FDA publishes Quality Metrics Guidance

In the last months, the U.S. Food and Drug Administration (FDA) has set up an initiative to use Quality Metrics for planning their risk based inspections. This development was triggered by the Food and Drug Administration Safety and Innovation Act (FDASIA; Title VII, section 706). The goal of the Guidance is to give FDA the authority to collect Quality Metrics from production sites supplying APIs, medicinal products, Biotech, OTC etc. to the US. They should provide data about the "quality level" in each manufacturing site. By this, FDA wants be able to see how well quality systems are maintained. In the future companies will need to conduct continual monitoring, assessment and reporting on the state of quality across their drug products and facilities regulated by FDA. This should then enable FDA to schedule inspections based on risk assessment, improve the efficiency and effectiveness of these inspections and also reduce product-related shortages and recalls. FDA also wants to "encourage the pharmaceutical industry to implement state-of-the-art, innovative quality management systems for pharmaceutical manufacturing".

What needs to be reported?

FDA asks for data to be compiled and reported on:

  • The number of lots attempted of the product.
  • The number of specification-related rejected lots of the product (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.

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.

Who needs to report?

FDA intends to request the submission of data from establishments that are required to register under section 510 of the Food, Drug and Cosmetic (FD&C) Act and that are subject to inspection under section 704 of the FD&C Act (704 allows inspections of regulated entities). Establishments that receive requests under section 704(a)(4) would be encouraged to submit quality metrics data also for certain foreign establishments that are not required to register.

So basically the Guidance applies to every legal entity engaged in the manufacture, preparation, propagation, compounding, or processing of a drug product for the US market or an API used in the manufacture of such a drug product. FDA sees the Quality Control Unit (QCU) generally to be the one to compile the reports.

How many reports should be submitted?

FDA intends to get one report for each finished dosage form and one report for each API of a covered drug product.

When do the reports should be submitted?

Reports should be submitted after request. Quality metrics data reports should be submitted for a one-year period that begins after FDA issues its requests. They should then be submitted within 60 days of the end date of the reporting period.

What will happen in the case of non-reporting?

This will change FDA's risk assessment and may lead to an earlier inspection. In addition, the respective products may be deemed adulterated and subject to enforcement action.

What are the challenges?

Certainly a challenge for both industry and FDA will be how to span the scope of all segments like branded, generic, biotech and OTC products, APIs, various finished dosage forms (solid oral, modified release, liquid, sterile, etc. and domestic and foreign products with possible language barriers. This will create a lot of data. And Quality Metrics are just one part of the picture, intended to be enhancing FDA's analysis but not replacing existing measures. The program will likely need to learn and evolve through continuous improvement.

Comments and suggestions regarding the Draft Guidance for Industry "Request for Quality Metrics" should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance.

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