August 2006

August 2, 2006
Pharmaceutical Technology Editors

Pharmaceutical Technology, Pharmaceutical Technology-08-02-2006, Volume 30, Issue 8

Ranbaxy issued three responses (March 20, April 20, May 25) to FDA's Form 483.

RESTRUCTURING

Pfizer To Phase Out Manufacturing at Groton

Pfizer, Inc. (New York, NY, www.pfizer.com) will phase out manufacturing operations in Groton, Connecticut, eliminating roughly 300 jobs.

The move would allow the company to expand its research and development operations in Groton near the 50-acre manufacturing site. Pfizer's Groton and New London sites in Connecticut are the company's largest research sites, employing roughly 6000 people.

The move is part of Pfizer's company-wide restructuring effort, announced in 2005, under which Pfizer hopes to save $4 billion annually by 2008.

Pfizer plans to begin cutting its Groton manufacturing operations in 2007. The facility makes active ingredients for several pharmaceuticals and animal health products, and the company plans to transfer the manufacture of those products to other plants.

–Patricia Van Arnum

FDA Withdraws 117 Inactive NDAs and ANDAs

Effective June 16, 2006, the US Food and Drug Administration (Rockville, MD, www.fda.gov) withdrew approval of 65 new drug applications (NDAs) and 52 abbreviated new drug applications (ANDAs). The holders of NDAs and ANDAs each notified FDA that their drug products are no longer marketed and requested that the approval of the applications be withdrawn. The applicants waived their opportunity for a hearing. The list is available in the Federal Register (Federal Register71 [116], [June 16, 2006]).

–Kaylynn Chiarello–Ebner

ACQUISITION

J&J to Buy Pfizer's Consumer Healthcare Business for $16.6 Billion

Johnson & Johnson Company (J&J, New Brunswick, NJ, www.jnj.com) agreed to buy the consumer healthcare business of Pfizer, Inc. (New York, NY, www.pfizer.com) for $16.6 billion in cash.

"This acquisition builds upon our broad base in healthcare products and our leadership objectives in the consumer, pharmaceutical, and medical devices and diagnostics markets," said William C. Weldon, J&J's chairman and CEO, in a company release. Pfizer's consumer healthcare business includes personal care and over-the-counter (OTC) products such as "Zantac," "Sudafed," "Neosporin," and "Benadryl." Overall, the business posted 2005 sales of $3.9 billion. J&J also will acquire the US OTC switch rights to "Zyrtec" (cetirizine), Pfizer's once-a-day, nonsedating prescription antihistamine, upon patent expiration.

Pfizer decided to sell the business following a review of its strategic options that the company had initiated in February. The deal is expected to close by the end of 2006.

Pfizer also announced that during 2006 and 2007, it will purchase as much as $17 billion of the company's stock by using the net proceeds from the sale of its consumer healthcare business and cash from ongoing operations.

–Patricia Van Arnum

REGULATIONS

Baxter Healthcare Signs Consent Decree

The US Food and Drug Administration (Rockville, MD, www.fda.gov) announced that Baxter Healthcare Corp. (Deerfield, IL, www.baxter.com) signed a consent decree relating to the company's "Colleague" volumetric infusion pump and "Syndeo" patient-controlled analgesic syringe pump.

Baxter will cease the manufacture and US distribution of both pumps until the company corrects manufacturing deficiencies and ensures that the devices comply with FDA's CGMP requirements and the quality system (QS) regulation for devices. Baxter also must hire an independent expert consultant to inspect its infusion-pump facilities and confirm to FDA that corrections have been made.

FDA will allow Baxter to keep providing routine service maintenance and to replace components and accessories for the Colleague and Syndeo pumps customers bought before Oct. 12, 2005. Baxter must provide FDA with a corrective action plan for bringing the devices currently in use into compliance with the Federal Food, Drug, and Cosmetic Act. The agency issued a Preliminary Public Health Notification dated April 28, 2006 with recommendations for users, titled "Important Safety Recommendations for Baxter's Colleague Infusion Pumps" (see http://www.fda.gov/cdrh/safety/042806-baxter.html).

FDA conducted its latest inspection of Baxter's Round Lake facility on June 20–30, 2005. The inspection uncovered faults such as Baxter's failure to establish sufficient management controls over its QS operations and corrective and preventive actions procedures. FDA discovered a design defect that causes the Syndeo device to stop functioning. The inspection also revealed a design defect related to the Colleague pump's temperature-sensitive Y2A crystal component that causes the unit's timing circuit to fail.

If Baxter completes corrective action and is allowed to resume the manufacture and distribution of the pumps, the firm will hire an independent auditor to conduct inspections of its domestic infusion pump facilities at least once a year for at least four years. The auditor will report the results of the inspections directly to FDA. If Baxter fails to comply with any provision of the decree or violates the Act or FDA regulations, FDA may order the firm again to stop manufacturing and distributing, recall the products, or take other action.

–Erik Greb

Office of Regulatory Affairs Undergoes Restructuring

The US Food and Drug Administration (Rockville, MD, www.fda.gov) is restructuring its Office of Regulatory Affairs (ORA) into two offices. The Office of Enforcement, headed by David Horowitz, will work to set ORA's priorities and develop policies and new methods. The Office of Regional Operations, headed by Diana Kolaitis, will take responsibility of operational aspects such as inspections and laboratory work.

The reorganization is part of FDA's continuing efforts to increase compliance and minimize risk.

–Maribel Rios

WARNING LETTER

Ranbaxy Labs

The US Food and Drug Administration's Center for Drug Evaluation and Research (Rockville, MD, www.fda.gov) issued a 7-page Warning Letter to Ranbaxy Laboratories (Himachal Pradesh, India, www.ranbaxy.com) for violations of US current good manufacturing practices (CGMPs).

FDA's concerns include:

  • Lab records did not include complete records of operating conditions and settings used for analysis or raw stability data acquired during drug product and lot testing (21 CFR 211.194[a][4]).

  • Ranbaxy did not establish and follow a written stability-testing program to assess drug-product stability and to determine storage conditions and expiration dates. Stability sample test intervals were undocumented (21 CFR 211.166[a][1]) and storage conditions were not adequately documented (21 CFR 211.166[a][2]).

  • The quality control unit does not have the personnel and the equipment to conduct proper drug-stability testing (21 CFR 211.22.[b]).

FDA said in its June 15, 2006 letter, "Until FDA has confirmed correction of the deficiencies observed during the most recent inspection and compliance with CGMPs, this office will recommend withholding approval of any new applications listing your Paonta Sahib facility as the manufacturer of finished pharmaceutical drug products."

–Kaylynn Chiarello-Ebner

WARNING LETTER

Sanofi Pasteur

Vaccine maker Sanofi Pasteur, Inc. (Swiftwater, PA, www.sanofipasteur.com) received a Warning Letter (http://www.fda.gov/foi/warning_letters/g5899d.html), dated June 30, citing "significant deviations" from current good manufacturing practices (CGMPs) in the production of monovalent concentrates used in the company's "Fluzone" influenza vaccine.

In late March, Sanofi Pasteur reported to FDA that some of the monovalent concentrates failed sterility testing. The source of the contamination has not been determined nor thoroughly corrected, which prompted FDA to issue the warning.

The cited deviations included:

  • On the Fluzone production floor, equipment and supplies exposed to "any potentially pathogenic agent" were not adequately separated from product manufacturing equipment and supplies to prevent cross-contamination (21 CFR 600.11[e][5]).

  • The company failed to establish a system for maintaining equipment to control aseptic conditions, to follow written procedures to prevent microbial contamination of sterile drug, and to ensure that errors are investigated (21 CFR 211.42[c][10][vi], 211.113[b], and 211.22[a]).

  • Appropriate written procedures to prevent microbial contamination of sterile drug products were not followed (21 CFR 211.113[b]).

  • The company did not establish that test methods used at the site are accurate, sensitive, specific, and reproducible (21 CFR 211.165[e]).

  • No event and relevant information associated with the manufacturing of a licensed biological product that deviated from CGMPs, regulations, standards, or specifications that may affect the safety, purity, or potency of a distributed biological product was reported to FDA (21 CFR 600.14[b]).

  • The company did not inform FDA's Center for Biologics Evaluation about a change to its licensed product-stability testing program (21 CFR 601.12[a]).

The letter said the deficiencies indicate the "quality control unit not fulfilling its responsibility to assure the identity, strength, quality, and purity of your drug product [21 CFR 211.22] . . . Failure to promptly correct these deviations may result in FDA initiating regulatory action without further notice."

According to FDA, the deficiencies should not affect Fluzone's availability for the 2006–2007 flu season.

–Kaylynn Chiarello-Ebner

REGULATIONS

Waxman Criticizes FDA's Enforcement Record

Coinciding with the 100th anniversary of the US Food and Drug Administration, (Rockville, MD, www.fda.gov), Representative Henry A. Waxman (D-CA) released a statement expressing his concern over "an agency that is adrift and floundering." FDA is in a state of "decline" and in the past five years "has seen its powers wither and its reputation plummet," he said. Waxman claimed that although the agency is "built on its scientific strength," it has "ignored and twisted science to reach preordained outcomes," and its enforcement presence has been "crippled," declining by 50% from 1154 Warning Letter violations in 2000 to 535 in 2005, and the number of seizures of "mislabeled, defective, and dangerous products has declined by 44%."

The congressman also released a report (available at www.democrats.reform.house.gov) concluding that FDA-headquartered inspectors "routinely reject the enforcement recommendations of career field staff." The report points to a 15-month investigational review of "internal agency documents" that show that FDA "overruled field inspectors and failed to bring enforcement actions" in at least 138 cases in the past five years involving drugs and biological products. Some cases also involved death and serious injury.

The report calls FDA's recordkeeping and case-tracking practices "inadequate," stating that the agency is "unable to track and maintain adequate records of agency enforcement decisions, an apparent violation of the Federal Records Act." The Act and agency procedures require FDA to keep records that document agency enforcement decisions. According to the report, however, "FDA officials explained that FDA could not provide prompt and complete responses [to House Government Reform Committee requests for relevant enforcement documents] because the agency lacks a system that enables it to track enforcement recommendations from field offices."

Although the report may have the support of other agency critics, some are also admitting that it will result in little, if any, change in FDA's enforcement practices. They point out that Waxman does not have the authority to call for oversight hearings to further investigate the report's claims. Other politicians allege that Waxman is using this report to attack the Bush administration and is politicizing a nonpolitical issue.

Meanwhile, the Pharmaceutical Research and Manufacturers Association (PhRMA, Washington, DC, www.phrma.

org) is reportedly "rejecting Waxman's allegations." Contrasting Waxman's conclusion that "The agency needs to chart a new direction," Alan Goldhammer, PhRMA's associate vice-president for regulatory affairs, told the Drug Industry Daily (June 28, 2006) that the organization sees nothing in the report "that would lead patients to question the safety and efficacy of the medicines that are prescribed to them."

–Maribel Rios

CONFERENCE ROUNDUP

PharmTech Annual Event Highlights Process Optimization, Product Quality

The PharmTech Annual Event (www.pharmtechevent.com) in Somerset, New Jersey targeted approaches to improving drug development and quality through optimizing processes, managing risk, and controlling variations in manufacturing operations.

Reducing variability. Identifying the cause of and controlling variability during mixing and blending operations presents unique challenges to manufacturers, said Fernando Muzzio, director of chemical engineering and the pharmaceutical engineering program at Rutgers University (New Brunswick, NJ, www.rutgers.edu). Weight variability, insufficient mixing, segregation, agglomeration, and false causes (e.g., sampling, analytical) all contribute to variations in content uniformity.

Mistakes in sampling, for example, are not uncommon, especially when a sample thief is used. "Thieves were not designed to be precision tools," said Muzzio, and failures such as sample transfer or material sticking may contribute significantly to variability in results. Developing predictive process understanding (i.e., PAT) by identifying critical inputs and outputs, characterizing multivariate relationships, implementing predictive control models, and designing processes for continuous feedback control also plays a part in reducing variability. Statistics are useful for handling changes in processing conditions and ingredient properties that may lead to process failures, he said, but "implementing the correct design of experiments to distinguish among the many possible causes for poor performance is very important."

Reducing variability through proper bulk drug characterization was a topic presented by Dina Zhang, senior investigator for Merck Research Laboratory (Whitehouse Station, NJ, www.merck.com). The discussion reviewed the characterization methods for dry and wet granulations and the benefits of analytical tools, including atomic force microscopy and inverse gas-phase chromatography. "Physical characterization is important in upstream and downstream development," said Zhang. Morphology, particle size, and flowability help in process selection such as direct compression, roller compaction, or wet granulation, while physical stability and dissolution studies facilitate formulation optimization for optimizing bioavailability.

FDA initiatives. Controlling variability and managing risk are becoming increasingly important as industry faces changes in FDA's approach to ensuring product quality. In a keynote address, former FDA investigator and compliance officer Philip Lindeman cited failure investigations, standard operating procedures (SOPs), aseptic processing, and validation as the top four Warning Letter citations in biologics. These areas also were within the 10 most common 483 citations in non-biologics, and GMP violations were the top reason for drug recalls.

Product safety and quality were drivers in FDA's revised investigation process into six systems, said Lindeman, senior compliance consultant for JM Hyde Consulting, Inc. (www.jmhyde.com). These systems include quality, facilities and equipment, materials, production, packaging and labeling, and laboratory control. "You're only as strong as your weakest system," he said. "For FDA, the most important factor in deciding whether deviations are significant is whether they represent a theoretical risk to the finished product or a danger to the patient."

CDER is advancing principles detailed in FDA's final report of the 21st Century Initiative to allow manufacturers to "assume more ownership and accountability for the manufacturing controls that will improve drug quality," said Jon Edward Clark, associate director of policy development and GMP at CDER's Office of Pharmaceutical Science. Under development is the adoption of an internal quality-management system, the adoption of a quality-assessment system, the wider use of PAT principles, promoting stronger hamonization (including collaborations with the Pharmaceutical Inspection Cooperation Scheme), and leveraging the International Conference on Harmonization's Pharmaceutical Development (Q8) and Quality Risk Management (Q9) guidelines.

Ajaz Hussain, PhD, former deputy director of CDER's Office of Pharmaceutical Science and current vice-president and global head of biopharmaceutical development at Sandoz, updated attendees on the current state of PAT and outlined remaining challenges. "PAT was positioned as a system, not technologies," said Hussain. PAT itself has merged into Q8 and Q9. For "continuous improvement," PAT–Q9 principles, making up the "design space" in development, must be integrated into manufacturing and quality assurance along with innovation and continuous improvement options.

Industry is in a state of limited and similar ability among competitors with regard to continuous improvement, noted Hussain. For a company to have more ability than its competitors on continuous improvement, it must build upon science of design (i.e., create a fundamental, reusable design knowledge base) and enable technology platforms, science and technology integration, and current and anticipated future customer needs. Ultimately, said Hussain, the ideal state would involve achieving and ensuring product quality and performance, understanding how formulation and process factors influence product performance, and being able to effect continuous improvement and continuous "real-time" quality assurance.

–Maribel Rios