Quality Testing of Difficult-to-Make Prescription Pharmaceutical Products Marketed in the US.

Importance Health care practitioners and patients must have information to support their confidence in the quality of prescription pharmaceuticals. Objective To determine whether there were clear and substantive differences in major quality attributes between difficult-to-make solid oral dosage form pharmaceutical products marketed in the US. Design, Setting, and Participants This quality improvement study analyzed US Food and Drug Administration-collected samples of 252 drug products marketed in the US and manufactured in the US, Canada, Europe, India, and the rest of Asia. These drug products were immediate-release solid oral dosage forms considered difficult to make on the basis of product quality history. This sampling included 35 innovator and 217 generic drug samples manufactured by 46 different firms containing 17 different active ingredients. Statistical analysis was performed from February to November 2019. Main Outcomes and Measures All products were tested within their shelf life on the basis of the legally recognized tests of the US Pharmacopeia for the major quality attributes of dosage unit uniformity and dissolution. These tests measure dosage consistency and drug release, respectively. The consistency of either attribute was used to calculate a process performance index to describe the variability in manufacturing. Results All 252 drug product samples met the US market standards for dosage unit uniformity and dissolution, although the process performance index (Ppk) for dissolution fell below the level of 4-sigma capability (ie, <1 error per 1600) for 11 different manufacturers and for generics in 4 of 5 regions, including the US. As part of a retrospective analysis, manufacturers performing above the median Ppk for either dissolution or dosage unit uniformity submitted fewer product quality defect reports (mean field alert reports of 0.22 and 0.63, respectively) than those falling at or below the median Ppk for these attributes (mean field alert reports of 2.1 and 1.7, respectively). Conclusions and Relevance All samples met the US market standards for dosage unit uniformity and dissolution, indicating acceptability for use by patients regardless of manufacturer or region. To our knowledge, this is the largest sampling study of pharmaceutical manufacturers for the US market and these data provide objective insight into the quality of prescription drugs with high manufacturing risks. Question Are there substantive differences in the major quality attributes of difficult-to-make pharmaceutical products manufactured throughout the world and marketed in the US? Findings In this quality improvement study, all of 252 drug product samples met the US market standards for the major quality attributes of dosage unit uniformity and dissolution, although there was evidence of differences in the consistency of these attributes among regions and manufacturers. Meaning These findings suggest that difficult-to-make prescription pharmaceuticals marketed in the US consistently meet quality standards even when manufactured outside the US. This quality improvement study examines quality testing of prescription pharmaceutical products that are manufactured in various regions of the world and marketed in the US.