CMOs Invest in High-Potency Manufacturing

Contract manufacturing organizations (CMOs) say robust demand for oncology and other high-potency drugs is driving demand for high-potency manufacturing. They are responding by expanding their capacity for clinical trials materials and commercial quantities.

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).

Market drivers

Strong growth in anticancer therapies and shifting patterns in drug development to more complex and potent compounds are key factors in driving demand for high-potency production capacity. "The market for small-molecule and biologic high-potency APIs has been growing at double-digit rates," says Dave Feldker, vice-president of manufacturing and US operations at SAFC Pharma (St. Louis, MO). SAFC Pharma is a CMO of small-molecules and specialized biologics, including high-potency compounds. "The number of customers we have has more than doubled to 350 over the past three years, with particular demand growth for biologic-HPAPI conjugates for oncology drugs."

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.

Dosage-form manufacturing

CMOs specializing in secondary manufacturing are moving forward with expansion plans as well.

Ben Venue is building a new $139-million, 240,000-ft² manufacturing plant for producing cytotoxic and genotoxic compounds. The facility will produce both commercial and clinical-trial materials. Construction is scheduled to be completed by the end of 2008. Qualification activities are expected to be completed in the first quarter of 2009, and facility approvals are anticipated for the second quarter 2009.

Patheon (Mississauga, Ontario) is investing $2.8 million to add a dedicated, 3386-ft² high-potency and controlled-substance manufacturing area at its Manati, Puerto Rico, facility. The production area will have capacity for high-potency (i.e., containment down to 1 μg/m³ OEL) and humidity-controlled solid-dosage form products. Construction is scheduled for completion by the end of September 2008. Last month, Patheon partnered with BSP Pharmaceuticals (Aarhus N, Denmark) to promote BSP's cytotoxic manufacturing capacity and development services. The move provides Patheon the ability to provide high-potency manufacturing services.

In June 2008, Pharmatek (San Diego) completed construction of a new 18,000-ft² facility for high-potency manufacturing of oral dosage forms. The facility includes analytical and formulation laboratories and two certified and validated ISO Class 8, US Class 100,000 CGMP containment suites for the manufacturing of high-potency and cytotoxic drug products for early-phase clinical trials. Certification and validation of the facility is scheduled to be completed in mid-August. The facility will become fully operational in the fourth quarter of 2008.

With the expansion, Pharmatek will offer analytical-method development, preformulation testing, formulation development, CGMP manufacturing for early-phase trials, release testing, stability testing and storage, and technical transfer for commercialization for high-potency compounds.

Earlier this year, Catalent Pharma Solutions (Somerset, NJ) added a Phase I sterile vial-filling suite in its Research Triangle Park, North Carolina, facility. The new suite can fill vials with most highly-potent compounds, traditional small-molecule drugs and biologics, as well as DEA (Drug Enforcement Administration) Schedule 1–5 compounds.

Issues in high-potency manufacturing

For now, there is no official guidance from regulatory agencies regarding the production and handling of HPAPIs. "The industry has been moving toward self-regulation, either via SafeBridge, or a five-tier system used by some pharmaceutical companies," says SAFC's Feldker.

SafeBridge Consultants (Mountain View, CA) provides third-party certification to evaluate 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. The "SafeBridge" potent-compound safety-certification program verifies performance with set criteria in management, evaluation, containment, control, and communication elements of potent-compound production operations. Elements of the program include onsite assessment of the potent compound manufacturing and laboratory areas and equipment, training, toxicology, and industrial hygiene (1).

SAFC's Madison site is certified by SafeBridge for handling products up to Category IV. Its St. Louis facility is completing the requirements for certification, notes Feldker. SAFC plans to seek certification for its new plant in Jerusalem after its completion in early 2009.

Specialized equipment for containment, operator training, and safety practices are required for high-potency manufacturing. "The concept to contain a product within a manufacturing suite is similar for both biologic and small-molecule HPAPIs as well as conjugates," says Feldker. "The development and manufacture of HPAPIs requires significant planning, proper equipment, and facility design, as well as implementation of the necessary procedures to safely handle the compounds. In addition to containment systems for solid, powder, and liquids handling, secondary protection is provided by protection suits and supplied air systems, customized for each particular project. Sound systems must be employed in all aspects of the HPAPI handling program, from initial project evaluation, through equipment cleaning, to disposal of process waste."

Other CMOs emphasize the importance of facility design and operation when working with HPAPIs. "A site must carefully assess each step of their operation for the risk of possible product cross-contamination, CGMP and regulatory compliance, and the potential for employee exposure to potent compounds," says Ben Venue's Hansbury. "A multidisciplinary team should be involved in this review, including personnel from production, engineering, quality, validations, and environmental health and safety. Tools such as failure mode and effect analysis or fault-tree analysis are helpful in defining and ranking risks. Processes need to be thoroughly understood and risks ranked to understand where to put forth the best investment to control risk. Using data such as environmental, air, and wipe sampling from current processes shows where more control may be needed. This approach was taken for the design and construction of our expansion," he says.

In its expansion, Pharmatek used a combination of facility-design elements and exposure-control systems. Key aspects included:

• Integration of clinical trial material storage, equipment storage, and equipment wash within the clean space

• Design of an alternating positive and negative pressure scheme to ensure containment and prevent cross contamination

• Design and integration of a development area to support GMP manufacturing

• Multiproduct suite design while controlling for unidirectional personnel and equipment flow

• Design and integration of soft-wall, barrier technology for process equipment.

Scott also outlines key issues to consider on an operational basis such as cleaning-method development and implementation, cleaning verification, the cost associated with single-use containment technology and gowning items, and hazardous waste disposal.

Patricia Van Arnum is a senior editor at Pharmaceutical Technology, 485 Route One South, Bldg F, First Floor, Iselin, NJ 08830 tel. 732.346.3072, pvanarnum@advanstar.com.

References

1. P. Van Arnum, "Investing in High-Potency Manufacturing," Pharm. Technol. 31 (11), 54–58 (2007).

2. PhRMA, "Medicines in Development for Cancer" (Washington, DC, 2008).