BUSINESS SLOWLY BUT SURELY A nitroglycerin transport truck at Dynamit Nobel.
THE CRAFT OF LIVING DANGEROUSLY Custom manufacturers willing to take a risk occupy a profitable pharmaceuticals niche KAREN J. WATKINS, C&EN NORTHEAST NEWS BUREAU
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OMETIMES THE SHORTEST ROUTE
to a desired fine chemical means working with phosgene, azides, or other dangerous chemicals or reaction conditions that can lead to a dangerous situation. For a select group of custom manufacturers, supplying chemicals based on this "dangerous chemistry" is a small but profitable niche. The laboratory route to a new fine chemical with potential pharmaceutical applications often relies on reagents such as diazomethane, a useful methylating agent that also happens to be toxic and explosive. In scale-up, a less direct, multistep synthesis is usually preferred for safety reasons. However, the development of a multistep synthesis can be complicated and time-consuming. And in a competitive pharmaceutical environment that stresses speed to market, there can be great advantages in taking the direct, "dangerous" discovery route—if, that is, one has a track record of safely dealing with dangerous chemistry For companies that want to save time but do not have this expertise or prefer not to attempt the direct route, several contract manufacturers, most in Europe, are willing to lend a hand. HTTP://PUBS.ACS.ORG/CEN
Most of these custom manufacturers have roots in the explosives or defense industries, where they learned the hard way how to handle dangerous compounds. This proprietary knowledge forms the foundation for their ability to compete safely Dynamit Nobel, for one, converted its explosives plant in Leverkusen, Germany, to specialty chemicals manufacturing in the 1970s. The switch was induced by the decline in the coal mining industry, one of its biggest customers for explosives. Dynamit Nobel Special Chemistry part of Dynamit Nobel's Dynamic Synthesis custom synthesis umbrella that also includes substituted aromatics and chiral molecules, specializes in azide chemistry It also offers processes based on carbon disulfide, hydrazine, nitromethane, hydrogen peroxide, and other tricky materials and reactions that are performed under Food & Drug Administration-approved current good manufacturing practice (cGMP) standards. The company is "constantly looking to enlarge our portfolio of danger-related chemistry," says Rainald Lohmar, director of development projects. The contract fine chemicals manufacturing part of Groupe SNPE also arose
from what the company terms "energetic materials," or explosives and propellants for the defense industry SNPE relies heavily on its expertise in phosgene chemistry, which it capitalized on after World War II. A governmentowned supplier of energetic materials to the French military, SNPE has gained a lot of experience in the design of energetic materials and their reactions, says Scientific Director Jean-Pierre Senet. The fine chemicals intermediates business, SNPE Chimie, has core capabilities inphosgenation, nitration, hydrogénation, and alkyl hydrazine synthesis. SNPE also practices dangerous chemistry in its Isochem subsidiary which focuses on pharmaceuticals, and in its agrochemicals business unit. Much of SNPE's phosgene chemistry, Senet says, is done at its Toulouse, France, site, where phosgene is generated in large quantities. Though phosgene is obviously dangerous, its chemistry is not, he contends, provided that plans are made to eliminate risk. T h e dangerous chemistry expert OmniChem, a member of the Ajinomoto Group, also has roots in the explosives business. The company that would eventually become OmniChem started in Belgium more than 200 years ago manufacturing black powder, a combination of potassium nitrate, sulfur, and charcoal used historically in blasting and firearms. In the mid-1970s, the company branched out to making bulk actives and synthetic intermediates for the pharmaceutical industry In the past two decades, the company has taken over firms through which it acquired a number of technologies and reactions, including azide chemistry, for which it is particularly well known today LIKE ITS EUROPEAN counterparts, Aerojet of Rancho Cordova, Calif, began its existence in the energetic materials business. Starting by making small rockets to help heavily laden bombers take off, Aerojet has concentrated on the propulsion business, particularly in solid- and liquidfueled rocket motors and engines. The energetic materials used in these motors were unique and unavailable elsewhere, explains Thomas G. Archibald, director of technology for Aerojet's fine chemicals business, so Aerojet built its own chemical plant to manufacture them. With C&EN
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BUSINESS the end of the Cold War, Aerojet needed to branch out into a different field and found that the pharmaceutical fine chemicals business was a good fit. The company is known for its expertise in the safe use of diazomethane. Diazomethane is also a primary specialty of a smaller, younger contract company, Phoenix Chemicals of Wirral, England. Phoenix, however, unlike the others, did not arise from an energetic materials background. Founded in 1991, the company grew out of a customer's need to make a product that involved handling bis(chloromethyl) ether, which is highly toxic and carcinogenic. As its business evolved, Phoenix decided to concentrate on its hazardousmaterials specialty, says Paul Dawson, who is the company's business development manager. What distinguishes Phoenix from larger companies is its use of continuous processing, in which only very small quantities of hazardous materials are present at a given time. Should an accident occur, the small inventory means that containment of the hazard would be relatively easy With
These custom manufacturers have roots in the explosives or defense industries, where they learned the hard way how to handle dangerous compounds. continuous processing, Dawson claims, conditions can be finely tuned to produce high-quality products in multiton quantities in equipment that may only cover an area the size of two desktops. Phoenix aside, there's a reason most companies involved in dangerous chemistries have a history in energetic materials. "Surprisingly, there is a major similarity between the defense chemical business and the pharmaceutical business," Archibald says. "In solid rockets, you can't test them. Ifyou do, they are consumed. Therefore, you must manufacture them under highly validated and controlled circumstances. With each motor comes a very large file of documentation." Likewise, in pharmaceutical production under cGMP, validated processes are required to avoid contamination or product variations. "The
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C & E N / AUGUST 13, 2001
care to detail for materials and methods is the same in both," he says. The need for special treatment means that not just anyone can get into the dangerous chemicals business. Depending on the country, companies must be able to process large amounts of authorizationrelated paperwork in order to transport, store, and use these chemicals. Furthermore, says Dawson, it is important to have an established reputation for technical competence—customers do not want to run the risk of an accident disrupting supply Preferably, a company interested in this business should possess a large site. Aerojet more than meets this goal. It's located on a 13,300-acre site in the California desert. Of course, it is highly desirable for such a plant to be isolated from people, but there are other considerations. For example, common sense dictates that a plant occupy an area over which installations can be spread out, with earth walls and bunker storage, so if there is a problem in one area, it won't spread to the others. In a regular chemical plant, facilities are clustered to minimize transfer distances, Lohmar says. SUCH CAREFULLY thought-out con struction is seen in Dynamit's Leverkusen plant. Though the plant is in a heavily inhabited area, near Cologne, it occupies a large area—almost 200 acres—and the facilities are surrounded by undeveloped land that belongs to the company "We are essentially an island," Lohmar says. SNPE does not have the luxury of an isolated site for its Toulouse plant. Though the plant was there first, houses have been built close by Because ofits location, SNPE must deal with the reluctance of the local population to accept a new dangerous material or process. When such reluctance arises, SNPE presents the risk and shows citizen associations, through plant tours and discussions, how the company is addressing the risk. By bringing the characteristics of the chemicals and processes out in the open and showing how it is taking all the necessary precautions to protect its workers and avoid environmental problems, SNPE can assuage the fears of the community, Senet maintains. Like SNPE's Toulouse plant, Phoenix's HTTP://PUBS.ACS.ORG/CEN
kets for diazomethane chemistry "This is used by companies that obtain a high value small Wirral facility is located close to resa useful reagent for a host of transformafrom their products and are under pressure idential areas. Phoenix' unusual process tions," Dawson says, "but most companies to produce very quickly, Lohmar notes. philosophy makes this possible, Dawson perceive it to be a hazardous material and Such firms are willing to pay a contractor to says. 'With the way we handle our work, don't want to handle it." take synthesis shortcuts. using continuous chemistry and handling small quantities at a time, we don't need a Lohmar contends that, for some prodSome of the main competitors of danbig site and huge reactors," he says. ucts, the dangerous synthesis is the inhergerous chemistry contractors are their own ently cheaper process because it uses fewer customers. Drug firms sometimes choose In addition to owning an appropriate to make pharmaceutical intermediates site, dangerous chemistry companies internally This tendency is particularly must follow rigorous construction pronounced when drug companies principles and develop special equipmerge, leaving them with more capacment technologies—all barriers to easy ity than they can use. Such companies entry by competitors. decide to "in-source" their requireBeyond meeting these requirements to take advantage of the excess. ments, these custom manufacturers T h e silver lining for dangerous count on their experience to minimize chemistry firms is that the kinds of the risk of an explosion. "A company reactions that they specialize in are must understand what it is dealing avoided even by merged companies with," Dawson says. "Knowledge is the with lots of spare capacity Ironically, key to handling these chemistries though, although they benefit from safely" A company should, for examthis reluctance, the companies doing ple, conduct explosion testing of matethe "dangerous" work would at the rials and equipment. same time like to convince the public Experience is perhaps the greatest that, as Archibald says, their chemistry barrier to entry for a company considis not at all "capricious." ering the dangerous chemicals business. Having trained personnel is crit- PURITY COUNTS A Rosenmond filter dryer Because of this perception problem, ical to success. Though they might be at Aerojet. some industry executives prefer not to expensive, special facilities and equip- ~ use the word dangerous to describe ment can always be purchased; people with their business. Phoenix refers to it as "hazsteps and less raw material than a long synthe requisite skills are not so easily obardous." SNPE is even more euphemistic, thesis sequence. However, he qualifies this tained, Lohmar says. By training operators by saying that dangerous chemistry is gencalling its processes "less conventional in the sensitive know-how that these comchemical technology," Senet says. erally not cheap. What a contract manupanies guard closely he adds, specialized facturer offers through its dangerous Some might say this industry niche is knowledge is transferred from generation chemistry capability, he says, is security trying to have it both ways—downplaying to generation of workers. and speed to market. the chemistry's danger while using it as an enticement to customers. Archibald looks Though difficult to get into, the rewards This speed brings cost-effectiveness— at it this way:
