The solubilities In C02 of three pure triglycerides (trllaurin, trimyrlstin, and tripalmitin) and their corresponding fatty acids (laurlc acid, myrlstlc acid, and palmitic acid) were measured at 313 K and at pressures between 8 and 30 MPa. The data were correlated by using a lattice model equation of state. Solubilities of members of a homologous series (fatty acid or triglyceride) decreased with Increasing molecular weight In accordance with previous findings. Solubilities of triglyceride mixtures In C02 were also measured. The solubility of the most soluble compound In the mixture was the same as the pure component solubility of that compound, but the solubilities of the less soluble species In mixtures were enhanced by the presence of more soluble triglycerides.

Three different authors have reported on the use of four different enzymes in supercritical fluids. Nakamura et al. (1986) have demonstrated that lipase carries out transesterification reactions in the presence of supercritical carbon dioxide. Hammond et al. (1985) have shown that polyphenyl oxidase is active in supercritical CO, and fluoroform. Randolph et al. (1985) have shown that alkaline phosphatase and cholesterol oxidase are active in supercritical C 0 2 . More recently, Randolph et al. (1988) have examined the effect of aggregation of cholesterol on cholesterol oxidase activity in CO, using electron paramagnetic resonance (EPR). They found that when cosolvents which promoted aggregation were added, the reaction rate increased in proportion to the amount of aggregation. To date, no data on the effect of pressure on reaction rate have been presented.The objective of this work is to determine whether pressureinduced changes in the physical properties of a supercritical fluid solvent affect the rate of an enzymatic reaction and if so, which properties are responsible for the change.The enzyme used in this work is lipase from Rhizopus arrhizius, which catalyzes the transesterification of triglycerides in the presence of free fatty acids and low water activity. It is not specific for any particular triglyceride, but only acts on the fatty acid residues at the 1 and 3 position of the glycerol backbone. Thus, the 2-substituted product is not formed. This leaves only two products, the 1-(or 3-) and 1,3-substituted triglycerides. A microbial lipase was chosen because it does not require cofactors and because different batches have a more consistent activity than a tissue-derived enzyme such as porcine pancreatic lipase.The reactants are trilaurin (LLL) and palmitic acid and the products are 1.2-dilauryl-3-palmitoyl-rac-glycerol (PLL) and 1,3-dipalmitoyl-2-lauryl-rac-glycerol (PLP). Since a small amount of water is present, the diglycerides 1,2-dilauryl-glycerol (LL) and 1 -palmitoyl-2-lauryl-glycerol (PL) are formed as

Purpose:The purpose is to determine the maximumtolerated dose, assess the toxicities, characterize the pharmacokinetic behavior, and seek preliminary evidence of biological activity of cantuzumab mertansine when administered as a weekly i.v. infusion without interruption.Experimental Design: Patients with incurable solid tumors that expressed the target antigen for cantuzumab mertansine, CanAg, were treated with doses of cantuzumab mertansine ranging from 40 to 138 mg/m 2 . The maximumtolerated dose was defined as the highest dose at which no more than 1 of 6 patients experienced dose-limiting toxicity. Plasma concentrations of cantuzumab mertansine and total humanized antibody were determined, and area under the plasma concentration-time curve (to the last measured concentration) was calculated.Results: Thirty-nine patients received a total of 280 weekly doses of cantuzumab mertansine. Acute, transient elevation of the hepatic transaminases and reversible fatigue were identified as the dose-limiting toxicities at the highest dose level. The maximum-tolerated dose was determined to be 115 mg/m 2 /week. Evidence of clinical activity was noted in 3 patients. Pharmacokinetic analyses revealed that the pharmacokinetic variability was moderate, without evidence of dose dependency. Furthermore, the drug had a long terminal half-life (ϳ40 h).Conclusions: This study identified a safe and tolerable dose of the novel immunoconjugate prodrug cantuzumab mertansine. The evidence of antitumor activity suggests that additional clinical development is warranted, with a focus on tumors that express high levels of CanAg and which are known to be sensitive to antimicrotubule agents.

An ambitious 10‐year collaborative program is described to invent, design, demonstrate, and support commercialization of integrated biopharmaceutical manufacturing technology intended to transform the industry. Our goal is to enable improved control, robustness, and security of supply, dramatically reduced capital and operating cost, flexibility to supply an extremely diverse and changing portfolio of products in the face of uncertainty and changing demand, and faster product development and supply chain velocity, with sustainable raw materials, components, and energy use. The program is organized into workstreams focused on end‐to‐end control strategy, equipment flexibility, next generation technology, sustainability, and a physical test bed to evaluate and demonstrate the technologies that are developed. The elements of the program are synergistic. For example, process intensification results in cost reduction as well as increased sustainability. Improved robustness leads to less inventory, which improves costs and supply chain velocity. Flexibility allows more products to be consolidated into fewer factories, reduces the need for new facilities, simplifies the acquisition of additional capacity if needed, and reduces changeover time, which improves cost and velocity. The program incorporates both drug substance and drug product manufacturing, but this paper will focus on the drug substance elements of the program.

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