Risk Mitigation in High-Potency Manufacturing - Pharmaceutical Technology

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PharmTech Europe

Risk Mitigation in High-Potency Manufacturing
A recently released industry guide outlines a science- and risk-based approach to control the risk of cross-contamination.

Pharmaceutical Technology
Volume 10, Issue 34, pp. 52-56

Investing in High-Potency Manufacturing

Micronization of high-potency active pharmaceutical ingredients at Powdersize’s Quakertown, Pennyslyvania, facility. (Figure is courtesy of powdersize)
High-potency manufacturing and related services represent an area of ongoing investment by contract manufacturing organizations (CMOs) and service providers. For example, Ben Venue Laboratories (Bedford, OH) recently constructed a new 225,000-ft2 manufacturing facility in Bedford, Ohio, for producing sterile finished dosage forms of cytotoxic and genotoxic products in clinical and commercial volumes. The facility is designed to provide containment for products with occupational exposure limits (OELs) as low as 0.1 g/m3 with engineering controls and potentially lower OELs when combined with personal protective equipment and administrative controls.

The facility was completed in 2010 and will be on line in the second quarter of 2011. The facility has three sterile filing lines and lyophilization capacity of nine lyophilizers. The facility is equipped and rated to handle flammable solvent and cosolvent formulations at both clinical and commercial scales. "This enables us to develop formulation approaches for molecules that may be difficult to solubilize in aqueous formulations," explains Darrell Jessee, vice-president of contract manufacturing services at Ben Venue. The facility also has a dedicated warehouse with temperature-controlled storage capabilities dedicated entirely to the cytotoxic/genotoxic products within the facility.

Boehringer Ingelheim Roxane (BIRI), which manufactures high-potency oral drugs as part of the contract manufacturing services offered at its facility in Columbus, Ohio, recently announced a $50-million investment to build a new 87,000-ft2 high-containment facility on its existing campus. The new facility is scheduled to be operational in the summer of 2011 and will be capable of handling materials up to an OEL limit of 0.1 g/m3 for oral forms of drug product with potent and cytotoxic active pharmaceutical ingredients (APIs), including steroids. This new facility will provide microdose formulation services for highly active APIs.

Powdersize (Quakertown, PA) recently expanded its milling and micronization services to include particle-size reduction of highly potent APIs and highly sensitizing compounds such as steroids and hormones. The company upgraded its facility in Quakertown, Pennsylvania, to include a new processing suite for processing highly potent compounds. A Universal Milling Containment isolator, designed by Powder Systems (Boise, ID), was completed and qualified in 2010. Placebo testing using lactose as a surrogate powder showed containment levels down to 10 ng/m3 . The facility has micronization capabilities, including 2-in., 4- in., jet mills, with scale-up potential to a 10-in. milling system within the isolator to accommodate research and development, clinical, and early commercialization volumes.

Carbogen Amcis (Bubendorf, Switzerland) opened a new high-potency API facility at the site of its parent company, Dishman Pharmaceuticals and Chemicals (Ahmedabad, Gujarat, India), in January 2010. The facility's large-scale capacity (currently up to 1600 L) will be capable of producing multimetric ton quantities of high-potency APIs (as low as < 1 g/m3 ). The facility complements Carbogen Amcis's high-potency API facilities in Bubendorf.

Aesica (Newcastle upon Tyne, UK) will invest 3 million ($4.7 million) in a new high-containment manufacturing facility at its Queenborough, United Kingdom, site. The new unit will include suites for granulation, tableting, and blister packing. The company expects the facility to be completed by May 2011.

SAFC, part of the life-sciences chemical company Sigma-Aldrich (St. Louis), announced the opening of a $30-million expansion to its manufacturing facility in Verona, Wisconsin, earlier this year. The new facility complements SAFC's existing 63,000-ft2 high-potency API site in Madison, Wisconsin, and houses commercial-scale reactors capable of producing batch sizes up to 4000 L. SAFC also completed an investment in Madison to increase current good manufacturing practice pilot-plant and large-scale kilogram laboratory high-potency API capacity. In St. Louis, Missouri, the company recently commissioned a suite for producing high-potency API conjugates. SAFC also invested $29 million to expand its large-scale production of bacterial and fungal fermentation-derived biologic high-potency APIs. The 50,000-ft2 facility is designed to produce secondary metabolites, cytoxins, and large-molecule proteins.

The CMO AMRI (Albany, NY) received certification by SafeBridge Consultants (Mountain View, CA) of its high-potency research laboratories and good manufacturing practice facilities in Rensselaer, New York. The certification shows that the company is proficient in the safe handling of potent APIs.—PVA

Formulation development forum: liposomal-based nanotechnology

Researchers at the University of Rhode Island (URI) in Kingston recently reported on controlling drug delivery using nanoparticles embedded in a liposome triggered by noninvasive electromagnetic fields. Bilayer-decorated magnetoliposomes (dMLs) were prepared by embedding small hydrophobic superparamagnetic iron oxide nanoparticles at various lipid-molecule-to-nanoparticle ratios within dipalmitoylphosphatidylcholine bilayers. The dML structure was examined by cryogenic transmission electron microscopy and differential scanning calorimetry, and release was examined by carboxyfluorescein leakage (1). The superparamagnetic iron oxide nanoparticles embedded in the shell of the liposome released the drug by making the shell leaky when heat-activated in an alternating current electromagnetic field operating at radio frequencies.


1. G.Bothun et al. ACS Nano 4 (6), 3215–3221 (2010).


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