BUSINESS BACKUP PROTECTION Aworker in protective gear handles potent materials in a glove box at ChemSyn.
HANDLE WITH ITH CARE Contract pharmaceuticalil manufacturers find a niche in handling high-potency >otency active ingredients KAREN J. WATKINS, C&EN NORTHED\ST NEWS BUREAU
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DRUG IS GOOD IF IT IS E F F E O
tive; it is better if it is effective at very small doses. The less of a drug that is administered, the lower the likelihood of harm ful side effects. But to be effective at low levels, a drug must be highly potent. And there's the rub: how to safely make a drug that can be effective even in very small quantities without harming lab or production workers. Pharmaceutical com panies are churning out more and more of these highly potent drugs, particularly as they address cancer, for which cytotoxic— cell-killing—treatments are the rule. Cytotoxic drugs and other potent phar maceuticals require a significant degree of containment. One such drug is mechlorethamine, a nitrogen mustard that is effective against a number of lymphatic cancers as well as normal rapidly dividing cells. MecWorethamine is corrosive to soft tissue, causes bone marrow suppression, has toxic effects on the gastrointestinal tract, and is toxic to embryos. Occupational exposure to minute quan tities of such a drug can produce life-threat ening effects, with symptoms that maybe incapacitating and may require immedi ate medical intervention. For that reason, HTTP://PUBS.ACS.ORG/CEN
companies have set occupational exposure limits (OELs)—the acceptable amount of the compound allowed in the air of a work ing area for these drugs—at 1 μg per m 3 as an eight-hour time-weighted average or lower. Some OELs are as low as 1 ngper m3. Particularly dangerous are those drugs that have no usual warning signs such as odor, irritancy, or rapidly occurring effects that alert a worker to their presence. Pharmaceutical compounds are classi fied by their toxicity and potency as well as their OEL. According to Claes Franzén, marketing manager for Malmô, Swedenbased DuPont Chemoswed, a contract manufacturer of active pharmaceutical ingredients (APIs), most people refer to a four-category system. In the system his firm uses, Category 1, the least toxic, allows no exposure over 1,000 μg per m 3 , and Category 4 limits exposure to less than 5 μg per m3. Other pharmaceutical com panies have established different OEL cutoffs for these categories. For Category 1, where the compound is an irritant or has reversible effects and good warning signs, it is sufficient to use good lab practices or standard manufac turing practices. For the highly potent compounds of Category 4, with acute and
irreversible effects, special procedures are required to handle powders and solutions, access to working areas is restricted, and special containment equipment is required for manufacture. The number of pharmaceutical com pounds that require some level of con tainment is increasing, Franzén says, and more and more chemicals are being considered potent. He notes there are three forces that drive the trend for more containment: APIs are becoming more targeted and more potent, awareness of crosscontamination problems is growing, and there is a heightened consciousness of the need to minimize the exposure to workers. The role of contract manufacturers in the high-potency drug business is expanding because these drugs are forming a larger portion of the API market and pharmaceutical companies are increasingly outsourcing their more potent products. The fraction of the API market devoted to highpotency compounds is still small—less than 5%—estimates Roger Laforce, senior manager of marketing and sales at Switzerlandbased Helsinn, a developer and producer ofAPIs. "It's a niche," he says. Others estimate the fraction as less than 10% of the global market, which is roughly $30 billion annually BUT THE SIZE of the high-potency market is deceptive, says Eric Smart, vice president of business development at Organichem, a custom manufacturer ofAPIs and intermediates. "These compounds are generally highly active and are dosed in very small amounts," he says, but the number of compounds is growing rapidly, particularly in the anticancer category Major pharmaceutical companies and many small biotech firms have cancer programs; in the case of the bio techs, cancer is a high-profile area that is likely to get funding. Smart says cancer research has blossomed lately, with paclitaxel being one of the most successful cancer products, spawning a huge number of drugs with derivative uses. Ά disproportionate number of the drugs in development are high potency" he says. The major competitors to contract manufacturers are the big pharmaceuti cal companies with internal capacity to meet their own potent compound needs, says Frank Gupton, technical director of process research at the U.S. affiliate of worldwide Boehringer Ingelheim Chem icals. The company has a kilogram-scale C&EN
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BUSINESS lab and pilot plant suitable for Category 4 compunds. Drug companies outsource their potent products in part to avoid the expense of having a complete high-potency safety program and equipment for drugs that are manufactured only on the gram or kilogram scale. Even the biggest drugmakers that produce most of their own APIs may elect to outsource their potent compounds, Franzén says, because they do not have suitable facilities and want to save capital investment. He asserts it's more cost-effective to take these products to an outside contractor that has all the equipment and programs in place to manufacture pure product safely ChemSyn Laboratories, for one, is manufacturing on the order of 40 or 50 different potent or cytotoxic active pharmaceutical ingredients at its facility in Harrisonville, Mo. Many of these compounds are on a scale of 1 to 10 kg per year since they are given at microgram dosages, says Phillip M. Chalabi, sales and marketing manager at ChemSyn, one of the leading producers of high-potency compounds. Furthermore, many pharmaceutical companies just don't have the facilities to do high-potency work, especially at the commercial scale. Particularly in small pharmaceutical companies and bio techs, Smart says, "there is no internal production, so these companies must get someone else to make their drugs on a developmental and commercial basis."
As companies put money into highpotency manufacturing, they must choose the levels of containment their plants will provide. To meet stringent containment requirements, makers of equipment to manufacture potent compounds have borrowed technology from the space and nuclear industries, Laforce says. For instance, "space suits" that protect workers and robots that manipulate items remotely are incorporated into highpotency manufacture. Not everyone agrees on what constitutes satisfactory containment, however, and different standards of what qualifies as safe handling proliferate. The philosophy of companies like ChemSyn is that there should always be primary and secondary containment, even when working on a laboratory scale. According to Chalabi, ChemSyn insists that personal protective gear— face shields, goggles, booties, and space suits that workers wear— should be considered as a backup; engineering controls such as glove boxes, clean-in-place systems, air handling, and containment are the primary mechanisms to protect workers and the environment. Chalabi contends that some contractors still use personal protective gear as the primary line of defense, using standard manufacturing equipment rather than equipment designed to contain materials. Ifet others working on a small scale employ glove boxes and do not use the secondary containment of a space suit. This strategy, Chalabi says, simply reflects a difference in philosophy. "The larger the scale, the greater the risk," he says, so the need for secondary containment is greater at the kilogram scale and higher. On top of safety considerations, though,
Laforce notes that practical issues arise. He points out that it is difficult and tedious to work for hours in cumbersome suits. "We don't view suiting someone up in a space suit for continuous manufacture as acceptable," agrees David McGee, marketing manager for Boehringer Ingelheim, although such containment maybe needed for bench-scale work to determine the risks of a newly discovered compound. Franzén says DuPont Chemoswed uses special suits only for emergency cases. As a result of the desire to avoid protective suits, a different concept has evolved at these firms: the use of isolation suites, or glove boxes, where the equipment in which the product is handled is reduced to the smallest possible space. With proper containment, according to this philosophy no special protective suit is needed for small-scale manufacture.
WHILE THE GLOVE-BOX strategy is appropriate for small quantities of highly potent materials, at larger production scales such an approach will not work. Workers need to be able to get to big pieces of equipment that cannot be contained within glove boxes. That is why, Chalabi says, gram-scale glove-box-oriented companies are forced to pass their projects to a larger scale manufacturer once they reach a size too big for them to handle. The greatest risk of exposure occurs when the high-potency API is in the solid powder form, Gupton says. A solid can easily enter the ambient air and contact an individual, so solids handling deserves the ONE INDICATION that the high-potency most attention in terms of containment. industry is growing is recent expansions on "Most of our focus is on charging systems, the part of contract manufacturers. For liquid/solid separation, and drying," he says. example, Ferro Pfanstiehl Laboratories "Once a material is wet and in a reactor, recendy completed a major expansion at its the risk of exposure is pretty well mitWaukegan, 111., high-potency unit. The igated from an airborne contamination company says it can now offer a full specperspective." trum of quantities, with reactors able to produce 30 kg of product in one batch. One consulting company, SafeBridge Consultants Inc. of Mountain Helsinn just built the Helsinn AdView, Calif, assesses how companies vanced Synthesis development and manmeet current industry standards and ufacturing facility in Biasca, Switzerland. recommends effective alternatives for This high-potency plant will produce the safe handling of potent comboth Helsinn's own antiemetic drug, pounds. SafeBridge, which was spun Palonosetron, as well as compounds for off from pharmaceutical company its outsourcing partners. Syntex/Roche in the late 1990s, agrees In December, Organichem broke with ChemSyn's philosophy of conground on a new high-potency facility tainment— that is, SafeBridge sees the in Rensselaer, N.Y., due to come special space suit as secondary proteconstream in the latter part of 2001. Part tion necessary to compensate for posof this expansion, dedicated to kilosible failure of the primary containgram-scale high-potency manufacture, ment: covered vessels, special fittings, is focused on a flexible manufacturing and special transfer equipment. setup since most of Organichem's high- CONTROLLED ACCESS A Ferro Pfanstiehl SafeBridge is attempting to recompotency work is directed toward sup- worker in protective clothing loads materials into mend guidelines for the industry porting drugs in clinical trials. an isolator suite through an access window. 32
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through a new certification program. In the SafeBridge certification process, two board-certified occupational health pro fessionals go through a facility, scoring it against 60 defined criteria to verify com pliance of the facility with both hard ware—the engineering controls and con tainment—and software, such as training, procedures, and practices. Gaps between the actual program and the desired program are identified so that the facility can correct deficiencies and be reevaluated. According to Allan Ader, prin cipal toxicologist and partner in the firm, and John Farris, president and managing principal, the program ensures a contract manufacturer's customers that the most up-to-date, scientifically proven methods for high-potency manufacture are being followed. One company Ferro Pfanstiehl, has been certified so far in the SafeBridge program. Ferro Pfanstiehl went outside to SafeBridge because, even though it had 18 years ofexpe rience in potent compound manufacture and knewwhat was needed to make commercial quantities safely 'Svhat we didn't have was a scientifically supportable means to know
we were assessing and managing risks prop erly" says David Lester, the firm's head of business development and marketing. Other companies are using part of the SafeBridge package. Organichem, for example, is using SafeBridge to assess the suitability of its contain ment equipment and procedures for the various types of compounds it handles. SafeBridge is also helping Organichem with the design of its new highpotency building. SafeBridge is the sole occupant of its niche, Ader claims. Other kinds of au diting and certification programs for regulatory compliance exist, such as ISO 9000 and ISO 14000, but no other consultants com prehensively focus on the safety and han dling of potent drugs. SafeBridge provides what it calls the "potent compound triangle" of analytical chemistry, toxicology, and industrial hygiene services needed for comprehen sive support of high-potency compound
production. Analytical chemists are needed to measure very low levels of potent com pounds, such as picograms of hormones. Toxicologists must be experienced in set ting occupational exposure limits of these compounds. And industrial hygienists are needed to perform the qualitative and quan titative assessment of workplaces for worker exposure. Whether or not certi fication like that offered by SafeBridge is necessary depends on who's talking. Ferro's Lester asserts that the SafeBridge approach is an emerging industry standard.
