An award-winning P2 success in the pharmaceutical industry

Facility researchers succeeded in developing a penicillin V isolation procedure that combined whole broth filtration with solvent substitution after they assessed potential pollution prevention opportunities and pilot-tested alternative methods and materials. Their efforts have reduced reportable releases from the facility by more than 1 million lb/yr.

The effort received a 1996 Governor's Award for pollution prevention. Click here to learn more.

The pharmaceutical complex consists of manufacturing, quality control and research laboratories, pilot plants, and administrative offices. Manufacturing activities include production of several pharmaceutical intermediates including 6-aminopenicillanic acid (6-APA) which is used worldwide in the production of anti-infectives such as amoxycillin and ampicillin.

The manufacturing process for 6-APA begins with the fermentation of penicillin V in a nutrient-rich aqueous broth. Next, the penicillin V is extracted in a solvent-based isolation process. After isolation, the penicillin V extract is enzymatically hydrolized to produce 6-APA.

Long-known to be a significant source of fugitive and point-source air emissions, the 6-APA manufacturing process was a ready pollution prevention target. Several obstacles, however, had to be overcome. For instance, in the highly-regulated pharmaceutical industry, even the simplest process modifications often require extensive pilot testing and lengthy regulatory approvals to confirm that the effectiveness and safety of the drug produced is not compromised. Process Description

The manufacture of 6-APA was a complicated multi-step process involving fermentation, extraction, concentration, crystallization, filtration, washing, and drying. The former isolation process used:

1. Methyl isobutyl ketone (MIBK) to perform whole

broth extraction of the penicillin V from the fermentation process.

2. Concentration of the penicillin V extract with

six Merco centrifuges (manufactured circa 1970).

3. Crystallization of penicillin V slurry by a

series of filtrations and washes using acetone.

4. Drying of the crystallized penicillin V product

to ready it for further processing (for example, 6-APA production).

Fueled by safety and environmental concerns associated with these processes, the facility organized a pollution prevention task force consisting of engineers and scientists from the facility's chemical development and manufacturing divisions. Their goal was to develop a process that would eliminate or materially reduce the use of toxic solvents used in the production of penicillin V.

Following a series of evaluations and pilot studies, the team identified three significant opportunities for pollution prevention:

• Replacement of the whole broth extraction step

with an ultrafiltration system

• Substitution of n-butyl acetate for MIBK as the

extraction solvent and completion of the extraction following filtration

• Replacement of the outdated centrifuges with more

technologically advanced centrifuges.

The ultrafiltration system separates the penicillin V from the fermented broth by passing the broth tangentially over a membrane at high velocity and pressure. Membrane surfaces are kept clean by the high velocity profile, and the pressure differential forces a clear liquid solution of the product through the membrane. This effectively filters the biomass and other insoluble impurities in the broth. The permeate is sent to a surge tank for further processing; the retentate, containing primarily mycelium, may be safely discharged to the process sewer system.

Risks of MIBK and n-butyl acetate

Another innovation in the new isolation process was substitution of n-butyl acetate as the extraction solvent rather than MIBK. MIBK is defined as a hazardous air pollution under the Clean Air Act and is a toxic chemical subject to reporting under community right-to-know laws such as SARA Title III. N-butyl acetate is nearly three times less toxic than MIBK and is not a SARA-reportable chemical.

Since the extraction now occurs after filtration, less solvent is involved. The efficiency of the extraction is also enhanced by the whole-broth filtration process because the number of centrifuges required for concentration is reduced. Furthermore, since the solvent extraction procedure is now physically isolated from the filtration system, the extraction process has been equipped with a separate collection system. Wastewater discharges from the new centrifuges are directed to an existing stripper system. Since this wastewater discharge no longer contains broth solids, the stripper is able to treat the effluent more efficiently, improving the effectiveness of solvent recovery operations.

Centrifuge operations were previously conducted in six Merco centrifuges - encased metal bowls suspended on a high-speed drive shaft and operated under atmospheric conditions. They were known to be a significant source of fugitive emissions of MIBK. These centrifuges were replaced with two enclosed units which reduce fugitive losses of MIBK and lower worker exposure. The new centrifuges also allow nitrogen-blanketing of the equipment. The only emissions from this equipment now are from conservation vents that are directed to an existing carbon adsorption VOC recovery system.

Cost/benefit analysis

The estimated capital costs to implement these changes were $10 million. New process equipment and advanced electrical controls made up 60% of this total. The $10 million of capital costs are offset by a 10% increase in production capacity. This increase is largely attributable to removal of the bottleneck that was the extraction process. This increased efficiency helped the facility realize additional cash flow of $4.9 million/yr resulting in an undiscounted payback period of 2.7 yr for this project.

Environmental benefits

Environmental benefits of the new isolation process include across-the-board reductions in chemical releases to the air, water, and land. Despite the 10% increase in production that accompanied this pollution prevention project, the facility has reduced actual solvent air emissions from this process by 75%. Furthermore, since n-butyl acetate is not a SARA-reportable chemical, the facility has reduced reportable releases by more than 1 million lb/yr.

Wastewater discharges of solvents have also been drastically reduced. Since extraction is now performed after filtration and the discharge from the new centrifuges has a dedicated collection system, the recovery efficiency of the stripper system is no longer inhibited by the presence of broth solids in the effluent. Furthermore, since less solvent is required to effect the extraction, there is a corresponding reduction in wastewater loadings.

Hazardous waste generated from the process has been reduced by 75%. The efficiency of the new isolation system is such that it has allowed the facility to remove the polish filtration step at the end of the process. Reduced usage of cartridge filters, filter paper, and other solid wastes have led to a 15,000 lb/yr reduction in off-site hazardous waste disposal.

Other Benefits

The company has garnered social rewards and improved safety conditions from this P2 initiative. The facility has benefited from improved public perception and better community relations. Indeed, having been awarded the 1996 New York State Governor's Award for Pollution Prevention, the facility has gained a great deal of positive press both in New York and nationally.
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Matt Traister is a managing engineer at O'Brien & Gere's Syracuse headquarters where he specializes in air pollution control and USEPA's Risk Management Program.