Contract Manufacturing Organizations Expand in High-Potency Manufacturing

A growing number of pharmaceuticals contain highly potent active ingredients, and select custom manufacturers are responding by expanding their capabilities.

High-potency active ingredients (HPAIs) are classified based on their inherent characteristics of toxicity and pharmacological potency as well as on their occupational exposure limits (OELs). Typically, active pharmaceutical ingredients (APIs) with OELs at or below 10 micrograms per cubic meter of air as an eight-hour time-weighted average are considered potent from an occupational health perspective, explains John Farris, president and CEO, SafeBridge Consultants, Inc. (Mountain View, CA, www.safebridge.com), a consultancy specializing in occupational and environmental toxicology, industrial hygiene, and analytical chemistry. Roughly 28% of the drugs currently on the market are considered potent by these criteria, explains Robert Sussman, managing principal of SafeBridge's East Coast office.

A cytotoxic suite at NPIL Pharma's high-potency manufacturing facility in Grangemouth, Scotland.

High-potency manufacturing may be generally categorized based on four levels of OELs (see Table I). The four categories range from Category I, low-potency compounds requiring conventional good manufacturing practices (GMPs), to Category IV, for which a high degree of containment is required.

Contract manufacturers expand

SAFC (St. Louis, MO, safcglobal.com), the custom-manufacturing arm of Sigma-Aldrich Corporation (St. Louis, MO, www.sigma-aldrich.com) is one of several contract manufacturing organizations (CMOs) that recently completed expansions in high-potency manufacturing. Earlier this year, the company completed a $12-million expansion program at its high-potency facility in Madison, Wisconsin.The 38,000-ft² expansion more than doubled the size of SAFC's existing 23,500-ft² building and its CGMP manufacturing capacity in Madison.

The expansion was driven by an increase in demand for custom chemical manufacturing services for HPAIs, including Category III and Category IV compounds.

The expansion adds new analytical laboratories, expanded research and development laboratories, three new kilo laboratories, a hydrogenation suite, a CGMP drying suite, and increased warehousing and storage capacity. The Madison site was the former principal manuufacturing site of Tetronics, which SAFC acquired in 2004.

Table I: Potency classification scheme (generic).

SAFC's Madison site was founded on the company's expertise in vitamin D chemistry for the scale-up and manufacture of difficult-to-synthesize vitamin D analogs. SAFC manufactures paricalcitol, the active ingredient in Abbott Laboratories' (Abbott Park, IL. www.abbott.com) "Zemplar," a synthetically manufactured vitamin D analog.

Ferro Pfanstiehl Laboratories, Inc. a subsidiary of Ferro Corporation (Cleveland, Ohio, www.ferro.com) also recently expanded its manufacturing capabilities for HPAIs. In August 2006, the company completed the commissioning of a new ICH Q7A-compliant, Class IV (performance-based exposure control level) containment facility in Waukegan, Illinois. The facility is designed for low-volume production of HPAIs, including small-molecule new chemical entities (NCEs) in early-phase development. The 2000-ft² addition offers production of preclinical through commercial quantities ranging from 1–5 kg, explains Peter Thomas, vice-president of Ferro's Organic Specialties Group, which includes Ferro Pfanstiehl. The new kilo laboratory complements current product batch capacities of 3–50 kg in Ferro Pfanstiehl's existing 1200-gal HPAI commercial containment facility in Waukegan.

Ferro Pfanstiehl Laboratories' Class IV 100-L glass-lined kilo laboratory–isolator system is designed to produce developmental high-potency pharmaceutical active ingredients.

The new kilo laboratory is the first phase of a multiphase capital building program supporting Ferro Pfanstiehl's HPAI business strategy. The company also recently completed the commissioning of a new CGMP supercritical fluid-based–particle-size engineering (SCF–PSE) pilot facility to provide regulated capabilities and expertise in particle sizing, purification, and formulation applications for client-sponsored preclinical and clinical studies. The new pilot laboratory is capable of handling both high-potency and and nonhigh potency SCF–PSE applications.

Ferro Pfanstiehl began its strategic capital spending program, inclusive of its HPAI strategy, by commissioning a 21 CFR Part 11-compliant analytical services laboratory in April 2004.

A key project in Ferro Pfanstiehl's HPAI program is the full development and commercial production of the HPAI decitabine. Decitabine is the active ingredient in MGI Pharma, Inc.'s (Bloomington, MN, www.mgipharma.com) "Dacogen" a fast-tracked orphan drug approved in May 2006 by the US Food and Drug Administration (Rockville, MD, www.fda.gov) for treating myelodysplastic syndrome. Ferro Pfanstiehl is producing commercial quantities of decitabine for MGI Pharma and also is providing clinical-trial material to support MGI Pharma's clinical-trial program to evaluate additional therapeutic uses for Dacogen.

Decitabine is Ferro Pfanstiehl's first client-sponsored high-potency NCE to gain FDA approval. The company, however, has more than 20 drug master files covering its existing HPAI, API, and high-purity low-endotoxin excipient-based products.

The project for decitabine is significant for Ferro as MGI Pharma expands the commercial potential of the drug. MGI Pharma recently signed a licensing agreement with Jannsen-Cilag GmbH, a subsidiary of Johnson & Johnson (New Brunswick, NJ, www.jnj.com) for exclusive clinical development and commercialization rights for Dacogen outside of North America. In August 2006, MGI Pharma received orphan drug designation from European regulatory authorities to use the drug for treating acute myeloid leukemia.

NPIL Pharma (Mumbai, India, www.npilpharma.com) is expanding its high-potency substance facility in Grangemouth, Scotland. The Grangemouth facility provides contract manu-

facturing of HPAIs (cytotoxics and prostaglandins) and preclinical and clinical development. The expansion includes recruitment of 16 additional technical and operational staff and a roughly $500,000 investment in containment upgrades. The hardware investment will bring more CGMP capacity for clinical trial materials on stream by the end of 2006.

The new containment upgrades to an existing GMP suite include additional high-integrity barrier isolation for the safe handling for Category IV-V toxins used for conjugation to monoclonal antibodies and targeting agents. NPIL Pharma gained the Grangemouth facility as part of its acquisition of the custom manufacturer Avecia Pharmaceuticals in December 2005.

Helsinn Advanced Synthesis SA (Biasca, Switzerland,www.helsinn.com) in July 2006 completed an expansion that added a production bay at its facilities in Biasca, Switzerland. The new bay increases multipurpose production capacity from 16 to 24 m³ , giving the company total capacity of 106 m³ . The new bay can be adapted with minor modifications to produce HPAIs at large scale between 10–50 kg, explains Gabriel Haering, director, commercial division, Helsinn. The expansion gives Helsinn two plants for manufacturing HPAIs from 1–10-kg batches up to multi-hundreds of kilograms. Helsinn also has on stream another HPAI plant for producing small clinical and registration batches (<500 g-batches) under CGMPs; it will be ready during the autumn 2006.

EaglePicher Pharmaceutical Services (EPPS, Lenexa, KS, www.eaglepicher.com) also expanded its high-potency manufacturing capabilities. In 2005, the company completed the addition of a commercial isolated suite for the manufacture of HPAIs. "The commercial suite complements our other high-potency isolated suites containing pilot-plant and kilo laboratory equipment," explains Scott Parker, EPPS's director of business development and sales manager.

The company has a Class 100,000 high-containment facility that is designed to use barrier technology for the synthesis, compound isolation, and drying of the high-potency API. Other design features include clean-in-place systems, validated computer controls, and separate air handling (high-efficiency particulate air handling, both inbound and exhaust).

Key projects by EPPS include the manufacture of several APIS used as anticancer agents, including camptothecin, paclitaxel, doxorubicin, and daunorubicin derivatives. Other programs include nanoparticles and the manufacturing of cytotoxic agents for coupling to antibodies for targeted delivery of high-potency APIs, explains Parker. EPPS supports scale-up from preclinical to commercial supplies of the high-potency API.

New players add HPAI capabilities

Dishman Pharmaceuticals & Chemicals., Ltd. (Ahmedabad, India. www.dishmangroup.com), which has been actively building its portfolio in custom synthesis, is building its capabilities in contract HPAI manufacturing. In May 2006, Dishman agreed to buy the former pharmaceutical services business of Solutia, Inc. (St. Louis, MO, www.solutia.com) for $74.5 million. The deal consisted of CarboGen and AMCIS (Bubendorf, Switzerland www.carbogen-amcis.com), contract manufacturers with facilities in Aarau, Bubendorf, and Neuland, Switzerland. With the acquisition, Dishman gains capabilities in high-containment manufacturing.

Another Indian player, Hikal, Ltd. (Mumbai, India, www.hikal.com) is building HPAI capabilities. In 2005, it opened a new small-volume HPAI plant in Jigani, India. The plant is capable of producing steroids and other high-potency molecules under CGMP conditions.

Certification in manufacturing HPAIs

To address the specialized capabilities for high-potency manufacturing, SafeBridge Consultants has developed a certification program that provides a third-party assessment of a company's ability to handle and manufacture potent compounds safely. SafeBridge offers the certification process for competency in the occupational health aspects of high-potency manufacturing.

To be certified by SafeBridge, a company must meet minimum criteria in the management, evaluation, containment and control, and communication elements of potent-compound safety. Elements of the certification program include an on-site assessment of both physical plant and equipment items (such as segregation of the processing areas, containment and process technology), and program items such as process safety, training, medical surveillance, industrial hygiene, toxicology, and environmental control.

In assessing the key areas for high-potency manufacturing, SafeBridge's Farris explains that manufacturing organizations usually understand the need for process containment and focus their efforts on the "hardware" side of the matter. This focus would include implementation of exposure-control technology such as isolators (sophisticated gloveboxes), direct connection for gravity transfers using split-butterfly valves, and process technology that eliminates transfer steps such as "one pot" multiprocess dryer granulators.

The program areas most commonly in need of improvement are the evaluation and communication elements or "software" side, he explains. These elements include thorough occupational and environmental toxicology evaluation of the material before processing, industrial hygiene air-monitoring studies during processing to measure exposures, and potent-compound awareness training for operators to provide detailed instruction into why the containment and controls are in place, and not just how to use the associated equipment.

"Investments in highly contained process equipment are prudent for manufacturing these high potency materials; however, they will only work as well as the operator's technique allows," explains Farris. "To achieve high performance form the operators, they must understand how their sometimes subtle actions can influence the air concentrations of the materials they are working with and, therefore, affect their exposure to the pharmaceutical substances."