Medical Device Manufacturing Environments - A commentary

By Scott Mackler

For those concerned with developing requirements for aseptic processing or semiconductor wafer fab environmental specifications, the choices are easy: there essentially are none! For critical environments regulated by the U.S. Food and Drug Administration (FDA), the compliance limits are widely published and understood. One could argue about how appropriate the guidelines really are, especially since environmental specifications are not product specifications and in light of the current focus on sustainability, the FDA guidelines may be deemed too conservative. However, the fact remains that the guidelines are clear and product safety is No. 1. Likewise, we can readily discern what the killer particle size is for die production based on line width, and go from there.
What about all of the other cleanroom applications? In particular, and of late, we have seen a trend of specifying pharmaceutical quality cleanliness grades creep into Class II and Class III medical device facilities. Whether this trend is due to pharma companies acquiring medical device firms as part of the global move toward consolidation, or perhaps regulators "borrowing" from the pharma cGMP guidelines, the end result is a non- value- added increase in capital and operating cost during a time when facilities can least afford such largesse.
The recommendations provided in the FDA “Guidance for Industry for Sterile Drug Products Produced by Aseptic Processing–Current Good Manufacturing Practice” often are used as an environmental specification in the absence of a specific guidance for medical devices. For many mature and well-controlled processes, there would appear to be no value added and no useful decrease in risk to be gained by arbitrarily imposing aseptic processing guidelines onto device manufacturing production lines.
So, while it may seem strange for a cleanroom consultant to take the position that a cleanroom is not required, what we are really doing is asking for a thoughtful diagnostic assessment before moving forward with seemingly arbitrary requirements just because “we have always done it that way.” I offer below the following excerpts in the sincere desire to help companies effectively optimize their business models. Note that “CNC” as used below refers to “controlled not classified”, a room that exhibits temperature and relative humidity control, however HEPA filters are typically not employed for final filtration.
The FDA Medical Device Quality Systems Manual makes the following statements:
“A controlled environment is, to various degrees, an integral part of most production facilities. Some environmental factors to be considered are lighting, ventilation, temperature, humidity, pressure, particulates, and static electricity. Section 820.70 (c), Environmental Control, of the QS regulation, is considered by the FDA as a ‘discretionary’ requirement: that is, the degree of environmental control to be maintained should be consistent with the intended use of the device and details of how to achieve this control are left to the manufacturer to decide.
“The manufacturer should analyze the operations to identify the controls needed for the finished device to meet the specifications and be fit for use. Many Class I and Class II devices may require only comfort HVAC or at best, CNC.”
Further, the FDA Medical Device Quality Systems Manual, Buildings and Environment section states the following while clearly recognizing that an environmental specification is not a product specification:
“…When it is necessary to control the environment, specifications for parameters such as temperature, humidity, colony forming units (CFUs), and particulates per cubic foot, etc., should be established. No FDA guidances for these parameters presently exist for environmentally controlled areas such as cleanrooms. Federal Standard Airborne Particulate Cleanliness Classes In Cleanroom and Clean Zones (FED-STD-209E) with its appendices is suggested as a resource for developing cleanroom standards such as particle counts per cubic foot. Federal Standard 209E defines various levels of environmental control such as Class 1000. A Class 1000 room contains no more than 1,000 particles 0.5 micron diameter or larger per cubic foot of air.”
Information may also be obtained from manufacturers of cleanroom equipment. Aseptic manufacturing and filling are usually done in a Class 100 or better cleanroom or bench. The Class 100 status is maintained during routine operations. During idle periods the particle count will generally be much lower than 100. Some manufacturers use a Class 10,000 cleanroom for the assembly and packaging of devices that will be terminally sterilized and where a low particulate count on the devices is desired.
For assembly of many types of convenience kits and assembly of medical devices that need to be free of visible particles, many manufacturers use an “industrially clean area or controlled environment area”. Such rooms are air conditioned and use furnace filters and, in some cases, pre-filters of much finer porosity than furnace filters are also used. The temperature is controlled by a standard room thermostat. Humidity variations are limited by common air conditioning. True air conditioning with cooling below the dew point and reheat are not necessarily used. Air velocity is determined for the air conditioning; and the room is known to have positive pressure with respect to other areas by a flow or pressure indicator.
A particle class is not specified. However, these manufacturers have established a controlled environment and appropriate specifications for temperature, cleaning, and contamination controls are in place. For example, filters should be replaced per schedule or as needed based on scheduled inspections. Any practices or factors from the following list that the manufacturer has deemed appropriate and elected to use should be specified and routinely performed or followed. Some additional factors that should be considered when planning and using a controlled environment include:

• proper attire and dressing anteroom;
• controlled use of, and entry into, controlled areas;
• prohibiting eating, drinking, smoking, or gum chewing;
• preventing use of lead pencils;
• regulating the storage of glassware and containers;
• preventing or controlling the cutting, tearing, or storage of cardboard, debris, etc.;
• cleaning the room and production equipment per written procedure;
• the original design and cleaning of work surfaces and chairs;
• selecting correct furniture and eliminating all nonessential equipment;
• controlling room air quality (amount of particulates, pressure, velocity, and exchange rate);
• eliminating electrostatic charges by controlling work surface composition or grounding;
• ensuring cleanliness of raw materials, components and tools;
• controlling the purity, sterility, and nonpyrogenicity of process water; and
• maintaining prefilters, HEPA filters, and electrostatic precipitators.
  

An appropriate system for regular monitoring should be established and maintained for each of these factors to be controlled for a given operation. This will ensure that equipment is performing properly and that the quality of the environment is within specifications. When a particle count Class is specified, monitoring of airborne particulates is usually done with an air sampler. Monitoring of work surfaces for microbes [colony forming units] maybe done with surface contact plates or settling plates. All sampling should be done per written procedure, and the data should be recorded. Further, periodic inspections of environmental controls and documentation of the inspections are required by the QS regulation. The inspection check off form or other record should be kept simple.
So, if in many cases all the facility operator is looking to do is control visual particulate (in the range of 50 microns more or less) and maintain a reasonable concentration of airborne microbial contamination, other than the fact that they expect to see, say a Class 10,000 cleanroom, because everyone else has one, what is the right answer?
A controlled environment is a system. A cleanroom does not make things clean, nor does it keep things clean. Products simply get dirty slower in a cleanroom. With the right combination of housekeeping, operating, and gowning protocols, as well as product, component, and materials cleaning and verification, it is possible to avoid the 60 or so air changes an hour over a HEPA that is so often specified without good reason.