October 2005

GUIDANCE

New Impurities Guidance May Speed Generic Approvals

The US Food and Drug Administration (Rockville, MD, www.fda.gov) released a new draft guidance that may speed generic approvals. The guidance, ANDAs: Impurities in Drug Products, describes the degradation-product information that generic drug manufacturers should include in their abbreviated new drug applications (ANDAs). This clarification, FDA officials say, will help companies submit the correct information, thus increasing the likelihood that their generic drugs will be approved, and approved more quickly.

"Deficiencies related to impurity specifications probably occur more often than any other deficiency in applications we see," says Gary Buehler, director of FDA"s Office of Generic Drugs (OGD). Those deficiencies result in a lot of "back-and-forth" discussions, Buehler says, between the agency and the sponsor company. Such dialogue means a longer review—often months longer—and delayed approval.

Buehler says that the new guidance will help reduce those discussions. "Our intention in putting out this guidance is to provide more predictability to the generic industry as to how they should prepare their applications," he says.

The draft guidance helps manufacturers understand which degradation products they should list in their ANDAs, how to set acceptance criteria, and what thresholds and procedures to apply when qualifying degradation products. The new guidance applies to generic drugs the guidelines established in the International Conference on Harmonization's Nov. 2003 guidance, Q3B(R) Impurities in Drug Products. "We want to make sure the policy for generic drugs is the same as [the policy for] innovator drugs," says Lawrence Yu, director for science at OGD.

Buehler says the guidance will also help ensure consistency among the 11 teams in OGD. "Because we hadn't clearly spelled out our policies with respect to impurities, we had difficulty sometimes with the interpretation of [those impurities] from division to division," he explains. "This gives [manufacturers] a clearer idea of what we would expect and also gives our own reviewers a clearer idea of what the office expects with respect to evaluating applications."

In some areas, the new guidance sets stricter standards for generic manufacturers, because some Q3B(R) thresholds are lower than the standards set in United States Pharmacopeia monographs, particularly for unspecified and unknown impurities. Nonetheless, Buehler and Yu don't expect a lot of industry comments on the draft. "The Office of Generic Drugs has been communicating with stakeholders and industry, so I think the industry will understand the approach and welcome a clear policy for impurities in generic drugs," says Yu.

–Laura Bush

MANUFACTURING

Improving Manufacturing Science Is Key, According to CDER Report

The FDA's Center for Drug Evaluation and Research (CDER, www.fda.gov/cder, Rockville, MD) issued its 2004 report to the nation, citing the center's key initiatives: improving the science of drug manufacturing, streamlining the path for developing new drugs, and improving methods for identifying and analyzing drug safety issues.

The report says that the center's overhaul of the pharmaceutical good manufacturing practices "encourages manufacturers to modernize their methods, equipment, and facilities to eliminate both production inefficiencies and undue risks for consumers." It also says the risk-based approach to inspections makes "better use of limited resources."

The 66-page report, Improving Public Health through Human Drugs, says CDER developed initiatives to improve drug safety, protect against bioterrorism, and accelerate drug development while maintaining its performance in reviewing new drugs and overseeing the safety of marketed drugs. During 2004, CDER approved 119 new medicines and 380 generic versions of existing drugs, and evaluated more than 400,000 reports of adverse drug events, including more than 20,000 submitted directly by individuals.

–Laura Bush

FDA

FDA Proposes Question-Based Review System for Generics

The US Food and Drug Administration's Office of Generic Drugs (Rockville, MD, www.fda.gov) is developing a question-based review system for its chemistry, manufacturing, and controls (CMC) evaluation of abbreviated new drug applications.

According to the agency's Aug. 31 white paper, the new "Question-Based Review (QbR) for Generic Drugs: An Enhanced Pharmaceutical Quality Assessment System," approach will focus on critical pharmaceutical quality attributes and is a practical implementation of the principles outlined in the agency's "CGMPs for the Twenty-First Century" and process analytical technology initiatives. The new system, the agency says, will close the gap between the "desired state" for pharmaceutical quality and the agency's existing CMC review practice.

Figure 1: ANDA submissions. Source: Lawrence X. Yu, "Question-Based Review for Generic Drugs: An Enhanced Quality Assessment System," presented at the GPhA Technical Committee Meeting, June 29, 2005.

The new system also will make it easier for generic-drug manufacturers to improve their manufacturing processes after approval (see "FDA Lowers Barriers to Process Improvement").

This October, members of the Office of Generic Drugs will make presentations at several industry meetings to explain the differences between the way generic-drug applications are submitted in the current system and how they will be presented in the QbR format. Presentations were scheduled for the American Association of Pharmaceutical Scientists' "Workshop on Pharmaceutical Quality Assessment," (Bethesda, MD, Oct. 5–7) and the Generic Pharmaceutical Association's Fall Technical Conference (Washington, DC, Oct. 24–26).

–Laura Bush

CHEMICAL REACTIONS

New Carbene-Based Catalyst Simplifies Chemical Preparations

A team of chemists from the University of California, Riverside (UCR, Riverside, CA, www.ucr.edu) has discovered a new carbene-based catalyst that makes chemical reactions faster and more economical.

Unlike most carbenes—catalysts that accelerate chemical reactions by attaching themselves to certain metals (e.g., palladium) and altering their properties to accelerate reactions—the UCR molecule has only one nitrogen atom, rendering it more flexible than the two-nitrogen structures previously thought necessary for efficient catalytic reactions. UCR's carbene-based catalysts protect the metals to which they bind, making them stable and long lasting.

Because of this longevity, the team can use very small amounts of catalyst, driving down reaction costs. In addition, the ligand used in the UCR process is less expensive than most ligands. "When you perform a catalytic reaction, even if you use 1% of catalyst, the price of the catalyst is very often a big percentage of the cost of the reaction. Therefore, the price of the catalysts is really an issue," says Guy Bertrand, lead author of the study and distinguished professor of chemistry at UCR. Another key aspect of the technology is that the new molecules work at room temperatures whereas other catalysts are only effective at very high temperatures.

The group is currently working to identify new reactions not yet possible with other catalysts and hopes to make their patented technology available for large-scale commercial use. French chemicals manufacturer Rhodia, which provided initial funding for the research, is currently in talks with UCR to license the technology. The National Institutes of Health recently awarded the researchers a four-year grant to continue work on the project.

–Kaylynn Chiarello

ORAL FORMULATION

NOBEX and Biocon to Codevelop Oral Peptide for Treating Congestive Heart Failure

NOBEX Corp. (Research Triangle Park, NC, www.nobexcorp.com) and Biocon Ltd. (Bangalore, India, www.biocon.com) will codevelop an oral formulation of human brain-type natriuretic peptide (hBNP) for the treatment of congestive heart failure. The program combines Biocon's peptide production capabilities with Nobex's peptide delivery technology.

The companies anticipate an investigational new drug application filing with the US Food and Drug Administration and with India's regulatory agencies in early 2007, with clinical trials beginning later that year.

The oral formulation of conjugated hBNP applies Nobex's proprietary amphiphilic oligomer technology to the hBNP endogenous peptide produced in the heart, and is known for its natriuretic, diuretic, vasorelaxant, and lusitropic properties. In 2001, FDA approved hBNP for administration as a continuous infusion in hospital settings (currently marketed by Scios, Inc., a Johnson & Johnson Company). Nobex and Biocon researchers hope an oral formulation of the drug will extend hBNP administration to outpatient use in subjects with early asymptomatic left ventricular dysfunction, as well as patients at high risk of acute decompensation of heart failure.

At the American Association of Pharmaceutical Scientists' Biotech conference held earlier this year, NOBEX researchers presented experimental results showing how BNP conjugates could be produced by coupling monodispersed low molecular weight (typically less than 500 Da) amphiphilic oligomers to the BNP therapeutic peptide. An amphiphilic structure has both a highly water-soluble end and a highly lipid-soluble end. The balance between the water-soluble and the lipid-soluble portions modify the chemical and biological properties of the drug to improve its characteristics and enable oral delivery. The study claims the conjugated peptides lead to increased shelf stability, a greater resistance to enzymes, better absorption into the body from the gastrointestinal tract, and longer circulation time in the body.

Another study (A. Cataliotti et al., "Oral Human Brain Natriuretic Peptide Activates Cyclic Guanosine 3', 5'-Monophosphate and Decreases Mean Arterial Pressure," Circulation 112, 836–840 [2005]) reported for the first time that "the Nobex-modifled hBNP had a significant reduction in mean arterial pressure and increased blood levels of a second messenger called cyclic GMP in an animal model. The study also showed the activity of the hBNP is maintained and its oral bioavailability is several times greater than the unmodified natural peptide at the same oral dose and the same liquid formulation."

–Maribel Rios

RECALL

Trypan Blue 0.06% Ophthalmic Solution

On Aug. 26, Custom RX Compounding Pharmacy (Richfield, MN, www.customrx.com) and FDA notified ophthalmologists, other healthcare professionals, and consumers about a nationwide recall of Trypan Blue 0.06% Ophthalmic Solution, used in cataract surgery, because it may be contaminated with Pseudomonas aeruginosa bacteria that, if applied to the eyes, might lead to serious injury or blindness.

Custom Rx Pharmacy requests that all unexpired syringes be collected and returned to the pharmacy. The product was distributed to hospitals and clinics ina Maryland, Minnesota, Illinois, Nebraska, North Dakota, Michigan, the District of Columbia, and Pennsylvania.

–George Koroneos

VACCINES

FDA Calls Chiron Facility Acceptable; GSK Gets Green Light For Flu Vaccine

The US Food and Drug Administration (Rockville, MD, www.fda.gov) has released the results of a nine-day good manufacturing practices inspection of Chiron's (Emeryville, CA, www.chiron.com) Liverpool facility, which manufactures "Fluvirin" influenza virus vaccine. FDA found Chiron's responses and proposed corrective actions to inspection observations to be "generally acceptable."

Chiron can now resume production of the Fluvirin vaccine for the US market by the 2005–2006 influenza season. "We are grateful for the direction and guidance the regulatory agencies have extended to us throughout this process, and we are proud of the dedication our employees have demonstrated in working toward this accomplishment," stated Howard Pien, CEO of Chiron, in a release. "We remain focused on our objective of delivering Fluvirin vaccine to the US market in support of public health efforts to prepare for the upcoming influenza season."

According to a release, Chiron's ability to deliver Fluvirin vaccine to the US market will depend upon successful production and final testing of the vaccine, as well as release of the vaccine by FDA. Chiron also expects that the Medicines and Healthcare products Regulatory Agency may again inspect Chiron's Liverpool facility before the company commences shipment of Fluvirin vaccine.

"We are pleased that the Chiron Corporation has taken steps to address issues at their facility in Liverpool as they prepare for the upcoming flu season," stated Jesse Goodman, FDA director of the Center for Biologics Evaluation and Research, in a release. "The letter that we issued to them this week is a positive development and shows significant progress on their part." Goodman says that additional work is still needed to determine the amount of vaccine Chiron may be able to supply the US market for the upcoming flu season.

In related influenza production news, GlaxoSmithKline (Philadelphia,PA, www.gsk.com) has received approval from FDA to produce the influenza vaccine "Fluarix." The vaccine was approved under the accelerated approval process, which allows drugs necessary for treating severe illnesses to be pushed through the approval process without undergoing broad clinical trials.

According to an Aug. 31 release issued by GSK, the company was pleased that it could bolster the country's supply of flu vaccine in time for the 2005–2006 flu season. "The shortage of flu vaccine last year was a reminder of the importance of vaccines in health care," Jean-Pierre Garnier, CEO of GlaxoSmithKline, said. "GSK worked quickly with government officials to make Fluarix available and increase supply at a critical time. We appreciate the spirit of cooperation and commitment on the part of the FDA and US Department of Health and Human Services."

–George Koroneos

WARNING LETTER

Similasan

On Aug. 16, The US Food and Drug Administration issued a Warning Letter to Similasan AG (Jonen, Switzerland, www.similasan.ch).

The agency's concerns centered on filling processes and handling of sterilization filters. The letter cited "inadequate" heat-penetration studies of the filter autoclaving process and challenged the company's practice of re-using filters as many as 50 times without bacterial retention tests.

The agency also was concerned about the controls to prevent microbial contamination of sterile eye drops, the lack of written procedures to validate filling processes, and incomplete production and control information in the batch records.

–Douglas McCormick

DRUG DELIVERY

Size Matters: New DNA Buckyball Building Blocks Could Help Deliver Drugs

Cornell University (Ithaca, NY, www.cornell.edu) scientists have pioneered a method of using nano-sized, DNA building blocks to form buckyballs for drug delivery applications.

Though the notion of using buckyballs (i.e., hollow nanostructures shaped like soccer balls or geodesic domes) for drug delivery is not new, the Cornell DNA-based material is novel. While most fullerene buckyballs are constructed of carbon atoms, the Cornell scientists have made a branched DNA–polystyrene hybrid. The synthetic DNA is engineered to have no genetic function and therefore can be used as the scaffolding rods to make the buckyballs.

For reasons still being explored by the group, DNA–polystyrenes spontaneously self-assemble to make a larger hollow structure that is exactly the same shape as one buckyball. The new structure is approximately 400 nm in diameter and has 15-nm rods forming the structure. "If you calculate the volume, our buckyball is about 200 million-fold larger than the buckminsterfullerenes (i.e., carbon bucky-ball 60)," notes Dan Luo, head of the research group and assistant professor of biological and environmental engineering at Cornell. "We don't know how they form it, but we estimate in our model, there are 19,000 of those building blocks that are self-aligned into one gigantic buckyball."

This larger size may help facilitate drug delivery, according to the group, because it falls within the ideal range of cell endocytosis. "In order words, the cell can eat up the buckyball structure and the drug can get inside the cell. We think it's biocompatible, but we're still doing research on that," explains Luo.

Because the structure is hollow inside and has crevices on the outside, the researchers hope the structure will be able to carry not only drug molecules, but also fluorescent trackers into the body, an application they are currently exploring. "We could use it like a barcode so that we can detect the molecule inside the cell," says Luo. "We are trying to use our engineering techniques together so that you not only have a drug delivery vehicle, but you have a tracking vehicle." The group also is exploring techniques to make their buckyballs easy to produce on a large scale.

–Kaylynn Chiarello

VACCINES

Genencor Wins Vaccine-Development Contract

The US Defense Advanced Research Projects Agency (DARPA, Arlington, VA, www.darpa.mil) has awarded Genencor International (Palo Alto, CA, www.genencor.com) a $700,000 contract to develop a process for rapidly manufacturing emergency vaccines and other therapies to combat biological threats. The contract calls upon the company's fungal-based protein-expression platform for large-scale production of monoclonal antibodies.

According to a company release, "The goal is to manufacture 10 million doses of vaccine within two months of identifying a biological agent." Further details of the contract have not been made available.

Genencor develops fermentation strains and claims expertise in genetic manipulation of eukaryotic and prokaryotic organisms. The company applies its capabilities in cloning, molecular genetics, DNA arrays, and proteomics to analyze and improve its production strains.

DARPA is the central research and development organization for the Department of Defense.

–Maribel Rios