Robert J. Pellizzi
Production managers in the medical device industry have long faced the need to determine the appropriate production environment for a given product. It is essential to decide whether a product or process calls for a clean manufacturing environment in which airborne particulates, temperature, humidity, airflow patterns, and other factors are controlled. Beyond that, production managers must also determine whether a clean workstation is sufficient or whether a cleanroom should be constructed.
In making the determination, questions to consider include: Does a cleanroom provide additional benefits that would justify the cost of building and maintaining one? What are the regulations surrounding cleanroom environments? What products or processes dictate the need for such an environment? This article reviews U.S. and foreign regulations and standards that address the need for a cleanroom or controlled environment. Although FDA's good manufacturing practices (GMP) regulation, International Organization for Standardization (ISO) 9000 quality systems standards, and European Norms (EN) documents provide guidelines for building and maintaining cleanrooms, none states what products or processes require such an environment.
DEFINING CLEANROOM
A cleanroom is designed to enable manufacturers to control particulate contamination, temperature, and, where necessary, humidity. It controls the introduction, generation, and retention of particles in the room, protecting the product or process from air- or humanborne contaminants. The main difference between cleanrooms and controlled environments is that cleanrooms must be certified by an independent agency such as the Institute of Environmental Sciences. When discussing cleanrooms, controlled means to develop a specification for a specific parameter, such as air quality, temperature, or humidity; monitored means to track the controlled parameter on a regular basis; and certification is a procedure to verify that the process is under control.
CONTROLLED ENVIRONMENTS
By contrast, a controlled environment is a specified working area that primarily controls one or more physical, chemical, or biological variables. Although a controlled environment is similar to a cleanroom in that it is controlled and monitored, a controlled environment is not certified. Moreover, it is not subject to federal cleanroom requirements for construction and operation.1 For example, one Florida device manufacturer uses a Class M6.5 (100,000) clean area. Technically, it is only a controlled environment because it does not meet airflow requirements established in Federal Standard (FS) 209E. It is, however, regularly monitored for particle concentration, and FS 209E requires that this information be available for FDA inspections or audits.
Once the need for a clean environment has been determined, the cleanliness level must be considered. Both cleanrooms and controlled environments require regular maintenance and cleaning. Each requires limits that dictate appropriate corrective action when the controlled parameter fails to meet established limits.2,3
REGULATORY REQUIREMENTS
The regulations do not indicate what environmental, product, or facility parameters to control. The regulations provide only the standards a company must meet after it decides to manufacture the product in such an environment. Using a controlled environment rather than a cleanroom often equates to significant cost savings during initial construction and in planned, periodic maintenance. The primary reason for building a cleanroom is to account for future economic considerations.4
Several regulations apply to production environments, and many sources provide guidelines for meeting standards set forth in the regulations.57 Section 820 of the Code of Federal Regulations addresses the requirements for medical devices; section 211 addresses pharmaceutical products; and FDA has published guidance based on FS 209E. ISO standards provide specifications to achieve a CE marking, and BS (British standard) 5295 provides standards for that nation. The EN documentation is a voluntary standard in use in Europe. GMPs and other regulations simply describe a set of criteria to which all products and processes--not the cleanroom itself--must adhere. The regulations require that the systems be in control. The methods needed to achieve control are not stated.
ISO standards and GMP regulations provide guidance for setting the parameters for controlling processes. This type of control enables companies to produce consistently good-quality products. The majority of the changes in the revised GMP affect design considerations. Another significant modification affecting cleanrooms is the change in language to coincide with the ISO 9000 series standards.
Although many regulations and standards provide guidelines for design and construction of controlled environments, none--GMPs, ISO 9000, or EN documents-- mandates cleanrooms for certain types of products. GMPs and ISO documents require that all processes be in control, and that certain product types be manufactured in a controlled environment. FDA does not determine whether a company should manufacture a given product in a cleanroom or controlled environment. However, for a company seeking a premarket approval, the approval process is easier if the product is manufactured in a cleanroom. If a company does not use a cleanroom, FDA requires that it validate the manufacturing processes and environment.
If all companies producing a similar product did so in a Class 10,000 cleanroom, then a competitor applying for approval would also likely need to have a cleanroom. Practices by other manufacturers often set the standards for environmental and process specifications. FDA recommends that if a cleanroom is not part of a company's plans, the company should provide documentation, including protocols, that validate the facility and processes.
HOW THE REGULATIONS FIT IN
The GMP sections 820.40 (building) and 820.46 (environmental conditions) state, in part: "Buildings in which manufacturing, assembling, packaging, packing, holding, testing, or labeling operations are conducted shall be of suitable design and contain sufficient space to facilitate adequate cleaning, maintenance, and other necessary operations." In the revised GMP, these sections have been deleted and the subjects are now addressed in section 820.70 (production and process controls):
(c) Environmental control. Each manufacturer shall establish and maintain requirements for the environment to which product is exposed. Where environmental conditions could have an adverse effect on a device's fitness for use, these environmental conditions shall be controlled, and procedures for such controls shall be established and maintained. Any environmental control system shall be periodically inspected to verify that the system is adequate and functions properly. Results of such inspections shall be documented and reviewed.
(f) Buildings. Buildings shall be of suitable design and contain sufficient space to perform necessary operations, prevent mix-ups, and assure orderly handling.
FOREIGN GUIDELINES
Section 3.1.1 of the British standard, BS 5295, states: "Ideally, buildings should be purpose-designed and built but whether newly constructed or modified, the following are basic considerations: part or all of the production shall take place in a controlled area or cleanroom. . ."
Section 4.9.1 of ISO 9001 (process control, general) states: [Manufacturers] shall identify and plan the production, and where applicable, installation processes which directly affect quality and ensure that these processes are carried out under controlled conditions." It also states, "controlled conditions shall include the following: documented work instructions and monitoring and control of suitable process and product."
THE BOTTOM LINE
The final decision for manufacturing in a cleanroom or controlled area is determined by ensuring that processes meet the specifications set forth in written procedures, with audits in place to provide a safe, efficacious product. The type of manufacturing area chosen should not only meet this basic requirement, but also take into account future use of the area and efficient use of available funds.
Much is written about cleanrooms: how to design, build, upgrade, clean, fix, and monitor them. There is very little, however, written on the circumstances that mandate a cleanroom or controlled environment. Some simple steps can make the decision-making process easier.
* Determine the product characteristics and end use, the processes, and the equipment necessary to produce the product. Carefully consider the product and the adverse effects various environmental conditions would have on it. This is particularly important when manufacturing integrated circuits. Consider the effect of humidity. Does the product contain metals that are affected by moisture? Will temperatures affect the hardness of plastic or rubber parts? Will humanborne contaminants adversely affect the process? Does the equipment need special venting, or does it generate a large amount of contamination?
* Decide which type of facility will meet the environmental requirements for the product, process, and equipment. It is important to analyze alternatives to having a cleanroom. For example, for a small packaging operation, a clean workstation or a clean work zone within the manufacturing area may be sufficient. It is also possible to isolate a particular piece of equipment to minimize noise level or contamination. These environments enable the company to establish a level of contamination control without having to construct a cleanroom. For each process parameter there must be a written specification, action limits, and a corrective action plan in place for when limits are exceeded.
* Provide necessary documentation. Formal documentation must detail training programs, processes, and the specifications for the product. Evaluate the regulations carefully.
A decision to build a cleanroom or to control a production environment is often affirmed in situations such as the following:
* The accounting department allocates enough funds to construct a Class 100,000 cleanroom. The company then must upgrade as more money becomes available.
* The engineering department indicates that a cleanroom or controlled environment would reduce the number of rejected products.
* The product's primary competition is produced in a cleanroom.
* Technical publications and industry trade shows indicate a new trend toward a particular class of cleanroom, or control of a specific parameter for some type of process.
* A prospective or long-time customer requests products built in a cleanroom or controlled environment.
* The marketing department can more readily tap a larger market if the company can demonstrate a high-tech image using state-of-the-art automated equipment.
* Having a cleanroom provides leverage for bidding on new jobs.
A recent trend indicates a general shift in the medical device industry away from cleanrooms. Construction costs for a cleanroom facility, along with its maintenance and certification, are extremely high. Average construction costs for a cleanroom range from approximately $260/sq ft for Class 100,000 to about $525/sq ft for Class 100. In addition to this sizable initial investment, normal maintenance costs are about $75/sq ft.
Pat Law of HepaTest, a cleanroom builder and certifier in Longwood, FL, recommends a program of tight limits of environmental parameters, a plan that includes action limits and corrective action when these limits are exceeded, and a monitoring program that includes complete documentation as an acceptable alternative to a cleanroom. Regardless of whether a company uses a controlled environment or cleanroom, self-audits and FDA audits must include data collected periodically to ensure parameters are under control.
THE FINAL STEPS
If eliminating airborne particulate contamination is crucial to a process or product, then a cleanroom is probably the best choice. A Class M5.5 (10,000) satisfies FDA requirements in most situations. This level provides a good background area when critical operations are set to cleaner standards by clean zones (laminar-flow workstations, for example).
When clean air is desirable but not crucial to the product, a cleanroom is unnecessary as long as formal specifications are stated as part of an investigational device exemption, 510(k), or other product application. Monitoring of all environmental parameters necessary to the process is required regardless of whether the product is manufactured in a cleanroom or in a controlled environment. Scientific testing and validation of a product and the processes necessary to produce it may preclude the expense of building and maintaining a cleanroom or controlled environment.
CHOOSING A DIRECTION
Several factors help determine the need for a particular type of facility: type of product, process, and equipment used to produce it, and supporting concepts such as potential business, image, or financial concerns. Emotion will play a part in the decision-making process. An industry rule of thumb states, "Cleanrooms should be two orders of magnitude cleaner than we really need."
The latest revision of the GMP differentiates devices for their design quality considerations. It also includes requirements for Class I devices. Such devices should be manufactured in a Class M6.5 (100,000) or better cleanroom. Packaging operations should take place in a much cleaner zone, preferably a Class 100.
Manufacturers interested in controlling a manufacturing environment or building a cleanroom should investigate the nature of the control or contamination process and its relationship to product yield. Although no formal declaration determines a manufacturing environment, manufacturers should evaluate the possible need for a controlled environment for all Class II and Class III devices.
REFERENCES
1. Schneider RK, Gerbig FT, Lemons R, et al., "What Class of Cleanroom Do You Really Need?" in Proceedings of Cleanrooms '91, Flemington, NJ, Witter Publishing, pp 101105, 1991.
2. Pellizzi RJ, "Cleanrooms and Controlled Environments: What is Needed? What is Recommended?" in Proceedings of Medical Design & Manufacturing East, Santa Monica, CA, Canon Communications, pp C1-1C1-4, 1994.
3. Hansz TE, and Linamen DR, "Planning, Design, and Construction of a New Cleanroom Facility," in Proceedings of Medical Design & Manufacturing East, Santa Monica, CA, Canon Communications, pp C2-1C2-32, 1994.
4. Matthews RA, "The Cleanroom Edge: Does Your Company Need It?," in Proceedings of Medical Design & Manufacturing East, Santa Monica, CA, Canon Communications, pp C2-1C2-32, 1995.
5. Code of Federal Regulations, 21 CFR 820.
6. "Working Draft of the Current Good Manufacturing Practice (CGMP) Final Rule," Docket 9ON-0172, Rockville, MD, FDA, Center for Devices and Radiological Health, 1995.
7. Quality Systems--Model for Quality Assurance in Production and Installation, ISO 9002, Geneva, Switzerland, International Organization for Standardization, 1987.
Robert J. Pellizzi is general foreman for Cordis Corp. (Miami Lakes, FL).
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