Just as everyone was putting their Christmas lights and mistletoes away and getting ready to usher in the new year, on December 28, 2016, FDA published yet another draft guidance regarding valid electronic submissions of manufacturing establishment information (MEI). The draft guidance, titled, “Providing Regulatory Submissions in Electronic Format—Submission of Manufacturing Establishment Information”¹ (the Guidance), discusses the requirements and implementation of the Federal Food, Drug, and Cosmetic Act (the FD&C Act) regarding valid electronic submissions of manufacturing establishment information (MEI). So, let us look and see what it is all about.

Background
Section 745A(a) of the FD&C Act applies to submissions under sections 505(b), 505(i), and 505(j) of the FD&C Act and under section 351(a) and 351(k) of the Public Health Service Act (PHS Act). These include certain INDs, NDAs, ANDAs and BLAs. Section 745A(a) also applies to all subsequent submissions, including amendments, supplements, and reports, to the submission types identified above. To implement the provisions of the section, FDA published a guidance titled “Providing Regulatory Submissions in Electronic Format—Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act” in December 2014, which was added by section 1136 of the Food and Drug Administration Safety and Innovation Act (FDASIA).² The provisions of this guidance became effective in December 2016 after the 24-month period from the publication of the guidance.

In the new Guidance, FDA made it very clear that in section 745A(a) of the FD&C Act, Congress granted explicit authorization to FDA to specify, by guidance, the electronic format for submissions under sections 505(b), 505(i), and 505(j) of the FD&C Act and submissions under section 351(a) and 351(k) of the PHS Act, which include MEI. It is interesting to note that the FDA also clarifies that the Guidance is not subject to the usual restrictions in FDA’s good guidance practice regulations, such as the requirement that guidances do not establish legally enforceable responsibilities.³ Thus, under current regulations at 21 CFR parts 314 and 601, applicants and holders of approved applications are required to submit contact information for each manufacturing establishment involved in the manufacture of the drug or biological product, as well as other information relating to the manufacture of the product.

Standardization
So, what prompted this guidance full of fancy abbreviations and tech talk? According to FDA, recently, the Agency has “noticed” that the required information on the manufacturing establishments is often provided in different sections throughout the application making the MEI difficult to find and time-consuming to review. Consolidating the required information in a single location in a standard format will facilitate an efficient review of all manufacturing establishments involved. Everyone concerned would agree that consolidation of the MEI will help eliminate the inclusion and maintenance of potentially outdated and erroneous information that might otherwise be retrieved from other Agency files and will enable proper identification and timely evaluation of manufacturing establishments for conformance with requirements, including current good manufacturing practices.

Therefore, the Agency is requiring that applicants consolidate the MEI into a single list of information about each manufacturing establishment referred to in an application to resolve this. This list must be submitted as one electronic file and must include the required information for each manufacturing establishment involved in the manufacture of the drug or biological product. Providing a Field Establishment Identifier (FEI) number is recommended, but not required.

The Guidance further elaborates that the MEI is comprised of the following: the establishment name and address that includes specific information regarding the physical location of all manufacturing sites including packaging and control sites for the drug substance as well as the drug product, Unique Facility Identifier (UFI), contact information for the person responsible for scheduling inspections and a list of specific manufacturing operations being conducted at the site.

Other than noncommercial INDs, all original (i.e., initial) NDAs, ANDAs, and BLAs, drug master files, biological product files and all combination products filed pursuant to section 505 of the FD&C Act or subsection (a) or (k) of section 351 of the PHS Act will require submission of this information in the Health Level 7 (HL7) Version 3: Structured Product Labeling (SPL) standard. It goes without saying that this information must be submitted electronically and maintained in this format for supplements and resubmissions to these application types.

The technical aspects
According to section 745A(a) of the FD&C Act, electronic submissions “shall be in such electronic format as specified by [FDA].” So, FDA has determined that MEI must be in the electronic format described above, using HL7 Version 3: SPL (Structured Product Labeling).  The MEI file must be included in eCTD Module 3, section 3.2.R Regional information. Applicants must name the file, “establishment-information- [Date of the submission (YYYY-MM-DD)].xml” with a corresponding leaf title of “Establishment-Information-[Date of the submission (YYYY-MM-DD)].” For those who care to know, XML stands for Extensible Markup Language, where it can be used to markup or “tag” text documents. The XML schema allows users to validate whether an XML document is correct before transmission to the Agency. Finally, XML allows extension of the elements in a document. To avoid redundancy, the following “Manufacturer” sections must simply link to the single 3.2.R Regional file described above, and no other files may be submitted in 3.2.S.2.1 Manufacturer(s) [Drug Substance] and 3.2.P.3.1 Manufacturer(s) [Drug Product]. And (I am not surprised) that the Agency may refuse to file or receive an electronic submission unless the MEI conforms to the format specified in this guidance: a consolidated file of MEI in HL7 Version 3: SPL.

Data universal numbering system and structured product labeling
As the industry has gone beyond the borders of the U.S. and truly become a global player, FDA had been requesting more and more information from the Industry about the facilities. Identification and designation of facilities has also evolved from Central File Numbers (CFN) to FEI to UFI. Although FDA has discontinued using CFNs, the fate of FEI is not clear. Currently, FDA requires facilities information in module 1 (form FDA 356h), module 2 (sections 2.3.S.2 and 2.3.P.3), and module 3 (sections 3.2.S.2, 3.2.P.3 and regional sections).  Most of the redundancies are due to requests from regulatory authorities.

DUNS number is one of the most recent facility identifiers that has been specified by the Agency. When the Agency first published a draft guidance related to the use of DUNS as a means of facility identification, BIO expressed its concern about it. In their comments to the docket (FDA-2013-D-0984) Biotechnology Industry Organization (BIO) stated that “although the use of the DUNS number allows for a number available in the public domain, the process for obtaining a DUNS number does not provide the necessary control to ensure the address registered for a site is accurate to prevent duplication of numbers for the same site or same site address.”⁴ BIO went on to suggest that FDA consider making the Global Location Number (GLN), obtained from GS1, the preferred UFI system. As BIO contended, the GLN contains embedded Global Positioning Satellite (GPS) coordinates to identify the unique geographic location of a manufacturing facility. The GLN provides for a unique number for a nominal cost to the manufacturer or Sponsor. The GLN, as an internationally recognized GS1 standard, also provides a means for global harmonization and eliminates the uncertainty of obsolete legacy identifiers.

Another firm pointed out (FDA-2013-D-0984) that the industry is having a very challenging time getting Establishment Registration Form Structured Product Labeling (ERF SPL) files to pass FDA validation due to discrepancies in the addresses that industry provides versus what appears in the Dun and Bradstreet database used for FDA validation. Foreign addresses are extremely challenging. Industry needs a way to verify the address that FDA sees prior to submitting the ERF SPL file to the FDA. This challenge has been discussed at the SPL Working group meetings and many companies are having the same issue regarding failing ERF SPL files. Dun and Bradstreet offered the possibility of a portal that industry could use to see the addresses in the Dun and Bradstreet database that the FDA uses to validate the ERF SPL files. This portal, showing real time data, would help alleviate the issue as well as provide efficiencies for the Agency, as fewer manual overrides would be requested.⁵ 

Some may question the expanded use of SPL/XML as other data format such as JavaScript Object Notation (JSON) may be more efficient or may replace XML in other applications. However, there are situations where XML may be better than JSON. As mentioned earlier, XML is extensible, allows markup and validation. Moreover, ICH has embraced XML as an integral part of HL7 standards and will continue to be used as we move to Regulatory Products Submissions (RPS). In addition, FDA has also specified XML for some Standardized Study Data components.

Looking ahead
XML evolved from SGML, which was designed to manage large volumes of textual information. For more than fifteen years, SGML has been used in publishing, telecommunications, and manufacturing companies to solve the same content management problems that XML addresses today. By separating the style of a document from its content and structure, XML contents provide different views to different audiences from a single source document. In MS Word or HTML systems, a separate version of the document is needed for each view. So, XML authoring systems provides a solid foundation for future growth as they are platform independent and can be upgraded with relative ease.

As discussed earlier, FDA is willing to replace some PDF content with XML. In this regard, we should also note that PDF is not an authoring format. You need another authoring tool such as Microsoft Office or an open source equivalent to create the source document and then render it to PDF format. So, at a very fundamental level, it a not an efficient process for content creation and presentation. Furthermore, in relation to eCTD compliant PDF format, you will need a proprietary version of Adobe Acrobat or equivalent to optimize the documents for submission purposes.

Authoring language such as XML and editors are readily available as open source tools. Moreover, eCTD uses XML as its backbone anyway. Other than executed source documents that are typically scanned which are further processed by performing Optical Character Recognition (OCR), a large part of an eCTD submission is made up of rendered PDF following authoring in Microsoft Office or equivalent. We know ICH has gone through an exhaustive evaluation of all relevant formats before deciding on PDF standard. However, that was more than a decade ago, and we have learned a lot about eCTD and related languages and formats. So, as FDA is promoting continuous improvement in terms of quality by design and other areas, it wouldn’t be totally inappropriate to revisit this technical issue as we move toward implementing yet another submission standard.

Finally, as consolidating required information in a single location in a standard format to facilitate an efficient review of all manufacturing establishments is the primary motivation for this initiative, we hope that FDA will take this opportunity to eliminate some of the redundancies that have crept up in the submissions over time. We look forward to more standardization to replace additional structured information that are provided as part of forms and tables with machine readable and multi-platform format such as XML/SPL. 

References

1. U.S. Food and Drug Administration, “Providing Regulatory Submissions in Electronic Format – Submission of Manufacturing Establishment Information”, Draft Guidance for Industry, December 2016, https://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/UCM534709.pdf
2. Providing Regulatory Submissions in Electronic Format — Submissions Under Section 745A(a) of the Federal Food, Drug, and Cosmetic Act, December 2014
3. 21 CFR Sec. 10.115 (d)
4. Comment on the FDA Notice on Draft Guidance for Industry on Specification of the Unique Facility Identifier System for Drug Establishment Registration, docket FDA-2013-D-0984-0004
5. Comment on the FDA Notice: Draft Guidance for Industry on Specification of the Unique Facility Identifier System for Drug Establishment Registration, docket FDA-2013-D-0984-0003

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Sharif Ahmed
Lachman Consultants

Sharif Ahmed is a Principal Consultant in the Regulatory Practice at Lachman Consultants. With nearly 30 years of progressive responsibilities in the pharmaceutical industry Mr. Ahmed is knowledgeable of the product approval processes of U.S. FDA and Health Canada. He provides services in regulatory affairs, quality, clinical and non-clinical development across many dosage forms for controlled, modified and sustained drug release products as well as active pharmaceutical ingredients.