US FDA Drops Plan To Simplify Pharmaceutical Plant Reporting
Executive Summary
Industry complained draft guidance would have made manufacturing establishment information harder to report, not easier.
The US Food and Drug Administration has gone back to the drawing board in its effort to consolidate the electronic submission of pharmaceutical manufacturing facility information after reviewing industry’s concerns about a draft guidance document.
The agency on 22 July withdrew the draft guidance that explained how it planned to implement a provision regarding manufacturing establishment information, or MEI, in drug applications that the FDA Safety and Innovation Act (FDASIA) added to the Food Drug and Cosmetic Act in July 2012.
The 29 December 2016 draft guidance would have streamlined review of manufacturing establishments by consolidating information in one location, the agency said in a withdrawal notice on its website.
However, the Pharmaceutical Research and Manufacturers of America took a different view, as did the Active Pharmaceutical Ingredients Committee of the European Chemical Industry Council. There were complaints that the draft guidance duplicated instead of consolidating reporting requirements, that it was unclear and somewhat counterproductive and, in some cases,unworkable.
The provision, which would have been a new section 745A(a) in the FD&C Act (21 US Code 379k-1), says certain regulatory submissions will have to be submitted in electronic format starting no less than 24 months after issuance of final guidance. The provision expressly allows the guidance to give a timetable for establishment “of further standards for electronic submission as required by such paragraph,” and to “set forth criteria for waivers of and exemptions from” the requirements set forth in the provision.
Heparin Crisis Showed Need For Facility Information
FDASIA provided Congress’ response to the 2008 heparin crisis, which among other things had exposed the poor state of the FDA’s records of pharmaceutical manufacturing establishments abroad.
In the run-up to the crisis, the FDA had approved a supplier of suspect heparin active pharmaceutical ingredient based on an inspection of what turned out to be some other company’s facility.
More broadly, the agency could not tell Congress with any certainty how many foreign facilities manufactured drugs for the US market.
Efforts to improve the agency’s manufacturing facility information began soon after authorities tried to track down the source of contaminated heparin anticoagulant linked to deaths of dialysis and surgery patients. (Also see "Electronic Registration to Aid FDA's Quest for Enhanced Global Oversight" - Pink Sheet, 1 Nov, 2008.)
Efforts have proceeded in recent years with “golden” manufacturing facility records (Also see "FDA Establishing ‘Golden’ Manufacturing Facility Records" - Pink Sheet, 29 Jan, 2016.) and new drug registration rules. (Also see "FDA Makes 'Significant Changes' To Drug Registration Rules" - Pink Sheet, 5 Sep, 2016.)
The FDA said it decided to withdraw the draft guidance after reviewing industry comments so that it could “reevaluate its approach to submission of manufacturing establishment information in drug applications.” The agency “will communicate publicly in the event that a new draft guidance on submission of manufacturing establishment information is issued.”
PhRMA Found Guidance Duplicative And Confusing
PhRMA complained that the way the FDA wrote the draft guidance would have created “an additional, duplicative MEI submission burden for sponsors instead of the stated goal of consolidation.”
Drug makers would have to begin submitting the facility information in the Health Level Seven international data standard’s Structured Product Labeling format while continuing to also submit it in an extractable format in the FDA’s 356h application form for marketing new drugs, biologics or antibiotics for human use.
PhRMA raised other concerns as well: the draft guidance was not detailed enough “to understand, anticipate and comply with,” was unlikely to assure consistent interpretation of Section 745A(a) of the FD&C Act and could set back efforts to harmonize applications globally with the electronic common technical document.
By recommending that sponsors identify facilities with an FDA Establishment Identification number, the draft contradicted previous guidance that called for industry to use the Data Universal Numbering System (DUNS) number instead.
The industry group also urged the agency to add a timetable for version updates of the SPL standard because even minor changes can force sponsors to conduct impact assessments, develop or buy new software, update data capture systems, retrain personnel and rework completed portions of submissions.
PhRMA asked for greater clarity on how the guidance would impact previously approved drug products. The group also wanted to know whether the new facility reporting requirements applied to all annual reports and supplements or just to those where the information changed.
An implementation guide should accompany the guidance with examples of format, structure and validation criteria, PhRMA said.
APIC Found It Approached DMFs Backwards
The Active Pharmaceutical Ingredients Committee of the European Chemical Industry Council raised concerns about the way the draft guidance would have required applicants to reference API supplier facilities information that typically appears in drug master files, or DMFs.
APIC said the draft guidance essentially forced DMFs to reference applications, which would not be feasible in the common situation where multiple applications reference a DMF.
APIC recommended reversing the logic used in populating drug substance manufacturer information in drug applications, saying it would “avoid confusion and … allow better control and traceability.”
Genentech Recommended IDMP Alternative
Genentech Inc. filed comments urging the FDA to consider aligning its electronic manufacturing establishment information with the ISO Identification of Medicinal Product, or IDMP, Health Informatics standard, ISO 11615, something the draft guidance had not discussed.
The FDA has been defining data sets based on the IDMP standard for its knowledge-aided and structured application initiative. (Also see "FDA Looks To Strengthen, Speed Drug Reviews With Flow Of Quality Data" - In Vivo, 17 Dec, 2018.)