May 15, 2009 (Vol. 29, No. 10)

Applying Operational Excellence Strategies to R&D and Production Marks Logical First Step

The first installment of this article (see GEN, April 1, 2009) discussed the rationale and strategies for greening pharmaceutical and biotech operations, particularly at the corporate and facility level. Here we examine laboratory and manufacturing initiatives that fall under the general category of green chemistry.

It is worth repeating that the most fundamental approach to sustainability involves operational excellence. Leaner, more efficient operations cannot help but consume fewer resources and generate less waste. Pharmaceutical and biotechnology companies have, historically, been slow to apply operational excellence to production and lab work, preferring to follow regulatory directives on implementation of science- and risk-based strategies.

Nevertheless, opportunities abound for more traditional “greening” of resource-intensive operations by applying the precepts of green chemistry to R&D, support services, and manufacturing.

AstraZeneca applies green chemistry to a portion of its process research and drug discovery efforts by minimizing use of hazardous reagents, substituting environmentally benign solvents wherever possible, and through chemical-waste minimization strategies. “If we must use hazardous solvents we try to minimize them and, whenever possible, recycle,” notes Andy Wells, Ph.D., senior principal scientist.

These practices provide dividends of lower cost and higher efficiency in addition to reducing research groups’ environmental impact. The company moreover takes a life cycle impact view of solvents that balances environmental friendliness with utility for a particular task.

Process R&D and some bulk drug chemistry groups have adopted similar approaches, but what is impressive is the company’s willingness to re-examine small molecule process chemistry, even for well-established products, to achieve additional cost-saving environmental friendliness. “These efforts may be driven by waste disposal, or volume, or efficiency, but where we can demonstrate benefit we will go back, even if it means submitting a supplementary NDA,” Dr. Wells explains.

He is of the opinion that any streamlining of manufacturing processes will, by necessity, be more environmentally friendly by virtue of reduced consumption of feedstock chemicals and usage of energy, water, and human resources. Regulatory initiatives such as Quality by Design, although not intended as environmental measures, have the effect of greening operations, he says.

Pharmaceutical processing generates some of the largest quantities of waste per weight unit of product produced of any industry in the world, but companies are fighting this trend vigorously.

Catalysis and biocatalysis are among the most effective green chemistry strategies. Both provide atom efficiency and opportunities to use renewable feedstocks and cofactors while avoiding hazardous or expensive reagents.

Several companies became significant players during the 1990s by selling and licensing catalysis technology. Among the leaders were ChiRex, ChiroTech (now part of Dow Chemical) and Catalytica (acquired by DSM in 2000). One of the remaining pure-play catalysis companies is Codexis, which specializes in enzyme-mediated chiral synthesis of active pharmaceutical ingredients and intermediates.

Enzyme reactions proceed at mild temperatures and pressures, employ no toxic metals, leave no significant waste, are atom-economic, do not require blocking or unblocking agents, and often use renewable feedstocks. For example, glucose can serve as the reducing agent for the transformation of a ketone into a chiral alcohol. The fact that nature designed enzymes to work in aqueous media is often listed as a green property, but for organic chemists hydrophilicity is a drawback.

Natural enzymes shun organic chemicals and solvents that are the staple of small molecule synthesis. Early enzyme-based processes, therefore, employed phase-transfer catalysts that ferried substrates from the organic phase to the aqueous phase. “When they were used, processes had to be engineered to satisfy the requirements of the enzyme,” says John Grate, Ph.D., senior vp at Codexis, “which led to sub-optimal processes.”

Codexis develops enzymes that have been modified through a technique it calls DNA shuffling, which can boost the reactivity of natural enzymes a thousand-fold while rendering them compatible with polar nonaqueous solvents used in drug-making. DNA shuffling creates enzymes that are stable, long-lived, and operate at high substrate loadings, Dr. Grate says. For asymmetric reactions the firm can produce whichever enantiomer is desired.

Codexis works closely with innovator and generic pharmaceutical companies. For example, Codexis supplied Pfizer with a chiral hydroxynitrile, an intermediate in the synthesis of atorvastatin, the active ingredient in Lipitor.

Merck has long been committed to environmental best practices that include greening its core chemistry. Among its initiatives are “green by design” processing with an emphasis on chemo- and bio-catalysis. Yongkui Sun, Ph.D., senior director for process research, describes the benefits to his company’s “triple bottom line” of economics, society, and environment.

“Catalysis reduces the number of process steps, reduces waste, and lowers the cost for manufacturing a drug substance,” adds Dr. Sun. Perhaps the standout example is Merck’s process for manufacturing its Januvia treatment for type 2 diabetes. The process utilizes an asymmetric hydrogenation step that reduces waste by 80% and the cost of manufacture by 70%, Dr. Sun says. Merck incorporated the step into its manufacturing process  approximately six months after demonstrating proof of principle.

Merck also has a strong program in enzymatic biocatalysis, particularly for asymmetric reduction. Merck scientists routinely use enzymes at “practical” substrate concentrations of up to 100 g/L without the need for phase-transfer catalysts.

Merck works closely with synthesis technology companies to bring innovative green chemistry, which is good news for companies that provide catalysts and related services. The Januvia hydrogenation, for example, was licensed from Solvias. Merck has in the past developed its own catalysts, “but from a strategic point of view the best path forward is to work with chiral technology companies,” Dr. Sun explains.

According to Codexis, catalysis is one of the most direct routes to inherently green pharmaceutical manufacturing processes.

In the Laboratory

Laboratories are a significant source of chemical byproducts, and within that setting HPLC instruments may be among the biggest generators of waste. Companies have learned that green chemistry approaches can work in the lab as well as during scale-up and production.

Solvent recycling through the diversion of HPLC effluent, particularly from isocratic runs, can save huge quantities of solvent. According to Michael Frank, product manager for Agilent’s liquid-phase separations group, diverted solvents are perfectly recyclable for subsequent HPLC runs provided they are not contaminated by analytes. “When compound comes off you divert the stream to waste. This is easily done using a refractive index detector.”

Agilent has been in the business of selling sub-2 micron HPLC columns since 2003. These columns are controversial in some quarters from the perspectives of acquisition cost, high pressure requirements, and what are perceived by some to be incremental benefits. But everyone agrees that narrow-bore columns save tremendous quantities of solvent over the course of a work week.

Reducing the cross section from 4.6 mm to 3 mm saves approximately 60% of solvent. Strategies that compress equilibration times can conserve even more. 

In HPLC, smaller is inherently greener by virtue of dramatically lower consumption of water, solvents, electricity, and consumables. Chromatographers interested in reducing HPLC solvent consumption to close to zero might consider HPLC Chip technology from Agilent, which reduces the plumbing of an HPLC system to a credit card-sized chip and interfaces directly with a mass detector. Analytical runs take a fraction of the time on HPLC Chip analyzers, and each run consumes microliters of solvent.

Acetonitrile has been in short supply worldwide for many months, a result of the economic slowdown (the solvent is a byproduct of acrylonitrile production). Frank reports prices as high as €150 per liter.

Most pharmaceutical companies are adopting green chromatography methods for prep work as well as for analysis. Supercritical fluid (SCF) chromatography, which uses liquid carbon dioxide collected from the atmosphere (and hence carries zero carbon footprint at point of use), is by far, the most popular and greenest alternative to traditional LC.

SCF-MS is significantly more gentle on the ion source of an MS instrument than water-based solvents. Turnaround time is, therefore, much shorter during analytical runs, a green advantage that is even more pronounced for preparative separations, where LC column equilibration times can run upwards of an hour. Using CO2-based fluids reduces equilibration time by 90%. And of course, SCF separations are considered sustainable for large-scale separations, as well.

Two other options also qualify as green prep separations methods. Steady-state recycling (SSR) is a discontinuous, single-column separation technique combining high throughput and low solvent consumption. Novasep, for example, offers CycloJet® steady-state recycling as an option on its Hipersep® preparative LC product line. SSR recycles unresolved fractions back into the column.

Simulated moving bed (SMB) chromatography, another solvent-sparing technique, uses counter-current flow of stationary and mobile phases in continuous mode. Developed in the 1960s for food applications, SMB is beginning to catch on in limited form for pharmaceutical separations.

Still the One

Drug makers have, for decades, recycled solvents from manufacturing operations. Recently rising costs for the acquisition and disposal of common solvents have created an opportunity to recycle at the laboratory level as well.

A number of companies provide equipment and services related to solvent recycling. Clean Harbors Environmental Services will pick up spent solvents from manufacturers and recycle them. 

Most stills are not industry-specific. CBG Biotech, for example, produces general-purpose recycling distillation units that cost between $8,000 and $40,000, depending on capacity and features. The CBG stills are green as they do not use cooling water, and the heat of vaporization is recaptured as the fluid condenses. With the aid of vacuum distillation, the stills can recycle solvents with boiling points of up to 300ºC.

CBG claims that its distillation units can reduce solvent consumption and recycling each by about 95%. For solvents like xylene and ethanol, recycling reduces purchases to negligible levels, saving about 93% of purchase costs.

Additional savings in solvent-related storage, handling, ordering, and administrative activities improve the economics even more. “It’s not unusual for customers to see a six- to twelve- month payback,” says Gerald Camiener, Ph.D., technical director.

Recycling is not a panacea, since the distillate is of slightly lower purity than the original feedstock. For HPLC solvents, which are frequently mixed with water, potential recyclers should be aware that common solvents like ethanol and acetonitrile distill as azeotropes. Ethanol water distills as a 5% water azeotrope, isopropanol-water is 12.6% aqueous, while the acetonitrile isotope consists of between 14% and 16% water.

Pharmaceutical/biotech labs are quite finicky about HPLC-grade solvents, so most distillates will be repurposed. One of CBG’s customers dilutes the isopropanol-water mixture down to 70% and uses it for disinfection. Other firms may use the acetonitrile-water mixture for chemical reactions, or perhaps use a secondary azeotrope to remove the water. “How customers used recycled solvents depends on their prejudices, and their ingenuity,” Dr. Camiener notes.

Point of Diminishing Returns?

Squeezing green efficiencies from upstream bioprocesses is difficult as biomanufacturing is green to begin with, at least compared with small molecule manufacture. Operational efficiencies, process de-bottlenecking, and unit operation schedule optimization can help, as can savings gained through more efficient heating, cooling, and material transfer.

Yet, these have paled against improvements in volumetric productivity, says Joseph Tarnowski, Ph.D., senior vp of biologics manufacturing and process development at Bristol-Myers Squibb. Rising protein titers save not only on ingredients and waste, but they reduce process volumes and processing times. These benefits come at the expense of placing more pressure on downstream operations, which must keep up with upstream output. Another rub of higher upstream productivity that is less easily resolved, is lower utilization of workers and equipment.

Dr. Tarnowski says that BMS is instituting additional efficiencies, like shortening capture chromatography operations or reducing the number of separations steps. Another initiative at BMS involves online mixing of buffers, which conserves process and clean-up water. BMS is also looking into replacing a WFI rinse at the beginning of vessel cleaning with rinsing with softened water. “We’re still consuming water, but it’s not of such high-purity.”

The drive toward sustainability will only work if companies examine the benefits and costs honestly, and if efforts are based on science and sound economics rather than public relations.

Joseph H. Kennedy, Ph.D., principal research scientist at Eli Lilly, has cautioned against a simplistic view of green chemistry, specifically in the preference for aqueous waste streams over organics. For example, recycling for many mixed organic-aqueous solvents may be more problematic than for pure organics. Even 100% aqueous waste streams pose disposal issues since they may not be flushed into municipal sewers but must be dealt with, often as biohazard waste. Companies must remove the water or burn the effluent, solutions that consume copious quantities of energy and carry an independent environmental impact.

Energy consumption, recyclability, and disposal costs, which together reflect environmental burden, should be considered on a case-by-case basis, says Dr. Kennedy. “Innately green solvents may not be all that green,” when all factors are considered—not just the elimination of organic solvents.

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