As of June 1st, 2009 the FDA will no longer accept Establishment Registrations or Product Listings submitted on paper for human prescription drugs, human over-the-counter drugs, or listed biologics and veterinary medicines. After that date, all such filings must be made electronically through the FDA's electronic submission gateway and encoded in XML, according to the rules set out in the HL7 Structured Product Labeling (SPL) standard and the FDA implementation guide. Medical devices are not currently included but are likely to be included in the future.
If you are involved in establishment registration and/or product listing for any FDA-regulated medicinal product, this new requirement is going to affect what you do and how you do it.
This article explains the regulatory and practical basis for these requirements and presents a brief explanation of the key components involved. I will also point out how the new requirements may change your workflow and identify sources where you can learn more about this subject.
The updated law requires that the FDA implement a means for submitting registration and listing information electronically, and that every company required by other parts of the law to submit such information is required to use the FDA-implemented electronic mechanism. This is not an FDA technology experiment---it is a fundamental change in the way this part of the business operates.
Since 31 October 2005, the FDA has required the content of labeling for human prescription drugs, including coded product information, to be submitted in SPL. Once approved, these labels are forwarded to the National Library of Medicine to be posted on the DailyMed web site, http://dailymed.nlm.nih.gov/dailymed. There you can search, display and download the XML for more than 4400 labels. In the future, all product listings will be sent to DailyMed.
From a practical perspective, the required process on the FDA side is essentially in place already. For the companies that must comply, there are already SPL software products and conversion services available from a number of vendors.
Since HL7 is an international standards body for health informatics, the SPL standard by itself can, in principle, be used for different kinds of labeling under different regulatory regimes. Therefore, the specific regulator, in this case the FDA, must produce a document, called an Implementation Guide, specifying how the elements of the schema are to be used to express the information required by the applicable laws. In particular, the regulator must specify the code sets used by their SPL implementation. These code sets represent controlled vocabularies that express certain information precisely. For example, the element that carries, say, dosage form as its content, is populated not by a typed-in text string but by a code value chosen from the list of codes associated with recognized dosage forms. As well as being valid against the SPL schema, SPL instances must also conform to the conditions set out in Structured Product Labeling Implementation Guide for FDA Drug Establishment Registration and Drug Listing.
An SPL instance consists of a header and body sections as conceptually illustrated in Figure 1.
The XML elements of the SPL header are shown in Figure II.
Unless the reader is familiar with XML, this diagram will seem very daunting. Don't worry, there is no need for a non-technical person to understand the details: your SPL software or your conversion service should protect you from all that. All you need to understand is the general principles and what information you have to submit electronically.
As shown in Figure II, each SPL instance must have a Globally Unique Identifier (GUID) created by a standard algorithm. A sequence of submissions, for example successive updates to a product listing, is uniquely identified by another GUID that appears in all instances of the sequence. The order of the sequence is given by an integer version number.
Business Entities in SPL R4
The name, address and contact information for every business entity involved in producing and distributing listed products must be supplied and kept up to date. These entities include every company that distributes listed products under its own label (a labeler), every company that owns or operates establishments involved in any way in producing such products (a registrant) as well as every such establishment and its US Agents and Importers in the case of foreign establishments.
Labelers are identified by their FDA-assigned labeler numbers (the first 4 or 5 digits of their NDC) and establishments by their assigned FDA Facility Identification (FEI) numbers, both of which have been required on paper submissions. A new requirement for electronic submissions is that each and every business entity must also be identified by a unique DUNS (Data Universal Numbering System) number obtained by registering with Dun & Bradstreet.
Business entity information is entered in elements within the Author element in the SPL header.
The FDA Implementation Guide specifies that companies must separately submit in a valid SPL instance:
The type of submission is indicated by the document type element value in the SPL.
A Labeler Information submission consists of an SPL instance comprising only the header, no sections, with the document type code "51726-8" NDC LABELER CODE REQUEST. In spite of its odd name this type of submission is required even for companies that already have a labeler number. It must be sent in before any Establishment Registration or Product Listing submission that references the labeler. If any of the Labeler information changes, an updated instance should be submitted.
An Establishment Registration submission consists of an SPL instance comprising only a header with the document type code "51725-0" ESTABLISHMENT REGISTRATION. Within various elements within the Author element of the header, the business entity information for the registrant is encoded first, followed by the business entity information for each establishment. Included with each establishment are codes for each manufacturing operation that the establishment can perform. If the establishment is located outside of the United States, the business entity information for the US Agent and for each Importer must also be included.
All establishments of a given registrant must be included in one SPL instance. Establishment Registration must be submitted prior to any Product Listing that references any of its establishments. Thereafter, Establishment Registrations must be submitted at least once per year and should be submitted anytime the information changes.
A Product Listing consists of an SPL header with body sections as illustrated in Figure I. Each major regulatory product class has its own SPL document type code, such as Human Prescription Drug Label, OTC Label, etc. The header contains the business entity information for the labeler, the registrant (if different) and each establishment involved in the manufacture of the product with the appropriate code indicating what operations were performed in that establishment. If the submitter wishes to keep any particular establishment confidential, there is a provision for so marking it, in which case it will be removed from the SPL sent on to Daily Med.
One SPL instance includes the product listing information for one or more individual products covered under one approved label. The encoding of this information is complicated but can be easily understood in a display form such as that used by the NLM, shown here in Figure III.
Not shown on the product data display form, but required for each individual product, is the marketing application (e.g. NDA/ANDA number), marketing status and dates. All inactive ingredients in each product must also be included, although the submitter can mark any of them as confidential so that they will be removed from the SPL sent to DailyMed.
The remaining sections carry the textual content of labeling. For Human Prescription Drugs and biological products, these sections are defined in 21 CFR 201.56 and .57; for human OTC drugs, they include the Drug Facts sections defined in 21 CFR 201.66.
For all types of product, a flattened image of the package must be included as a jpeg file and the text of the principal display panel must be included as the content of a specified section.
Product listings must be submitted at least twice per year if there are any changes to product data or content of labeling, and should be submitted as soon those changes occur.
The Submission Gateway
Each SPL file must be named using the GUID that identifies the instance, placed in a folder with any associated image files and then submitted through the FDA's Electronic Submissions Gateway. Companies must first register for an account to use the gateway. Submissions are validated electronically and acknowledgements or rejection notices are sent by email.
In the context of paper submissions, it was often the case that those responsible for drug listings worked independently of those responsible for content or labeling submissions. In the context of electronic submissions, those activities must work together to produce a sequence of SPL versions that contains the current, correct and complete information in each version submitted. Similarly, establishment registrations on paper could be sent by each individual establishment in a company.
Now, in addition, all establishments must be included in each submission. When there is a change to the information concerning one establishment, the current, correct and complete information about all establishments must be present in each version submitted. If an establishment was listed in one version and is not present in the next, it will be treated by the FDA as if it had been closed.
Moreover, some care must be taken to ensure that any change in labeler, registrant or establishment information that might be used in a product listing is submitted before there is any reference to it in another submission.
The automated validation of submissions will be much faster than the processing of paper submissions but it will also be much stricter, so you will need to respond to rejections and submit corrected SPL promptly to keep everything current and in sync.
There is a joint FDA/HL7/Industry/vendor SPL working group that shares information and concerns between the various parties involved. This group maintains a wiki at http://spl-work-group.wikispaces.com/ where you can find more information, make contact with sub-groups representing specific industry groups (e.g. generics, OTC, etc), and locate vendors who make SPL products or provide conversion services.
Keith Thomas has more than 40 years of experience in information systems design and implementation, much of it in the development of cutting-edge software for information retrieval and document management applications. He is the author of more than 50 papers and co-author of a book on open systems.
Keith joined i4i in 1997 as Director of R&D. For the past eight years, he has focused on the application of XML authoring and metadata-based document management in the pharmaceutical industry. He now works part-time as their Product Strategist, advising the company on regulatory initiatives and industry trends that affect their SPL products and representing them in the joint HL7/PhRMA/FDA SPL Implementation Working Group, where he is co-chair of the Technical Team and a member of the Leadership Team.
Keith also continues to teach graduate courses in the Faculty of Information at the University of Toronto, where he has been an adjunct faculty member since 1980.
He can be reached at firstname.lastname@example.org.
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