COVER STORY

SAFETY FIRST
Containment is key
in high-potency
manufacturing at
SAFC Pharma’s pilot
plant in Madison, Wis.
SAFC

CONTAINED CHEMISTRY
Synthesizing HIGHLY POTENT COMPOUNDS is a lucrative and
growing niche for custom chemical manufacturers
ANN M. THAYER, C&EN HOUSTON

LEVERAGING the ever-improving un- about $48 billion in global sales, reports market for all. “Many custom manufactur-
derstanding of disease along with new the market research firm IMS Health. The ers are investing in this area,” says Enrico T.
technologies for discovering molecules sector is growing 12–15% per year, or more Polastro, vice president and senior industry
with medicinal powers, pharmaceutical than twice as fast as the overall pharmaceu- specialist with Arthur D. Little Benelux, not-
research has been hitting upon increas- tical market. That’s why custom chemical ing that demand continues to be strong.
ingly potent compounds, ones that work at suppliers that can manufacture potent Custom manufacturers themselves
doses of less than 10 mg. Compare this to a compounds for drug industry customers estimate that active pharmaceutical in-
typical 325 mg dose of aspirin. More effec- occupy an attractive niche. And those with gredients (APIs) for oncology products
tive drugs are good news for patients, since conjugation expertise sit in an even more account for up to 30% of drug development
smaller doses can mean fewer side effects. appealing niche within the high-potency projects. And IMS predicts that 25 to 30
Steroids, hormones, prostaglandins, and area (see page 28). new chemical entities for oncology will
chemotherapeutics are examples of drugs Given these prospects, more and more be introduced by 2012. Those figures look
typically classified as potent. Of these, new contract chemistry firms are advertising promising to suppliers that have the manu-
cancer drugs are generating the most inter- their high-potency manufacturing capabili- facturing muscle, and many are bulking up
est. In fact, 750 cancer therapies are in de- ties. Whether such claims are warranted is a through acquisitions and expansions.
velopment, according to a new survey by the sore spot for many contractors, who aren’t Success isn’t ensured, however, since a
industry group Pharmaceutical Research happy about the proliferation of small-scale company must achieve critical manufac-
& Manufacturers of America. They include suppliers. Others say there is room in the turing standards, most importantly keep-
targeted drugs, potent chemotherapies, and
highly potent cell-killing or cytotoxic agents
conjugated to delivery molecules.
Oncology is already one of the largest
“Because the quantities are smaller, a lot
drug product sectors, accounting today for of companies think this is easier to do.”
WWW.C E N- ONLI NE .ORG 17 J UNE 16, 20 0 8
 COVER STORY

ing workers safe and products uncontami- Merck & Co. safety professionals published
nated. For the workers involved in manu- in 1996. Under the Merck system, drugs
facturing highly potent APIs, acceptable that fall into band 1 require conventional
occupational exposure limits (OELs)—or current Good Manufacturing Practices
the airborne concentration of material (cGMP), whereas band 5 specifies no hu-
averaged over eight hours, considered safe man intervention. “You can use any system
for a majority of healthy workers—can be you want, but it should be adapted for your
as low as nanograms per cubic meter. company’s products and work environ-
In order to determine the potential risk ments,” Farris says.
of exposure, com- He also recom-
panies set their own OH mends keeping
limits by looking at O O any system simple.
a compound’s phar- OH “Then people will
macologic potency, OH understand it and
toxicity, and other are likely to use it,”
effects. Although O H he explains. These
O OH O O
there’s some dis- H3C systems are key risk
agreement about communication
what is occupation- OH tools that immedi-
ally “potent,” the NH2 ately tell an opera-
drug industry typi- Doxorubicin
tor what to expect
cally uses that rating and how to proceed,
for compounds with he points out. What-
OELs at or below 10 μg/m3; for those that ever system companies use, they’ll likely
are highly selective for a receptor or en- synthesize potent, cytotoxic, or other-
zyme inhibition; and for those that may be wise dangerous compounds in contained
carcinogenic, mutagenic, or teratogenic at environments.
low doses. For small-scale synthesis, containment
Complicating definitions further, each in a ventilated enclosure or simple glove
drug developer or manufacturer uses occu- box alone may suffice, whereas larger
pational exposure bands (OEBs) in the ab- procedures can involve equipment fit-
sence of OELs for early stage compounds. ted with special valves or glove boxes for
These OEBs or occupational health cat- direct charging of discharging materials.
egories use potency and toxicity criteria At even larger scales, manufacturers use
to determine the control measures they’ll isolators—sophisticated glove box-like
employ. In a four-band system OEB 3 usu- chambers that can be integrated with
ally corresponds to a 10 μg/m3 OEL; manu- bigger vessels or equipment—or even
facturing products that are OEB 3 or higher environmentally controlled rooms and
requires special “engineering controls,” facilities containing a combination of these
or containment technologies. OEB 3 also equipment types.
tends to be the default band when informa- Nonpotent drugs often are produced by
tion on a compound is limited. the ton. Because highly potent drugs are
used in much smaller amounts, facilities
THE USE OF control bands has grown usually considered “pilot scale” or smaller
over the past 20 years, notes John P. Far- may be large enough to produce commer-
ris, president of SafeBridge Consultants cial quantities of a few kilograms per batch
in Mountain View, Calif. In the late 1980s, and up to a few hundred kilograms per year.
when he was employed by the steroid Polastro says annual world demand for
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producer Syntex, Farris participated in an potent chemotherapies, such as irinotecan

industry-led effort that established the or topotecan, is tens of kilograms. For cy-
OEB process and tried, unsuccessfully, to totoxics, such as doxorubicin, an adequate
unify the bands. He formed SafeBridge in annual supply is just 1–10 kg.
1998 to offer toxicology, industrial hygiene, When a pharmaceutical company as-
and analytical chemistry services around sesses which custom chemical makers have
potent compounds. Since then, he says, what it takes for high-potency manufactur-
SafeBridge has determined OEBs for more ing, the differentiating factors include fa-
than 2,500 compounds, the majority of cility design, containment level, analytics,
which fall into band 3 or 4. monitoring capabilities, and operational
Many companies use SafeBridge’s four- scale, along with procedures, training, and
band system, or a five-band alternative that experience. The package of services often

WWW.C E N- ONLI NE .ORG 18 J UNE 16, 20 0 8

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 COVER STORY

includes dedicated labs for R&D and qual- ferred between vessels. “And protective Some producers of potent drugs, espe-
ity control. suits are only redundant, not primary, pro- cially those in Europe where changes are
“There are contenders and there are tection. Anything else is not acceptable,” coming faster, already operate this way. In
pretenders,” Farris says, and drug devel- he adds. “The contenders understand this.” response, pharmaceutical industry groups
opers need to know are promoting the use of risk-based assess-
the difference when MUCH OF what’s been ments to determine what manufacturing
evaluating suppliers. OH done to define and strategies, and physical and procedural
In recent years, the handle these biologi- controls, adequately allow for multiprod-
words “potent drug cally potent materials uct, rather than dedicated, facilities. An
manufacturing” have has been undertaken example is the International Society for
H
been appearing all over by industry. At present, Pharmaceutical Engineering’s Risk-based
tradeshow booths. “Did Food & Drug Adminis- Manufacturing of Pharmaceutical Prod-
these people just spring H tration guidelines only ucts (Risk-MaPP) program.
up overnight?” he asks. address cross-contam- High-potency production expertise
“Some did and some ination as it relates to had long resided in-house at the major
have been working at product quality and pharmaceutical companies. But as part of
this for a long time and safety; worker safety the drug industry’s recent manufacturing
understand it.” HO OH falls under the purview consolidation, a few firms have shed some
For example, Farris of occupational health capabilities. In the U.K., Merck sold a plant
and others in the indus- Paricalcitol regulators. In Europe, to Aesica Pharmaceuticals and Pfizer sold
try say simply isolating however, drug regula- a facility to India’s Piramal Healthcare.
a room and putting workers in protective tors also consider worker and environmen- Roche, which bought Syntex in the mid-
suits doesn’t qualify as containment. “The tal concerns when they inspect a facility, 1990s, sold a former Syntex site in Mexico
room by itself cannot be containment,” he Farris says. Regulatory moves are afoot in- to Dr. Reddy’s Laboratories.
says. Instead, the process equipment must ternationally to require dedicated facilities Boehringer Ingelheim Chemicals (BIC),
be contained so that there are no releases for certain classes of compounds, such as the API-producing arm of the German drug
to the workroom when materials are trans- cytotoxics and reproductive hormones. company, is particularly active in the high-

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Since 1999, the contract-manufacturing
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50–500-g batches. It already can manufac-
ture hundreds of kilograms and may add
another 600-L unit or a large-scale plant
for making 30–300-kg amounts.
Meanwhile, Switzerland-based Cilag,
part of Johnson & Johnson’s worldwide
manufacturing network, is becoming more
aggressive in pursuing work from third
parties, says Hans Lehner, Cilag’s general
manager for chemical operations. Its four-
year-old high-containment plant has three
independent cGMP equipment trains op-
erating at the 60-, 250-, and 400-L scales.
The Cilag facility can handle OEB 4 com-
pounds, which under J&J’s system requires
worker exposures be no more than 500 ng/
m3, and has achieved limits of 10 ng/m3 and
below, says Urs Thurnheer, Cilag’s director
for scale-up and new product introduction.
“It’s a fully enclosed operation, so there
is no open product from the discharging
of raw materials to final dispensing of the
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 COVER STORY

Once a product is made, ment. Overall, good ergonomics

however, the work is far from CONTAINMENT CONTROLS contribute to increased safety,
done. One of the most time-con- Exposure limits determine manufacturing safeguards managers say. And glove boxes
suming aspects of high-potency are often designed to comfort-
OCCUPATIONAL
manufacturing is cleaning to EXPOSURE LIMIT BAND PRODUCTION REQUIREMENTS
ably fit individual workers.
ensure worker safety and avoid >1–10 mg/m3 1 Good manufacturing practices Accident rates can rise the
product cross-contamination, >0.1–1 mg/m3 2 Good manufacturing practices longer operators must work in
Thurnheer explains. The clean- (with local exhaust ventilation) containment areas, so shifts
ing process can take weeks. >0.01–0.1 mg/m3 3 Essentially no open handling may be shorter than in plants
And, from start to finish, the (ventilated enclosures required) making conventional pharma-
>0.001–0.01 mg/m3 3+ Virtually no open handling (containment
entire production process must ceutical chemicals.
systems required)
be monitored to ensure that ≤0.001 mg/m3 4 No open handling
Ash Stevens, which produces
the containment measures are (closed systems required) several highly potent anticancer
working. ≤0.001 mg/m3 5 No manual operations/human intervention compounds such as the nucleo-
At its plant in Schaffhausen, (robotics or remote operations required) side derivatives clofarabine
Switzerland, Cilag makes bor- for Genzyme’s drug Clolar and
SOURCE: Merck & Co.
tezomib, the API in the multiple 5-azacitidine for Vidaza (devel-
myeloma drug Velcade. Devel- oped by Pharmion and now part
oped by Millennium Pharmaceuticals, in engineering controls much more than the of Celgene), also produces compounds for
Cambridge, Mass., the drug was licensed older technology where they had to wear the National Cancer Institute. With ves-
outside the U.S. to J&J. Detroit-based cus- suits, which is a very uncomfortable work sels up to 500 gal, the company focuses on
tom manufacturer Ash Stevens supplies environment,” says Stephen Munk, Ash API volumes of less than 1 metric ton per
Millennium in the U.S. Stevens’ chief executive officer. year, Munk says. It recently installed two
In the Cilag and Ash Stevens plants, as Still, some manufacturers use personal filter-dryers that can handle between 5 and
in many others, personal protective equip- protective equipment along with engineer- 50 kg each.
ment has been supplanted by engineering- ing controls for extra precaution or as a last Because of the operational challenges,
based safeguards. “People like having line of defense if there is a loss of contain- custom manufacturers can charge premi-

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um prices for making highly potent APIs. Some companies clearly rank as the
Of course, production costs are higher too large-scale producers that can take highly
and it’s not clear if the high-potency manu- potent products beyond the lab and early
facturing business offers better profit mar- clinical trial stages. “We see a lot of com-
gins. Either way, custom manufacturers say petition at the smaller scale with people
demand for these services is strong. adding kilogram suites,” says Aslam Malik,
For similar operational and cost reasons, president of Ampac Fine Chemicals (AFC),
many pharmaceutical firms are outsourc- based in Rancho Cordova, Calif. “In 2007,
ing their highly potent drugs. Some large we made over 2 metric tons of several dif-
drug developers have more projects than ferent highly potent APIs.” Now Available from FMC
they can handle internally, or they don’t Operating with OELs as low as 0.2 μg/
wish to support specialized production m3, AFC has three facilities with reactors
facilities for small-volume products. Oth- ranging from 20 to 200 gal and has been
ers simply are outsourcing more. And small producing commercially since the early
drug companies without manufacturing 1990s. In 2004, the company added a six-
capabilities are a large customer group. 75-mm-column simulated moving-bed
chromatography unit to its smaller high-
TO GET INTO the business, several potency facility, and in 2006 it upgraded a Lithium Aluminum Hydride
custom chemical firms have acquired larger facility. Malik says he’s considering
high-potency operations. Aptuit gained further expansion in 2009.
its three-suite facility with its 2006 acquisi- Larry Zeagler, AFC’s executive director
tion of EaglePicher Pharmaceutical Ser- for commercial product management, also
vices. Likewise, Albany Molecular Research sees opportunity in noncytotoxic drugs
Inc. fully acquired Organichem in 2003. outside the oncology area. These products
According to AMRI, it can handle materi- likely would fall in an OEB 3 category, or
als with OELs under 1 μg/m3 in reactors maybe OEB 4, he says, which means con- Lithium Borohydride
of up to 1,200 L and batch sizes of 50–100 tainment will be required. The quantities
kg. AMRI recently added a non-GMP high- would be larger than for highly potent APIs
potency development lab to accommodate but less than for nonpotent ones. “There
increased customer orders. seems to be a need for more intermediate- O

In late 2007, Germantown, Wis.-based scale manufacturing,” he says. O Al H

O
Cambridge Major Laboratories acquired Like AFC, Ferro Pfanstiehl Laborato-
ChemShop in the Netherlands and has al- ries has been in this business for about 20
ready started expanding the high-potency years. According to the company, it is able Lithium-tri-(t-butoxy)-
kilolab and pilot-plant facilities there. to produce toxic and cytotoxic APIs and Aluminum Hydride
The company can handle compounds at a intermediates in amounts up to 50 kg using
SafeBridge OEB 3 or Merck 4 reactors up to 300 gal.
level, says Peter Van Tilburg,
NH2
In 2001, Ferro Pfanstiehl CHALLENGE
president of CML Europe. It was initially SafeBridge certi-
just commissioned two new fied. SAFC, part of Sigma-
US
N N
cGMP suites with up to 100-L Aldrich, became certified in s!VAILABLEGLOBALLY
capacity for producing hun- O N 2002 at its Madison, Wis. site
dreds of grams at a time to sup- HO and in 2006 Almac Sciences in s6ERSATILEANDHIGHLYEFFICIENT
port customers’ early develop- O Northern Ireland passed the REDUCINGAGENT
ment work. bar as well. Almac’s certifica- s,!(FORMULATEDIN4(&OR
“Because the quantities are HO HO tion included its engineering 4(&4OLUENE
smaller, a lot of companies controls, cGMP kiloscale
think this is easier to do,” operations with containment s,"(AND4",!(SOLUTIONS
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Azacitidine
Van Tilburg says about high- to 0.1 μg/m3 for cytotoxic BOTHIN4(&
potency manufacturing. “But compounds, and its operating
it’s a completely different ballgame—you procedures and practices. Contact Us.
need different people, different expertise, “Four companies have successfully gone
We are “more than lithium.”
different equipment, and different motiva- through our program and have some ele-
tion.” For these reasons, companies won’t ment of SafeBridge certification,” Farris
succeed simply by throwing a lot of money says. At present, several other companies
at building capacity, he says. Nor will those are looking at the certification process,
who invest a nominal amount in limited which reviews 60 different criteria and
equipment, says another manager, adding includes an on-site assessment, with vari- fmclithium.com [email protected]
that “it’s not enough just to buy a glove box ous levels of interest. “We’re hoping to get +1.704.868.5300 1.888.lithium
and say you can do high potency.” the number of certified companies up to

WWW.C E N- ONLI NE .ORG 23 J UNE 16, 20 0 8

 COVER STORY

“It’s just not enough to buy a glove box secondary metabolites, cytotoxins, and
proteins. The $29 million cGMP plant is
and say you can do high potency.” scheduled to be completed in early 2009,
Feldker says, and will include 1,000- and
4,000-L tanks for large-scale bacterial and
maybe a dozen over the next two to three tency manufacturing. In 2004, it acquired fungal manufacturing. Operating at OEB 4,
years,” Farris notes. the Madison-based firm Tetrionics. Since SAFC hopes to obtain SafeBridge certifica-
Although both large and small custom- then, it has expanded capabilities for mak- tion there, Feldker says.
ers will audit a supplier’s operation, large ing highly potent small molecules and bio- SAFC is wagering on the high-potency
drug companies tend to take more notice logics. To carve out its sizable position, the area because of anticipated double-digit
of SafeBridge certification, company man- company has invested $45 million over the growth rates. “Many large pharmaceutical
agers say. Not only may the bigger firms be past 18 months, Feldker says. companies had held this technology cap-
more familiar with high-potency manufac- SAFC just spent $4.5 million to increase tive but now are starting to outsource quite
turing, but they also have more established its cGMP pilot plant and large kilo-lab a bit more,” Feldker says. About 80 or 85%
occupational health and safety staff who capacity in Madison. The expansion added of SAFC’s high-potency projects are cancer
will evaluate contractors as part of their two 400-L and two 100-L reactors, giving therapeutics.
risk management activities. it capabilities for projects from develop- “We have over 350 projects for highly
ment-scale up to commercial-scale. The potent compounds with customers,” Feld-
SAFEBRIDGE CERTIFICATION is “almost company also installed solid-form testing ker says. For several years, SAFC has been
like a permit,” says David Feldker, SAFC and analysis equipment as part of its high- the exclusive supplier of paricalcitol, the
Pharma vice president for manufacturing potency offering. And in St. Louis, SAFC active ingredient in Abbott Laboratories’
and U.S. operations. “Knowing that we are has just added a suite to supply early-stage thyroid drug Zemplar. “We have several
certified at our site in Madison, Wis., gives clinical-trial quantities of highly potent late-stage products and hopefully in the
customers the confidence that our engi- conjugated APIs. next year, if everything is working right,
neering and personnel controls are in line SAFC’s single largest investment is in a we’ll have some approvals coming our
with what is needed.” new facility in Jerusalem for fermentation- way,” he adds.
SAFC has made a big push into high-po- derived highly potent APIs, including Lonza also is betting big, having an-

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nounced about $100 million in invest- large-scale 1,200-L equipment and can
ments to add a commercial-scale conjuga- handle OEB 5, or 1 μg/m3 levels.
tion facility and expand into large-scale Investing nearly $12 million, France’s
production of potent APIs. A new 40,000-L Groupe Novasep opened a high-potency
facility in Visp, Switzerland, will be running cGMP plant in Le Mans earlier this year. In
in July, says Stefan Stoffel, head of opera- addition to contained synthesis under OEB
tions for Lonza’s exclusive synthesis busi- 5, corresponding to 0.1–5 μg/m3 OELs, the
ness sector. It will be capable of handling company says it offers large-scale prepara-
compounds with OELs down to 1 μg/m3. tive chromatography for highly potent
The unit is designed for large-volume compounds. It specializes in the semisyn- Specialty Ligands from FMC
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some of them in tens OH expanding as well. It has
O
of tons quantities that H added two production
N N B
we can cover with the N OH lines, each with 800-
larger facility.” Lonza H and 1,600-L vessels.
O
also has two plants with N The addition allows
630- and 2,500-L reac- it to handle projects
tors for producing com- Bortezomib
ranging from lab scale
mercial quantities of up to 250-kg batches in
more potent drugs with 6,000-L reactors. Ex-
OELs of less than 1 μg/m3. cept for this largest scale, which operates
These facilities complement existing at a 1 μg/m3 exposure limit, OmniChem’s
lab-scale capabilities for smaller quantities containment level is 0.1 μg/m3.
or even more highly potent compounds. Meanwhile, Uquifa, the pharmaceutical
“There is a limited group of companies that division of the British firm Yule Catto, is a
can make products in the variety that we relatively new entrant to the high-potency
can,” Stoffel says. “We started up small and area, having added its facility outside of
have expanded because of the steep increase Milan, Italy, about two years ago. The com-
in projects that we have in the pipeline.” A pany can handle compounds with OELs of
majority of Lonza’s large-scale capacity is 1–10 μg/m3, says Charlie Johnson, Uquifa’s
committed to specific customers’ orders, head of sales and marketing. Along with de-
and it is already anticipating the construc- velopment labs, its production capabilities
tion of another train in the API plant. include 250- and 1,200-L reactors to make $4".P0IS
5- and 50-kg lots. s.OTPATENTED
BETWEEN 2006 AND 2007, customer “Associated with our high-potency unit s%QUIVALENTORBETTERTHAN44"0
inquiries nearly doubled and the trend has is a pilot plant for the upstream stages of INCOUPLINGREACTIONS
continued, Stoffel says. Contracts for high- synthesis,” Johnson explains. “The idea is
ly potent products, unlike traditional APIs, to bring convergence to the synthesis so "OTHARE
are often multiyear, single-supplier agree- that the potency is built into the molecule s5SEDASALIGANDINMETAL
CATALYZEDCOUPLINGREACTIONS
ments. Two factors play into this: the small late in the process and the upstream stages
s5SEDIN3UZUKI (ECK 
product volumes and the limited number can be handled in a conventional plant.”
3ONGASHIRA FORMYLATIONS 
of suppliers. Lonza already is producing Uquifa is targeting oncology products, AMINATIONS ANDHYDROGENATIONS
five commercial products in the areas of including cytotoxics, and some newer s5SEDINCATALYTICPOLYMERIZATION
oncology, immunosuppression, and veteri- cytostatic drugs, Johnson says. “There is a
R EQUEST MO RE AT A DINFO NOW.O RG

REACTIONS
nary medicine. distinct trend in the drug industry to move s!VAILABLEFROM&-#
In early 2007, Lonza bought the biobusi- away from traditional chemotherapeutic
nesses of Cambrex, which included anti- agents, such as cytotoxics and oncology Contact Us.
body production for a cytotoxic conjugate. hormones, to more targeted therapies,” he
We are “more than lithium.”
Cambrex retained its small-molecule fine points out. Although these drugs are not
chemicals business, which has been active highly potent or toxic but rather specific
in the high-potency area for 10 years. The for disease targets, they still will have to be
company just opened a five-suite develop- produced in contained facilities.
ment and kilo-scale lab facility for highly According to the market research firm
potent compounds in Charles City, Iowa, Datamonitor, sales of cytotoxics will fmclithium.com [email protected]
says Eric Neuffer, vice president for sales grow about 1% per year over the next few +1.704.868.5300 1.888.lithium
and business development. It also has years and then start to decline. Several

WWW.C E N- ONLI NE .ORG 25 J UNE 16, 20 0 8

 COVER STORY

BAND AID
Allowable exposure bands determined by a compound’s characteristics
CRITERIA BAND 1 BAND 2 BAND 3 BAND 4
Exposure limit >1,000 μg/m3 >100 μg/m3 >1 μg/m3 <1 μg/m3
Potency (dose/day) >100 mg/day 100–10 mg/day 10–0.1 mg/day <0.1 mg/day
Acute toxicity None to slight Slight; reversible Moderate to severe Extreme to lethal
Acute adverse effects None Minor; reversible Moderate to severe; reversible Severe; irreversible
Acute warning properties Excellent Good Fair to poor Poor to none

Onset of symptoms Immediate Immediate Immediate to may be delayed Delayed to none

Chronic adverse effects None to minor Minor to moderate Moderate; irreversible Severe; irreversible to lethal
Mutagenicity None Yes Severe Severe
Neurotoxicity Minimal Moderate Moderate (immediate or Life-threatening
delayed)
Teratogenicity None Yes Severe Severe
Reproductive disorders No effects to readily Readily reversible Slowly reversible to Irreversible
reversible irreversible

Sensitization potential Not a sensitizer Mild to moderate Moderate to severe Extreme

Carcinogenicity None Suspected Suspected Confirmed in animals and
(confirmed in animals) humans
Epidemiology No confirmed effect Studies ongoing Defined medical case studies Clear correlation
Inhalation/dermal exposure Minimal risk Moderate risk Significant risk Significant risk
Irritation potential (skin/eye) None/Mild to moderate Yes/Severe Severe/Severe Severe/Extreme

NOTE: Compiled from company information for four-band system.

high-profile cancer drugs—topotecan from multiplying and include, for example, can make a fuller assessment of the mole-
(GlaxoSmithKline’s Hycamtin), irinote- tyrosine and aurora kinase inhibitors, will cule and really start to build a scientifically
can (Pfizer’s Camptosar), temozolomide grow at double-digit rates. justifiable occupational exposure limit.”
(Schering-Plough’s Temodar), gemcitabi- “Our strategy is to target late Phase II Up to this point, because the volumes are
ne (Lilly’s Gemzar), capecitabine (Roche’s through to commercialization,” Johnson small, compounds usually can be safely
Xeloda), and docetaxel (Sanofi-Aventis’ says. Phase II clinical trials, where drug ef- handled in glove boxes.
Taxotere)—have or will come off patent ficacy is starting to be tested, is a preferred The drug company may provide the toxi-
in the next five years and fuel the gener- capture point because a supplier can bring cology and other data to the manufacturing
ics market. Sales of antihormonal cancer its chemical development expertise to bear partner or may simply inform the partner
therapies are already falling. before a process gets locked down. “Phase as to what control band it believes is need-
Meanwhile, sales of small-molecule II is also usually the point at which the toxi- ed. Custom manufacturers say they often
cytostatic drugs, which stop cancer cells cology profile becomes more mature, so we will conduct this analysis again or even

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WWW.C E N- ONLI NE .ORG 26 J UNE 16, 20 0 8

get an outside, independent assessment if facility will be a very nice crossover,” says ity restraints, Griffiths says. “Demand is
there’s any ambiguity or disagreement. Carbogen CEO Mark Griffiths. “It will go very strong and the reality is you won’t win
“Ultimately, it’s our responsibility, be- from 630 L up to 1,600 L, with the capacity projects unless you create the capability,”
cause if we are going to be manufacturing to go larger.” The facility will operate under he explains. “You have to have the capabili-
these products it’s our duty to protect our Carbogen’s own OEB 3 (less than 10 μg/m3) ties to show customers, and then they will
personnel,” Johnson says. The OEB also and OEB 4 (less than 0.3 μg/m3) limits. come. Most companies are not going to
determines whether a product must be Carbogen, which has been in the high- make a financial commitment to you until
manufactured in a high-potency plant at an potency business since 2002, is responding they see the facility and understand how
associated higher cost. to increasing customer demand and capac- you are going to run it.” ■
Custom manufacturing firms are accus-
tomed to optimizing processes. But unlike
in traditional API synthesis, manufacturers
of highly potent compounds don’t typi-
cally emphasize yield or tweaking a process
during scaleup in pursuit of every penny of
savings. It’s hard enough to get processes
to work under contained conditions, and
the small-volume products are less cost-
sensitive anyway. As such, large-scale,
low-cost assets don’t necessarily make a
company more competitive.

ALTHOUGH competition from low-cost

Asian producers is not yet a factor in highly
potent, custom-made APIs, many Western
suppliers say they anticipate that it eventu-
ally will become a factor. Many older anti-
cancer drugs are generic products, such as
doxorubicin, Polastro points out, and Asian
generic drug firms are playing a role. For
example, Dr. Reddy’s and Ranbaxy Labora-
tories in India are touting their high-poten-
cy manufacturing capabilities.
For now, a few Asian custom manufac-
turers have bought or built high-potency Do you suffer
capabilities. In 2005, India’s Hikal opened
a small plant, and Piramal Healthcare from production
acquired Avecia’s U.K.-based business. In
2007, Piramal added a high-potency con- bottlenecks?
jugation suite in Scotland, where it already
had five OEB 4 or 5 suites for making cyto-
toxics, cytostatics, and conjugates.
“We see a lot of growth opportuni-
ties in the small-molecule and finished Siegfried provides first aid when you need to scale up your pharma fine chemicals
dosage formulations areas,” says R. capacity, or take care of production shortfall constraints. We are a capable and
Ananthanarayanan, president of Piramal flexible outsourcing partner for cGMP, non-cGMP intermediates, and finished APIs.
Pharma Solutions. Depending on what
A rapid technology transfer and professional project management ensures
scale plant it finds it needs, the company
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is considering expanding production for efficiency. That’s why Siegfried is known for reliability and Swiss quality – at an
highly potent small molecules in either the affordable cost. Try us out; we’ll deliver – when substance matters.
U.K. or India.
Carbogen-Amcis, which was acquired by
India’s Dishman Pharmaceuticals & Chem-
icals in 2006, also bridges geographies. It
Siegfried (USA), Inc., www.siegfried-usa.com
operates established lab- to medium-scale
facilities in Switzerland and is building a Milton Boyer, Phone +1-877-763-8630
high-potency facility in Bavla, India, which Siegfried Ltd, www.siegfried.ch
is scheduled to open in early 2009. Dirk Sartor, Ph. D., Phone +41 62 746 12 29
“In Switzerland, we go up to 630 L for
high-potency manufacturing, and this

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