February 2006

February 2, 2006
Pharmaceutical Technology Editors

Pharmaceutical Technology, Pharmaceutical Technology-02-02-2006, Volume 30, Issue 2

Preliminary results from a clinical trial of Sanofi Pasteur's (Lyon, France, www.sanofi.com) H5N1 prepandemic influenza vaccine indicate the vaccine is safe and was well-tolerated in 300 healthy volunteers. This study is the first trial of an H5N1 prepandemic influenza vaccine candidate that compared vaccines with and without adjuvants.

INFLUENZA PREPAREDNESS

H5N1 Flu Vaccine Proven Safe

Preliminary results from a clinical trial of Sanofi Pasteur's (Lyon, France, www.sanofi.com) H5N1 prepandemic influenza vaccine indicate the vaccine is safe and was well-tolerated in 300 healthy volunteers. This study is the first trial of an H5N1 prepandemic influenza vaccine candidate that compared vaccines with and without adjuvants.

The 30 μg-dose vaccine (with adjuvant) is given in two doses, but the company also noted that immune responses were detected in several volunteers who received smaller doses. Follow-up studies still under development will be performed using a scaled-up production method that will mimic the manufacturing scale used during a true pandemic.

–Kaylynn Chiarello-Ebner

INFLUENZA PREPAREDNESS

Sanofi Pasteur and BD Team Up to Produce Microneedle Vaccines

Sanofi Pasteur, the vaccines business unit of Sanofi-Aventis (Lyon, France, en.sanofi-aventis.com), will collaborate with BD (Franklin Lakes, NJ, www.bd.com) to develop microneedle vaccines with BD's patented "Micro-Delivery System."

Microneedles have generated much excitement among drug delivery experts as a painless, effective way to deliver vaccines and injectable drugs to patients. Because the needles are micro-sized (in the 100–1000 μm range), they are small enough to deliver macromolecules without reaching the nerves that cause pain. And, because the microneedles target the top capillary-rich layers of the skin, researchers anticipate that the vaccines will be adsorbed into the blood quickly and induce a better immune response than traditional vaccines.

At present, BD and Sanofi Pasteur are in human clinical trials with a micro-delivered influenza vaccine and will continue to test the delivery system on other vaccines. Microneedles will be prefilled with vaccine for easy administration. Said Alexandre Conroy, president of BD's Medical–Pharmaceutical Systems, in an official release, "In practical terms, the BD Micro-Delivery System has the potential to increase a patient's acceptance as well as enable vaccination of more people with less vaccine."

–Kaylynn Chiarello-Ebner

Recall: Bedford Laboratories

Bedford Laboratories, a division of Ben Venue Laboratories, Inc. (Bedford, OH, www.benvenue.com), has voluntarily recalled one lot of "Methotrexate" for injection (preservative free), USP 1 g/vial (NDC55390-143-01), lot no. 859142, exp. 09/07, because the active drug substance used to manufacture the lot contained low levels of ethylene glycol. Preservative-free Methotrexate is the only acceptable formulation for intrathecal administration. Healthcare professionals and suppliers should not distribute these vials and should contact Bedford Laboratories for return instructions.

INFLUENZA PREPAREDNESS

New Bill Could Waive Vaccine Maker Liability

On Dec. 19, the House approved a Republican-initiated list of liability protections for vaccine makers.

To make mass quantities of pandemic vaccines, drug companies say they need protection against lawsuits if the vaccines cause dangerous side effects. The waiver under debate offers injured victims little if any compensation in the event of a pandemic outbreak, except in the case of willful misconduct (as determined by the secretary of the Department of Health and Human Services). This section can be waived in certain emergencies.

Meanwhile, House Democrats who oppose this waiver are putting together a counter-plan. They claim the unprecedented, broad waiver offers the public no protection and will make first responders and others hesitant to use pandemic vaccines. Democratic lawmakers such as Henry Waxman (D-CA) and Nita Lowey (D-NY) are proposing another plan that would provide compensation and a means to sue the government in the event the vaccines cause harm.

The waiver is attached to a pending Department of Defense appropriations bill (Biodefense and Pandemic Vaccine and Drug Development Act of 2005) that could pass before the end of the year.

–Kaylynn Chiarello-Ebner

INFLUENZA PREPAREDNESS

Roche Selects 12 Potential Manufacturing Partners for Tamiflu

Roche has established a shortlist of 12 potential partners that met the company's criteria for helping to enhance the global supply of its "Tamiflu" (oseltamivir) neuraminidase inhibitor. Although the names of the companies were not released, Roche already has granted its first regional sublicense to China's Shanghai Pharmaceutical Group (Shanghai, China, www.pharm-sh.com.cn).

Separate reports have confirmed that the list includes generics manufacturers Teva Pharmaceutical Industries (Israel, www.tevapharm.com) and Mylan Pharmaceuticals (Canonsburg, PA, www.mylanpharms.com).

Roche evaluated nearly 200 requests from manufacturers hoping to take part in the company's Global Tamiflu Supply Network and help meet the 300 million capacity target of Tamiflu by 2007. Candidates were assessed for their ability to increase the global availability for pandemic use without negatively affecting Roche's own production capability. Criteria included the ability to contribute to critical manufacturing steps (e.g., bio fermentation, azide chemistry, and combined alcohol granulation and capsule filling) or the ability to fully produce Tamiflu in substantial quantities through contract manufacturing using approved Roche processes and technology transfer and by means of issued sublicenses or deblocking licenses.

The 12 potential partners will be invited for further "in depth negotiations," according to the company.

In a company statement, William M. Burns, CEO Roche Pharma Division, explained, "As yet we have not identified anyone who could significantly speed up the agreed delivery timelines for the first half of 2006, but we have been able to identify partners to insure against breakdowns in supply and partners to broaden geographic coverage. Based on the current orders we have received from governments around the world, our capacity to produce 300 million treatments by 2007 is significantly ahead of demand."

Meanwhile, Roche is negotiating with local partnerships in Asian countries, especially Taiwan, Vietnam, Korea, Malaysia, and India, and emphasized its willingness to discuss supplying government orders in Thailand, Philippines, and Indonesia, where Tamiflu is not patent protected.

Tamiflu is designed to be active against all clinically relevant influenza viruses by blocking the action of the neuraminidase enzyme on the surface of the virus. When neuraminidase is inhibited, the virus cannot spread to and infect other cells in the body. In studies involving animal models, Tamiflu was shown to be effective against the currently circulating avian H5N1 strain.

–Maribel Rios

GUIDANCE

FDA Issues Dispute-Resolution Guidance

On Jan. 11, the US Food and Drug Administration (Rockville, MD, www.fda.gov) issued its Guidance for Industry: Formal Dispute Resolution: Scientific and Technical Issues Related to Pharmaceutical CGMP as part of its initiative on Pharmaceutical CGMPs for the 21st Century.

The 13-page guidance for human and veterinary drug makers (both small molecule and biological) outlines a two-tier process for addressing disagreements over Form 483 inspection observations. Increasingly complex processes, coupled with last year's Federal District Court decision, in which a federal court found for a Utah medical device company in its dispute with FDA over CGMP interpretations, may prompt more regulated manufacturers to challenge inspection reports with which they disagree.

The guidance states: "When a scientific or technical issue arises during an inspection, we recommend that the manufacturer initially attempt to reach agreement on the issue informally with the investigator."

If the dispute cannot be resolved, the manufacturer should begin a formal resolution request within 30 days of receiving the Form 483.

At Tier One, the dispute is taken to FDA's Office of Regulatory Affairs through the district office, and will then involve the appropriate FDA center (i.e., the Center for Drug Evaluation and Research, the Center for Biological Evaluation and Research, or the Center for Veterinary Medicine). The Agency then has another 30 days in which to respond (though extensions are permitted).

If the drug maker disagrees with the Tier-One decision, it can then make a Tier-Two request, for review by a Dispute Resolution Panel (part of the FDA Commissioner's Office). The panel includes representatives from each of the program centers and from the Office of Regulatory Affairs, plus the head of the agency's Council on Pharmaceutical Quality. Officials involved in the Tier- One decision will be excluded from the panel. The panel can call for "internal and external experts" and for legal advice. The panel has 90 days in which to meet to review the dispute and then 30 days in which to issue a response.

–Douglas McCormick

SECURITY

Pfizer Combats Counterfeiters with Item-Level RFID Labels

Pfizer (New York, NY, www.pfizer.com) took a big leap in combating the infiltration of counterfeit product into the supply chain when it announced that all bottles of its anti-impotence drug "Viagra" will soon include a radio frequency identification (RFID) label (tag) that allows distributors to verify the product's authenticity.

Peggy Staver, Pfizer's director of trade product integrity, told Pharmaceutical Technology that the product could be scanned using RFID readers at any point along the supply chain, right up until the point of dispensing. Scanned data is sent to Pfizer instantly where the product is authenticated. Staver explains that although the RFID chips are affixed to every product at the bottle level and the case and palate level, Pfizer is not pressuring distributors and pharmacists selling Viagra to immediately purchase RFID scanners. "This is just another safety measure that we offer to help make the supply chain safer," Staver says.

Two years ago, retail juggernaut Wal-Mart (Brisbane, CA, www.walmart.com) demanded that its top 100 distributors become RFID-ready by 2005. The retail industry is using the technology more for efficient inventory tracking than for security measures, however. Although it is slow to jump on the RFID bandwagon, US Food and Drug Administration gave the pharmaceutical industry its approval to begin piloting the new technology in 2004.

Rather than use basic prewritten RFID tags that offer zero ability to modify the digital license plate encoded on the chip, Pfizer has opted for a "TAGSYS" label that can be written directly on the line, thus giving the company full control of the information on each bottle. Staver says these tags also were chosen because it gives the company more flexibility as RFID technology expands.

At this time, Pfizer is not using RFID to track and trace product through the supply chain. As the technology becomes more widely adopted, however, Pfizer says it would consider using RFID's expanded features to further boost the company's anticounterfeiting capabilities.

Staver also insists that after the product is dispensed to the customer, there is no way to further track the drug or obtain personal information from the customer.

"The Viagra project is a major milestone for item-level RFID in the pharmaceutical industry and can be viewed as a significant precursor to establishing the long anticipated e-Pedigree," said Elie Simon, CEO of TAGSYS, in an offical statement. "By tagging individual bottles of Viagra, Pfizer is taking some very positive steps to further secure the pharmaceutical supply chain."

–George Koroneos

OBITUARY

Hubert J.P. Schoemaker, Centocor Founder

Hubert J.P. Schoemaker, founder of Centocor (Horsham, PA, www.centocor.com) and Neuronyx (Malvern, PA, www.neuronyx.com), died on New Year's Day at his home in Paoli, Pennsylvania. He was 55 and had been diagnosed with medulloblastoma, the brain cancer that finally caused his death, in 1994.

As his obituary in the Jan. 4 Philadelphia Inquirer (http://www.philly.com/mld/philly/news/obituaries/13543201.htm) noted, "As chairman of Centocor and cofounder of what later became the Eastern Technology Council, Dr. Schoemaker mentored many executives at area biotech firms, and helped elevate biotechnology into a growth industry in Southeastern Pennsylvania. He downplayed his role in shaping the industry, and instead credited Centocor's employees, legislation that commercialized science, Wall Street investors, and America's entrepreneurial spirit."

From biotechnology's earliest days, Schoemaker was, nonetheless, very visible as a spokesman for both Centocor and the industry. He helped found Centocor in 1979, piloted the company through the collapse of its sepsis therapy in 1992, served as chairman while the company recovered and became profitable, and left only when Johnson & Johnson bought Centocor in 1999.

At that point, Schoemaker founded Neuronyx to use "adult bone marrow-derived stem cells to repair, regenerate and remodel tissue in acute and chronic disease settings."

In 2005, Schoemaker received Pennsylvania Bio's lifetime achievement award, which has now been named after him.

Schoemaker was born in the Netherlands and moved to the United States in his late teens, earning his bachelor's degree in chemistry from the University of Notre Dame and his doctorate from the Massachusetts Institute of Technology. He is survived by his wife, Anne Faulkner Schoemaker, his parents, Paul and Betty Schoemaker; three daughters Maureen, Katherine, and Anne; a son, Matthew; a stepson, Jonathan Saruk; a brother; three sisters; and his former wife, Ann McKenzie.

–Douglas McCormick

CONSOLIDATION

Bristol-Myers Squibb to Cut Costs by $500 Million

Delays in developing the Type 2 diabetes medication "Pargluva" (muraglitazar) have forced Bristol-Myers Squibb (BMS, New York, NY, www.bms.com) to reevaluate its productivity plans to reach a minimum of $500 million in savings by 2007.

So far, the company has cut costs by an estimated $200 million in 2004 and 2005 by reorganizing its US and European sales forces, restructuring its pharmaceutical development division, and outsourcing its information technology division.

"We continue to examine our operating model to focus resources and work on high-value priorities," stated Peter R. Dolan, chief executive officer of BMS in a release. "We intend to simplify and streamline business processes, governance and decision-making, and we expect to build new capabilities to execute our strategy over the long term."

According to the company, "Pargluva" will not contribute to the company's near-term revenue and earnings. The drug was put on hold in October after FDA officials notified the company, and its collaborator Merck, that it would require substantial safety data before the drug could be put on the market. With fears that the drug would take approximately five years to approve, BMS said that it has chosen to look at other options and might even terminate the product's development.

BMS did not specify where cuts would be made, but noted that the number of sales representatives had been reduced by 30% over the past five years. "Now that Pargluva will not be part of the portfolio in the near term, the company is considering a range of options to utilize this freed up capacity within the sales force," the release stated.

–Douglas McCormick

WARNING LETTER

Nephron Pharmaceuticals

On Dec. 20, the US Food and Drug Administration posted a Warning Letter issued Sept. 28 to Nephron Pharmaceuticals Corp. (Orlando, FL, www.nephronpharm.com) by the agency's Florida District Office (Maitland, FL).

The warning cited the respiratory therapy company for failing to adequately report postmarketing adverse drug experiences (PADEs) and for lapses in current good manufacturing practice (CGMP) in the production of albuterol sulfate inhalation solution, ipratropium bromide inhalation solution, racepinephrine inhalation solution, and sodium chloride inhalation solution.

The cited CGMP deficiencies included: lack of written provisions for reviewing complaints; failure to investigate batch failures or discrepancies; failure to establish process controls for identity, strength, and purity; deviations from established specifications without justification; and lack of calibration and inspection records for manufacturing equipment.

FDA's warning letter indicated that the company's May 25 response "appears to be adequate," but also said, "we are concerned that your firm may not fully understand the role of the quality control unit in your overall manufacturing process."

–Douglas McCormick

REGULATIONS

Schering-Plough Meets FDA Deadline for CGMP Improvements

Schering-Plough (Kenilworth, NJ, www.sch-plough.com) met a Dec. 31 deadline to revamp its current good manufacturing practices, as mandated by the US Food and Drug Administration in a 2002 consent degree.

According to the company, Schering-Plough completed all of the 212 significant steps and 30 validation actions required by the FDA, and is awaiting approval by the agency and third-party certification after an upcoming review process.

It has taken nearly three-and-a-half years for Schering-Plough to revalidate and work out deficiencies in their manufacturing plants that led to $500 million in fines and the suspension of approximately 70 products.

Safety Alert: BacT/ALERT System Users

FDA is informing the healthcare community about a database corruption situation that may lead to a failure to report positive cultures or cause a delay in appropriate patient therapy when using the "BacT/VIEW" data management feature of bioMérieux's (Marcy l'Etoile, France, www.biomerieux.com) "BacT/ALERT" system. Database corruptions can interrupt communication between the BacT/VIEW computer and a site's laboratory information management system–laboratory information system (LIMS–LIS). Although this type of corruption will not affect the accuracy of bottle results, it can delay the transmission of these results to a site's LIMS–LIS system.