To consider the controls needed for clean environments in this market as simplistic would be a mistake, especially with the rise of bioMEMS
by Chris Anderson
If there is such a thing as a typical clean environment for medical device manufacturers it would be an ISO Class 8 (Class 100,000) cleanroom accompanied by strict procedures to eliminate any chance of biological contamination on the finished product. In most cases, ESD, AMD and other considerations that are top-of-the-mind when it comes to running a cleanroom in the IC sector hold very little sway in medical manufacturing.
But, to consider the controls needed for clean environments in this market as somewhat simplistic would be a mistake. Still, given the relatively “dirty” environments typically employed, the medical device industry is diverse and the needs for a variety of controlled environments stretch from ISO Class 8 (Class 100,000) rooms to ISO Class 6 (Class 1,000) and even ISO Class 5 (Class 100). Many manufacturers that were interviewed for this story can see the day in the not-too-distant future when their operations will need to be even cleaner than they are today.
At Haemonetics Corp., a manufacturer of blood handling and blood component separating devices, the company's cleanroom is as sophisticated as any in the IC industry, says Bob Ebbeling, senior vice president of manufacturing.
The 30-year-old Braintree, MA, company has moved up the evolutionary clean environment chain over the years. Its current ISO Class 7 (Class 10,000) room operates at a much higher level, with monitored particle levels routinely registering around ISO Class 5. Using the lessons he has learned over the past 15 years, Ebbeling has a warning for others preparing to build their own cleanrooms. “You just can't go with the lowest square-foot bid from a contractor,” he says. “It's important to understand exactly how the cleanroom operates, the systems used and how that affects the movement of particles.” Having that information is vital to creating the clean space a medical manufacturer will need for its particular product.
Clean and sterile
While medical device manufacturers pay attention to the particle levels in their clean environments, they are equally stringent about preventing biological contamination of their products. The need to control what the industry calls “bioburden” has very little to do with the operation of the cleanroom per se.
“Our procedures for gowning, ingress and egress are very detailed,” says Nigel Wilkinson, vice president of regulatory affairs and quality at Smith & Nephew, a U.K.-based manufacturer of endoscopy and arthroscopy instruments. “And our standards for employee hygiene are very prescriptive.”
Photos by Carita Stubbe and provided by courtesy of MicroCHIPS Inc.
For Smith & Nephew and other medical manufacturers, this means that clean environment employees who are feeling a bit under the weather are evaluated by the production staff. If they are deemed too sick, they are re-assigned to other duties outside the cleanroom until they are considered sufficiently well so as not to pose a threat of contaminating the product.
“Like most cleanrooms, the biggest concern and source of contamination is the people who work there,” says Al Descoteaux, director of quality assurance at Nypro Inc., a contract medical device manufacturer in Clinton, MA. “That means we have to train our workers in the proper procedures and what they always need to do before entering the room.”
At Haemonetics, after new employees are trained in proper procedure, they are teamed with cleanroom veterans who've maintained a level of performance and can help the new employee habituate the anti-contamination procedures.
While limiting bioburden is best accomplished before an employee sets foot in the cleanroom, most medical devices that will make any kind of contact with the patient also are sterilized before shipping. So why is there such a fuss about bioburden and particle levels?
“Sterilization only does so much; it kills anything that might be living on the device,” says James Transue, director of product development for Micro Stamping Corp., Somerset, NJ. “But even if it is dead stuff on the product, you don't want very much of it, and the only way to control it is to have a method of limiting the amount that could get on the finished product.”
In the future there may be other pressing reasons for limiting bioburden and particles, says Steve Cassaro, supervisor of micro labs at the Petaluma, CA, manufacturing facility of Guidant Inc., a maker of implantable cardiac devices. “Right now we have two basic methods of sterilization: ethylene oxide and gamma radiation,” he says. “In the case of radiation it is an overkill situation. But in the future we may be looking at delivering more precise doses of radiation based on the level of bioburden, which would mean a much shorter sterilization cycle time.”
The need to be cleaner
Many companies operating in the medical device industry don't see a cleaner future for their operations. Primarily because of the nature of their products, the need to move beyond ISO Class 8 is an expense with no benefit.
At Haemonetics, this is not the tack the company has taken. “We feel it is very important to our customers that we be very clean in what we do,” says Ebbeling. “We've learned our lessons on how to run our clean environments and we feel it is a competitive advantage for us to be as clean as we are.”
Haemonetics chooses to be cleaner. But other sectors of the industry-particularly devices using micro electromechanical systems (MEMS)-have many of the same contamination control requirements as the IC industry and thus need to be cleaner.
These devices-bioMEMS-can be as small as a grain of rice and combine an integrated circuit with devices such as pressure sensors and fluid-flow controls. The applications of bioMEMS are numerous-ranging from implants that can measure the pressure inside a glaucoma patient's eye and devices designed for the timed release of medication to sensors used on the tips of minimally invasive surgical instruments.
“In the future we may be looking at delivering more precise doses of radiation based on the level of bioburden, which would mean a much shorter sterilization cycle time.”
– Steve Cassaro
“Our clean requirements are really no different than the requirements of others in the IC industry,” says Dr. Douglas Sparks, vice president of operations with Integrated Sensing Systems Inc., a maker of pressure sensors and fluid-flow MEMS. “The one thing that is different is that we monitor our environments for bacteria.” As a result, the five-year-old company based in Ypsilanti, MI, runs an ISO Class 5 (Class 100) cleanroom.
Other MEMS companies are in the early stages of product prototyping and are essentially discovering as they go what level of cleanliness they need to make a viable product. Such was the case at BioMicro Systems, a Salt Lake City-based start-up that has developed fluid-control devices used to control DNA and protein samples.
It currently operates in an ISO Class 8 (Class 100,000) environment out of necessity. “Our devices have micro channels as small as 20 microns that very precisely control the flow of fluids,” says Ming Lei, senior microfluidics engineer with BioMicro. “At one time we were operating in a lab without environmental controls and the results were just terrible, because the smallest piece of dust can affect the liquid flow within the channels.”
Not surprisingly, product quality has gone up since the move to the cleanroom, but Lei predicts that the operation may need to get even cleaner in the future. “We are developing new devices with smaller channels, so it is very possible that we will have to move up to an ISO Class 7 (Class 10,000) room, at least, perhaps within a year.”
MicroChips Inc. in Cambridge, MA, is another bioMEMS company whose device controls the flow of fluids. In MicroChips' case, it is a two-centimeter-square implantable device that delivers regular doses of medication, over a period as long as a year. While the opening where the medication is delivered is as small as 50 microns, Jack Herman, vice president of product development, says there has yet to be a case where a particle has obstructed this opening. “We've already capped that 50-micron opening as part of the MEMS process and etched the reservoir. Because these reservoirs are only exposed in the IC MEMS fab environment, cleanliness of the opening will not be a risk for us.”
Unlike many medical device companies, MicroChips also pays strict attention to ESD. “We are very conscious of surface charge, particularly of the silicon, because it can affect our filling capability,” says Herman. “We are typically depositing in a liquid filling situation maybe 100 nanoliters of liquid. We like to control the drop shape, and that needs to line up fairly precisely for us to use an automated filling system.”
When it comes to medical devices, there is one other player that bears mentioning-the Food and Drug Administration (FDA). Both fledgling medical device manufacturers and established companies with new products must pass muster with the FDA through a series of trials to prove that the new device does what it's intended to do and doesn't cause harm to the patient.
While the approval process is rigorous, the FDA is not nearly as prescriptive in telling device manufacturers either how to run their manufacturing operations or how clean they need to be. More important is that the company has a solid quality program in place and that it performs according to the plan.
Though the FDA can spot-check a company at any time, those companies that have proven themselves to be reliable are not usually subjected to such inspections. “We have a very good relationship with the FDA,” says Connie Speck, director of quality assurance with Guidant. “They will usually let us know when they are going to come by.”
In the end, the cleanliness drivers in the medical device industry are not regulatory; rather the means each particular company has discovered is the best method of delivering quality products to the market. In essence, the cleanroom drivers of the medical device industry are no different than others that require controlled environments.