Scaling Up an Immobilized Enzyme System
BECAUSE OF THEIR ABILITY TO CATALYZE CHEMICAL REACTIONS at temperatures from approximatery 4 deg. to 80 deg.C and at standard pressure, enzymes have been used by man since ancient times. The use of enzymes has gradually been extended into a variety of fields including brewing, food preparation and production, textiles, tanning, and medicine. More recently, immobilized enzymes have been used to improve control, improve product, and reduce cost. Immobilized enzymes are enzymes attached or adsorbed onto water-insoluble matrices such that they can be separated from the liquid medium containing the enzyme substrate and product.
Although Nelson and Griffin (1) first reported immobilizing enzymes in 1916, there was little interest in their use until the 1950's and 1960's when studies by Bar-Eli and Katchalski (2), Zittle (3), MacLaren (4), and Mitz and Summaria (5) appeared. This activity culminated in the development of the first industrial immobilized enzyme process, which was commercialized by Tanabe Seiyaku Company, Ltd., Osaka, Japan, in 1967 (6).
By 1971 when the first Enzyme Engineering Conference was held in Henniker, New Hampshire, a large proportion of the conference was devoted to immobilized enzymes. During these early years there was, understandbly, a lack of appreciation for the problems and implications of scaling up such systems. Unfortunately, this lack of understanding has persisted to a significant degree through the intervening years.
At the second Enzyme Engineering Conference in 1973, Havewala and Pitcher (7) presented studies on an immobilized glucose isomerase system that for perhaps the first time included an analysis of mass transfer, kinetics, temperature effects on activity, and stability, as well as other considerations of importance required for designing large-scale systems. By 1975 many studies dealing with the engineering of immobilized enzyme systems were appearing. By the late 1970's, immobilized glucose isomerase had become a major commercial success, making possible the production of high-fructose corn syrup.
Today most immobilized enzyme systems in commercial use consist of cells immobilized or entrapped in a water-insoluble matrix, or similarly immobilized cell extracts, or partially purified enzymes. In almost all cases these processes use only one enzyme even if others are present, as in the case of cell extracts. Table 1 lists several commercial and potentially commercial systems that have been developed within recent years.
Because enzymes are catalysts, their cost may be only a fraction of the value of the products they make possible. The enzyme market (approximately $400 million per year) supports several multibillion-dollar industries. Immobilized enzymes constitute only a fraction of the total enzyme market. One difficulty has been that the high initial cost of developing an immobilized enzyme system cannot always be recovered by the enzyme supplier. The strong technical proprietary positions necessary to allow higher valuations of such systems have frequently not occurred.
Assuming a proposed immobilized enzyme system has met the economic and market criteria, what approach should one follow? Developing and scaling up such a system is a large and complex optimization problem where in a number of interdependent decisions...