The attractiveness of using biocatalysis can be assessed by considering the benefits, drawbacks, and cost of biocatalytic systems. Benefits may include a route with fewer intermediates, or intermediates with higher yield and higher quality; these changes could result in fewer unit operations and fewer intermediates to assay, hence lower cost of goods. Other benefits may include decreased emissions of volatile organic compounds (solvents), decreased cost of remediating solvent-laden waste streams, and decreased solvent recovery operations. A significant benefit may be increased flexibility in selecting equipment to prepare the API.
Drawbacks of biocatalytic systems can include a potentially significant time to develop a biocatalytic process, unless a commercially available biocatalyst can be suitably employed. Ownership of intellectual property and licensing should be clearly addressed before a contract research organization develops a biocatalyst specifically for the API. If only one vendor can supply the biocatalyst, contracts must be carefully composed to ensure reliable delivery at an attractive price. Conditions and compounds that inhibit the biotransformation must be identified and controlled, similar to other catalytic processing. If the biocatalyst must be shipped to the site of API manufacturing, stability of the biocatalyst should be considered.
Recently authors have reviewed in detail the factors for estimating the cost of a biocatalyst [Tufvesson, P.; Lima-Ramos, J.; Nordblad, M.; Woodley, J.M. Org. Process Res. Dev. 2011, 15, 266]. (These authors did not estimate the cost of developing a biocatalyst.) With high fermentation yield the cost of the biocatalyst decreases; not all enzymes may be produced in high titer. To increase the turnover number an enzyme may be purified or even immobilized. The extent of purification has a great impact, with costs increasing as the processing evolves from whole cells to crude enzymes to purified enzymes to immobilized enzymes. As production volume increases the cost of the biocatalyst decreases, as expected through economy on scale. Costs associated with equipment may be detailed for an in-house COG estimate, or may not be mentioned in a proposal by a contract manufacturing organization.
Many factors should be considered to assess the desirability of a biocatalytic process. The “greenness” of a biocatalytic process must include the operations and waste both in the process and in generating the biocatalyst. Ultimately the acceptability of the cost of a biocatalyst must be judged relative to the value of the product. The value of increased flexibility in equipment choice and improved ruggedness in quality of a product may not be quantifiable before routine manufacture of an API. Nonetheless biocatalytic processes may provide clear advantages even early in the development of API candidates.
