Introduction to FDA Structured Product Labeling - SPL R4
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SPL Technical Requirements

Document and Submission Types

Business Requirements: DUNS Numbers, NDC Code, Establishment Identifier and Marketing Categories

SPL Code Systems - Document Sections, Ingredients, Indications, Contraindications, Units of Measure etc.

Creating an SPL File and Validation Procedures

Electronic Submission

Glossary

SPL Technical Requirements

What is Structured Product Labeling?
The Structured Product Labeling (SPL) specification is a document markup standard that specifies the structure and semantics for the regulatory requirements and content of the authorized published information that accompanies any medicine licensed by a national or international medicines licensing authority. 
Like most documents, an SPL document has sections and sections contain text (paragraphs, lists, tables); SPL documents can be rendered and published in these standard narrative presentations. At the same time, the SPL specification provides semantic markup that permits extraction of relevant data embedded in the narrative so that it can be used for other purposes. 
In other words, SPL markup of a product labeling document both preserves the human readability of the content and facilitates machine processing of that content.

The SPL specification includes a detailed description of an information model for structured product labeling documents as well as the XML representation of that model. 
The information model is based on the HL7 Reference Information Model (RIM) and uses the HL7 Version 4 Data Types.

Substantially SPL, Structured Product Labeling, is an XML file that must meet the structural and data information content criteria defined by the SPL definition.

Scope of Structured Product Labeling

The scope of the SPL specification is the standardization of the markup of the content of product labeling, establishment registration, NDC labeler code request etc. documents for the purpose of review, editing, storage, dissemination, analysis, decision-support, and other re-use. 

The SPL specification is a markup specification for the regulatory content of a product labeling document. 
This specification is not specific to the U.S. realm, but does fulfill identified regulatory requirements for the content of drug product labeling described in U.S. regulations 21CFR201.56 and 21CFR201.57 for prescription drug labels and 21CFR201.66 for over-the-counter drug labels. 
The specification can be extended to accommodate the requirements of drug product labeling in other realms. However, it is also not necessarily restricted to use for drug labeling. This specification is extensible such that future versions could accommodate specifications for other product labeling document types (e.g., blood, vaccine, veterinary drug, food, dietary supplements, and device labeling).

The SPL Specification
The SPL specification has been built by HL7: Health Level Seven is one of several American National Standards Institute (ANSI) -accredited Standards Developing Organizations (SDOs) operating in the healthcare arena. Most SDOs produce standards (sometimes called specifications or protocols) for a particular healthcare domain such as pharmacy, medical devices, imaging or insurance (claims processing) transactions. Health Level Seven’s domain is clinical and administrative data.

SPL Data and Code Systems

Depending on the Submission and Document Type following structured data is required

• Document Version, Revision, First Approval etc.

• Registrant, Establishment, Manufacturer, Relabeler, US Agent, Importer etc.

• Product Trade name, Generic name, Company Information and Legal Authenticators

• Product characteristics such as Color, Size, Flavor etc.

• Ingredients and Eccipients (Inactive Ingredients)

• Packaging

• Marketing Status, Registration Information

• Indications and Contraindications

• Preconditions such as Co-Administration, Patient Age and Maximum Dose

• Drug Interactions and Adverse Reactions

SPL uses different Code Systems to identify data in the XML file such as Company Information, Product Ingredients, Dosage Forms, Packaging Types, Document Sections etc. 
The Code Systems used are listed below. More detailed information about Code Systems is listed later in this document.

SPL File Viewing
Once the XML file has been built, it can be viewed with Microsoft Internet Explorer. The rendering occurs by using the FDA Style sheet provided online.

SPL Document Creation and Submission Workflow - Overview

1) Create the XML SPL File according to your submission needs (e.g. Product Label, Establishment Registration, NDC Labeler Code Request), by adding all relevant data such as DUNS Numbers, NDC Labeler Codes, etc.

2) Validate your XML SPL File online with Pragmatic Data Validator: http://validator.pragmaticdata.com/validator-lite/validator/spl/

3) Correct any errors and revalidate online until the Pragmatic Data Validator reports no error.

4) Submit your SPL XML File trough your FDA Test Account

5) If the FDA response is positive, submit the SPL XML File to your FDA Production Account

Document and Submission Types

SPL electronic submissions are regulated by different FDA Centers,  depending on the target application field of the product.

• CDER - Center for Drug Evaluation and Research - Human Drugs

• CBER - Center for Biologics Evaluation and Research - Blood Processing / Vaccines

• CDRH - Center for Devices and Radiological Health - Medical Devices

• CVM - Center for Veterinary Medicine - Animal Health
  

Following Document and Submission Types are currently required in SPL format.

Business Requirements: DUNS Numbers, NDC Code, Establishment Identifier and Marketing Categories

DUNS Number
Data Universal Numbering System (D-U-N-S®) Number

The Data Universal Numbering System, abbreviated as DUNS or D-U-N-S is a system developed and regulated by Dun & Bradstreet (D&B) which assigns a unique numeric identifier to a single business entity. This numeric identifier is then referred to as a DUNS number. It was introduced in 1963 to support D&B's credit reporting practice. It has gained wide acceptance globally and is a common standard. Its users include the European Commission, the United Nations and the United States government. It is recognized, recommended and/or required by more than 50 global, industry and trade associations. The DUNS database has over 57 million entries for businesses throughout the world

Dun & Bradstreet assigns and maintains a database of the D-U-N-S® Numbers, which serve as unique identifiers (codes) of business entities. Upon application, each business entity (e.g., registrant, establishment, importer, US agent) is assigned a distinct site-specific 9-digit D-U-N-S® Number. 

The site-specific D-U-N-S® Number for an entity is a useful resource for FDA in identifying and verifying certain business information for that entity, e.g., trade names used by the entity, addresses, additional ownership information, such as the name of each partner or the name of each corporate officer and director, and the State of incorporation. 

If the D-U-N-S® Number for a location has not been assigned, a business may obtain one for no cost directly from Dun & Bradstreet (http://www.dnb.com). 
If the business entity does not submit a D-U-N-S® Number with its submission, FDA intends to make arrangements for obtaining a D-U-N-S® Number for that entity.

See following resources

DUNS homepage: http://www.dnb.com

DUNS FAQ http://spl-work-group.wikispaces.com/DUNS+Number+FAQ

NDC Product Code/ Labeler Code

The National Drug Code (NDC) is a universal product identifier used in the United States for drugs intended for human use. 
The Drug Listing Act of 1972[1] requires registered drug establishments to provide the Food and Drug Administration (FDA) with a current list of all drugs manufactured, prepared, propagated, compounded, or processed by it for commercial distribution. 
Drug products are identified and reported using the NDC.

National Drug Code Format
The NDC is a unique 11-digit, 3-segment number assigned to each medication listed under Section 510 of the U.S. Federal Food, Drug, and Cosmetic Act. The number identifies the labeler or vendor, product, and trade package size.

The first segment, the labeler code, is assigned by the Food and Drug Administration (FDA). A labeler is any firm that manufactures, repacks or distributes a drug product. 
The second segment, the product code, identifies a specific strength, dosage form, and formulation for a particular firm. 
The third segment, the package code identifies package sizes. 
Both the product and package codes are assigned by the firm.

The NDC will consist of three parts, each separated by a hyphen in the following configuration: 5-4-2.

Each item is barcoded with a Universal Product Code that begins with a 3 (UPC-A) or 03 (EAN-13). The remainder of the numbers are the NDC number, plus the check digit.

An asterisk may appear in either a product code or a package code. 
It simply acts as a place holder and indicates the configuration of the NDC.
Since the NDC is limited to 11 digits, a firm with a 5-digit labeler code must choose a 4-digit product code and 2-digit package code.

See following resource:

NDC Information FDA http://www.fda.gov/Drugs/InformationOnDrugs/ucm142438.htm

FDA Establishment Identifier

The FDA Establishment Idetifier (FEI) is a 12 digit number assigned by FDA for Establishments involved in the production, import and marketing of a drug product in the USA: Manufactureres, Re-Labelers, Re-Packagers etc.


See following resource:

FDA Website: http://www.fda.gov/

Marketing Categories

See following resource:

FDA Website: http://www.fda.gov/

SPL Code Systems - Document Sections, Ingredients, Indications, Contraindications, Units of Measure etc.

The SPL specification requires different information to be coded using FDA and other code systems. This document section gives information about the code systems and their use.

Overview

LOINC

Logical Observation Identifiers Names and Codes (LOINC) is a database and universal standard for identifying medical laboratory observations. It was developed and is maintained by the Regenstrief Institute, Inc., a US non-profit medical research organization, in 1994. LOINC was created in response to the demand for an electronic database for clinical care and management and is publicly available at no cost. It is endorsed by the American Clinical Laboratory Association and the College of American Pathologist. Since its inception, the database has expanded to include not just medical and laboratory code names, but also: nursing diagnosis, nursing interventions, outcomes classification, and patient care data set.

LOINC applies universal code names and identifiers to medical terminology related to the Electronic health record. The purpose is to assist in the electronic exchange and gathering of clinical results (such as laboratory tests, clinical observations, outcomes management and research).

LOINC Codes are used in SPL for:

• SPL Document Type Coding

• SPL Product Label Document Sections and Subsections

See following resources:

Official LOINC website http://loinc.org/

FDA Product Label Section Headings: http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm162057.htm

FDA SPL Document Types: http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm162063.htm

NCI Thesaurus

Published monthly by National Cancer Institute (NCI), this reference terminology and biomedical ontology is used in a growing number of NCI and other systems. It covers vocabulary for clinical care, translational and basic research, and public information and administrative activities. The NCI Thesaurus provides definitions, synonyms, and other information on nearly 10,000 cancers and related diseases, 8,000 single agents and combination therapies, and a wide range of other topics related to cancer and biomedical research. It is maintained by a multidisciplinary team of editors, who add about 900 new entries each month.

FDA collaborates with the National Cancer Institute Enterprise Vocabulary Services (NCI EVS) to maintain code sets for dosage form, routes of administration, package types, DEA schedule, product color, product shape, flavors, business operations, marketing categories and equivalence codes. 

NCI Thesaurus is used in SPL for:

• Business operations - such as Manufacture, Repack, Relabeler etc.

• Data Confidentiality

• Dosage form, product characteristics, DEA schedule, unit of presentation, route of administration and equivalent codes

• Indications and Contraindications

• Drug Interactions

See following resources:

NCI Website: http://www.cancer.gov

NCI EVS website http://evs.nci.nih.gov

FDA Website: http://www.fda.gov/

UNII - Unique Ingredient Identifiers

A US government standard for drug ingredient and food allergen identifier.

The overall purpose of the joint FDA/USP Substance Registration System (SRS) is to support health information technology initiatives by generating unique ingredient identifiers (UNIIs) for substances in drugs, biologics, foods, and devices. 

The UNII is a non- proprietary, free, unique, unambiguous, non semantic, alphanumeric identifier based on a substance’s molecular structure and/or descriptive information.

The procedures and management of the SRS is provided by the SRS Board. The SRS Board includes experts from both FDA and USP. The SRS operating procedures defined by the SRS Board are detailed in the SRS Manual.

UNII Codes are used in SPL for:

• Product Active Ingredients

• Product Inactive Ingredients

• Reference Drugs

• Medical Device Components

See following Resources:

UNII Codes @ FDA Website 
http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm162523.htm

Unified Codes for Units of Measure (UCUM)

The Unified Codes for Units of Measure (UCUM) is used for the unit of measure whenever it occurs in SPL:

• Product Active Ingredients
• Product Inactive Ingredients
• Packaging

See following resource:

Units of Measure @ FDA   
http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm168397.htm

ISO 3166-1 Alpha-3 Country Code

In SPL, country information whenever requested has to be entered in the ISO 3166-1 Alpha-3 Country Code format.

See following resource:

ISO 3166-1 Alpha-3 Country Code  http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm162567.htm

Creating an SPL File and Validation Procedures

Depending on the Document Type submitted the SPL File Structure and Data content must match the FDA SPL definitions.
There are several sets of rules defined, which may change continuously, the document gives only an overview.

For detailed information about SPL file creation please see http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/default.htm

Validation Rules for Establishment Registration and Product Listing cab be found here:
http://www.fda.gov/downloads/ForIndustry/DataStandards/StructuredProductLabeling/UCM180988.pdf

Creating the SPL file

The SPL Document File name being submitted to FDA must be the SPL Document ID. 
If the SPL submissions contains images they must be located in the same folder as the SPL.
In this case the Submission must be Zipped and the name of the ZIP file must match the Document ID.

DUNS Numbers must have 9 Digits, numeric only no hyphens (-)

US Agent and Importer: Only Name, DUNS Number, Mail and Phone is allowed

Labeler: On Establishment Registration no Labeler Information must be added.

Phone Numbers: Must Start with + and be separated by -, no blanks.

Product - Dosage Form Display Name: Code and Name must be selected from the List Provided @ http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm162038.htm

NDC Product Code must be Labeler Code and Product Code in Form NNNNN-NNNN

Product Ingredients: Active Ingredients must not have any Reference Product Set.

Unit of measures must match the UCUM codes http://www.fda.gov/ForIndustry/DataStandards/StructuredProductLabeling/ucm168397.htm

Ingredients must be coded by using UNII codes for Substances and UCUM codes for units of measure.

Validating the SPL File

FDA is collaborating with Pragmatic Data on software to validate SPL Release Four files using Schematron technology.

The Validator can be accessed online under:  http://validator.pragmaticdata.com/validator-lite/

Submit your SPL document or ZIP package online.

Correct possible errors and validate until the SPL Validator reports no more errors.

Once the SPL File is error free, it can be submitted to FDA.

Electronic Submission of SPL files

The Food and Drug Administration (FDA) Electronic Submissions Gateway (ESG) is an Agency-wide solution for accepting electronic regulatory submissions. The FDA ESG enables the secure submission of regulatory information for review.

The FDA ESG is the central transmission point for sending information electronically to the FDA. Within that context, the FDA ESG is a conduit along which submissions travel to reach their final destination. It does not open or review submissions; it automatically routes them to the proper FDA Center or Office.

The electronic submission process encompasses the receipt, acknowledgment of receipt (to the sender), routing, and notification (to a receiving Center or Office) of the delivery of an electronic submission.

The FDA ESG supports the receipt of guidance compliant electronic regulatory submissions of up to 100GB in size to CBER, CDER, CDRH, and CVM. The FDA ESG also supports the receipt of AERS reports and AERS attachments.

The FDA ESG is accepting registration requests for new test accounts as described under "Set up an Account". Please read this section and the ESG User Guide (PDF) carefully before submitting your registration request. Companies planning to transmit regulatory submissions via the WebTrader option will be asked to send a .pdf or eCTD based test submission that is 7.5 GB in size. Based on pilot testing with Industry volunteers, the FDA recommends that submissions greater than 15 GB and less than 25 GB in size be sent overnight starting at 5PM EST to ensure receipt by the targeted FDA Center during the next business day.

The FDA continues to expand ESG capabilities. These plans include receipt of:

• Electronic submissions for the Center for Food Safety and Nutrition;

• Electronic submissions for the Office of Orphan Product Designations; and

• Vaccine Adverse Event Reports (VAERS).

The list of electronic regulatory submissions that can be received by the FDA ESG will be expanded as the FDA promulgates additional electronic submission guidance documents and extends this capability to new operational units within the FDA.

See following Resources:

Overview Electronic Submissions: http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/ucm165573.htm

Setting up a WebTrader Account Checklist http://www.fda.gov/ForIndustry/ElectronicSubmissionsGateway/ucm114831.htm

FDA Electronic Submission Gateway User Guide http://www.accessdata.fda.gov/esg/userguide/webhelp/default.htm

Glossary