Request for Quality Metrics: Guidance for Industry (July 2015) is a significant draft guidance you need to address in terms of the Annual Product Reviews (APRs) that are conducted annually, and what should be included either within the APR or as a separate analysis.
The guidance applies to both APIs and FDFs (finished dosage forms). As a proactive measure, we are suggesting that you initiate this system by the time you are in Phase 3 clinical development, if not earlier, depending if you are on a fast track development cycle or expedited review. This will facilitate compliance with management and cross functional departments on the expectation of what is important to analyze during development as you enter the life cycle for the product, even though it is in development.
Our experience is such that companies lose a lot of valuable information during development, because it is not analyzed adequately and used to make incremental improvements during clinical manufacturing.
FDA notes that the following baseline quality metrics will be requested as part of their risk based analysis that could either reduce or increase the inspection frequency at a site. FDA hopes to reduce inspection frequencies for companies that have robust quality metrics.
- The number of lots attempted of the product. (See 21 CFR 211.165, 211.188)
- The number of specification-related rejected lots of the product, rejected during or after manufacturing. (See 21 CFR 211.192, 165(f))
- The number of attempted lots pending disposition for more than 30 days. (See 21 CFR 211.188. Under current good manufacturing practice, deviation investigations and final disposition decisions must be completed in a timely manner. Note that the request for lots pending disposition more than 30 days was selected as a measurement tool and not intended to clarify the timely manner in which disposition should be completed. Further, a lot may be subdivided or grouped after the first attempted lot is initiated. Each subsequent subdivision or grouping is considered a separate lot. These data will be used to verify data validity supporting the lot acceptance rate metric).
- The number of out-of-specification (OOS) results for the product, including stability testing. (See 21 CFR 211.160(a). For the purpose of this guidance, this includes: (1) finished product and stability test results only and, (2) all finished product and stability test results that initially appear as OOS, even if invalidated by a subsequent laboratory investigation).
- The number of lot release and stability tests conducted for the product. (See 21 CFR 211.165, 211.194(a), and 610.1. If a lot release or stability test is conducted multiple times for a lot, each test should be counted.)
- The number of OOS results for lot release and stability tests for the product which are invalidated due to lab error. (See 21 CFR 211.160(a). While this guidance is requesting data specific to lot release and stability tests, FDA recognizes the importance of other types of testing (e.g., in-process testing, environmental testing, raw material and packaging component testing).
- The number of product quality complaints received for the product. (This quality data is the total number of all product quality complaints, as defined in the Glossary. This does not include multiple counting of the same product quality complaint if the complaint receiver forwards the complaint to individual manufacturers for further investigation).
- The number of lots attempted which are released for distribution or for the next stage of manufacturing the product. (See 21 CFR 211.150(b)).
- If the associated annual product reviews (APRs) or product quality reviews (PQRs) were completed within 30 days of annual due date for the product. (See 21 CFR 211.22(d); 211.180(e). The data for APRs and PQRs not completed within 30 days was selected as a measurement tool and not intended to clarify the timely manner in which APRs and PQRs should be completed).
- The number of APRs or PQRs required for the product. (See 21 CFR 211.22; 211.180(e).
In the draft guidance document, FDA lists four quality metrics it intends to calculate for each product and establishment, where applicable. Note that the expectation is to complete APRs within 30 days and not within 3 months as most companies specify in their SOPs.
- 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.
Download a copy of the draft guidance here.