A cross-industry forum on benchmarking critical quality attribute identification and linkage to process characterization studies.

Identification of Critical Quality Attributes (CQAs) and subsequent characterization in process development studies are the key elements of quality by design (QbD) for biopharmaceutical products. Since the inception of ICH Q8R2, several articles have been published on approaches to conducting CQA risk assessments as well as the application to process understanding. A survey was conducted by multiple companies participating in an International Consortium working group on the best practices for identifying CQAs with linkages to process characterization (PC) studies. The results indicate that the companies surveyed are using similar approaches/timing to identify CQAs during process development. Consensus was also observed among the companies surveyed with approaches to linkage of CQAs to process characterization studies leading to impact to control strategies and lifecycle management.

Physical and chemical compatibility of drotrecogin alfa (activated) with 34 drugs during simulated Y-site administration.

PURPOSE: The physical and chemical compatibility of drotrecogin alfa (activated) (recombinant human activated protein C) during simulated Y-site administration with drugs commonly used to treat patients with severe sepsis was determined. METHODS: Thirty-four drugs were investigated for visual compatibility with drotrecogin alfa, and included cardiovascular agents, conscious sedative agents, antibiotics, blood products, and other supportive care drugs. The physical and chemical compatibility of drotrecogin alfa with these drugs was determined using a well-established experimental model to simulate Y-site administration. Drotrecogin alfa (activated) was prepared as 100- and 1000-microg/mL solutions in 0.9% sodium chloride injection. All other drugs were prepared at maximum concentrations commonly administered in the clinical setting. Visual compatibility was assessed by visual inspection (observations of haziness, color change, or precipitate formation) and pH measurement at 0, 30, 60, and 240 minutes after mixing. RESULTS: Of the 34 test drugs, 8 were defined as visually compatible with drotrecogin alfa; these drugs were further assessed for chemical compatibility with drotrecogin alfa. The protein content, potency, and purity of drotrecogin alfa were determined at 0, 60, and 240 minutes after Y-site mixing as indicators of chemical compatibility. Six drugs (ceftriaxone, cisatracurium, fluconazole, nitroglycerin, potassium chloride, and vasopressin) were determined to be chemically compatible with drotrecogin alfa; two drugs (cyclosporine and ticarcillin-clavulanate) were chemically incompatible with drotrecogin alfa after Y-site mixing. CONCLUSION: Ceftriaxone, cisatracurium, fluconazole, nitroglycerin, potassium chloride, and vasopressin were physically and chemically compatible with drotrecogin alfa in a simulated Y-site infusion; 28 other drugs were incompatible with drotrecogin alfa.