FDA hones initiative focus to get it right the first time

By Mark A. DeSorbo

ROCKVILLE, Md.—Six months after it announced a plan to significantly revamp current good manufacturing practices (cGMPs), the Food and Drug Administration (FDA) in late-February announced that it had accomplished its initial objectives to modernize regulations, specifically targeting firms with lapsing aseptic processing practices through more sophisticated inspection models.

“We hope that by undertaking this initiative, we will help manufacturers in getting it right the first time,” says Janet Woodcock, director of the FDA's Center for Drug Evaluation and Research (CDER) and chair of the cGMP Intiative Steering Committee. “We hope this will encourage manufacturing practices that will decrease [product] recalls.”

Along with righting the wrongs of shoddy drug manufacturers and enhancing inspection practices, additional FDA accomplishments toward Pharmaceutical cGMPs for the 21st Century: A Risk Approach include:

  • Supporting manufacturing innovations by allowing drug makers to make certain changes to processes without federal approval;
  • Launching a program to identify and address inconsistencies in the issuing of warning letters;
  • Improving dispute resolution procedures for better resolution of scientific and technical issues;
  • Clarifying language used to communicate deficiencies observed during inspections; and
  • Providing a progress report that considers adding product and technical specialists to inspection teams to improve the inspection process.

“The goal is to try to facilitate early resolution rather than to allow disputes to drag on,” says David Horowitz, director of CDER's Office of Compliance. “We're also looking at how our limited intervention will have the greatest risk.”

The idea of better intervention comes at a time when repeat offenses are becoming commonplace among big pharmaceutical companies, like Schering-Plough and Abbott Laboratories. Yet, the FDA says biannual inspections of drug manufacturing facilities will not resume in the near future even though enforcing a law that is not only timely, but also perfectly aligned with the cGMP initiative.

“For many years, the FDA has not had the resources to conduct biannual inspections,” Horowitz told CleanRooms. “It's been especially difficult to keep up with compliance issues, and that's why we are focusing on drug manufacturers with non-compliance problems because they pose the most risks to public health.”

Asked if the FDA defined risk by a new product having safety or contamination problems, or if the risk was from traditional manufacturing companies not following the right procedures, Horowitz and Woodcock reiterated the FDA's mission is to protect the health of the American people by focusing on the quality, safety and effectiveness of drugs.

“Regardless if it's a traditional manufacturer or not, we have to construct more and more sophisticated [inspection] models to do so,” Woodcock adds.

Another noted accomplishment was a move to clarify the verbiage in the Code of Federal Regulations (CFR) 21 Part 11, which calls for electronic records and signatures for such cleanroom practices as environmental monitoring. [See “Guidance withdrawal too good to be true,” p. 6]

“There are no increasing requirements on companies,” Woodcock adds. “When Part 11 guidance is finalized, it will narrow the scope for companies.”

Joseph Famulare, director of the Division of Manufacturing and Product Quality in the Office of Compliance, agrees, saying a narrower scope will facilitate an initiative goal to encourage manufacturing innovations.

“We want to get back to our original intention for [requiring] electronic record keeping,” he adds.

Other accomplishments announced by the FDA include planning public workshops on the scientific foundations of the initiative to help shape the FDA's next implementation steps; hiring experts in pharmaceutical technology; and collaborating with academic groups and other outside experts.

“FDA expects to complete and publish a comprehensive implementation plan for this cGMP initiative by mid-year,” Woodcock adds. “These initial accomplishments are the first steps toward achieving FDA's goals for a 21st century regulatory system for pharmaceutical manufacturing.”

Additional information on the initiative can be found online at

Contamination control to prove vital in NASA mission to Mars

If NASA sticks to schedule, rovers will hit ground free of any earthly life forms

By Hank Hogan

PASADENA, Calif.—Martians, if any exist, will witness a strange site twice during January 2004.

That's when two NASA Mars Exploration Rovers will come to a bouncing stop, deflate cushioning airbags and begin to crawl across the Martian surface.

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Engineers on the Mars Exploration Rover project make necessary adjustments to an engineering model of the rover in Jet Propulsion Laboratory's ISO Class 8 cleanroom. The Rovers are designed to collect and analyze rock and soil on Mars without contaminating the environment.
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Capable of trekking up to 100 meters a day, the rovers will collect and analyze rock and soil. These robotic geologists will owe part of their performance to a cleanroom, and any hypothetical Martian may owe its continued existence to the resulting contamination control.

Randy Lindemann is lead mechanical engineer for the rovers. As such, he was involved in the final assembly and testing of the robots at the Jet Propulsion Laboratory (JPL). For Lindemann, cleanrooms are critical for this delicate task. “Cleanrooms are important for all flight projects and to my knowledge are always used for subsystem and system level integration and test,” he says.

In the rovers' case, this integration and test was done at JPL's spacecraft assembly facility, an 80¥120¥44-foot ISO Class 8 cleanroom. After that, the rovers were packed up and shipped to Cape Canaveral. This was done in time to meet the mid-2003 launch dates for the two robots, with the assembly and testing taking place months before.

The use of a cleanroom, according to Lindemann, is dictated by two mission needs. The first is for the rovers to work flawlessly. When the robots are on Mars, it won't be possible to haul them back and pop in replacement parts. Instead, the rovers and all the scientific instruments on them have to function as designed and intended.

“We need our hardware clean of contaminants so that sensitive instruments and optics on cameras aren't fouled or have reduced capability because of a particle or molecular contamination,” explains Lindemann.

This same need for reliability and contamination-free performance applies to surfaces meant to reject, absorb or isolate instruments from heat and light. The requirement extends to device electronics, in general, because contamination could lead to electrical shorting or other problems.

The mission calls for the rovers to roam the surface for at least 90 Martian days, collecting data under the direction of researchers on Earth. While the rovers may operate in harsh surroundings full of dust and temperature extremes, they can at least start out clean and with the greatest possible reliability and performance.

That planetary environment, however, is the other reason to start with clean rovers. No life has ever been found on Mars, although there are some theories that at one time the planet was less hostile to life than it is now. One of the goals of the rovers is to look at Mars' climate and water history. Landing sites were specifically selected to help in this search. And that leads to another reason for, and form of, contamination control—one that any native Martian species would appreciate.

As Lindemann notes, “We need to make sure we aren't taking earthly life forms to another planet and thereby polluting future science capabilities.”

Koller assumes PDA post

By Mark A. DeSorbo

Neal G. Koller: the new PDA president
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BETHESDA, Md.—Neal G. Koller has taken the reins as president of the Parenteral Drug Association (PDA), succeeding Edmund M. Fry, who resigned from the post after 11 years last September to join IVAX Pharmaceuticals (Miami, Fla.).

Koller comes to the international association for pharmaceutical science and technology with more than 22 years of experience in medical devices and biopharmaceuticals, and says he is “truly excited” about the opportunity to lead PDA and looks forward to “building upon the strong foundation of the organization.”

Floyd Benjamin, chair of the PDA board of directors, says that he is pleased that Koller accepted the position. “His track record as a highly successful global manager in this industry will insure that PDA maintains its strategic focus in this challenging environment,” Benjamin adds.

Most recently, Koller served as president of WelCare Group, (Rome, Italy). Prior to WelCare, he was president and chief executive of Dovetail Technologies Inc. (College Park, Md.). Koller also has a long affiliation with Sherwood Davis & Geck (Mansfield, Mass.), subsidiary of Wyeth Pharmaceuticals (Collegeville, Pa.).

Standard aims to reduce FOUP fire hazards

By Mark A. DeSorbo

NORWOOD, Mass.—In its latest installment of guidelines geared to reduce fire hazards and property losses within chip fabs, FM Approvals has issued Approval Standard 4911, “Wafer Carriers for Use in Cleanrooms,” which provides manufacturers and end users with parameters to earn certification from the nationally recognized testing laboratory.

FM Approvals, a division of the risk management insurance organization FM Global (Johnston, R.I.), issued the 4911 because front-opening unified pods (FOUPs) that are presently used by the semiconductor industry to store and transport wafers are made of polycarbonates and polypropylene, which can pose fire hazards.

Heron Peterkin, FM Global's semiconductor industry engineering leader, explains that a typical fab may use 5,000 to 10,000 FOUPs, which are stored in stockers or mini-stockers and managed by a high-voltage robotic handling system, a key ignition source.

“If there's an ignition source, which is commonly electrical, there are plenty of air spaces between the carriers and the wafers, so FOUPs will burn quite well. It's a perfect configuration for burning and it will go up like a stack of wooden pallets,” Peterkin says. “So, for insurance purposes, we'd like to see FOUPs made of non-propagating materials.”

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A stocker-simulation apparatus was used to perform tests at FM Global's Technology Center in West Glocester, R.I.
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The 4911 standard addresses two separate classifications: Class 1A is for situations when the FOUP is designed and approved for use anywhere in a cleanroom, including a stocker environment; and Class 1B when the carrier is designed and approved for use within a stocker environment only.

“One class is for a wafer carrier that can be stored on shelves, and the other is for a wafer carrier that will be stored in stockers, which applies to 300-mm protection,” Peterkin adds.

Peterkin, Peter Wu, a senior research scientist for FM Global Research, and Jeff Gould, FM Approvals' technical team manager, met with end users as well as “a couple” wafer manufacturers, whom Peterkin declined to identify, to discuss what parameters FOUP makers follow when choosing materials used in fabrication.

Tests were conducted at FM Global's Technology Center in West Glocester, R.I.

“And we burned a lot of wafer carriers,” Peterkin adds.

According to a report, the exposure used to qualify Class 1A wafer carriers is typical of a cleanroom, simulating a one-gallon acetone spill fire. The Class 1B wafer carriers represented the conventional exposure in a stocker environment, a robot-picker fire centered in a 3-foot-wide stocker fire.

The FM Global Research test apparatus consisted of two parallel walls, each with six shelves that could individually accommodate two FOUPs for a total of 24 wafer carriers per apparatus. Tests were limited to 10 minutes.
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The test apparatus consisted of two separate freestanding vertical-angle iron frames, with rigid plywood backing attached to the inner surface of each frame. An additional layer of 1-inch insulation board was secured to the plywood backing, while walls were separated 3 feet to allow room for the robotic handling system.

“We performed 10-minute tests, which are somewhat shorter than the usual test, but we needed to set limitations,” Gould says. “We established the top of the array as the pass/fail criteria for flame propagation and monitored smoke generation, which must be less than the established limit.”

In evaluating Class 1A wafer carriers, the outcome of testing had to result in the ability of call components to resist flame propagation and smoke contribution limits.

The performance was considered satisfactory if the flame propagation index (FPI) was less than or equal to 6.0; the smoke damage index (SDI) was less than or equal to 0.4; and 99 percent (by weight) of all materials used in fabrication of the wafer carrier met the requirements of FM Global's 4910 standard. [See “Cleanroom fire safety enters new era,” CleanRooms, June 2002.]

For Class 1B wafer carriers, the results were limited to the ability of an array of wafer carriers to resist flame propagation and some contribution limits. Performance was considered satisfactory if flames did not propagate to the top of the array during the test, the smoke yield was less than or equal to 0.02 ounces after eight minutes of sand-burner operation, the total smoke generated after eight minutes was less than 0.35 ounces, fire did not propagate to the back of the array and the units did not display excessive melting or dripping.

The standard does not address toxicity or out-gassing of materials in fire conditions, but does demonstrate the importance of limiting fire spread and damage without requiring fixed fire protection, the team concluded.

“This is the impetus of what the industry really needs to make better materials for wafer carriers,” Peterkin adds. “Our hope is that we can remove another combustible item from the fab.”

Guidance withdrawal too good to be true

By Mark A. DeSorbo

ROCKVILLE, Md.—The phone in Randall Woods' office began ringing off the hook shortly after the Food and Drug Administration (FDA) announced its withdrawal of a proposed guidance calling for electronic records and signatures for such practices as environmental monitoring.

One of the calls fielded by the Office of Compliance team leader was from Bart Groninger, one of many who read the news about the Code of Federal Regulations (CFR) 21 Part 11 in FDAnews, a daily e-newsletter covering agency activities.

“Usually, I scan the newsletter and dump it, but when I saw the part about Part 11, it was like a 25-foot wave coming at us,” says Groninger, sales and marketing manager for particle counter-maker Climet Instruments Co. (Redland, Calif.). “My first reaction was that this was great, and that it would make things a lot easier, but I found out the wording was a little more dramatic than it had to be.”

The item in the FDAnews said the withdrawal was unexpected and categorized it as a “harbinger for wider change.”

Although the article did indicate the change was necessary to reflect the goals outlined in the FDA's current good manufacturing practices (cGMPs) initiative, Pharmaceutical cGMPs for the 21st Century: A Risk-Based Approach, a reader had to purchase the online newsletter for $8 to learn that the agency was planning to publish a revised guidance by the end of February.

Woods, however, assured a plethora of callers that the guidance for pharmaceutical, food processing and other life sciences environs wasn't simply going away.

“Basically, the reason for the withdrawal is to save companies from spending unnecessary time and money to comply with this, when, in fact, there may be a difference between the draft and what is forthcoming in a guidance document that will be published at the end of this month,” he says.

The goal of the new guidance, Woods says, is to clarify any misconceptions from prior regulations, preserve technological innovations, ensure public health safety and maintain consistency with the agency's initiative to revamp cGMPs.

[Woods] handled it well. He was refreshingly open,” Groninger adds. “The government is trying to look at things sensibly and not leave material out there that is spurious and out of line with their initiative.”

TIR, Aketon partner to develop cleanroom lighting and ceiling package

By Mark A. DeSorbo

VANCOUVER, BRITISH COLUMBIA—TIR Systems Ltd., a specialty lighting manufacturer, and Aketon Technologies, a Corvallis, Ore.-based maker of cleanroom ceiling systems, have teamed up to minimize an expensive and contaminating problem in fabs and pharmaceutical facilities: Fluorescent bulb maintenance.

“It can be substantial,” says Karim Kanani, TIR's market manager for corporate identity. “We've heard some astronomical figures from a variety of problems from fluorescent maintenance in these highly controlled environments; from breakage to cleanup to loss of production time.”

Cleanrooms rated as high as ISO Class 3, Kanani says, have long been targeted by TIR for its Solid State Lighting (SSL), which uses high-output light-emitting diodes (LED). “These LEDS are more energy efficient, consuming seven to eight times less energy,” he adds. “They also have a longer life, up to 100,000 hours, whereas fluorescent light has a life of 10,000 to 20,000 hours.”

Lighting has often been a challenging and sometimes overlooked aspect in the cleanroom, and Brian Mazur, director of sales for Aketon Technologies' Cleanroom Group, believes the package will allow wafer and drug manufacturers to reduce “operating costs and downtime.”

TIR will develop products that integrate directly into Aketon's modular ceiling systems for fabs and pharmaceutical cleanrooms, which are installed in new as well as retrofitted facilities. The plan calls for a pilot facility to be installed sometime this year with production to begin later in 2004, says Kanani.

“Another goal for us is to provide an alternative to the 'white light' that is being dominated by the fluorescent industry,” he adds. “This is a first step towards that.”

Feds investigating “white” particles in blood, refusing to confirm findings

By Mark A. DeSorbo

ATLANTA, Ga.—A Deerfield, Ill.-based drug and medical device maker says the white particles found in donor blood contained in 100 of its pack units are natural forms of clotting, but federal health officials refused to confirm those findings and at press time were still trying to determine what the fragments are and where they came from.

“Our analysis of additional samples from the American Red Cross indicates that the particles are blood-related,” says Tanya Tyska, a spokesperson for Baxter International. “The particles are consistent with white blood cells, platelets and other blood components, and clotting and aggregation are normal functions of blood.”

A spokesperson at the Food and Drug Administration's (FDA) Center for Biologics Evaluation and Research (CBER) declined to comment on the matter and referred CleanRooms to an FDA “talk paper,” which indicated no adverse events, to date, had been reported.

“The exact nature of the particulate matter is under investigation,” the talk paper indicates, noting Baxter's “preliminary” results. “Testing completed to date by the Centers for Disease Control and Prevention (CDC) has found no evidence of infectious agents.”

Initially, the investigation focused on blood and blood components contained in bags manufactured by Baxter that came from Red Cross blood centers in the southeastern United States, including parts of Tennessee and Georgia. The FDA did not provide specifics, but said that it has also received other reports of visible particle concentration in different bag types from other locations and blood banks.

“It is unclear at this time whether all reported observations are similar, or whether all represent abnormalities,” the FDA states.

In the wake of the discovery, which limited blood usage and canceled elective surgeries in hospitals throughout the southeast, the agency has issued recommendations to the blood industry for additional inspection measures and announced that an “interim guidance” for enhanced visual inspection of all blood and blood components would be published.

“This interim guidance is a precautionary measure as the FDA continues to actively investigate reports of units of blood and blood components containing white particulate matter,” the talk paper indicates.

According to the FDA, blood and blood components may, at times, contain small numbers of particles composed of clumped cells or globules of normal substances.

Abnormal particles and increased numbers of particles have recently been noted in some blood units by experienced observers, the agency reports.

However, the FDA says, “the recently increased intensity and enhanced methods of inspections are likely contributing to reporting of some particles that may, in fact, be normal occurrences.”

While the investigation continues, the FDA is asking all blood establishments to implement enhanced visual inspection procedures. If abnormalities are detected, the agency requests that blood establishments quarantine the products and report findings expeditiously to the FDA by sending an e-mail message to [email protected] or by calling 800-835-4709.

Rodents, insects and birds plague food processors

By Mark A. DeSorbo

ROCKVILLE, MD—The Food and Drug Administration (FDA) says it smells a rat—several, to be exact—within a number of food processing and distribution facilities.

In early February, the United States filed a complaint for permanent injunction against SCT Corp., a Baltimore-based firm doing business as Jeppi Nut Co.

An inspection by the FDA found that articles of food at three of SCT's facilities were contaminated with “rodent and insect filth and held under generally unsanitary conditions.”

Listed in the injunction are Theodore Pavlos and Marina Lillie, who referred calls to their attorney Richard Silverman, a food and drug lawyer with the Washington, D.C.-based firm Hogan and Hartson.

Silverman says the injunction came as a surprise because he and company officials had already told the FDA and the Department of Justice that the age of the buildings and their downtown Baltimore location made compliance difficult.

“The company concluded that because of the age of the buildings and their location in downtown Baltimore, where there's a lot of construction and is not a healthy environment, they would have to relocate to remain in compliance,” says Silverman, adding that Jeppi Nut would be moving to a suburb, Timonium, within weeks. “We have been working with the FDA and Department of Justice to resolve the matter and, hopefully, it will be resolved soon.”

The complaint alleges that Pavlos and Lillie have been operating three different facilities in Baltimore under “egregious unsanitary conditions on food products and food packaging.”

“FDA also observed violations involving food processing equipment and various structural defects that provided rodent entry points,” according to the agency.

The FDA is also investigating a number of instances involving rodents and contamination at San Diego Products Inc., a San Marcos, Calif.-based food processor, and Doerle Food Services Inc. (New Iberia, La.).

According to a warning letter, dated January 13, the FDA determined that products were “prepared, packed or held under unsanitary conditions” at San Diego Products.

The conditions observed by compliance officers included rodent activity on food contact surfaces within production, mechanical and packaging rooms. “Rodent pellets, fur and partially consumed nuts were observed on top of the packaging machine stored in the warehouse,” the warning letter says.

Other pest activity noted by compliance officers at San Diego Products included flies; ants around the top rim of a freezer storing dried shrimp and nuts; spiders in packaged products; and dead insects and cobwebs in areas above packing machine hoppers.

San Diego Products was also cited for not providing personnel with suitable outer garments to prevent food and contact surface contamination and for using a rusty, non-stainless steel cement mixer to mix products and spices.

At Doerle Food Services, FDA compliance officers noted, “evidence of rodent and bird activity was observed on and near foods stored in your warehouse” in a warning letter that was also dated January 13.

“This evidence included rodent excreta pellets, rodent-gnawed food packages and bird excreta droppings,” the letter says. “Evidence of bird excreta droppings was observed on the surfaces of food container for several different food products, including grape juice, sugar and seasoning. Evidence of rodent activity was observed on and around food products, including yellow corn meal and sugar.”

By law, Doerle and San Diego Products had to respond within 15 business days of receiving their respective warning letters. Each had to indicate the steps that were taken to eradicate problems and explain if a corrective action could not be completed within that time period.

Canadian biotech company unveils genome-based contamination control technology

SASKATOON, Saskatchewan—Hollywood woos viewers with police dramas that often feature a criminal being sent up the river because his or her DNA was found at the crime scene.

But a biotechnology firm developing genome-identifying platforms wants the life sciences community to tune into its microbial fingerprinting technology that could ensure safer food and drugs and minimize the outbreak of nosocomial infections.

Bio-ID Diagnostic Inc., a six-year-old company based here, is preparing to bring its Multigen technology to market, and principal researcher T.V. Moorthy and executive chairman Roger Hodkinson are hoping it will pique the interest of government-led safety initiatives and ultimately replace presently used microbiology methods that date back to Louis Pasteur.

Kirk Multatz, a research assistant at Bio-ID Diagnostic Inc., loads samples onto an automatic sequencer. The company’s Multigen technology can detect up to 25 organisms in a single sample.
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Such present-day methods, which involve swabbing and culturing, took the Food and Drug Administration (FDA) several days to positively identify the source of a listeria outbreak in the northeastern United States. [See “Welcome back to the jungle?” CleanRooms, February 2003, p. 18]

Calling traditional methods “time-consuming, costly and inaccurate,” Moorthy and Hodkinson say the Multigen technology goes right to the source—DNA and RNA—to simultaneously flush out multiple organisms in a matter of hours.

“In food, we can find E. coli 0157:H7, salmonella, campylobacter and listeria. During hospital admissions, we can screen patients and find super bugs, such as staphylococcus, which can significantly reduce nosocomial infections,” Moorthy says, adding that Multigen can also detect microbial contaminants in drugs.

Like most DNA and RNA testing, the Multigen technology requires the use of a sequencer, some of which fit on desktops, says Hodkinson, an Edmonton pathologist.

Multigen, however, does not require the use of polymerase chain reaction (PCR), which can be problematic, requires a cleanroom and only allows one target to be sequenced at any one time. Instead, the technology uses a proprietary target sequencing method that takes different signatures from the DNA of organisms.

The process, Moorthy explains, involves preparation of DNA, amplification of target DNA segments, like microbes, cycle sequencing using Bio-ID's proprietary modified primers and polyacrylamide gel electrophoresis, the migration of charged suspended particles or molecules through a solution in an electric field.

Multigen, Hodkinson says, can detect up to 25 organisms in a single sample.

“Some organisms are bacteria. Some are viruses. Some are protozoan. We don't have to worry about all the separate culture processes. We go straight to the genome to tell you what it is,” Hodkinson says. “We can also tell you if that bug is alive, just by looking for the RNA.”

“And it is also so sensitive that you can identify one bacterium in a 10-gram sample,” Moorthy adds.

Hodkinson claims that the cost of Multigen would be, at most, half of what current PCR-based DNA testing presently goes for.

“If it's testing the municipal water supply, we can do it for about a tenth of the typical cost of $500,” he says. “We're hoping that suddenly we'll see more industries start testing on a daily basis instead of a quarterly basis and that our technology will transform regulations for numerous sectors.”

Whether it is a food processor, a drug maker or a municipal water department, Moorthy and Hodkinson say Bio-ID can develop “menus” for clients seeking specific types of contamination.

Bio-ID also hopes to develop the Multigen technology as a quality control label.

“Whether it's a pound of hamburger, a water bill or bottle of aspirin, it can be marked as being quality assured, similar to what Underwriters Laboratories does,” Hodkinson adds.


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