Bristol-Myers Squibb Initiative - Green Engineering

For the United States pharmaceutical industry to grow and develop in a sustainable way (while at the same time meeting current and future EPA regulations), adoption of green engineering principles is necessary from R&D through manufacturing. Through this project, a student-faculty team is working with Bristol-Myers Squibb scientists and engineers to develop green engineering protocols that can be adopted by the pharmaceutical industry. This project is sponsored by the Pollution Prevention Grants Program and the Conservation Challenge Grants Program of EPA Region 2 which includes New Jersey, New York, Puerto Rico, the U.S. Virgin Islands and the Tribal Nations in those states. Greater detail on this project is provided in Slater et al. .

The majority of drug products made through organic synthesis routes require many sequential reaction steps, large quantities of organic solvents (with varying degrees of toxicity), and are made in batch processes. All of the above are not optimal from a green engineering manufacturing standpoint. A significant reduction in the use of solvents, in terms of quantities and toxicity, can be made if investigations into the early stages (Phase I or II) of drug development are performed. It is important to work with drugs in Phase I or II of development, since these changes can be incorporated into the final manufacturing steps that are approved by the FDA. By Phase III, "synthesis lock" and "process lock" prevent innovations from being easily implemented. The team is working on developing a heuristic that pharmaceutical companies can follow in the development of new drugs.

The specific objectives of this project are to identify reductions in the use of hazardous chemicals in a drug synthesis. The Rowan team first met with the Bristol-Myers Squibb staff and discussed several possible drugs at various stages of development that we could examine. A confidentiality agreement was signed which limits the amount of information we can reveal about the drug and the manufacturing process. A cancer drug in the early stages of development was selected. The team then met to set and review project goals/objectives.

The initial part of the project involved a review of process development documentation and a pilot plant visit to understand equipment issues. The basic data on raw materials, products, byproducts of the process were analyzed. Green engineering metrics for lab-scale (discovery), intermediate and pilot-scale processes were compared. Life cycle assessment was made using overall material and energy balances along with environmental performance tools. Tier 1 tools such as economic criteria, environmental criteria, exposure limits, toxicity weighting in analyzing various drug production pathways.

Since organic solvents typically account for 80% of all chemicals in a pharmaceutical process, a significant part of the work focuses on process modifications to reduce solvents used. Several process opportunities for greener processes were explored. A life cycle assessment is conducted to compare these alternatives and show broader impacts on the ecosystem (greenhouse gas production, etc). These alternative production routes include new solvents and processing methods. Throughout this process, we are in constant contact with Bristol-Myers Squibb R&D staff and get feedback for continuous improvement of our approach. The analyses of these alternative approaches are presented to the company in bimonthly progress meetings.

The process improvements made by the Bristol-Myers Squibb scientists have been quantified by the student and faculty team using several approaches. The student team investigated and applied metrics for process, safety and environmental impacts.

Solvent selection and use was also measured by a unique solvent selection spreadsheet that quantifies all of the various process streams into one value that can represent the greenness of the process. This facilitates the comparison of process improvements for the different drug synthesis routes using one unifying index that combines various environmental and safety metrics such as TLV (threshold limit value), ingestion toxicity, biodegradation, aquatic toxicity, carcinogenicity, ozone depletion, global warming potential, half-life, smog formation, acidification, soil adsorption and bioconcentration factor.

Students working on this project gained familiarity with the issues and concerns of pharmaceutical R&D. Valuable insight was gained into the factors determining the cost of pharmaceutical end products: not only the cost of drug development, but the cost of manufacturing according to good manufacturing practices (GMPs). The importance of greener manufacturing processes, and particular the need for reduction of solvent use were realized.

This project required intensive application of concepts learned in the classroom, with emphasis on separation techniques and membrane separations in particular. Working on a project with frequent deadlines for EPA and industrial deliverables provided students with experience in meeting "real-world" deadlines. Frequent meetings provided experience in preparation for different types of interactions with faculty, engineers, and industrial executives. Professors are concerned with the technical details of work, whereas the executives are interested in the impact of the project on the company. One undergraduate student working on this project noted that most pharmaceutical researchers have advanced degrees, and has decided to attend graduate school to prepare for a career in pharmaceutical R&D.