In the July 28th, Federal Register, (Under “Meetings”) FDA announced the availability of the draft guidance “Request for Quality Metrics-Guidance for Industry.” Although there are “requests” for quality metrics in the guidance, the bulk of the document tells industry what quality metrics they will be reporting, at least initially.
FDA primarily cites Sections 706 and 707 of the Food and Drug Administration Safety and Innovation Act (FDASIA) as authority for its plan to require most Finished Dosage Form (FDF) and API manufacturers to supply specified quality metrics. Section 706 states that FDA “…may require the submission of any records or other information that FDA may inspect under Section 704 of the FD&C Act, in advance or in lieu of an inspection by requesting the records …” The stick is provided, per FDA, by Section 707 of FDASIA which makes a drug “adulterated” if the owner, operator or agent of the establishment manufacturing the drug “…delays, denies or limits an inspection…”, i.e., the request from FDA for quality metrics constitutes a component of their statutory authority to inspect manufacturing facilities, so a failure to comply with the planned request for quality metrics would constitute impeding or denying an inspection, and potentially effect inspection frequency of the establishment. (Yes, this is in a guidance and the guidance does have the usual, “doesn’t bind me, doesn’t bind you” language at the beginning)
The guidance repeatedly cites the proposed quality metrics as a potentially useful tool in avoiding drug shortages. FDA also asserts a number of other reasons for the creation of the quality metric program in how it intends to use the quality metrics:
“FDA intends to use quality metrics data to further develop FDA’s risk-based inspection scheduling, to identify situations in which there may be a risk for drug supply disruption, to improve the efficiency and effectiveness of establishment inspections, and to improve FDA’s evaluation of drug manufacturing and control operations. FDA expects that the initial use of the metrics will be to consider a decreased surveillance inspection frequency for certain establishments.”
Aha, there’s the carrot in that last one. In brief, firms that measure up well during inspections and turn out to have favorable metrics may be tagged for less frequent inspections. FDA also point out that the metrics may allow them to focus on firms which pose significant risks to consumers, including drug shortages However, how exactly that’s going to play out is still undetermined. FDA hasn’t even determined how they’re going to look at the data:
“FDA intends to evaluate whether data reported by manufacturers is consistent with the Agency’s understanding of the specific quality data requested (e.g., definitions). In addition, we intend to evaluate how best to interpret and use the metrics. For example, is it more meaningful to compare metrics for different products within the same establishment, or for the same product manufactured at different establishments, or as an establishment-specific trend over time? Is it more appropriate to use certain metrics to compare all types of establishments (or a subset making the same dosage form or same drug) against each other? What is the best way to compare metrics for products that vary in manufacturing complexity (e.g., biotechnology and biological products are often considered more complex to manufacture)?”
In the guidance FDA also gives itself the option of making any changes it sees fit to the metrics once things get underway.
So who will have to report quality metrics? The guidance lists the following:
“FDA intends to request quality metrics data from owners and operators of each establishment that is (1) required to register under with FDA under section 510, and (2) engaged in the manufacture, preparation, propagation, compounding, or processing of the FDF of a covered drug product, or an API used in the manufacture of a covered drug product. For purposes of these requests, a covered drug product would mean a drug product that is:
- subject to an approved application under section 505 of the FD&C Act or under section 351 of the PHS Act.
- marketed pursuant to an OTC monograph.
- a marketed unapproved drug product.”
This includes (but is not limited to) contract laboratories, contract sterilizers, contract packages, and other establishments engaged in the preparation, propagation, compounding, or processing of the FDF or API for a covered drug. Notably, foreign establishments that are not required to register are not included, but covered establishments are encouraged to provide the metrics whenever they can access the information
Something that will require some sorting out is who reports in the case where a number of firms are involved in the manufacture of the FDF, a fairly common situation these days.
“FDA intends to ask industry to submit one report for each FDF and one report for each API of a covered drug product, which includes quality metrics data from each covered establishment that has the requested data. FDA believes that, as part of its responsibility for oversight and controls over the manufacture of drugs to ensure quality, one establishment will already possess or have access to all of the quality metrics data needed to submit such reports — for example, through contract or because all of the covered establishments with quality metrics data related to a FDF of a covered drug product or API used in the manufacture of a covered drug product will be under common ownership or control. This establishment should combine the data so that a single report is submitted for each FDF and each API. In this guidance, we refer to the establishments that submit reports to FDA as “reporting establishments.”
So what exactly will firms have to report for each FDF? FDA specifies 10 items:
- The number of lots attempted of the product.
- The number of specification-related rejected lots of the product, rejected during or after manufacturing.
- The number of attempted lots pending disposition for more than 30 days.
- The number of OOS results for the product, including stability testing.
- The number of lot release and stability tests conducted for the product.
- The number of OOS results for lot release and stability tests for the product which are invalidated due to lab error.
- The number of product quality complaints received for the product.
- The number of lots attempted which are released for distribution or for the next stage of manufacturing the product.
- If the associated APRs or PQRs were completed within 30 days of annual due date for the product.
- The number of APRs or PQRs required for the product.
Using the reported data described above, FDA intends to calculate the following quality metrics for each product and establishment, where applicable:
- Lot Acceptance Rate = 1 – x (x = the number of specification-related rejected lots in a timeframe divided by the number of lots attempted by the same establishment in the same timeframe).
- Product Quality Complaint Rate = the number of product quality complaints received for the product divided by the total number of lots of the product released in the same timeframe.
- Invalidated Out-of-Specification (OOS) Rate = the number of OOS test results for the finished product invalidated by the establishment divided by the total number of OOS test results divided by the total number of tests performed by the establishment in the same timeframe.
- Annual Product Review (APR) or Product Quality Review (PQR) on Time Rate = the number of APRs or PQRs completed within 30 days of annual due date at the establishment divided by the number of products produced at the establishment.
FDA also proposes some optional metrics, dealing with Quality Culture, including Senior Management Engagement and CAPA Effectiveness, and Process Capability /Performance. Further, FDA solicits input from all concerned for revisions to the proposed metrics or any additional metrics which would be useful. (Hence the “Request” in the title of the Guidance)
FDA plans to implement the program once the guidance is finalized and the initiation is announced in the Federal Register. FDA plans to send requests for the metrics to the effected registered establishments, while reporting the metrics will be done via the ESG. The guidance includes a proposed sample worksheet for assembling the requested data.
The guidance is worth a thorough reading. Although the metrics that will be initially required don’t deviate that much from the contents of a typical Annual Product Review, the program will at minimum require a somewhat significant application of resources. After that, it depends what FDA decides to do with the information.
Prepared by Bill Stoltman, JD, Camargo’s Senior Director of Quality Assurance and Compliance