January 2007

January 2, 2007
Pharmaceutical Technology Editors
Pharmaceutical Technology
Volume 31, Issue 1

Defects in Herceptin vials stem from a fault in the packaging process.

DRUG DELIVERY

Drug-Loaded Nanoparticles Image, Track, and Destroy Cancer Tumors

Ann Arbor, MI (Nov. 15)—Scientists at University of Michigan's Comprehensive Cancer Center (www.cancer.med.umich.edu) have devised a nanoparticle system that delivers a photodynamic drug directly to brain-cancer tumors. The particles carry "Photofrin" (Axcan Pharma PDT, Inc., Birmingham, AL, www.photofrin.com), a cancer treatment that cuts off blood flow to the tumor, but minimizes damage to healthy tissue caused by free Photofrin in the system. Iron oxide, a contrast agent, enhances magnetic-resonance imaging of the particles, and a laser light activates the drug to collapse the vessels supplying blood to the tumor.

Funded by a nearly $12-million contract from the National Cancer Institute, the research study showed that the system avoids the challenges encountered by other brain-cancer delivery methods, including overcoming the blood–brain barrier, while attacking the tumor with higher doses.

So far, the delivery system has been tested in cell cultures and animal models. If the nanoparticle system proves effective in humans, scientists hope to re-examine previously developed drug candidates that were discontinued because of adverse side effects in patients.

Results of the study have been published in Clinical Cancer Research (Nov. 15, 2006).

–Maribel Rios

REGULATIONS

Von Eschenbach Confirmed as FDA Commissioner

Washington, DC (Dec. 7)—One of the last acts of outgoing Senate Majority Leader Bill Frist (R-TN) was to push through confirmation of Andrew von Eschenbach as the official head of the US Food and Drug Administration (Rockville, MD, www.fda.gov). Frist had to invoke a seldom-used legislative procedure to overcome a number of "holds" on confirmation by fellow senators with serious grievances against the agency. But in the end, the Senate strongly endorsed FDA's new leader Dec. 7 with an 80–11 vote in favor of confirmation.

Von Eschenbach became acting head of FDA in September 2005 following the abrupt resignation of Lester Crawford from the job, and he was nominated to be commissioner in March 2006. Confirmation of the former director of the National Cancer Institute initially was delayed by Democrats angry about FDA's refusal to approve an over-the-counter version of the emergency contraceptive pill, "Plan B." More recently, other senators mounted protests over the sale of the abortifacient "RU-486" and FDA opposition to importation of drugs from overseas. Sen. Charles Grassley (R-IA) was furious over FDA's failure to provide all the information he demanded about possible fraud in clinical studies for the antibiotic, "Ketek."

The new commissioner will have to deal with these and a myriad of contentious issues as the official head of this high-profile agency, which has been attacked in recent years for lax oversight of drug safety, too-slow approval of new generic drugs, conflicts of interest among advisory committee members, and overly favorable treatment of Big Pharma. Von Eschenbach has weathered the drawn-out confirmation process by limiting his public comments to the need to spur innovation to reflect great progress in molecular biology, but he now will have to directly address these and other tough regulatory and legal issues. Inadequate agency funding and the need to renew the prescription drug user fee program are at the top of the list.

The confirmation opens the door to stability in the FDA Commissioner's Office: over the past decade, no commissioner has served for more than two years, prompting last September's Institute of Medicine report, The Future of Drug Safety: Promoting and Protecting the Health of the Public, to note that "instability in the Office of the Commissioner has been a serious problem for FDA and CDER in particular. A large, complex, science-based regulatory agency cannot perform optimally in the absence of stable, capable leadership and clear, consistent direction" (1).

Reference

1. Institute of Medicine, Board on Population Health and Public Health Practice, Committee on the Assessment of the US Drug Safety System, The Future of Drug Safety: Promoting and Protecting the Health of the Public, A. Baciu, K. Stratton, and S.P. Burke, Eds. (National Academies Press, Washington, DC, 2006), www.iom.edu/CMS/3793/26341/37329.aspx, accessed Sept. 28, 2006.

–Jill Wechsler

ANALYTICAL TECHNOLOGY

X-ray Microscopy Method Sheds Light on Nanoscale Reactions

Argonne, IL (Nov. 9)—Researchers from Argonne National Laboratory's Chemistry Division (www.anl.gov) and Xradia (Concord, CA, www.xradia.com) have developed a novel X-ray microscopy technique that allows molecular observations of the reactivity of solid surfaces at the nanometer scale, including interfacial reactions such as ion adsorption and catalytic reactions.

Combining X-ray reflection and high-resolution microscopy, the noninvasive method also permits scientists to observe sub-nanometer-sized interfacial features in real time and image the topography of a solid surface without the need for probe tips near the surface.

The technique implements the concepts of phase contrast microscopy, which allows colorless specimens or finely detailed organisms to appear more clearly at high magnifications by retarding the phase of highly reflective light from objects, such as granules, with a high refractive index. This correction is not performed with commonly used microscopy methods such as bright-field microscopy.

Funding for the research was provided by the US Department of Energy's Office of Basic Energy Sciences, and results were published in Nature Physics (2006).

–Maribel Rios

DIVESTMENT

Cardinal to Sell $1.8-Billion Contract-Services Unit

Dublin, OH (Nov. 30)—Cardinal Health (www.cardinal.com) announced plans to divest its Pharmaceutical Technologies and Services (PTS) segment, "a business that manufactures or packages 100 billion doses of medication every year for pharmaceutical and biotech firms, employs approximately 10,000 at more than 30 facilities worldwide and generates $1.8 billion in revenue," according to a company statement.

The portion of PTS slated for sale develops and manufactures oral and sterile medication in nearly all dosage forms, and holds patents for softgel and "Zydis" fast-dissolve technologies. The business "is also the largest contract packager of pharmaceuticals," according to Cardinal. The spun-out business should generate more than $300 million in earnings before interest, taxes, depreciation, and amortization, according to Cardinal's estimates.

Cardinal will retain PTS's Martindale and Beckloff Associates groups, "two businesses that support the generic pharmaceutical market." Martindale develops generic, intravenous medicines, supporting Cardinal's hospital business, and Beckloff provides regulatory consulting services, including for generic products. Combined, the retained businesses have ~400 employees in the US and UK.

The sale will help Cardinal focus on serving healthcare provider customers, such as hospitals and pharmacies, and on its generics business.

In a Nov. 30 conference call, Cardinal CEO R. Kerry Clark said that the company hopes to close the sale in the middle of 2007. He declined to say whether the company was currently in discussions with a potential buyer.

"In the coming years, Cardinal Health will focus more on our products and services that help providers improve the safety and productivity of healthcare," said Clark in the prepared statement. "While synergies clearly exist between PTS and our other businesses, we believe there is greater customer and shareholder value in the expansion of our supply-chain and medical and clinical products businesses domestically and internationally. These segments align with our core competencies and customers, and we see significant opportunities for future growth and improved return on capital."

The company expects to use proceeds of the sale to repurchase Cardinal Health shares.

–Douglas McCormick

ASEPTIC PACKAGING

Vial Defects Detected in Roche's Herceptin in Europe

London (Nov. 22)—The European Medicines Agency (EMEA, www.emea.eu.int) reports a defect in some vials of "Herceptin" (trastuzumab), the anticancer treatment by Roche (Basel, Switzerland, www.roche.com), that have been distributed in Europe. As a result, The EMEA's Committee for Medicinal Products for Human Use outlined a plan, formulated in conjunction with Roche, for visually reinspecting and replacing defective vials. The plan seeks to identify and remove defective vials while maintaining supply of the drug.

Herceptin is packaged in a 15-mL, clear, glass vial. The defect stems from a fault during the packaging process that caused cracks in the shoulders of the vials in a small percentage of cases, reports EMEA.

"There is a risk that cracked vials may lead to a loss in sterility, which can cause infections in patients. While testing indicates that the cracks have no effect on the sterility of the product, the company has been advised as a precautionary measure to reinspect the vials and replace the cracked vials," said EMEA in a press release.

Only vials packaged from March 2006 are affected by the defect. Roche received ~20 complaints of cracked vials from hospitals in France, Germany, Ireland, and the United Kingdom. In most cases, the vials broke when the flip-top cap was removed. In two cases, only cracks were reported. Following the reports, the company inspected 13,000 packaged vials and found that 1 in 1000 had a cracked bottleneck. Cracked vials may still be in circulation.

Roche has provided every hospital and treatment center using Herceptin with instructions for examining vials for cracks. Roche has further committed to ensure that all hospital reports back its findings and no hospitals use any affected vials found. Only batches distributed before November 2006 are affected.

The EMEA asked Roche to submit weekly status reports on the progress of the recall activities and the numbers of defective vials identified, pending resolution of the situation. Inspections of specific good manufacturing practices also will be conducted.

–Patricia Van Arnum

STANDARDS

USP Opening Office and Laboratory in China

Rockville, MD (Dec. 4)—The US Pharmacopeia (USP, www.usp.org) plans to open a 10,500-ft2 site in Shanghai in February 2007. The facility, in Shanghai's Zhangjiang Hi-Tech Park, will support collaborative testing, technical assistance, customer service, and training. John Hu, PhD, international vice-president, China currently oversees the site and projects and the hiring of approximately 15 people to work in the facility.

The USP-China facility is the latest of a series of USP activities in China. In 2005, USP signed a Memorandum of Understanding with the Chinese Pharmacopoeia and the National Institute for the Control of Pharmaceutical and Biological Products.

The Shanghai office will be the organization's second international facility. USP-India Limited opened an office-and-laboratory complex in Hyderabad in February 2006. The organization also operates a European sales office in Basel, Switzerland.

"USP's site in China further demonstrates USP's commitment to working globally to ensure good pharmaceutical care for all," said USP executive vice-president and CEO Roger L. Williams, MD, in a prepared statement. "The facility will help strengthen our relationships with Chinese manufacturers and government agencies who are similarly dedicated to promoting the availability of good quality medicines."

–Douglas McCormick

GSK to Acquire Antibody Developer Domantis for $454 Million

London (Dec.8)—GlaxoSmithKline PLC (GSK, www.gsk.com) agreed to acquire Domantis Ltd. (Cambridge, UK, www.domantis.com), a developer of antibodies, for £230 million ($454 million) in cash.

Domantis will become part of GSK's Biopharmaceutical Center of Excellence for Drug Discovery (CEDD).Domantis will continue to operate from research and development laboratories in Cambridge,United Kingdom.

Domantis specializes in domain antibodies (dAbs),therapeutic molecules that have the benefits of both small molecules and conventional antibodies.dAbs are small in size and highly stable,which allow for a choice of therapeutic formats, delivery formulations,and manufacturing options.Similar to human antibodies, dAbs are designed to have specificity and high affinity for the biological target of interest.dAbs may be administered in inhaled,topical,and potentially oral formulations as well as by injection and infusion.

Ian Tomlinson,cofounder of Domantis,will continue to manage the company's Cambridge laboratories and will serve as a GSK executive in the Biopharmaceu-tical CEDD.

–Patricia Van Arnum