In the Field: News

INTERACT in MARCH & APRIL...

Worth attending

9th Pittsburgh Conference on Analytical Chemistry and Applied Spectroscopy

Venue: Mar. 1–Mar. 7,

New Orleans, LA

More info: www.pittcon.org

DCAT Week Drug, Chemical, & Associated Technologies Association

Venue: Mar. 10–Mar. 13,

New York, NY

More info: www.dcat.org/

32nd Annual International Good Manufacturing Practices Conference

Venue: Mar. 10–Mar. 13,

Athens, GA

More info: www.georgiacenter.uga.edu/ppd

WBF 2008 North American Conference: Shaping the Future of Manufacturing

Venue: Mar. 24–Mar. 27,

Philadelphia, PA

More info: www.wbf.org

PDA Annual Meeting

Venue: Apr. 14–Apr. 18,

Colorado Springs, CO

More info: www.pda.org/annual2008

Expofarma Interphex 2008

Venue: Apr. 9–Apr. 11,

Mexico City, Mexico

More info: www.expofarmainterphex.com

INTERPHEX 2008

Venue: Mar. 26–Mar. 28,

Philadelphia, PA

More info: www.interphex.com

See Pharmaceutical Technology's special Show Guide Supplement.

To recommend books, events, or websites, email ptpress@advanstar.com

Can They Meet Industry's Interests?

In a recent Pharmaceutical Technology online poll, you—our readers—said Presidential Candidate Mitt Romney would best advance the pharmaceutical industry's interests (26%) as compared to Senator Hillary Clinton (24%), Senator Barack Obama (16%), Senator John Edwards (11%), Senator John McCain (8%), Mike Huckabee (8%) and Rep. Ron Paul (0%). Now that a series of voting primaries across the nation have narrowed the choices for the national Democratic and Republican convention delegates, we'd like to hear more from you. We plan to interview the final candidates later this spring. What would you like us to ask them? Send your questions to adrakulich@advanstar.com (*At press time, Romney and Edwards had dropped out of the race.)

Facility Roundup

Highlights from the past month's expansion and rationalization announcements.

World Briefs

ASIA & PACIFIC

Tokyo's Eisai acquired MGI Pharma (Bloomington, MN) for approximately $3.9 billion in a cash tender offer followed by a short-form merger of Eisai's acquisition vehicle, Jaguar Acquisition, with MGI PHARMA. As a result, MGI PHARMA became a wholly owned subsidiary of Eisai Corporation of North America. • Contract research organization PPD (Wilmington, NC) expanded its laboratory services into China through an exclusive agreement with Peking Union Lawke Biomedical Development. • Amgen (Thousand Oaks, CA) is partnering with the Osaka, Japan-based research firm Takeda Pharmaceutical Company to develop and commercialize 13 of Amgen's molecules. Takeda is also acquiring all the shares of Amgen's Japanese subsidiary, Amgen KK. • DuPont (Changshu City, China) hopes to establish a broader fluoroproducts-manufacturing base in China with the opening of a fluoropolymer production plant in Changshu City.

EUROPE & MIDDLE EAST

Amira Pharmaceuticals (San Diego, CA) and GlaxoSmithKline (Middlesex, United Kingdom) have agreed to develop, manufacture and commercialize "FLAP" (5-lipoxygenase activating protein) inhibitors for the treatment of respiratory and cardiovascular disease. • Swiss-based Octapharma will relocate its US headquarters to offices in Hoboken, New Jersey. The company's marketing and sales operations moved to Virginia in mid-February. • Dr. Willmar Schwabe Pharmaceuticals (Karlsruhe, Germany) intends to gain access to the United Kingdom market via its recent acquisition of MH Pharma (Marlow, UK). • GE Healthcare (Chalfont St. Giles, UK) has reached agreement to acquire Whatman (Maidstone, UK), a supplier of filtration products and technologies. • FDA issued a warning letter to Novartis Vaccines and Diagnostics (Cambridge, MA) regarding its Marburg, Germany, facility for deviations from current good manufacturing practices, including faulty production and process controls, incomplete failure investigations, and unvalidated cleaning procedures. • PPD (Wilmington, NC) agreed to purchase InnoPharm (Smolensk, Russia), one of the first CROs in Russia and pioneer of implementing good clinical practice in the former Soviet Union. • Natoli Engineering (St. Charles, MO) and Casburt TMS (Stoke-on-Trent, UK), a provider of tablet manufacturing solutions, launched Natoli Europe to cover tablet production, training, and production optimization through the development of a UK-based "Center of Excellence."

LATIN & SOUTH AMERICA

MDS Pharma Services (King of Prussia, PA) established an office in São Paulo, Brazil. The new office is part of the company's nearly two dozen other late-stage clinical trial management offices in 21 countries in Africa, Asia Pacific, Europe, Latin America, and North America.

WHERE IS THAT?

• Changshu City is a county-level city located in the southeast of Jiangsu Province. Surrounded by Shanghai in the east, Suzhou and Kunshan to the south, Wuxi to the west, and the Yangtze River to the north, Changshu has a population of 1.04 million and a GDP that ranks among the top 10 counties in China. In fact, the Jiangsu Changshu Southeast Economic Development Zone is home to some 2000 foreign-funded enterprises from 50 different countries and regions. For those considering an office or home location there, Changshu has been honored as a National Model City for Living Environment and National Ecological Model Area.

• São Paulo, the capital of Brazil, is the third largest populated city in the world and is expected to be the 13th richest city by 2020. A key global financial center, São Paulo's economy has a growing services sector. The government is planning to build the first ethanol-duct in the world in São Paulo.

Whatever Happened to...the Case Regarding Terminally Ill Patients?

by Angie Drakulich

In Pharmaceutical Technology's October 2007 issue, we wrote "Who's in Charge?" about a decision by the US Court of Appeals for the District of Columbia (Abigail Alliance v. Andrew Von Eschenbach), which stated that the due process clause of the Fifth Amendment does not extend to terminally ill patients who seek experimental drugs. The Abigail Alliance for Better Access to Developmental Drugs had argued that due process should protect "persons in mortal peril" to "try to save their own lives." The Court rejected that argument.

Since that time, the alliance, along with the Washington Legal Foundation, filed a petition for a writ of certiorari. They asked the US Supreme Court to reinstate a 2006 decision by the appeals court panel that a terminally ill patient has a constitutional right to access investigational drugs when there are no other FDA-approved treatment options.

The US Food and Drug Administration does offer a "compassionate use" provision in which terminally ill patents can access experimental drugs, but it is not very effective. The agency grants investigational drug access to only about 650 people a year for all drugs and diseases, according to an April 2007 Wall Street Journal article—compare that number to the 550,000 cancer patients who die each year.

Despite these statistics, FDA and the Bush administration urged the Court not to hear the Alliance's case. US Solicitor General Paul D. Clement, for example, wrote in a court brief that, "allowing patients to obtain and use unproven drugs carries a host of risks and potential detriments for the public health." He offered FDA's expanded drug access program as an alternative. In late 2006, the agency began developing a Proposed Rule on Expanded Access to Investigational Drugs for Treatment Use. Public comments were due this time last year but the rule is still pending.

In mid-January, the Supreme Court officially declined to hear the case. So until another case comes along, access to experimental drugs for the terminally ill is in the hands of FDA.

Zone in on: MANUFACTURING

Consistent Capsule Filling

by Erik Greb

To ensure an effective treatment, a patient often must take equal doses of an active pharmaceutical ingredient (API) at regular intervals. Powder-in-capsule dosage forms must maintain a consistent ratio of API to excipients as well as a consistent amount of each ingredient. Pharmaceutical manufacturers must therefore achieve content and fill-weight uniformity.

Producers of powder-in-capsule dosage forms face several obstacles to reaching these goals, however. One major challenge is filling capsules with powders having poor flow properties or that are highly cohesive. Karl-Heinz Seyfang, division leader of pharmaceutical services at Harro Höfliger Packaging Systems (Allmersbach im Tal, Germany), says that filling capsules with those kinds of powders is particularly challenging at fill weights of less than 10 mg. The challenge results from the variance introduced by the confinement step, which separates the dose from the bulk powder. To overcome this problem, Harro Höfliger equips its capsule-filling machines with a vacuum-drum filling system. This system doses powders at low fill weights by using a vacuum to draw the powder from a small hopper into bores on the drum.

Reuben Zielinski, senior director of technical operations at Catalent Pharma Solutions (Somerset, NJ), remarks that his greatest challenge is ensuring smooth material flow at high encapsulation-machine speeds. Zielinski says maintaining good flow requires vibratory action, but notes that this technique can reduce capsules' content uniformity. "For this reason, we run our encapsulation machines only as fast as the gravity feed will allow," he explains.

Another potential threat to content uniformity is powder segregation, Seyfang observes. To be certain that segregation has not occurred, a capsule-filling machine "must be equipped with process analytical technology devices such as a near-infrared spectrometer, a UV–vis spectrometer, or other technologies to verify API content." Zielinski says Catalent takes samples throughout the capsule-filling process, according to company testing protocols, to monitor content uniformity.

A powder's physical properties are not the only influences on content and fill-weight uniformity, however. Zielinski points out that manufacturers must consider the properties of their production machinery. He names the thickness of the encapsulator's dosing disk as an example.

"We have found that the machined tolerances on dosing disks can affect the fill-weight accuracy," he explains. Because the diameters of the disk's through-holes accommodate standard capsule sizes, the dosing disk's thickness determines the accuracy of capsule fill weights.

After they are filled, capsules must be checked. In addition to having the proper dosing system, Seyfang notes, a capsule-filling machine "must include an appropriate tare and gross check-weighing system to neutralize capsule-shell weight variance." He recommends encapsulators that weigh capsules both before and after filling.

Yet weight-checker data should not necessarily be taken at face value. Zielinski cautions that a manufacturing plant's inherent vibrations affect the location of the weight-checker. "These vibrations cause displacements that in turn can cause an abnormal amount of rejected capsules because of the sensitivity of the load cells," he says.

Manufacturers achieve content and fill-weight uniformity by taking into account several factors. Filling equipment must operate precisely at high speeds and must also be validated to ensure that capsules meet label claim specifications. Also, facilities produce dosage forms of consistent quality when equipment operators are well trained and experienced. The facility environment must be monitored, as well: temperatures must be kept within 15–25 °C and relative humidities should be maintained within 35–55% to enable good powder flow.

Attention to critical details such as these helps produce uniform and effective products for end users.

Want more manufacturing analyses? Subscribe to our new Equipment & Processing Report, a monthly electronic newsletter, at pharmtech.com/enews.

Zone in on: REGULATION

FDA to Allow Off-Label Information

by Angie Drakulich

The US Food and Drug Administration issued a draft guidance Feb. 15 on "Good Reprint Practices" regarding the distribution of medical or scientific journal articles and reference publications that involve unapproved uses of FDA-approved drugs and medical devices.

"Articles that discuss unapproved uses of FDA-approved drugs and devices can contribute to the practice of medicine and may even constitute a medically recognized standard of care," said Randall Lutter, FDA deputy commissioner for policy, in an agency release.

Industry has been asking for clarification of "off-label" use and promotion since late September, when Section 401 of the Food and Drug Administration Modernization Act expired. Section 401 provided guidelines allowing the dissemination of information on unapproved uses of FDA-approved products.

While the new draft guidance answers this call, some individuals claim the language may be too simple, and that it has been released too quickly. Rep. Harry Waxman (D-CA), chairman of the House Oversight Committee, wrote FDA Commissioner Andrew von Eschenbach twice in the past few months, questioning the way in which the agency was pursuing the guidance. He said he had "significant concern" about the guidance proposal as it would "allow drug and device companies to use journal articles to promote potentially dangerous uses of drugs and medical devices without prior FDA review and approval." Rep. Waxman and others also speculated that industry representatives have been pushing the agency to release the guidance, according to several media reports.

Rep. Waxman has said that the rule would give pharmaceutical companies too much leeway with off-label use and marketing. Compared to Section 401, the draft guidance seems to allow for easier dissemination of articles on unapproved uses of drugs and may encourage companies to carry out fewer clinical studies. The draft guidance gives manufacturers just a few principles to follow when distributing scientific or medical journal reprints, articles, or reference publications. For example, the draft calls for manufacturers to ensure that the article or reference be published by an organization that has an editorial board, and disclose any conflicts of interest for all authors or contributors to the article. In addition, articles should be peer-reviewed and published in accordance with specific procedures such as with a bibliography, but without any highlighting by the manufacturer.

The draft guidance does warn against distribution of special supplements or publications "that have been funded by one or more of the manufacturers of the product in the article," as well as against articles that are "not supported by credible medical evidence."

Public comments on the draft guidance are due Apr. 21.

Zone in on: INGREDIENTS

Recalled Ingredient Made in China

by Susan Haigney

The US Food and Drug Administration revealed in mid-February that the active ingredient used in the production of Baxter International's (Deerfield, Illinois) recalled drug heparin was made in a plant in China. At press time, it was not known whether the ingredient played a role in the approximately 350 adverse reactions and four deaths possibly caused by the blood thinner. The possible involvement of a Chinese factory in the production of a recalled drug, does however, renew concerns regarding Chinese-made products.

According to the Wall Street Journal, China is the "world's largest producer of active pharmaceutical ingredients" and FDA admits it had not inspected the particular Chinese plant due to a mistake in paperwork (plans for an inspection were immediately made by FDA). Critics say that the failure of FDA to inspect foreign manufacturing facilities continues to put consumers and patients at risk. A Baxter spokesperson told the WSJ that the company has had a 20-year relationship with the Chinese supplier and that the supplier has made the specific active ingredient for 30 years. According to the spokesperson, no changes were recently made at the Chinese plant. Baxter temporarily halted production of heparin in February after reports of four patient deaths and allergic reactions that included stomach pain, vomiting, low blood pressure, fast heart rate, and fainting. Baxter is a major producer of heparin, providing half of the nation's supply. APP Pharmaceuticals (Schaumburg, Illinois) acquires the active ingredient for its heparin blood thinner from a Chinese plant as well but has, reportedly, not experienced the same adverse effects.

A recent Pharmalot.com interview with Prof. Michael Santoro at Rutgers Business School discussed whether the pharmaceutical industry should "get out" of China. Do you think industry, or Congress, should cut commercial ties with China for the time being? Email ptweb@advanstar.com

Susan Haigney is coordinating editor of the Institute of Validation Technology journals.

SAY WHAT?

Industry Perspectives

"Our industry is small and people move around. Even when a project ends, you will see the same people again, sometimes on a different project with a different company. As such, it's important to form good working relationships with people, not just companies."

Charles Younger, PhD, Director of Project Management, Quotations, Finance and Systems, Pharmaceutical Development Services–Canada, Patheon, 2007 AAPS Conference