FDASIA 706 and 711 Have Come Home to Roost

By Jay W. Cormier –

On Monday, after seeking input from a number of large industry stakeholders and floating the idea for some time, FDA announced the availability of a Draft Guidance entitled “Request for Quality Metrics.”  The Draft Guidance formally presents FDA’s current thinking and intentions regarding the collection and use of quality metrics – a broad new initiative that will see the collection and review of potentially large swaths of new information that was previously difficult for FDA to collect and assess systematically.  FDA intends to use these data to make risk-based decisions when assigning facility inspections and to identify potential drug shortage issues earlier so that issues can be corrected before a shortage happens. 

For those who don’t make quality metrics a topic of regular conversation, FDA’s legal authority started almost three years ago when FDASIA was signed into law.  Within its 140 pages were two short sections that, on their own, seem entirely separate.  Section 711 of FDASIA added a new sentence to the end of Section 501of the FDCA, and read, in its entirety:

For purposes of paragraph (a)(2)(B), the term ‘current good manufacturing practice’ includes the implementation of oversight and controls over the manufacture of drugs to ensure quality, including managing the risk of and establishing the safety of raw materials, materials used in the manufacturing of drugs, and finished drug products.

Recall that Section 501(a)(2)(B) is the statutory requirement that all human and animal drugs be manufactured under cGMPs; it is the source of the regulations at Parts 210, 211, 225, and 226, as well as the litany of guidance that governs drug substance and drug product manufacturing.  The other FDASIA provision, Section 706, added a new subparagraph to Section 704(a) of the FDCA that states, in relevant part:

Any records or other information that the Secretary may inspect under [Section 704] from a person that owns or operates an establishment that is engaged in the manufacture, preparation, propagation, compounding, or processing of a drug shall, upon the request of the Secretary, be provided to the Secretary by such person, in advance of or in lieu of an inspection, within a reasonable timeframe, within reasonable limits, and in a reasonable manner, and in either electronic or physical form, at the expense of such person.

Put these two provisions together in a room (or coop, rather) and the result is something new – FDA’s Draft Guidance.  Using these two authorities, the Draft Guidance asserts that keeping records of quality metric inputs is part of cGMPs, because a company, under the amended Section 501(a)(2)(B), has an obligation to implement and have oversight over process quality controls, and that FDA has a right to “request” that companies provide such information, under the new Section 704(a)(4), in advance of (or in lieu of) a facility inspection.  I use quotes around “request” because, according to the Draft Guidance, failing to comply with a quality metrics request under 704(a)(4) does two very unwelcome things:  (1) it renders your products adulterated under Section 501, and (2) is considered a refusal of an inspection under Section 704.  Both of these are prohibited acts, subject to FDA’s full panoply of enforcement tools (injunction, seizure, and criminal prosecution, to name a few).  So, a “request” for quality metrics is just a nice way of making a demand for quality metrics. 

In the Draft Guidance, FDA defines quality metrics to include:

• Lot acceptance rate
• Product quality complaint rate
• Invalidated out-of-specification (OOS) rate
• Annual Product Review (APR) or Product Quality Review (PQR) on-time rate

In order to calculate these metrics, FDA will be asking manufacturers to provide:

• Number of lots attempted
• Number of lots pending disposition for more than 30 days
• Number of lots released
• Number of OOS results
• Number of lots rejected due to OOS
• Number of release and stability tests conducted
• Number of OOS results that are invalidated due to laboratory error
• Number of product quality complaints
• Number of APRs and PQRs required
• Number of APRs and PQRs completed within 30 days of due date

Importantly, although all draft guidance documents are submitted for public comment, FDA specifically asks manufacturers to comment on several specific items, including:

• Whether FDA should allow manufacturers to submit additional optional metrics, including, among others:
• The extent of senior management involvement in APR and PQR review and approval
• How many CAPAs identify training as a root cause
• Whether a facility calculates a process capability or performance index for each product’s critical quality attributes
• What the most efficient timing for submission of quality metrics may be, for example:
• Within a specified period of time after the FDA request
• At the same time that the APR/QPR is submitted
• Whether FDA should allow for explanations to be included with the submitted data (FDA says that it can’t guarantee that it will review these comments)

As far as who all of this will apply to, FDA hasn’t specifically said which manufacturers will need to submit.  FDA does say, however, that, as a general matter, these requests would only be made of facilities registered under Section 510 of the FDCA as manufacturers of drug substances and drug products for NDA/ANDA-approved drugs, OTC monograph drugs, and marketed unapproved drug products. 

When FDA decides to make a request of a manufacturer, FDA states that it will do so first by publishing the request in the Federal Register.  We expect that FDA will make general requests from specific types of facilities (e.g., human prescription drug substance manufacturers) rather than publish the full listing of every facility that must comply with a given request. 

FDA’s Draft Guidance states that quality metric requests would not be made of a lengthy list of facilities, including: drug compounding facilities, outsourcing facilities, medical gas manufacturers, and manufacturers of blood, cell therapy, gene therapy, and vaccine products, as well as those that manufacture allergenic extracts and tissue based products.  A full listing of these types of facilities can be found on page 2 of the Draft Guidance. 

FDA asks for comments to be submitted by September 25th.