April 2007

April 2, 2007
Pharmaceutical Technology Editors
Pharmaceutical Technology
Volume 31, Issue 4

BIO Raises Concerns About Studies on Follow-On Biologics; Green Chemistry Reduces Costs and Waste; Novel Polymer–DNA Delivery System; WHO Stresses Lack of Capacity for Pandemic Flu Vaccine; EGA Concerned About Regulatory Workload in Approving Generics

BIOLOGICS

BIO Raises Concerns About Studies on Follow-On Biologics

Washington, DC (Feb. 22)—The Biotechnology Industry Organization (BIO, Washington, DC, www.bio.org) criticized two separate studies respectively released by the Pharmaceutical Care Management Association (PCMA, Washington, DC, www.pcmanet.org) and Express Scripts (St. Louis, MO, www.express-scripts.com) regarding the cost savings, interchangeability, and market penetration of follow-on biologics.

BIO criticized the studies as legislative debate for establishing a regulatory pathway for approval of follow-on biologics continued. Express Scripts cited savings of $71 billion over 10 years and $3.5 billion in the first year if a regulatory pathway for approving generic biologic-based products is established. The study may be found at http://www.express-scripts.com/ourcompany/news/outcomesresearch/onlinepublications. The PCMA study also analyzed potential cost savings and can be found at http://www.pcmanet.org/newsroom/2007/Documents/EN%20Paper%20on%20Follow-on%20Biologics%20Jan.%202007.pdf.

"As a result of numerous flawed assumptions and the lack of any credible evidence to support these alleged savings, we believe these studies should be rejected as unscientific and unreliable," said BIO President and CEO Jim Greenwood in a prepared statement.

"This debate should be focused on and driven by credible science, fact-based studies, and patient safety," he continued. "These studies fail to meet these standards. They cannot be relied on in lieu of a more rigorous analysis. Congress should recognize these flaws and misleading assumptions and reject these studies as it evaluates proposals regarding follow-on biologics."

Among its criticisms, BIO said that assumptions of interchangeability of biologics were faulty and resulted in overestimates of potential cost savings. The BIO study pointed out that the US Food and Drug Administration (Rockville, MD, www.fda.gov) has not yet determined how interchangeability can be established for complex proteins.

BIO also criticized the PCMA study for overestimating the market penetration of follow-on products. "The PCMA study assumes that for every biologic that comes off patent, there will be an associated follow-on product," said BIO. "There is no credible evidence to suggest that it is scientifically possible to develop a follow-on for every biologic that is currently on the market. Further, many biologics have a limited market, and therefore, it likely will be economically less attractive for companies to pursue manufacturing of follow-ons for many of these products."

BIO's full response to the studies may be found at http://www.bio.org/healthcare/followon/20070222.pdf.

-Patricia Van Arnum

GENERICS

Congressional Bill Establishes Biogenerics Approval Path

Washington, DC (Feb. 14)—A congressional team has reintroduced the "Access to Life-Saving Medicine Act," which establishes a process through which the US Food and Drug Administration (FDA, Rockville, MD, www.fda.gov) can approve generic copies of biologic drugs. Some congressional leaders are calling for the bill to be attached to the Prescription Drug User Fee Act, slated for reapproval this year, but no plans for this have been set. If approved, the act would provide FDA with the process for comparing biogenerics and the respective innovator drugs without the need for the generics firm to conduct clinical trials.

The bill was proposed during a previous session of Congress, but because the bill was not passed at the end of the session, it had to be reintroduced.

Under this law, FDA would have the "discretionary authority in selecting certain studies and tests needed to approve biogenerics or follow-on drugs."

On his Web site, Rep. Henry Waxman (D-CA) stated, "Introducing fair competition for biotech drugs is essential to keep life-saving treatments affordable. "The Generic Pharmaceutical Association also has stated its strong support of the bill, saying it will provide an abbreviated approval pathway for safe, effective, and affordable biogenerics to consumers.

-Maribel Rios

INGREDIENTS

Green Chemistry Reduces Costs and Waste

University researchers are investigating green-chemistry applications that could reduce costs and improve efficiencies for pharmaceutical manufacturers. Ecologically sustainable techniques being studied could save industry money by reducing pollution and waste, simplifying manufacturing processes, using fewer resources, and improving product yield.

Catalysts and separations

Separations can account for as much as 80% of the cost of chemical processes, and the solvents used often harm the environment. Homogeneous catalysts, however, could be recovered and recycled easily and safely using solvents called gas-expanded liquids. Professor Charles A. Eckert, PhD, of the Georgia Institute of Technology (Atlanta, GA, www.gatech.edu) explains that gas-expanded liquids are miscible gas–liquid mixtures that allow scientists to perform reactions at low pressures. Researchers first cause a reaction in a homogeneous solution and then add a gas to the solution. The gas splits the solution into two phases to "separate the product in one phase and the catalyst in the other phase for reuse," Eckert says. Because this technique allows catalysts to be recovered, it is economical and minimizes waste.

Scientists could reduce waste further by using smart solvents. Smart solvents can be modified to replace less-efficient solvents with undesirable characteristics. According to Eckert, scientists can "turn a switch, literally," to cause smart solvents to exhibit a step change in properties. Eckert's research team created a smart solvent with properties similar to those of dimethyl sulfoxide, but with a low boiling point. Because the solvent, called piperylene sulfone, is easy to separate from a product and reuse, its application could lower costs and minimize waste.

Metabolic and biochemical engineering

Active pharmaceutical ingredients (APIs) can be found in nature, but natural APIs may be present only in low concentrations. Extracting them is often difficult, expensive, and disruptive to sensitive ecosystems. Synthesizing the APIs is an alternative, but the process can be complicated and expensive.

Certain organisms produce enzymes that catalyze reactions yielding APIs. Saving the organisms to reuse catalytic enzymes would reduce the costs of drug synthesis. Tonya Peeples, professor at the University of Iowa (Iowa City, IA, www.uiowa.edu), seeks to use biochemical engineering to develop solvent-tolerant microbial systems for aerial oxidations and aromatic compounds. Solvent-tolerant organisms could withstand organic solvents and could catalyze more reactions to increase yield.

Synthesizing pharmaceutical intermediates

Manufacturers routinely look for stategies to improve production efficiency. One option is to increase yield. Jack Rosazza, professor emeritus of the University of Iowa, says a research team is pursuing reactions that might produce pharmaceutical intermediates on a large scale. Researchers are using complex enzymes called dioxygenases to produce chiral intermediates such as alpha naphthol with pharmaceutical applications. "What we develop with alpha naphthol," Rosazza says, "should be applicable to almost any aromatic material that could serve as a potential feedstock for making pharmaceutical intermediates." Improved chemical reactions could save time and costs by increasing the efficiency of synthesis.

Oxidations can be used to produce pharmaceutical intermediates. These reactions generally are avoided, however, because they generate pollution and require dangerous reagents such as explosive peroxyacids. Professor Horacio Olivo of the University of Iowa is conducting research that gives manufacturers a safe way to perform oxidations. Olivo uses lipases to generate peroxyacids in situ, so chemists do not have to handle them. The lipases then can be recycled and reused. In addition, Olivo uses ethyl acetate as a solvent for oxidations. Ethyl acetate is environmentally benign and does not require cleanup or special handling like chlorinated solvents do. Olivo's techniques greatly improve safety, reduce pollution, and involve reusable materials. All of these advantages may translate into significant cost savings for manufacturers.

-Erik Greb

DRUG DELIVERY

Nanotubes Show Drug-Delivery Potential

London (Feb. 1)—Researchers at the University of London's (www.lon.ac.uk) School of Pharmacy have chemically modified carbon nanotubes to enable them to enter human cancer cells. Crossing biological barriers is the key step to using nanotubes as drug-delivery mechanisms.

The nanotubes were modified by various functional groups and incubated with live cells, including mammalian, bacterial, and fungal cells. The study showed that the various types of nanotubes showed "a capacity for cellular uptake and cross-intracellular movement without causing cell death," according to a university press release.

Kostas Kostraelos, deputy head of the Centre for Drug Delivery Research, led the research team. He explains that the nanotubes moved through the cells either as individual nanotubes or as small bundles, acting as "nanoneedles" into the plasma membrane without damaging or killing the cell.

The team plans to study the behavior of the nanotubes with various cell types and conduct toxicity studies.

-Maribel Rios

DRUG DELIVERY

Novel Polymer–DNA Delivery System

Enschede, Netherlands (Feb. 26)—Scientists from the University of Twente's MESA+ Institute for Nanotechnology (www.utwente.nl/en) have designed a novel delivery system by combining synthetic iron-containing polymers with DNA macromolecules.

When the polymer is wrapped around the DNA, they are bonded electrostatically, and the process generates spherical, porous structures capable of carrying and delivering drugs and DNA fragments. The pores are larger than 50 nm.

Local delivery is possible using small molecules to oxidize the iron and break the bond between the DNA and polymer. This process also can be used to free DNA fragments from the sphere and apply them in gene therapy.

Company Notes

The research team, led by professors Julius Vancso (MESA+ Institute for Nano-technology) and Helmuth Mohwald (Max Planck Institut fFCr Kolloid und GrenzflE4chenforschung, Golm, Germany, www.mpikg-golm.mpg.de), published their study in the Feb. 26 issue of Angewandte Chemie International Edition.

-Maribel Rios

VACCINES

WHO Stresses Lack of Capacity for Pandemic Flu Vaccine

Geneva, Switzerland (Feb. 16)—During a two-day meeting, the World Health Organization (WHO, www.who.int/en) announced "encouraging progress" in the development of a pandemic influenza vaccine. Nonetheless, with a current capacity estimated at less than 400 million doses per year of the trivalent seasonal influenza vaccine, WHO emphasized that the industry still "lacks the manufacturing capacity to meet potential pandemic influenza vaccine demand."

Currently, 16 manufacturers from 10 countries are advancing prototype vaccines against the H5N1 virus, and more than 40 clinical trials have been completed or are ongoing.

More than 100 influeza-vaccine experts attended the meeting, reviewing information on more than 20 projects involved in H5N1 vaccine development.

Company Notes

As part of its 2006 global influenza action plan, supported by a $10-billion funding by the United States, WHO is working with several vaccine producers to establish vaccine-production facilities in developing countries.

-Maribel Rios

DRUG APPROVAL

EGA Concerned About Regulatory Workload in Approving Generics

Brussels (Feb. 13)—The European Generic Medicines Association (EGA, www.egagenerics.com) raised concerns about what it terms "the serious lack" of resources available to member states in the European Union (EU) to deal with the regulatory workload and bottleneck in new registrations caused by the new Decentralized Procedure (DCP) for approving drugs in Europe.

While welcoming the DCP, EGA raised issues about delays in the regulatory approval process. "The EGA has welcomed the introduction of the Decentralized Procedure," said Greg Perry, director general of EGA, who spoke at the 6th Annual EGA Regulatory and Scientific Affairs Conference in Brussels in mid-February. "It is a great improvement to the marketing authorization process compared to the older Mutual Recognition Procedure."

The DCP eliminated the first national approval step from the mutual-recognition procedure and the associated delays, said EGA. This change resulted in fewer "rounds of time-consuming questions, and all the serious questions are raised together instead of at various times in the process," said EGA.

Roughly 300 generic-medicines applications were filed under the DCP in 2006, according to EGA. In 2006, 70% of the procedures completed under the DCP (40 out of 57) were for generic products.

EGA said that the generic drug industry is the leading user of DCP, and its use of the procedure will increase as patents on reference products continue to expire, new member states enter the EU, and the governments of EU member states seek to increase the use of generic drugs.

To date, only nine of 27 member states have indicated a willingness to act as a Reference Member State (RMS) for applications, and EGA said it can take as much as one year to receive a confirmation that a member state will act as the RMS.

To address that problem, the EGA proposed an increase in work sharing between agencies in areas such as variations, pharmacovigilance assessment, reducing the repetition of assessments, and a move to a more harmonized EU approach. EGA also asked companies to keep agencies better informed of any changes in their plans to submit applications.

-Patricia Van Arnum

WARNING LETTER

FDA Issues Warning Letter to Bell-More Laboratories

Rockville, MD (Jan. 5)—The US Food and Drug Administration (www.fda.gov) issued a Warning Letter to Bell-More Laboratories (Hampstead, MD, www.bell-more.com) following the agency's August 2006 inspection of the company's Hampstead pharmaceutical facility. During the inspection, the agency documented deviations from current good manufacturing practices that caused Bell-More's finished products to be adulterated. The agency asserted that Bell-More's inadequate controls and documentation create the potential for the migration of potent compounds throughout the facility.

The deviations enumerated in the letter include the failure to establish defined areas or other control systems to prevent contamination or mixups for handling and manufacturing potent compounds (21 CFR 211.42[c]); the failure to keep records for the maintenance, cleaning, and sanitizing of equipment (21 CFR 211.67[c]); the failure to adequately validate cleaning procedures for manufacturing and packaging equipment (21 CFR 211.67[a]); the failure to establish and follow procedures to prevent microbiological contamination (21 CFR 211.113[b]); the failure to establish written procedures for production and process control designed to ensure drug product identity, strength, quality, and purity (21 CFR 211.100[a]); and the failure to establish sampling plans, test procedures, and laboratory control mechanisms for testing the finished-product sterile evacuated vials (21 CFR 211.160[a]).

Company Notes

Bell-More Laboratories is a contract pharmaceutical manufacturer specializing in the custom lyophilization of small-volume parenteral drugs in vials and syringes.

-Erik Greb

WARNING LETTERS

Warning Letters Demand Stop to Unapproved Ergotamine Manufacture and Distribution

Rockville, MD (Mar. 1)—Sending Warning Letters to eight manufacturers and 12 distributors, the US Food and Drug Administration (www.fda.gov) ordered a stop to the manufacture and distribution of unapproved drug products containing ergotamine tartrate. The action does not affect FDA-approved products containing ergotamine. Most of the companies receiving the letters have omitted from their drugs' labeling a critical warning regarding the potential for "serious, possibly fatal, interactions with certain other drugs," including potent CYP 3A4 inhibitors, according to the agency.

"Unapproved drugs pose real risks to the American public," said Steven Galson, MD, director of FDA's Center for Drug Evaluation and Research, in a public statement. "It is central to our mission to ensure a safe and effective drug supply for the American public."

FDA estimates that less than 2% of prescribed drugs on the market are unapproved and continues to combat the marketing of unapproved drugs through its Unapproved Drugs Initiative.

Companies receiving the Feb. 26 Warning Letters are Actavis Totowa LLC; Anabolic Laboratories; Bio Pharm Inc.; Breckenridge Pharmaceutical Inc.; Centrix Pharmaceutical Inc.; DRX Pharmaceutical Consultants Inc.; DSC Laboratories; Excellium Pharmaceutical Inc.; Ferndale Laboratories, Inc.; IVAX Pharmaceuticals Inc. (formerly Goldline Laboratories Inc.); Kaiser Foundation Hospitals; Lini Inc.; Murfreesboro Pharmaceutical Nursing Supply; Nucare Pharmaceuticals, Inc.; Qualitest Pharmaceuticals, Inc; Sandoz, Inc.; The Harvard Drug Group LLC (formerly Major Pharmaceuticals Inc.); United Research Laboratories Inc. and Mutual Pharmaceutical Company; and Vintage Pharmaceuticals Inc.

-Maribel Rios

RESTRUCTURING

Bayer HealthCare Plans 6100 Job Cuts Worldwide

Berlin (Mar. 2)—Estimating it would save approximately EUR 700 million ($918 million), Bayer HealthCare (www.bayerhealthcare.com) will integrate the activities of its Pharma division with those of the former Schering AG, Germany. The company confirmed the action would eliminate nearly 6100 jobs worldwide, including 1000 in the United States and 3150 in Europe. Some 1850 production positions and 1400 global research and development functions will be cut by 2009.

Bayer Healthcare officials state the action is intended to "create slimmed-down and efficient structures and do away with double functions and overlaps."

"We said right from the start of the integration that job cuts would be necessary in order to achieve the synergy targets," said Werner Wenning, chairman of the Bayer AG Group Management Board and the Supervisory Board of Bayer Schering Pharma. "These essential streamlining measures are to be fairly implemented in a socially acceptable process, balanced across the globe. This includes the reduction of the number of locations, cutting down on structural and personnel overcapacity, the concentration of research and development activities, as well as the harmonization of structures and processes in marketing and administration."

-Maribel Rios