A Systematic Analysis of the Effect of Extraction Solvents on the Chemical Composition of Extraction Solutions and the Analytical Implications in Extractables and Leachables Studies.

Assessment of extractables and leachables (E&L) released from the pharmaceutical container closure systems (CCS), single-use polymeric processing materials (PPM), and medical devices is one of regulatory requirements in the submission and approval of pharmaceutical products and medical devices. The analytical activities involved in E&L studies are the solvent extraction of test articles, followed by instrumental analysis to determine both concentration and identities. Most E&L publications today are centered around the latter part, and the effect of extraction solvents on the chemical composition of extracts in the number, concentration and molecular weight (MW) has not been systematically delineated and conceptualized to the best of our knowledge. The focus of this study is on a systematic review and analysis of the effect of solvents on the composition of extracts based on an extensive collection and study of relevant publications. The details of the discussions include: (1) the solvent extraction processes; (2) the degree of solvent-material interactions; (3) the material swelling and diffusion rate of material constituents; (4) the MW impact from swelling; and (5) finally, the conclusion of the dependency of chemical compositions in final extracts on solvent. Experimental data have also been collected and presented to support the conclusions of the study. The implications of the solvent-dependent chemical composition on analytical measurements of E&L by using both chromatography-based and gravimetric methods are briefly and critically discussed at the end.

Impact of formaldehyde, acetaldehyde, and N-(3-(Dimethylamino)propyl)methacrylamide on the efficacy of the human derived coagulation factor IX.

Polymer-borne leachables such as formaldehyde, acetaldehyde, and N-3-(Dimethylamino)propyl)methacrylamide (DMAPMA) may interact with therapeutic proteins. In this study, the leachables were spiked into human derived coagulation factor IX (FIX) at concentrations of 1, 10, 50, 100, and 500 µg/mL, corresponding to a leachable - FIX ratio of 0.5, 5, 25, 50 and 250 %, respectively. The spiked samples were visually inspected, and pH was measured. No visual effects were observed, and pH was within the drug product's specified range. Recovery experiments were performed and no loss of leachables was identified. Protein structure analysis revealed that formaldehyde reacted with lysine contained in two different positions of FIX, in a concentration-dependent manner starting at 10 µg/mL (5 %). The clotting activity of FIX was measured. The activity of the samples spiked with 500 µg/mL (250 %) of formaldehyde dropped by more than half. The activity of the samples spiked with acetaldehyde began to drop at 50 µg/mL (25 %) and continued to decline in concentration-dependent manner. DMAPMA did not impair the activity of FIX. The findings conclude that depending on the concentration, some leachables may react with or modify therapeutic proteins, potentially causing an undesired pharmacological effect however, this is specific to each protein.