December 2005

MANUFACTURING

Roche Puts Hold on Tamiflu in United States; Plans New US Manufacturing Facility

Roche (Basel, Switzerland, www.roche.com) has put a temporary halt on the distribution of the antiviral treatment, "Tamiflu" (oseltamivir phosphate), a neuraminidase inhibitor, to the United States in an effort to deter companies from stockpiling the treatment for employee use, according to an article in the Oct. 27 edition of The New York Times.

According to the report, the hoarding is a reaction to the recent avian flu pandemic, which has killed more than 60 people in Asia, but has not threatened the United States. Roche representatives stated that there are currently sufficient allotments of the antiviral in the United States and additional quantities will be released as the need arises. Nonetheless, wholesalers were advised to limit the amount of drug distributed to pharmacies to "preserve their inventory until the beginning of flu season."

Roche also has suspended shipments to Canada and limited supplies to Germany and Switzerland, according to The Times.

Cipla Prepares to Market Generic

Despite acknowledging possible patent infringement battles, Cipla Ltd. (Bombay, India, www.cipla.com) announced that it will make and commercialize a generic version of Tamiflu.

At a US selling price of $60 per treatment, Tamiflu is currently in high demand and in critically short supply amidst growing concerns of worldwide shortages of flu vaccines and growing fears of an influenza pandemic.

Roche has been under increasing pressure to license generic versions of the antiviral, which was designed to fight a multitude of influenza viruses and has demonstrated, in animal models, effectiveness against the H5N1 strain believed to cause avian flu.

Legally, generic manufacturers cannot sell the patented drug in Western nations. Nonetheless, all national patent laws, including those of the United States, allow governments to cancel patents during emergencies and either buy generics or force innovators to license their formulations to competing companies.

Meanwhile, Roche reiterated that it has been working with many governments over the past few months to determine their needs for stockpiling Tamiflu and that it is willing to enter discussions with governments and private companies on the production of Tamiflu for emergency pandemic use.

In an Oct. 18 company release, Roche CEO William M. Burns said, "In support of the global effort to fight a potential pandemic, we would be prepared to discuss such sublicenses to increase the manufacturing of Tamiflu, provided such groups can realistically produce substantial amounts of the medicine for emergency pandemic use in accordance with appropriate quality specifications, safety, and regulatory guidelines."

In the release, Roche also announced that it received approval from the US Food and Drug Administration to provide an additional capsule-manufacturing site in the United States for Tamiflu. As the company reported, "this facility is part of a network of more than a dozen production sites for Tamiflu worldwide, more than half of which are with third-party manufacturers."

–Maribel Rios and George Koroneos

LEGAL

US District Court Rejects FDA Suit to Block Device Manufacturer

In a decision pharmaceutical compliance professionals are calling highly significant for the industry, the US District Court of Utah found in favor of device-maker Utah Medical Products (Midvale, UT, www.utahmed.com) on Oct. 21, dismissing US Food and Drug Administration motions to shut the company down in a dispute over what constitutes compliance with Quality System Regulation (QSR, 21 CFR 820).

In Aug. 2004, FDA's Center for Devices and Radiologic Health asked the court to enjoin the $26-million maker of extruded and injection-molded plastic specialty medical devices from manufacturing more products until it corrected alleged defects in its quality-control procedures.

According to the decision handed down by District Court Judge Bruce S. Jenkins, FDA never claimed that Utah Medical's products were unsafe. Rather, a series of Form 483 observations dating back to 2001 faulted the company for documentation and procedures.

The agency contended that failure to comply with the regulations "in a manner that has been found acceptable to FDA" rendered Utah Medical's products by definition "adulterated." Utah Medical, on the other hand, argued that it did have validated processes and procedures in place to ensure product quality, meeting the regulatory requirements in fact, so that the company was compliant whether or not FDA liked the way it was done.

Judge Jenkins found for Utah Medical on three key points: that the company adequately validates its manufacturing process, that the company adequately validates its software, and that the company does have a uniform complaint-handling process—all in compliance with the Quality System Regulation.

In dismissing FDA's motions to force compliance, Judge Jenkins wrote:

"It seems to me that a recurring problem in this extended and in some instances 'nitpicking' case is a failure of the regulator and the regulated to communicate. It appears to me they have often talked past each other and, while using the same words, have meant entirely different things. This seems to be a common characteristic of both, arising in part because of the general nature of the regulations themselves, which have the virtue of generality and the vice of imprecision. This endemic problem is perhaps augmented by decision-makers who themselves rely too much on inspectors' reports without taking a fresh look themselves at ongoing changes made by Utah Medical in response to questions raised. . .

"As this case progressed, the court wondered how it had evolved into a litigation with hundreds of exhibits, endless depositions, and high-cost 'experts.'

"The common mission of the manufacturer and the regulating agency is a safe product and the adoption of manufacturing processes which ensure safety.

"Product safety is not an issue in this case. Processes and procedures are. 'Validation' is the key word, and [as] has often been noted, 'many roads lead to Rome.'

"The fact that the road chosen by Utah Medical may be different in degree than that thought to be appropriate by a regulator, does not mean that it is wrong, or in violation of the regulations...

"It makes no sense for the court to order Utah Medical to do something they are already doing."

For the full decision, see http://www.utd.uscourts.gov/reports/media/img1021.pdf, pages 135–149.

An FDA spokesperson commented, "FDA has always taken the position that there is no one way to satisfy GMP and our FRs say this explicitly. The disagreement here was over the roads that [Utah Medical] had selected. FDA thinks they don't satisfy GMP; the court disagreed. We see no effect of this decision beyond the facts of this case."

–Douglas McCormick

FDA

Proposed CDER Reorganization

The US Food and Drug Administration's Center for Drug Evaluation and Research (CDER, Rockville, MD www.fda.gov) Director Steve Galson circulated a memo outlining a proposed reorganization that would bring the Center into alignment with FDA's Critical Path Initiative and "improve regulatory and drug development science."

Observing that, "To date, the Center has not been staffed to support needed work on the critical path and has not been configured to provide organizational 'ownership' of these activities." Galson made a series of proposals to support the Critical Path Initiative, increase safety oversight, and encourage cross-office activities (see http://www.pharmtech.com/pharmtech/article/articleDetail.jsp?id=197355 for chart):

• Create a new office to catalyze Critical Path activities. This new group would absorb the current Office of Clinical Pharmacology and Biopharmaceutics and the Office of Biostatistics.

• Create a new group to report to the Office of Medical Policy to address Critical Path projects in the area of clinical trial design and analysis.

• Appoint a new associate center director to focus on broad drug safety policy and safety communication.

• Consolidate certain drug safety-related activities to report to this new associate center director, including two MedWatch and the Drug Safety Oversight Board staff.

• Realign the pediatric drug development review staff so that they report directly to the Office of New Drugs.

• Establish the Office of Counterterrorism and Emergency Operations, which will report directly to the Office of the Center director.

• Realign the Division of Scientific Investigations (DSI) from the Office of Medical Policy into the Office of Compliance.

"As I emphasized in my State of CDER address," Galson wrote, "making organizational changes—moving boxes on a chart-only sets the stage upon which the Center priorities can best be addressed. A reorganization is not designed to achieve instant solutions to the challenges CDER faces, although I believe it will address many of the criticisms and suggestions which have been offered on how to approach our work, including drug safety. I truly hope that the proposed realignment will merely create a more efficient and effective environment to further the Center's activities. Other important changes in policy or processes (including decision-making) will continue to be discussed and implemented as needed to achieve our shared goals for CDER."

–Douglas McCormick

ACQUISITION

Novartis Buyout of Chiron

Novartis (Basel, Switzerland, www.novartis.com) has signed an agreement to acquire Chiron (Emeryville, CA, www.chiron.com) for $5.1 billion, after initially being rejected by the vaccine manufacturer several weeks ago. According to the merger agreement, Novartis will purchase the 58% of Chiron shares that the company doesn't already own at $45 per share.

"Our plan is to turn around the Chiron vaccines business, which will require investments in R&D and manufacturing to increase quality and capacity, so that we can better meet customer demand and address public health needs. Together with the dynamically growing diagnostics business, vaccines will form a new division, while biopharmaceuticals will be integrated into the existing pharmaceuticals business of Novartis," said Daniel Vasella, chairman and CEO of Novartis.

Novartis will gain Chiron's blood testing business, which Novartis may use as for future molecular diagnostics development, as well as a portfolio of products for cancer and infectious disease that the company hopes will strengthen its specialty pharmaceutical portfolio and oncology pipeline.

As previously reported in Pharmaceutical Technology, Chiron has been plagued with quality problems at its European plants. In July, the company announced that its Marburg, Germany plant would not be supplying its "Begrivac" influenza vaccine to non-US markets for the 2005–2006 flu season. And, the year-long ordeal at the company's Evans Vaccines "Fluvirin" plant in Liverpool may finally be drawing to an end, though FDA's approval last month of the first three post-shutdown Fluvirin lots does not mean that the vaccines are ready for sale.

–George Koroneos

FDA

CDER 2005 Product Approval Totals

The US Food and Drug Administration's Center for Drug Evaluation and Research has released New Drug Application approval totals for calendar year 2005. The list for the year to-date includes 12 new molecular entities, one new salt or ester, 36 new formulations, seven new combinations, and 12 new manufacturers. The list includes 15 priority-review products and one biological license application for Biomarin's priority-reviewed "Naglazyme" (galsulfase). The full list is available at www.fda.gov/cder/rdmt/ndaaps05cy.htm.

MANUFACTURING

Miniaturization in Pharmaceutical Processing

Pressures to save active ingredients are driving formulation developers toward smaller-scale laboratory processes, while pressures to save time put a premium on more-accurate laboratory-scale tools.

As a result, noted the moderator of the AAPS session,"Miniaturization in Pharmaceutical Processing," Colin M. Minchom, PhD, vice-president for pharmaceutical development services at Patheon (Mississauga, ON, Canada, www.patheon.com), formulators are groping toward miniaturized processes that model production-scale with increasing fidelity—despite the paucity of publications and rationalized information.

Peter York, PhD, of the Institute of Pharmaceutical Innovation at the University of Bradford (Bradford, UK), opened the session by formulating the formulation challenge: the industry demands robust, scalable formulations to support early clinical trials and maximize the number of screens from a minimum quantity of product, all while reducing time and cost.

Bruno Hancock, PhD, research fellow at Pfizer (Groton, CT, www.pfizer.com), closed the session by saying, "We are using miniaturized tools on a daily basis to predict formulation performance."

According to Hancock, success may require a creative leap in framing questions and examining assumptions. Most of what we know about bulk powder behavior has been handed down from the mining and chemical industries, where bulk means a box-car load. Pharmaceutical materials change behavior with changes of scale. One of the formulator's first tasks is to ask, What makes sense?

For example, said Hancock, hundreds of suppliers sell laboratory-scale formulation equipment of various types, but few are explicitly designed to reproduce the key characteristics of production-scale machinery. It is time, said Hancock, to "throw out some of the things we've used in the past," and replace them with rationally scaled-down devices directly derived from the process-scale. The result, Hancock noted, need not look or work like its larger cousin, as long as it faithfully mimics the machine's effects on the drug product.

The "Holy Grail" of this rational approach is, of course, accurate simulation based on either first principles or well-designed and well-tested empirical models.

To the question, How small can you go? in formulation development batches, Hancock said the answer depends on the effect the researcher is trying to simulate. It makes no sense to try to model powder flow on the behavior of a single molecule. And the modeler must be conscious of how changes of scale dictate material properties over the continuum of size from the quantum level to bulk tablets. For example, the surface area–volume ratio increases as the scale shrinks; surface effects soon dominate. As a rule of thumb, said Hancock, formulators should strive for methods that yield predictable results from samples on the order of magnitude of a single dose. He offered examples, including predictions of powder flow from small shear-cell data and extrapolations of roller compaction performance from "mini-ribbons."

–Douglas McCormick

FORMULATION

Lyophilization Experts Show How to Avoid Common Formulation Mistakes

When it comes to developing a robust lyophilization process, formulators can "pay now or pay later," said Jeff Schwegman, PhD, founder and chief scientific officer for BioConvergence. Because 30% of new drugs in clinical trials are biotech-based therapeutics (compared with 7% 10 years ago), more than ever, the US Food and Drug Administration is paying close attention to lyophilization data and questioning pharmaceutical companies about their development cycles, especially cycle development transfer, shelf-temperature mapping, dryer-to-dryer comparison studies, formulation time, process validation, and cycle deviation. Consequently, this is pushing formulators to optimize formulation variables, conduct additional testing during early-stage development, and understand critical process parameters, equipment qualifications, and manufacturing conditions that can affect formulation behavior at a large scale. Not taking the time or effort to achieve these goals during early development could lead to redundancies in formulation work—a reality observed too often in today's practices.

During the AAPS presentation, "Physio-chemical Characterization to Support Lyophilization Cycle Development and Scale-Up," Schwegman focused on how proper physiocharacterization can be used to diagnose common problems such as loss of potency, collapse, and meltback. For example, differential scanning calorimetry and freeze-drying micro-scopy are valuable tools to determine whether a substance is crystalline, amorphous, or a combination of both; whether a formulation will require annealing; and what the annealing conditions should be based on warming curves and specific glass-transition and eutectic temperatures. Such curves can be useful to avoiding mistakes such as unintended crystallization of the product and vial breakage.

Formulation variables also must be optimized to achieve good product stability during freeze drying and subsequent storage of lyophilized biopharmaceuticals. For example, one mistake formulators often make, said Byeong Chang, PhD, founder of Integrity Biosolution, LLC, is not taking time-dependent factors into consideration when determining degradation rates. Often, formulators try to optimize the process by focusing on the data at only one accelerated temperature condition (e.g., at 40°), without conducting tests to see how the degradation can change over a temperature range.

Knowing what is going on in the environment of the lyophilizer, especially by conducting tests at various points in the chamber, and clearly understanding manufacturing objectives is another essential for avoiding common mistakes, says Edward Trappler, president and founder of Lyophilization Technology. "The product dictates the process," said Trappler, as he presented several "checklists" for understanding key product attributes, including equipment qualification and capacity. Equally important, he said, is identifying technology transfer aspects such as attributes of the active pharmaceutical ingredient, batch size and uniformity, and process reproducibility.

–Maribel Rios

FDA

New FDA Guidance

The US Food and Drug Administration (Rockville, MD, www.fda.gov) released a new guidance covering the content of electronic common technical document (eCTD) submissions. The new Guidance for Industry: Providing Regulatory Submissions in Electronic Format—Human Pharmaceutical Product Applications and Related Submissions Using the eCTD Specifications, updates the Aug. 2003 draft guidance on the same topic.

The new guidance provides more specificity than earlier guidances regarding the organization of electronic submissions, and harmonizes the organization and formatting of multiple submission types. The International Conference on Harmonization (ICH) developed the CTD and the eCTD for marketing-approval applications (ANDAs, BLAs, NDAs), but according to the new guidance, they can apply to other submission types such as INDs and master files. More details regarding the ICH eCTD can be found in the ICH guidance document M2 eCTD: Electronic Common Technical Document Specification.

The new FDA guidance is available at: http://www.fda.gov/cder/guidance/6766fnl.htm

–Laura Bush