In today's competitive market, many outsourcing companies claim to run top-of-the-line cleanroom facilities for packaging sterile medical devices. But not all cleanrooms are the same.

It is important to understand that fundamental differences exist between cleanrooms for medical device manufacturers and cleanrooms for manufacturers of machinery, optical products, high-end electronics, and other devices not intended to penetrate the skin or interact with open wounds. Medical OEMs that produce orthopedic or spinal implant technologies, for example, require cleanrooms that demonstrate extremely low bioburden rates as well as those that can restrict airborne particles. Airborne particles are the enemy of hard drives and microchips, whereas both particles and microorganisms pose a threat to medical devices.

Medical device OEMs need cleanrooms that have an established platform of technology and biocontamination protocols that extend through component preparation, product assembly, packaging, and testing of sterile medical devices and surgical products.

Since quality is a key factor in the success or failure of many medical device manufacturers, how does a medical device maker search out a facility that packages a product to current rigorous standards? This article presents 10 questions that medical device manufacturers should ask potential partners and themselves when choosing a cleanroom service provider.

1. Does the Cleanroom Actually Exist, or Is It Simply a Marked-Off Area?

Many outsourcing companies recognize the value of cleanroom services to their customers. However, some have not invested the time, attention, and financial resources necessary to build a cleanroom facility that meets the sterilization standards required by medical device manufacturers. Cleanrooms must be constructed with the proper components in order to meet these standards. These components include a separate air-conditioning system and sealed, particle-free ceiling tiles. Also important are plenum grids that enable proper placement of HEPA filtration units at optimal locations as well as hollow-wall air returns that allow previously cleaned air to be recycled. Such returns extend the life of the HEPA filters cleaning the air.

Ideally, cleanrooms should employ technologically advanced systems that control airflow direction and rates. They should also use calibrated and validated equipment to measure pressure, relative humidity, particles, and temperature within the operating space. Equipment, workspace fixtures, and accessories and supply bins can all be cleanroom certified, meaning that each item reduces particle production and can be thoroughly cleaned to limit biocontamination. Cleanroom specialists wear protective garments and are trained in sterilized packaging techniques, cleaning protocols, and system-monitoring practices. Personnel and packaging materials enter the cleanroom through air-lock doors on entrances and exits that maintain the appropriate room pressure and temperature.

The best way for an OEM to know whether a cleanroom is truly clean is to audit the facility. Ask the outsourcing partner to provide an in-depth tour, and then ask to see the outsourcer's annual cleanroom calibration data and quarterly bioburden test results.

2. Is the Cleanroom Fully Integrated into the Quality System?

The integration should include comprehensive corrective and preventive action protocols to thoroughly address all cleanroom excursions. Outsourcers have a responsibility to their customers to measure, track, and realign any potentially harmful conditions in the cleanroom. Outsourcing companies that take this responsibility seriously are always on the lookout for opportunities to improve their cleanroom systems.

The outsourcer should have a written plan that it can provide to OEMs. Such a plan should provide for revision procedures for aberrant excursion measures and have defined alert and action limits (similar to those for any other department). The plan should also cover cleanroom maintenance and technician training and include up-to-date drawings for equipment placement within the cleanroom. As part of the response plan, any equipment or gauges used to measure cleanroom contaminants must be regularly calibrated and recorded in a calibration log. The best cleanrooms develop their protocols so the parameters dovetail with the standards for their class of cleanroom.

An OEM should engage an outside auditor to assess the validity of the outsourcer's overall plan. The auditor should also perform regular evaluations of how well the outsourcer is adhering to its own processes and how effectively it responds to any quality concerns.

In addition, the cleanroom's pressure, temperature, and humidity levels must stay within the action limits defined by the revision procedures. The company must also perform quarterly bioburden assessments, track excursions, and record how problems have been addressed and corrected.

Finally, training records for the cleanroom technicians must match up with the current quality control plan, the drawings used to show equipment placement must be current, and the cleaning log should be used and kept up-to-date. If any of these actions are not performed or are underperformed, the OEM should view that as a red flag.

3. Does the Cleanroom's Layout Promote Efficiency and Reduce Biocontamination?

Cleanrooms are expensive to build and maintain, and for this reason, each square foot of a cleanroom facility is valuable. The more streamlined the packaging progression by way of the assembly process and traffic patterns, the more cost-efficient the overall sterilized packaging service will be for an OEM. Moreover, the design of a cleanroom also contributes to the flow of air in and out of the room, which relates to the number of particles and microorganisms in the air and on work surfaces.

A well-conceived cleanroom layout, including placement of workstations and machines in relation to walls, enables air to move with uniform velocity and along parallel flow lines, also known as laminar flow. Laminar flow reduces turbulence, which in turn reduces particle production and the introduction of microorganisms. OEMs should seek out packaging partners that consider airflow concerns as well as production capacity when designing their cleanroom footprint.

4. Is Cleanroom Maintenance a Priority?

It sounds obvious, but it bears repeating that a cleanroom is only as good as it is clean. Contamination, in the form of particles and microorganisms, can come from spills and leaks, employees' skin and clothing, cleaning chemicals and debris, and other outside agents. Many providers of cleanroom packaging services build state-of-the-art facilities that could conceivably address the sterilization requirements of medical device manufacturers. But such cleanrooms cannot consistently prevent the contamination of an end product if they are not maintained with strict protocols. In addition to using proper cleaning procedures, outsourcing partners should use only cleaning products, from disinfecting solutions to tools, that are certified for use inside cleanrooms.

Effective management of the cleaning process is also critical. Outsourcers should employ a regular schedule of facility maintenance that is documented, tracked, and trended to prevent quality breaches. Regular testing of potentially contaminated surfaces should be part of these standard operating procedures. OEMs should review the outsourcing company's maintenance log records to evaluate the strength of the maintenance program and, more importantly, its implementation.

5. Is a Validated Ultrasonic Clean Line Attached to the Cleanroom?

When a product arrives at an outsourcing company's facility, it is just beginning its journey through a minefield of opportunities for contamination. Without an ultrasonic clean line to give products the once-over before they enter the cleanroom, products bring with them all the biohazards they have picked up along the way. The end result is increased bioburden within the cleanroom and increased risk of product contamination. Companies without clean lines attached to their cleanrooms are often forced to clean products in the machine shop before the products go through processes like receiving, inspection, and etching. With cleaning as the last step before the product enters the cleanroom, much of the variability is removed. The chances of bioburden spikes are limited to the packaging process, which is the easiest to control because it occurs within the cleanroom.

Ultrasonic lines differ, but an effective line might use several deep-water tanks in which devices are submerged for a three-step cleaning process that employs ultrasonic sound waves. In the first tank, products are lowered with a robotic arm into heated water mixed with a mild detergent. Sound waves create implosions as bubbles hit the products and remove particles. The second tank is the first of two rinse tanks. The water in the second tank, also heated, removes the detergent and any remaining particles with sound waves as well as with cascading water that comes from tank three. Products are moved to the third tank for a final rinse and are then air-dried or dried with hot-air dryers. Using a robotic arm throughout the cleaning of a particular product enables the outsourcer to maintain process consistency for all items.

However, having a clean line attached to the cleanroom is only the first step. For outsourcers to effectively utilize their clean lines, they must perform regular validation testing, including bioburden and, specifically, endotoxin levels. Such validation testing confirms that the clean line is actually reducing the potential for contamination. Medical device OEMs should know at which point their product is cleaned prior to packaging. They should seek outsourcing partners with validated clean lines that serve as the last stop on the road to the cleanroom.

6. Has the Cleanroom Been Audited Multiple Times?

Outsourcers should welcome audits, as painful as they might be. They should accept audits from any source, including clients, FDA, and ISO registrars. Audits should be seen as opportunities to consider an objective view of a company's cleanroom policies and procedures and a possibility to enhance the sterility of its cleanroom facility.

Audits are often performed for a number of reasons. FDA audits may occur as a part of a client's application to market a new invasive device. Or, an audit may be a spot-check of a particular vendor. The best outsourcing companies will take the opportunity to gain the confidence of FDA by demonstrating both their expertise and their willingness to learn from the experience and further refine their processes.

Gaining ISO cleanroom certification is another important measure for outsourcers to take. Although some ISO auditors are less stringent because they lack expertise in a particular discipline, most have technical experience in auditing sterile packagers and employ microbiologists who specialize in sterilized cleanroom procedures. In any case, outsourcers must ensure that microbiological controls and particulate counts are audited annually by an outside entity, and OEMs should ask how often and by whom a potential outsourcing partner is audited. In addition, it is important for OEMs to examine the observations that resulted from those audits and how those recommendations were incorporated into the outsourcer's overall quality control plan.

7. Is the Cleanroom Staffed with Experienced Sterile Packaging Technicians?

There are at least three ways cleanroom personnel can affect bioburden levels in a sterile environment. Those ways include what they wear, how they behave, and how they help maintain cleanroom protocols. People in general are a leading dissemination source of particles and microorganisms through their hair, skin, clothing, cosmetics and perfume, and respiratory emissions. Cleanroom specialists are trained to limit cosmetics and perfumes and to wear garments appropriate for specific cleanroom standards, such as gowns, caps, shoe coverings, gloves, and even face masks. Behavioral requirements, including rate of movement, minimize the transfer of microorganisms and particles.

Finally, regular training reinforces the importance of cleaning procedures and facility maintenance. Medical device OEMs should choose outsourcing partners that hire sterile packaging technicians with cleanroom experience and that invest in their personnel by providing specialized training.

8. Is Testing Paramount?

Even with all the necessary pieces in place, a cleanroom can be a toxic environment if a system breaks down. Outsourcers that use testing to remain vigilant can assure their clients that products meet the highest sterilization standards. Tests that should be performed quarterly include testing of bioburden levels, such as microbial air and surface tests, and dose audits to ensure that products meet validation specifications.

Endotoxin levels in the water of the ultrasonic clean line should also be tested regularly to avoid any contamination to products before they enter the cleanroom. And, of course, all test results must be tracked and trended. A cleanroom should have extremely low bioburden levels, meaning that there are low amounts of bacteria and mold in the air and on surfaces.

Outsourcers should maintain the trend reports to document low bioburden levels. Low bioburden counts are generally 5 CFUs (colony-forming units) or fewer for surface readings. For air readings, low bioburden counts are usually 20 CFU or fewer.

Testing offers an outsourcing company the chance to increase the frequency of cleaning, switch cleaning solutions, or modify maintenance protocols if necessary. OEMs should consider the testing performed, as well as the quality of the test results, a make-or-break part of an outsourcing partnership.

9. Does the Cleanroom Run a Particulate-Monitoring System?

Some outsourcers measure particulate levels every minute at each workstation using a particulate-monitoring system (PMS). This additional testing provides the proof that products were packaged within acceptable particulate levels and provides an opportunity to correct an excursion issue before products ship out. A PMS can provide tight real-time monitoring and control.

Until recently, monitoring particulates has been reserved for firms in the pharmaceutical industry. Today, more and more medical device OEMs are in search of companies that run cleanrooms that meet rigorous sanitation requirements. The U.S. standard (Federal Standard 209E) for cleanliness results in a distinction of Class 100,000, Class 10,000, or higher (see Table I). This distinction reflects the number of particulates found in the air. For example, a Class 10,000 cleanroom is one that requires that there be no more than 10,000 particulates in the air at a given time.

A PMS allows for real-time measurement of particulates, relative humidity, pressure, and temperature at one-minute intervals, 24-hours a day, via sensors mounted above workstations throughout the cleanroom. The sensors take readings and report back to computer software that sends an alert if any measurement falls outside of an approved range. Currently, few outsourcing companies use a PMS for sterile medical device packaging. In fact, most outsourcers take quarterly readings and use those results to certify that all products processed within that quarter were packaged at acceptable levels.

The benefit of having a PMS is that if the particulate levels rise significantly, the outsourcer can make an appropriate adjustment right away. Quick adjustments help ensure that all packaged products meet the OEM's quality specifications.

10. Do I Trust This Company?

To provide its OEM partners with packaged medical devices that come as close as possible to sterilized perfection, an outsourcing company must meticulously plan and construct a cleanroom, establish an interrelated set of protocols, and adhere to strict guidelines. Trusting that an outsourcing partner has the expertise and integrity necessary to run an effective cleanroom can be a tall order for OEMs. There are many opportunities for error throughout the process, and every product that clears the sterile packaging process and is then distributed has the potential to aid or to harm a patient. A single product recall that results from compromised sterility of an improperly packaged device can be catastrophic, in terms of both potential patient risk and the OEM's financial survival.

Medical device manufacturers, which often must rely on outsource partners to provide outstanding packaging services, should know as much as possible about the cleanrooms that process their products. As OEMs search for an outsourcing partner that they can trust, there are a few factors they should consider carefully. The best outsourcing partners will be those that can demonstrate their cleaning standards and capture the details in their logbooks. In addition, the company's training of its staff, the frequency of its testing and auditing, and its ongoing improvements to the cleanroom are also critical.

Conclusion

Medical device manufacturers are under both cost pressures and intense scrutiny over quality concerns. The race to enhance market performance often requires OEMs to rely on outsourcers to provide critical functions, such as sterile packaging. Outsourcing can be highly effective but can also jeopardize product quality. Finding the right outsourcing relationship becomes even more important as the standards for sterilized packaging are strengthened in the United States and abroad.

To choose the best outsourcer to provide sterilized packaging services, OEMs must evaluate each potential provider's approach to cleanroom design and operation. The variety of factors that make a cleanroom service successful boil down to one essential ingredient: the integrity of the outsourcing company. It is the OEM's responsibility to assess the outsourcer's level of competence through facility inspections, periodic reviews, and the imposition of specific requirements for testing and reporting. Trust can be earned, but OEMs should make their outsourcing partner earn that trust again and again.

Kelly Lucenti is president of Millstone Medical Outsourcing (Fall River, MA). He can be reached via e-mail at [email protected].

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