Critics say FDA cGMP initiative bite is more than it can chew

By Mark A. DeSorbo

WASHINGTON, D.C.—Complying with a law that requires biannual inspections of drug manufacturing facilities will not happen any time soon, but the Food and Drug Administration (FDA) in the same breath says its initiative, Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach, will preserve public safety while paving the way for drug makers to produce innovative medicines.

This has pharmaceutical and biotechnology industry experts and observers scratching their heads, questioning the scientific validity of the effort and suggesting the FDA's edifice of comprehensive goals for current good manufacturing practices (cGMPs) may be no match for the “big bad reality wolf.”

“It's policy reflecting reality,” says Jim Hall, life sciences leader at PA Consulting Group (Cambridge, Mass.), which advises such drug makers as AstraZeneca, Pfizer, and GlaxoSmithKline.

Critics of the FDA cGMP initiative believe that while it may be wise to monitor manufacturing practices, a drug company producing a new product may have more problems.
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And that sentiment was reflected in a recent Quick Vote poll on, in which 58 percent of the respondents believe the reasoning behind the FDA initiative is because the agency's back is against the wall. The remaining 42 percent were equally split, saying either the FDA was calling the shots or it was too hard to tell.

Kenneth Kaitin, director of the Tufts Center for the Study of Drug Development (Boston, Mass.), says the industry is deeply concerned over the enforcement of cGMPs, describing it as a “catastrophic problem.”

“The idea of revisiting [cGMPs] is needed, but before the industry jumps on the bandwagon, it wants to know if the agency is just catching up or if its problems are too big to correct,” Kaitin says.

Those same critics, he explains, would also have preferred legislation, instead of regulation. That way cGMPs would have been law, and shoddy manufacturing, which has caused deaths and serious illnesses in the past, would have been a federal offense.

Another Quick Vote poll also indicates that many believe cGMPs should be legislation, with 47 percent believing it's a punishable crime when contaminated food or drugs reach the market. Another 36 percent say “regulations are righteous,” but 17 percent still say the situation is too tough to call.

Essentially, Kaitin says, FDA, by law, is being mandated to come up with laws with exceptions.

“Does the FDA need flexibility? What constitutes a violation? One could argue that it should be legislation,” Kaitin adds. “Right now, [the FDA initiative] is just another obstacle for an industry already buffeted by economic and political winds.”

PA Consulting's Hall agrees, saying larger pharmaceutical companies are “nervous.”

“They worry about the FDA changing the process of compliance audits or inserting something into cGMPs to help the FDA do their job better, but makes it even more complicated for the them,” he adds.

In late August, Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research (CDER), announced the launch of the initiative, saying significant changes in the pharmaceutical industry have occurred over the last two decades, resulting in incremental adjustments to FDA's regulatory approach to quality. [See “cGMPs back under FDA microscope,” Sept. 2002, p. 1, and “FDA cGMP initiative: A streamlining step in the right direction,” Oct. 2002, p. 1]

Larry D. Sasich, a pharmacist who works for the consumer watchdog group Public Citizen in Washington says the initiative raises a host of questions and is wondering why 4,300 manufacturing facilities were evaluated in 1980, and only 1,600 inspections were conducted by the FDA in 2002.

While it is aware of the biannual inspection regulation, CDER has said publicly that regular evaluations are not likely to start in the near future because of short staffing, although it has managed to hand down record fines to drug makers—$500 million to Schering-Plough (Kenilworth, N.J.) and $100 million to Abbott Laboratories (Abbott Park, Ill).

“Janet Woodcock is saying all this at the same time Schering-Plough and Abbott Labs are in trouble,” says Sasich, referring to fines the FDA handed down for shoddy drug manufacturing [See “Abbott haunted by compliance woes,” December, p. 1, and “Drug makers back in FDA hot water,” June 2002, p. 1].

Hall poses this question regarding the FDA's definition of risk:

“Is it a risk that a new product will have safety or contamination problems, or is the risk greater from a traditional pharmaceutical company not following the right procedures?”

Schering-Plough, Hall points out, is now pegged on the FDA's watch list, and while it may be wise to keep an eye on its manufacturing practices, a drug company producing a new product is more likely to have problems.

“Past performance is no indication of future performance. The FDA traditionally goes after administrative problems that are supposed to identify other problems,” he says. “I would rather see the process cater to the product and the patient, but instead, it's all about administration and procedures.” lll

CR East Aseptic Guidelines Panel: Is the FDA moving with the times?

By Mark A. DeSorbo

BOSTON—When the U.S. Food and Drug Administration's (FDA) proposed revision of aseptic guidelines was released this past September, it marked the first step toward revision since 1987 and was a solid indication that the agency was moving along with the times.

However, the pharmaceutical industry is learning that it has its work cut out during the crucial comment period.

For example, the guidelines call for a Class 1,000—not an ISO Class 6—area in a drug-making environment.

“A Class 1,000 area is a classification that does not exist anywhere,” says

Art Vellutato, Jr., vice president of technical sales and marketing for Veltek Associates Inc. (Phoenixville, Pa.). “It's causing a lot of grief and problems because that means someone is going to have to break through the ceiling and put in new filters, and the industry is not sure of the reasoning.”

Moreover, the proposal, Sterile Drug Products by Aseptic Processing, Draft Concept Paper, classifies cleanrooms according to Federal Standard 209E, which was made obsolete in November 2001, once international cleanroom standards of ISO 14644 were introduced.

The release of the concept paper will indeed force the FDA and the pharmaceutical industry to closely review the content of this critical guidance document, and Vellutato says it is time for contamination control professionals applying current good manufacturing practices (cGMPs) to speak up and be heard.

Vellutato, who serves as president of the Delaware Valley Chapter of the Parenteral Drug Association (PDA; Bethesda, Md.), will be moderating Special Interest Group: New FDA Aseptic Guidelines Considered, a new conference session at CleanRooms East 2003, which will be held at Boston's World Trade Center, March 17-19.

The CleanRooms Group has also invited officials from the FDA to participate in what Vellutato says is a session designed to be an interactive discussion between the audience and moderators to outline and discuss the main sections that are included or not included in the FDA's concept paper.

“Basically, what I hope to do at this session is to start a dialogue and go through the paper piece by piece,” he says. “It will be a round table discussion, and we hope to develop a listing of the points that are controversial and then forward them to the FDA with the goal of developing a better document.”

So far, the only organization to comment on the concept paper has been PDA.

In a 7-page manifesto submitted to the FDA last October, PDA outlined four areas of concern: Best practices and cGMPs, technical issues and unconventional terminology, scope and harmonization.

Acknowledged in the documents were representatives from large drug makers, including Merck & Co. (Whitehouse Station, N.J.), GlaxoSmithKline (Triangle Park, N.C.) and Pfizer Inc. (New York City), as well as several consultants, including James Agalloco, of Agalloco & Associates (Sommerville, N.J.) and James Akers of Akers Kennedy & Associates (Kansas City, Kan.).

“New guidance is urgently needed by both the industry and FDA. The current patchwork of 'requirements' has little relevance to what is actually needed to manufacture a sterile product by aseptic processing,” according to PDA.

While PDA believes the concept paper contains useful guidance for pharmaceutical companies and FDA field investigators, the standard should also enable firms to know what to expect during FDA inspections of aseptic processing areas and ensure that validation observations are based on current guidance that is “rooted in appropriate technology, science and best practices.”

Vellutato, who also chairs a PDA special interest group on cleaning and disinfection, says other groups should seize the opportunity to comment on the FDA's concept paper.

“This has been too consultant-oriented, and not enough cGMP facilities have commented,” he adds.

The concept paper is located at To register for CleanRooms East 2003, contact Lisa Gowern, registration coordinator, at (603) 891-9267, or e-mail at [email protected]. lll

New ISO standard to clear the air on testing, metrology

14644-3 aims to fill the many holes left in existing standards

By Hank Hogan

ROLLING MEADOWS, Ill.—Cleanrooms may be spotless, but when it comes to cleanroom testing, contamination control practitioners often find themselves in a murky situation in regards to assessing critical parameters.

Help is on the way in the form of ISO 14644-3, which covers cleanroom metrology and test methods.

A draft of 14644-3 was recently released for public comment, while a final version of the document may not emerge until late 2003 or later. According to industry players, there could be quite a bit of feedback on 14644-3 since it's aimed directly at the gaping holes left by existing standards.

According to Ken Goldstein, president of Phoenix-based Cleanroom Consultants, “The current documents only talk about particles in the air. Everything else about cleanrooms—velocities, pressures, temperatures, humidity, vibration, lighting, electrostatic discharge, etc.—is not contained in there at all.”

Even in the case of particles, existing documents leave something to be desired, says Goldstein. The problems are not with airborne contaminants that range in size from 0.1 to 5.0 microns. Those are routinely monitored with laser-based counters and the testing process is relatively straightforward.

However, Goldstein notes that there can be issues at either end of the size range. On the very small end, ultra-fine particles are too tiny to be detected by laser particle counters. On the very large end, macroparticles are frequently missed due to the design of particle counters. These large particles cannot enter the counting chamber and, hence, go undetected.

The new standard addresses testing of both of these extremes through the use of special equipment and methods. The proposed standard also outlines how to monitor and test such parameters as airflow and pressure differential, filter leakage, and airflow visualization and direction. Additionally, ISO 14644-3 covers such issues as temperature and humidity testing, electrostatic discharge measurement, as well as various other critical parameters.

The document, at least in its current form, does have some drawbacks. It doesn't provide any sort of classification and can be somewhat skimpy on test details. It also doesn't address viable testing—the type of measurement designed to spot bacteria and other microorganisms.

These biologically related test and measurement issues are covered in another ISO standard currently being prepared.

ISO 14644-3 does offer a starting point for cleanroom testing, and Goldstein believes that's worthwhile. However, the current state of the standard presents would-be cleanroom testers with a dilemma. On one hand, the document is available. But on the other, it lacks some details. Another problem is that the current version almost certainly won't be the one ISO finally enshrines. And so those who want to put it into practice need to proceed with care. lll

USDA beefs up meat testing program

By Lynn Tryba

WASHINGTON, D.C.—In the wake of an outbreak of listeriosis in the Northeast that killed seven people over the summer and led to the largest meat recall in U.S. history, the U.S. Department of Agriculture (USDA) has intensified its testing program for plants making ready-to-eat processed meat such as hotdogs and deli meat.

Not every company that produces ready-to-eat meat will come under tighter scrutiny. Instead, the program targets companies working without an evaluated environmental testing program designed to find and eliminate listeria.

Companies must adhere to Sanitation Standard Operating Procedures (SSOPs) and the Hazard Analysis and Critical Control Point (HACCP) system that calls for testing in critical places in the production process where contamination can occur. But until now, the USDA only required tests for listeria in products, not in plant environments.

Companies that already do environmental tests for listeria but choose not to share the data with the USDA will also fall under the intensified testing program, according to the directive drafted by the USDA's Food Safety and Inspection Service (FSIS).

Under the directive, USDA inspectors will increase tests of final products and test food contact surfaces and plant environments for listeria. According to the directive, environmental samples may be taken from such items as mop handles, aprons, floors, drains, walls and overhead structures. Food contact surfaces may include conveyor belts, tabletops and knife blades. The samples will be collected while the product is being produced.

If listeria contamination is found in a plant, the USDA will ask for a voluntary recall.

In mid-October, a Wampler Foods plant in Franconia, Pa. recalled more than 27 million pounds of meat after identical strains of the listeria monocytogenes bacteria responsible for the Northeast outbreak were found in its floor drains.

Listeria, responsible for about 500 deaths annually, is difficult to combat. It's often found in the intestines of healthy animals, including humans, and in soil, water, and vegetation, and it can grow under extreme heat—up to 150 degrees—as well as in refrigeration. Pasteurization and heating procedures used in making ready-to-eat meats kill the bacteria, but contamination can still occur after processing if good manufacturing practices are not followed.

While most recalls are triggered when pathogens are found in products, such measures tend to escalate into “major recalls under special circumstances,” says Jenny Scott, senior director of food safety at the National Food Processors Association (NFPA) in Washington, D.C. The environmental testing at Wampler showed many instances of microbial pathogens.

“It clearly looked like an environment out of control,” Scott says.

The Center for Science in the Public Interest in Washington, D.C., expresses frustration with the USDA's directive, pointing out in its latest executive summary that the program “can delay the recall and increase the number of illnesses linked to an outbreak.”

The nonprofit group has asked President Bush to unify all of the federal food safety activities within a single, independent agency able to mandate recalls.

Others don't see that as the primary challenge to safe food. Instead, they advocate the more widespread use of available technology.

“If we implemented the technology available, there would be a significant decrease in illnesses and recalls,” says Andy Vestal, an associate professor at the Institute of Food Science and Engineering at Texas A&M University.

Vestal advocates irradiation delivered by gamma rays or electron beams as the most-effective microbial kill step.

In the meantime, the USDA has joined with scientists to develop rapid pathogen detection methods. Standard environmental monitoring tests now take about 48 hours to show results, according to Scott, of the NFPA. lll

The nation's largest meat recall in U.S. history has triggered the U.S. Department of Agriculture (USDA) to beef up its testing program for plants making ready-to-eat processed meat such as hotdogs and deli meat.
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System gives employers the upper hand on cleanliness

New “smart badge” reminder could impact healthcare, food, as CDC mandates washing procedures

Mark A. DeSorbo

CHARLOTTE, N.C.—The shigellosis outbreak here all started when a homeless man, who lived with several large families, came in contact with a Mecklenburg day-care employee who changed jobs three times in a week and a half.

That employee transmitted bacteria to children at several centers, and the kids, most under the age of 5, took the highly contagious, feces-spread intestinal infection home. By early December, more than 350 were sickened by such symptoms as stomach pain, diarrhea, vomiting and fever.

Barbara Jacocks, director of the Mulberry Presbyterian Church child development center, says the entire incident could have been avoided with one simple procedure.

“The bottom line on the whole thing is wash hands, wash hands, wash hands,” she says.

It is also the bottom line in healthcare, food service and cleanroom manufacturing environments, where there is not yet an established way of confirming if employees are actually washing their hands on a regular basis.

A Weymouth, Mass.-based company is attempting to turn the tables on this situation. UltraClenz says that its touch-free Pro-giene hand-washing system holds personnel in critical environments accountable for perhaps the simplest form of contamination control.

“Pathogens that enter the body through the mouth are killing people today,” says John T. Miller, vice president of worldwide sales for UltraClenz. “Without regular hand washing and glove changes, food can be contaminated and pharmaceutical batches can be messed up, and that's expensive.”

The system, which is distributed by Micronova Inc. (Torrance, Calif.), works with a smart-badge system. The badge alerts a worker that it is time for a wash when a tiny amber-colored light in the badge turns red. When the employee approaches the automatic faucet and touch-free soap dispenser, the badge triggers a voice-automated system that can instruct an employee in numerous languages when to wet hands, get soap, scrub and rinse.

“It won't let me get water mid-cycle,” Miller says. “It requires you to stay there for a 10-, 20- or 30-second wash and then tells you when to rinse.”

Once the wash is complete, system software logs it in real time, so that it not only holds personnel accountable, but it also helps pinpoint where the breach occurred in the event that a product was contaminated.

This type of technology is already being implemented at Johns Hopkins Hospital in Baltimore, Md., and the Food and Drug Administration's (FDA) Center for Disease Control and Prevention (CDC) is changing hand-washing standards for the nation's hospitals, clinics and doctor's offices, mandating that soaps in the forms of foams, gels and rinse contain at least 60 percent isopropyl alcohol.

The CDC reports that more than two million patients acquire infections each year in U.S. hospitals, resulting in 90,000 deaths.

At Johns Hopkins, a system detects the movement in and out of patient rooms as well as hand-washing practices.

If a doctor or nurse does not wash, a message sounds as they leave the room.

“We did that so the message wouldn't fall into the background,” Dr. Pamela Lipsett, director of the surgical intensive care unit, told The New York Times. And the message works.

Hand washing has increased 40 percent, while infectious disease has decreased by 50 percent, says Sandra Swoboda, a nurse in the intensive care unit.

“In our unit,” she says, “big brother watching us is a benefit.” lll

The Pro-giene system from UltraClenz alerts critical environment personnel when it's time for a hand wash. When the employee approaches the automatic faucet and touch-free soap dispenser, the badge triggers a voice-automated system that can instruct an employee in numerous languages when to wet hands, get soap, scrub and rinse.
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