Patricia Van Arnum

Classification of high-potency drugs

Cytotoxic drugs, prostaglandins, opiates, and certain hormones may be classified as potent compounds. High-potency active pharmaceutical ingredients (HPAPIs) are classified based on their inherent toxicity, pharmacological potency, and occupational exposure limits (OELs). Typically, HPAPIs with OELs of 10 μg/m³ of air as an 8-hour-time-weighted average are considered potent from an occupational health perspective. The generally accepted practice within the pharmaceutical industry is to use a categorization or banding system based on the API's potency or toxicity. These performance-based OELs, or hazard categories, incorporate four-, five-, or six-band systems. The number of bands is usually based on the number of different containment environments that can be described (1).

IMAGE COURTESEY OF SAFC.

Oncology drugs were the largest therapeutic class by value in 2007, accounting for $41.4 billion or 6.2% of the global pharmaceutical market of $663.5 billion, according to IMS Health. (These figures include prescription and certain over-the-counter drugs data and represent manufacturers' prices). Global sales of oncology drugs increased 16.2% in 2007, exceeding the pharmaceutical industry's overall growth of 6.4%, according to IMS.

Prospects are equally sanguine. Global sales of cancer drugs are expected to increase at a compounded annual rate of 12–15% to reach $75–80 billion by 2012, according to IMS. In 2008, sales are expected to exceed $48 billion. IMS expects that 25–30 new chemical entities for treating cancer will be introduced during 2008–2012. And there are 750 new anticancer drugs in clinical development, according to a recent report by the Pharmaceutical Researchers and Manufacturers of America (2).

Oncology drug are not the only part of the high-potency story. "While anticancer therapies are a key driver for the demand for high-potency and cytotoxic manufacturing, there is also increasing demand from other therapeutic areas," says Tim Scott, president of Pharmatek (San Diego, CA), a pharmaceutical-chemistry development organization. "For the most part, past drug pipelines were on the drug-development path of least resistance," says Scott. "Now that those compounds have become exhausted, companies are turning to more challenging drugs, and many of these molecules are highly potent or toxic."

Others agree. "The trend is moving toward more specific and potent therapies that are more biologically active in smaller doses," says Peter Hansbury, vice-president of contract manufacturing services for Ben Venue Laboratories (Bedford, OH), a CMO of sterile drug products.

API production

To meet this demand, CMOs are expanding primary manufacturing capacity for HPAPIs and antibody drug conjugates (ADCs). ADCs are monoclonal antibodies linked to cytotoxic small molecules.

SAFC has invested $45 million in high-potency expansions during the last 18 months. In late 2007, it began operations of a new 600-ft² HPAPI conjugation suite at its St. Louis, Missouri, manufacturing facility. The suite is designed for producing early-stage clinical supplies and has capabilities to expand production into commercial scale in multikilogram quantities.

The company invested $4.5 million to expand current good manufacturing practices (CGMP) capacity on a pilot-plant and kilo-laboratory scale at its facility in Madison, Wisconsin. This investment follows a $12-million, 38,000-ft² HPAPI expansion at its Madison facility, which was completed in 2006. SAFC is investing $29 million for a new facility for large-scale production of bacterial and fungal fermentation-derived HPAPIs in its Jerusalem, Israel, facility. The expansion is scheduled for completion in 2009.

Feldker also points to the possibility of further expansion. "Our growth has been limited by the ability to add capacity, and we are evaluating the potential for additional expansions."

Novasep (Pompey, France) invested EUR 8 million ($12.7 million) in a new high-potency CGMP HPAPI manufacturing plant in Le Mans, France, which opened earlier this year.

Carbogen Amcis India, the Indian subsidiary of Carbogen Amcis (Bubendorf, Switzerland), plans to open a high-potency manufacturing facility in Bavla, India. The facility will be located on the Bavla site of its parent company, Dishman Pharmaceuticals and Chemicals (Ahmedabad, India). The building's framework is erected, and the fit-out of the facility is underway. The facility is expected to be operational by the first quarter of 2009.

The facility will have an operational floor space of 4300 m². It will hold four segregated high-potency cells, each of which will be fitted with three reactors and a filter dryer. The reactors will range in size between 630 and 1600 L. The Bavla facility will be complementary to the company's Categories 3 (OEL < 10 μg/m³ ) and 4 (OEL < 3 μg/m³ ) facilities in Bubendorf. The new Indian facility will also have several contained development laboratories and additional space for subsequent fit-out of further high-potency manufacturing cells.

Earlier this year, AMRI (Albany, NY) completed a new 1500-ft² GMP high-potency development laboratory suite at its facilities in the Albany area.

Lonza (Basel, Switzerland) will bring on line a commercial-scale plant for ADC production in Visp, Switzerland, in the second half of 2008. The plant will initially be capable of producing more than 100 kg of ADCs per year, and future expansion plans are built into the design. Lonza operates laboratory-scale production and brought small-scale pilot facilities on stream in 2007.

NPIL Pharma (Mumbai) commissioned its sixth high-potency-substance production suite at its Grangemouth, Scotland, facility earlier this year. The suite came on stream during the first quarter of 2008 following an investment of $270,000. The new suite is optimized for GMP manufacture of ADCs, will run batch sizes of 500–1000 g, and can produce as much as 50 kg annually.