• The most recent Establishment Registration has no business operation qualifiers — unless the only business operations are analysis (C25391), API manufacture (C82401), or medicated animal feed manufacture (C84635).
• The most recent Establishment Registration asserts the qualifier Manufactures human over-the-counter drug products (C106645).
• The most recent Establishment Registration lacks an FEI number — a second ID with root 2.16.840.1.113883.4.82 — for each establishment. In that case a full registration carrying FEI numbers is required.

A No Change Notification is also rejected if the underlying Establishment Registration has been inactivated by an FDA Agency Initiated Compliance Action. If your renewal bounced and nothing about your facility changed, check these four conditions before checking your XML.

Labeler code request: the initial-request asymmetry

An initial labeler code request is structurally different from every subsequent version of the same document, and the difference is a frequent rejection cause:

• On the initial request, submit one ID only — the DUNS number, and leave the NDC labeler code field blank. The NDC/NHRIC labeler code ID (root 2.16.840.1.113883.6.69) must be absent.
• On every version after FDA assigns the code, there are two IDs: the DUNS number and the assigned NDC/NHRIC labeler code. No other ID roots are permitted.
• The labeler code extension is 4 or 5 digits.
• A labeler code must not have been associated previously with a different set ID, and a set ID must not be associated with any other labeler code. One set ID, one labeler code, permanently.

Maintenance obligations that are easy to miss: labeler code information must be updated within 30 days of any change to contact information, to the type of activities the entity performs (manufacturer versus distributor), or to the type of drugs the code will be used for. If the code transfers through merger or acquisition, or the company name changes, every product listing under that code must also be updated with the new labeler name. And a labeler code with no associated drug listings may be deactivated after two years.

Drug listing: the required data elements

A single drug listing SPL may cover multiple NDCs provided they all share the same content of labeling. FDA requires:

• Full proposed NDC for products and packages.
• Proprietary and non-proprietary name. Where a drug has no proprietary name, the established name goes in the proprietary name field. Neither name may contain special symbols such as ® or ™; the non-proprietary name carries no suffix and is capped at 512 characters.
• Dosage form and route of administration, coded from FDA terminology with display names matching codes. If the product has parts, the form code is KIT (C47916).
• Each active ingredient: name, UNII (code system 2.16.840.1.113883.4.9), and amount/strength with an appropriate unit.
• Each inactive ingredient: name and UNII. Amounts are optional.
• A .jpg of the outer packaging and principal display panel of each drug product in the submission, placed in the Package Label.Principal Display Panel section (LOINC 51945-4).
• Name and DUNS number of every establishment involved in manufacturing the product.

Timing. Initial listings are submitted within three days after initial registration of the establishment. Updates follow any change as soon as possible, and in all cases no later than the following June or December.

The validation rules that actually cause rejection

The implementation guide states its conformance rules as numbered validation procedures. The ones below are the ones that reject otherwise well-formed, schema-valid files. Rule numbers are from Version 1, Revision 202312080859.

File and packaging rules

Rule	What it requires	What trips it
2.1.2.1–2.1.2.3	XML declaration is version 1.0 / UTF-8; an xml-stylesheet reference to accessdata.fda.gov/spl/stylesheet/spl.xsl; schemaLocation for urn:hl7-org:v3 is accessdata.fda.gov/spl/schema/spl.xsd	Locally-pathed or http:// schema and stylesheet references left over from a vendor template
2.1.2.4–2.1.2.5	No processing instructions other than the xml and xml-stylesheet declarations; no XML comments at all	Authoring-tool comments, changelogs or commented-out sections left in the file
2.1.2.6	The SPL file name is the document ID followed by .xml	Renaming the file to something human-readable, or reusing the previous version’s file name after generating a new document ID
2.1.2.7	A submission contains only the .xml and, where relevant, .jpg images. PDFs are allowed only for document types 75030-7 and 82351-8	Shipping a cover letter, a README, or a PDF of the label alongside the SPL
2.1.2.8	Every image file in the submission is actually referenced from the SPL	Leaving an unused or superseded label image in the folder
2.2.3.3, 2.2.3.5–2.2.3.7	Images are image/jpeg, named .jpg, under 1 MB, and referenced at least once in section text	High-resolution carton scans exported straight from artwork
2.1.1.2	No data elements or attributes beyond those the guide describes	Vendor-specific extension attributes

Identity and versioning rules

Rule	What it requires	What trips it
2.1.1.7, 2.1.3.2–2.1.3.5	Document ID is a GUID with lower-case letters, no extension, matching no other ID in the document and unique across all documents	Upper-case GUIDs; copy-pasting an ID from a previous file
2.1.3.16	Version number exceeds every previously submitted version for that set ID	Resubmitting a corrected file at the same version number after a rejection
2.1.3.17	The set ID has not already been referenced as an RPLC related document from a different set ID	Continuing to version a document family that was formally replaced
2.1.3.7–2.1.3.9	Document type code system is 2.16.840.1.113883.6.1, the code is on the Document Type list, and the display name matches the code	A display name edited for readability while the code stayed the same

NDC and product-code rules

Rule	What it requires	What trips it
3.2.1.2–3.2.1.5	The NDC product code has two hyphen-separated segments; the labeler segment is numeric; segments follow a 4-4, 5-4 or 5-3 pattern	Hand-built codes, or a leading-zero labeler segment stored as a number
3.2.1.10	The labeler segment matches a labeler code already associated with this labeler’s DUNS in a previously submitted labeler code SPL	Listing before the post-assignment labeler code SPL was filed
3.2.1.11–3.2.1.13	All top-level products in a document share one labeler segment, and all NDC product codes from a given labeler have consistent length	Mixing 5-3 and 5-4 configurations across a portfolio
3.2.1.14	One product data elements section per NDC — the same product is not described twice	Duplicated product blocks after a merge of two listing files
3.2.1.30–3.2.1.36	For a previously submitted NDC, the product name, non-proprietary name, active ingredient UNIIs and strengths, dosage form, size, shape and colour must all be the same as the most recent submission — unless there is no marketing status other than new or cancelled	Reformulating or renaming under an existing NDC instead of issuing a new one

Rules 3.2.1.30 through 3.2.1.36 are the substantive ones. An NDC is not a slot you can re-point at a changed product. If the active ingredient, strength or dosage form differs from what was last accepted, the submission fails and the correct action is a new NDC product code — not a version bump.

Ingredient and strength rules

Rule	What it requires	What trips it
3.1.4.4	Units come from the UCUM units-of-measure list	Free-text units such as “mcg/mL” written in a non-UCUM form
3.1.4.6	All ingredients in a product share the same denominator value and unit	Expressing one active per tablet and another per 100 mg
3.1.4.9, 3.1.4.11	The same UNII is not used more than once per product; the ingredient name matches the UNII	Listing a salt and its base as separate ingredients that resolve to one UNII; a name edited away from the FDA preferred substance name
3.1.4.3, 3.1.4.5	Numerator and denominator values are greater than zero; for percentages the numerator unit is not 1	Percent strengths encoded as a unitless ratio
3.2.3.7	The strength numerator is mass-based (mg, g), not volume-based — except for ingredients such as water, alcohol and gases	Liquids specified as mL of active per mL of product
3.2.3.9	For Bulk Ingredient, Drug for Further Processing, Human Compounded, Human OTC and Human Prescription document types, the numerator unit cannot be “1”	Unit-of-presentation strengths carried over from a non-U.S. dossier
3.2.5.1–3.2.5.6	Where the class code is ACTIR, an asEquivalentSubstance reference ingredient is present with a UNII and matching preferred substance name	Basis-of-strength expressed as active moiety without the reference ingredient element
3.2.6.2	A Human OTC Drug Label carries at least one inactive ingredient — unless the actives comprise 100% of the product, the inactive ingredient section (51727-6) says “none”, or there is no marketing status other than new or cancelled	Omitting excipients on an OTC listing without using the “none” convention

Marketing category and application number

The marketing category code and the application number are validated against each other. The ID extension must carry the prefix the category implies: ANDA for C73584, BLA for C73585, NDA for C73594 and NDA authorized generic C73605, IND for C75302, ANADA for C73583, NADA for C73593 and Conditional NADA C73588. Device categories have their own patterns — Exempt device (C80438) takes a three-letter extension, Humanitarian Device Exemption (C80440), Premarket Application (C80441) and Premarket Notification (C80442) each take their own prefix. Categories such as Bulk Ingredient (C73626) take no application number at all. A category-to-prefix mismatch is a rejection, not a warning. If you are choosing between marketing application types in the first place, see our comparison of NDA, BLA, 505(b)(2) and ANDA pathways and the guide to the ANDA generic-drug approval pathway.

The cross-document rule that rejects the most drug listings

Validation procedure 4.1.4.5 is the one worth memorising. Every establishment DUNS cited in a drug listing must have been submitted in an Establishment Registration (51725-0) on or after 1 October of the previous year — or, if the registration is older than that, it must have been followed by a No Change Notification (53410-7) between 1 October and 31 December of the previous or current year. The registration must also not have been inactivated by an FDA Agency Initiated Compliance Action. The only carve-out is where all products have marketing status completed.

The practical consequence: a contract manufacturer’s lapsed registration rejects your listing, not theirs. If you cite a CMO, a packager or a testing site by DUNS, that site’s registration currency is now your submission’s problem. Confirm every cited establishment on DECRS before you submit — this is the same supplier-qualification discipline that a GMP audit applies to a GMP facility, expressed as a validation rule.

Content-of-labeling section rules

For Human Prescription Drug Label and several CVM types, the file must contain at least one content-of-labeling section besides the SPL Listing Data Elements Section (48780-1) and the Package Label.Principal Display Panel (51945-4) — with carve-outs for Bulk Ingredient, Drug for Further Processing, Unapproved Medical Gas, the three “manufactured under contract” categories, bulk compounding ingredients and Export Only. Principal Display Panel sections are validated as the last sections of the document. A listing that contains only data elements and a carton image, for a product type that requires labeling text, fails.

The annual calendar

Almost every recurring SPL obligation lands in the same quarter:

Window	Obligation
1 October – 31 December	Annual establishment registration renewal; No Change Notification (53410-7) submissions; blanket no-changes certification for drug listings that were not listed or updated during the calendar year
Every January	FDA inactivates human drug listings not certified during the renewal window. Inactivated listings are removed from the NDC Directory and other listing publications
Within 5 days	Registering a U.S. establishment after introducing drugs into commercial distribution
Before import	Registration of a foreign establishment
Within 3 days	Initial drug listing after initial establishment registration
Within 30 days	Updating labeler code information after a change of contact, activity type or drug type
No later than the following June or December	Any drug listing update
2 years	How long a labeler code with no associated listings may survive before deactivation; also the maximum lead time for reserving an NDC

The blanket certification is a genuine convenience — one submission per year covers all products that need no updates — but only inside the October-to-December window. Outside it, certifying a listing means submitting an updated listing SPL for each NDC.

Authoring and submission channels

FDA names three ways to produce and transmit SPL:

• FDA Direct — FDA’s own web application (formerly branded CDER Direct). Handles creation and submission in one place; its “create new version” workflow preserves the set ID for you, which removes a whole class of versioning errors.
• SPL Xforms — FDA’s forms-based authoring tool, with a separate CVM variant for animal drugs.
• Commercial third-party, conversion-vendor, or in-house tools.

Everything except FDA Direct and Xforms must be transmitted through the Electronic Submissions Gateway Next Generation (ESG NextGen). This is the routing rule that surprises teams who assume the gateway is only for applications. Note that ESG is transport, not validation: a file can transmit successfully and still fail SPL validation afterward.

SPL is a distinct standard from the eCTD — an SPL is a single HL7 CDA-derived XML document about a product or facility, whereas eCTD is the folder-and-backbone structure that organises an entire marketing application. Content-of-labeling SPL files travel within eCTD submissions for applications; registration and listing SPLs do not. See eCTD structure for clinical submissions for how the two fit together.

The SPL-to-DailyMed publication chain

Once FDA accepts an SPL, it flows to public destinations, and the distinctions between them matter more than most summaries admit:

• DailyMed, run by the National Library of Medicine at NIH, publishes the labeling as HTML, PDF and XML, and offers bulk downloads and web services for the full corpus.
• FDALabel and the FDA Online Label Repository draw on the same underlying database as DailyMed but present different search functions and result displays.
• The NDC Directory and the Comprehensive NDC SPL Data Elements File (NSDE) carry the listing data elements rather than the labeling text — these are the machine-readable products most downstream systems actually consume.

Two caveats stated by NLM itself, and routinely misunderstood by teams treating DailyMed as an approval record:

• “NLM does not review any SPL content prior to publication.” Appearing on DailyMed is not a quality signal about the content.
• DailyMed shows the most recently submitted, currently “in use” labeling, which may not be identical to the most recent FDA-approved labeling available at Drugs@FDA, and whose contents may not have been verified by FDA.

For an authoritative record of what FDA approved, go to Drugs@FDA for drugs and therapeutic biologics, or FDA’s Biologics Products & Establishments listings for allergenics, blood products, cellular and gene therapy products, plasma derivatives and vaccines. DailyMed is the right source for what is currently in distribution; it is the wrong source for what was approved.

Beyond registration and listing

The same SPL machinery carries several other reporting obligations, each with its own document type and validation section: REMS documents (see also REMS), lot distribution reports, GDUFA self-identification of generic drug facilities, sites and organisations, DSCSA annual reporting by wholesale distributors and third-party logistics providers, 503B outsourcing facility registration and product reporting, and — since 2023 — cosmetic product facility registration and product listing under its own implementation guide. Indexing SPL, a separate document family, carries pharmacologic class and product concept indexing rather than labeling.

Device listing under SPL exists but is a narrower path than most device work: UDI and the GUDID handle device identification, and 510(k) and PMA handle premarket review. Blood and tissue products use ISBT 128 codes, which SPL validates as a distinct item-code system alongside NDC/NHRIC and GS1.

A pre-submission checklist

1. Confirm the document type code against FDA’s current Document Type terminology file, and that it matches the type of the previous version under this set ID.
2. Confirm the set ID is unchanged, the document ID is new and lower-case, and the version number is higher than anything previously accepted.
3. Check every cited establishment DUNS on DECRS for current registration (procedure 4.1.4.5).
4. Confirm the FEI number is present for each establishment if you intend to renew by No Change Notification.
5. Verify the marketing category matches the application-number prefix.
6. For any previously submitted NDC, diff the name, UNIIs, strengths and dosage form against the last accepted version — differences require a new NDC.
7. Check ingredient denominators are consistent, units are UCUM, and no UNII repeats within a product.
8. Confirm images are JPEG, under 1 MB, referenced in text, and that no unreferenced files are in the package.
9. Strip comments and stray processing instructions; confirm the schema and stylesheet references point at accessdata.fda.gov.
10. Rename the file to document ID + .xml and confirm the package contains nothing else but referenced images.
11. Run the file through FDA’s published SPL terminology files for validation — the marketing category, dosage form, business operation qualifier, product concept and application-number validation files are downloadable and encode much of what the server will check.

Frequently asked questions

What does SPL stand for, and what is it technically?

Structured Product Labeling: a document markup standard approved by Health Level Seven (HL7), based on the Clinical Document Architecture and the HL7 Reference Information Model, and adopted by FDA for exchanging product and facility information. In practice it is an XML file plus, usually, one or more JPEG label images.

Do I need a labeler code if I do not list any drugs?

No. FDA’s guidance is explicit that if you do not have to list drugs, you do not need to apply for a labeler code, and that a company that does not manufacture or distribute drugs in the U.S. should not apply for one. Generally only drug manufacturers and distributors need one.

Can one drug listing SPL cover several NDCs?

Yes — provided all the NDCs share the same content of labeling. They must also share a labeler segment and consistent NDC configuration length.

Why was my No Change Notification rejected when nothing changed?

Most likely one of four conditions: it was submitted outside 1 October – 31 December; the underlying registration lacks FEI numbers; the registration has no business operation qualifiers (outside the analysis / API manufacture / medicated feed exceptions); or it asserts the “manufactures human OTC drug products” qualifier. Each of these requires a full Establishment Registration instead.

What happens if I miss the annual listing certification?

Every January, FDA inactivates human drug listings that were not certified during the preceding October-to-December window. Inactivated listings are removed from the NDC Directory and other listing publications — which propagates to pharmacy systems, payers and data vendors downstream.

Can I change the strength of a product under the same NDC?

No. Validation procedure 3.2.1.32 requires the active ingredient UNIIs and strengths to match the most recent submission for that NDC, except where there is no marketing status other than new or cancelled. A formulation change needs a new NDC product code.

Is DailyMed the same as FDA-approved labeling?

No. DailyMed shows the most recently submitted, currently “in use” labeling. NLM states that it does not review SPL content before publication and that the content may differ from the FDA-approved labeling at Drugs@FDA and may not have been verified by FDA.

Which SPL version should I be working from?

The SPL Implementation Guide with Validation Procedures, Version 1, carries a revision string — the version described on this page is Revision 202312080859, dated December 2023. Because the guide is revised without changing its “Version 1” label, the revision string is the only reliable way to identify which rule set you hold. FDA’s SPL schema package was last updated 25 April 2016 and the stylesheet 24 October 2016; the terminology files used for validation are updated far more often, and should be re-downloaded rather than cached.

Where do the validation rules actually live?

In the implementation guide itself, as numbered “Validation Procedures” under each structural section — plus the downloadable SPL terminology files for validation (marketing categories, dosage forms, business operation qualifiers, product concept validation, PLR content-of-labeling and application-number validation, among others). Both are published on FDA’s Structured Product Labeling Resources page.

Sources

• FDA, Structured Product Labeling (SPL) Implementation Guide with Validation Procedures, Version 1, Revision 202312080859, December 2023 (CBER/CDER/CVM/OCS).
• FDA, Drug Registration and Listing Instructions, and the sub-pages How to Register a Drug Establishment, How to Request a Labeler Code and How to List a Drug — content current as of 3 August 2026.
• FDA, Structured Product Labeling Resources (schema, stylesheet, terminology files, document type list, SPL guidance documents).
• National Library of Medicine, About DailyMed.

This page sits in CASRAI’s laboratory compliance and quality cluster. Related reading: Certificate of Analysis for the parallel question of what a document must contain to be relied on, 21 CFR Part 11 for the electronic-records rules governing the systems that generate these files, and orphan drug designation for one of the marketing categories SPL encodes.