Understanding the Critical Components of a Successful Cleanroom & Barrier Isolator Project

by Hank Rahe

A number of publications describe the clean room environment required for an i.v. preparation area.(1-5) The engineering detail required to specify and develop the facilities and equipment is lacking in the routine literature and training that are available to pharmacists. To provide a quality, cost-effective i.v. area, it is essential to understand the basic components of a cleanroom and a carrier isolator system. The technology for each has several elements that directly affect the cost, efficiency, and dependability of the system. Understanding and evaluating these components are critical to a successful project. Written specifications based on pharmacists' needs will help ensure compliance by vendor companies.

Most states require that i.v. products be prepared in a class 100 environment, as defined by Federal Standard 209E, "Airborne Particulate Cleanliness Classes in Cleanrooms and Clean Zones."(4) A cleanroom is defined as a room in which the concentration of airborne particles is controlled and that may contain one or more clean zones. The clean zone is a defined space in which the concentration of airborne particles is controlled to meet a specific cleanliness class. The purpose of Federal Standard 209E is to establish standard classes of air cleanliness that are based on specific concentrations and sizes of airborne particles. The document prescribes methods of verifying air cleanliness and requires that a plan be established for monitoring air cleanliness. The cleanliness classes define the maximum number of particles of a prescribed size allowable in a cubic foot of air. For example, class 100 describes air with now more than 100 particles of a size of 0.5 um or larger per cubic foot.

The standard requires verification and monitoring of airborne particulate cleanliness. Factors required under this section include frequency, environmental test conditions, and particle counting. Frequency indicates that, after initial verification, tests shall be performed at periodic intervals or as otherwise specified. Environmental test conditions define specific operational conditions, which include the status of the cleanroom during verification (i.e., as-built, at rest, operational, or as otherwise specified) and environmental factors such as air velocity and pressurization. Particle counting is a means of verifying air cleanliness with an appropriate counting method.

Four basic components define a controlled environment like a cleanroom and a barrier isolator system: the physical structure, the internal environment, interaction technology, and monitoring systems. Properly understanding and selecting each of the components and specifying needs to a vendor will provide an aseptic environment. To provide an aseptic environment, an effective sanitization program must also be implemented.(1,6)

Cleanroom and laminar-airflow technology

Cleanroom and laminar-airflow technology was developed primarily to protect the product within the laminar-airflow environment. It also has an application for personnel protection when combined with the proper level of precautions. The lower protection limit is approximately 30 ug of airborne active-substance particles per square foot.

Phsycial structure. Selection of materials and the method of construction affect costs. The selection of construction materials should be made on the basis of durability, whether the material’s surfaces can be cleaned and sanitized and how easy it is to do so, resistance to chemicals, and location. Construction materials come in two basic types, hard shell and soft shell. Soft-shell, or flexible, plastic cleanrooms are not as durable as hard- shell cleanrooms and have surfaces that are usually more difficult to clean and sanitize; therefore, they should be considered only temporary.

Typical specifications for defining a hard-shell cleanroom are as follows:

  1. Walls may be modular, having locking panels with all joints sealed or epoxy-coated wallboard. All coverings and sealing materials shall be resistant to cleaning and sanitizing agents. Materials should be approved by the Food and Drug Administration (FDA) and the U.S. Department of Agriculture (USDA).
  2. The walls and ceiling must have smooth, cleanable surfaces. The interface with the floor and ceiling should be sealed with FDA – and USDA – approved materials and coved to facilitate cleaning.
  3. The floor shall be covered with sheet vinyl that is heat sealed or thin-set epoxy resin. The floor surface shall be seamless and cleanable. All coverings and sealing materials shall be resistant to cleaning and sanitizing agents. Materials should be FDA and USDA approved.
  4. Architectursl details, such as windows, doors, pass-throughs, and utility penetrations, shall be as ledge free as possible. Window and door frames are to be constructed with double panes and flush frames.
  5. The ceiling shall be constructed of epoxy-coated gypsum board or in-laid panels. If the inlaid panel option is chosen, the panels must be impregnated with material that makes them impervious and hydrophobic. Panels are to be sealed or gasketed to the frame and tied down. The frame materials of construction shall be epoxy coated or anodized.
  6. Ceiling penetrations are to meet the following requirements: (a) sprinklers should be flush mounted, (b) lighting fixtures should be flush mounted, with smooth, sealed, airtight, exterior-mounted lens surfaces, and (c) utility penetrations are to be caulked or sealed with approved materials.
  7. The cleanroom design should contain a pass-through for materials entering the room from the anteroom. This reduces the potential for contamination by lessening traffic between the two rooms.

Internal environment. The internal environment is created by filtration of the air entering the room through a high-efficiency particulate air (HEPA) filter. The classification of the air quality, in terms of particulates, is a function of the number of air changes, the efficiency of the filters, and activities occurring in the area. The integrity of the environment is created by the physical structure and the pressure differential compared with adjacent areas. People are the primary source of particles generated in a cleanroom. The amount of particles generated is a function of the number of people, the quality of gowning, and the physical activity of the people.

Typical specifications for the internal environment are as follows:

  1. Good cleanroom design should be followed in the placement of incoming HEPA-filtered air sources and the room air returns. The room should be mapped to determine uniform air quality.
  2. HEPA filters are to have manufacturers’ certifications indicating a minimum efficiency rating of 99.97% removal of particles larger than 0.3 um.
  3. The HEPA filters are to be flush mounted and sealed into the ceiling grid.
  4. The cleanroom is to be designed and evaluated to meet the proper classification while it is in operation. The number of air changes is a function of the classification of the cleanroom and the activity taking place in the area. For example, class 100,000 would have 20 air changes per hour, class 10,000 would have 50 air changes per hour, class 1,000 would have 80 air changes per hour, and class 100 would have 100 or more air changes per hour.
  5. The cleanroom must have a positive pressure differential relative to the surrounding areas that can be monitored.(7,8) All openings, including doors and pass-throughs, need to have adequate seals to maintain the positive pressure differential.

Interaction technology. Interaction technology for cleanrooms includes two elements: the movement of materials into the area and the movement of people. Typically, the contamination challenge to the cleanroom created by the movement from a noncontrolled environment is significant and requires an overdesign of the air-handling systems. To overcome this problem, an anteroom with a high classification is used to buffer the shock to the operational cleanroom. A class 1,000 cleanroom would typically have a class 10,000 anteroom. To minimize the material transfer impact, pass-throughs are used to reduce the movement of people within the environment.

Proper gowning of personnel is critical to the successful operation of a cleanroom. An excellent reference for proper gowning is available. (9)

Typical specifications for interaction technology include the (1) size and location of entrance doors and the (2) size and location of pass-throughs.

Monitoring systems. Monitoring systems should include a means of indicating that the cleanroom is functioning properly. The variables monitored are the pressure differential between the outside environment and the cleanroom, temperature, and, in some cases, humidity. Control data should be recorded on a routine basis.

A typical specification for a monitoring system is that the system should provide instrumentation for determining the temperature and pressure differential.

Important things to consider in selecting cleanroom vendors

Before choosing a cleanroom vendor, review state regulations to ensure that the type of cleanroom you are considering will meet them. Check with the ruling body to answer any questions you may have. Specify that the cleanroom and the anteroom must meet a given classification during normal activity. Define normal activity, including movement, gowning strategy, and number of personnel present in the cleanroom and anteroom. Write a clear and detailed specification. Require vendors to do an onsite inspection of your facility before developing a quotation. Check clearance above ceilings – cleanrooms require 18 to 24 inches of clearance for mechanical equipment. Ask vendors about their technical support in terms of documentation, procedures, and in-service training. Get a detailed written quotation.

Develop a plan for installation that will provide for continued operation of the pharmacy and address problems related to construction. Check mechanical systems to ensure that the cooling systems have the capacity for the additional loads. Check the electrical requirements to ensure that adequate capacity is available. Develop procedures and in-service training programs for gowning, de- gowning, and proper cleanroom techniques. Provide for proper locker facilities where personnel may safely store items, such as jewelry, that cannot be worn in the cleanroom.

Budget for the additional cost of gowns and support materials. A single gown of the type required to work in a class 1000 cleanroom can cost $100 to $150. Gowns should be changed at least daily. Gowns are the only way of containing particulates shed by personnel. Allow additional time for personnel to enter and exit the cleanroom. Ask for and check vendors' references from similar projects.

Barrier isolation technology

Barrier isolator technology was developed to remove people from the environment in which i.v. products are prepared. Removing the person from the environment eliminates the primary source of contamination. Good aseptic technique in the handling of products and support materials is still required, with the notable exception of placement restrictions within the environment. Barrier isolator workstations consist of a physical structure, an internal environment, interaction technology, and a monitoring system.

Evaluation of each component of barrier isolator systems should be made on the basis of durability, functionality, and cost. Durability involves selection of materials of construction, types of filtration, and interaction techniques. Functionality involves movement of materials into and out of the workstation, personnel interfaces (ergonomics), and the ability to change the system to meet future needs. Cost involves initial capital cost, operating cost, and productivity of the workstation in the pharmacy.

Physical structure. Physically, a barrier isolator system has either a hard shell or a soft shell. A hard shell can be made of plastic, plexiglass, or stainless steel; a soft shell is usually made of a soft plastic film.

When choosing construction materials for the shell, consider the durability and integrity of the system, whether it has cleanable surfaces, and the visibility of internal operations. The best alternative for your application will meet these criteria. Durability and integrity of the barrier isolator shell will depend on the environment in which the workstation is to be placed, the process and tools involved in the activity, and the frequency of use. The cleanability of surfaces involves the quality of finish, welds or joints, and corners. Materials used for gasketing should be checked for durability when exposed to cleaning agents, as well as product compatibility. If possible, test the actual barrier isolator or visit a pharmacy currently using the workstation. The best construction material is stainless steel type 316L, followed by stainless steel type 304L, engineered plastic, painted or coated steel, acrylic or rigid plastic, and flexible plastic.

Typical specifications for the physical structure of a barrier isolator system are as follows:

Internal environment The major paradigm shift required for barrier isolator systems is the amount of airflow needed within the internal environment as compared with laminar-airflow technology. Although some barrier isolator systems use laminar-airflow technology, it is not necessary to provide the class 100 conditions required for that technology. FDA recognized that turbulent- airflow barrier isolator systems with significantly less airflow are as effective as laminar-airflow systems and provide class 100 conditions for aseptic manipulation of i.v. products.(8,11)

Barrier isolator systems, by the nature of their construction, give the impression of increased safety. Although there is no requirement for filtration of the exhausted air, it is good practice to use a HEPA filter for any air leaving the barrier isolator. FDA has expressed concern about any unprotected openings during routine operations and encourages manufactures of barrier isolator systems to protect any openings with HEPA filters, or a tortuous path for egress, so that contamination cannot easily enter the environment via that route.

Typical specifications for defining the internal environment are as follows:

The environment surrounding the barrier isolator workstation should have controlled conditions that provide personnel comfort and meet USP requirements for pharmaceutical product storage and handling. A controlled conditions that provide personnel comfort and meet USP requirements for pharmaceutical product storage handling. A controlled but unclassified area is consistent with FDA guidelines.(10)

Barrier isolator workstations are closed systems, meaning that there is at least one level of protection between the outside environment and the inside environment. This level of protection is provided by air locks or more advanced transfer technologies for material movement and by high-integrity filters for the movement of air. For i.v. and cytotoxic preparations, the level of protection is a function of the quality of the barrier.

HEPA filtration is able to capture particles larger than 0.3 um very efficiently, but vapors or very small droplets can pass through even this level of filtration. Ultra-low particulate air filters are efficient down to 0.1 um but not smaller particles or vapor. Some manufacturers of barrier isolator workstations have developed technology that will capture even vapor. This technology should be requested when cytotoxic preparations will be handled.

Venting moves the contamination out of the pharmacy but may expose unsuspecting people. Because of their location, vents could reintroduce the material into the building air handlers or building air currents and cause it to be present, in surprisingly high concentrations, in entryways or courtyards. Capture is always preferred.

Transfer and interaction technologies

Transfer technologies. The transfer technology is a major part of the cost of manufacturing a barrier isolator system and should be selected according to the level of protection provided. Available technologies are rapid transfer ports (RTP), air-lock, and laminar-airflow interfaces. The RTP technology has proven successful in the pharmaceutical industry when high-integrity transfers are required, It is both expensive and slow. Air locks are areas that act as transfer or transition areas between two independent areas. The area inside an air lock becomes a buffer for each of the adjacent areas. A laminar-airflow area adjacent to the barrier isolator structure offers a means of introducing materials into the unit.

Interaction technologies. Interaction technologies allow people to interact with the process of equipment contained in the barrier isolator system. Two interaction technologies are glove ports and half-suits. Both require the person to work through gloves. Gloves should be selected depending on the type of material, thickness, and tactility. Nonlatex materials, such as nitrile rubber, eliminate concern about allergic reactions. Thickness determines durability and tactility – the ability to feel and manipulate materials inside the workstation.

Glove ports are the most commonly used technique for interaction. The sleeve- and-glove arrangement can be either on or two pieces. The one-piece option has slightly more integrity, while the two-piece option offers a better fit for gloves and the capacity for multiple users. Also, it is less expensive, since only the gloves are changed.

Length of reach and weight of items to be lifted are important issues when choosing between half-suits and glove ports. The average reach is approximately 22 inches. Half-suits were developed to increase lifting capabilities and expand areas of reach within the barrier isolator workstation. Initial designs involved coated fabric and a full view, attached helmet. Disadvantages of the half-suits are difficulty cleaning, difficulty entering and exiting, and person hygiene issues created by multiple users.

Typical specifications for defining interaction technologies are as follows:

Monitoring systems. Monitoring systems are used to determine that the workstation is operating within the design parameters. Gauges, with visual readouts, should be included and checked regularly.

A typical specification for interaction technologies is that the barrier isolator must have positive pressure, capable of maintaining a range of air pressures equivalent to 0.025 to 1.0 inches of water pressure. Pressure indication is required.

Important things to consider in selecting barrier isolation vendors

Before choosing a barrier isolator vendor, make sure you review the rules and specifications to ensure that the type of barrier isolator system you are considering meets them. Check with the ruling body to address any concerns or questions. Consider the total cost of each alternative by evaluating durability, capital cost, operating cost, and efficiency. Lower initial cost may not be the most cost-effective alternative. Ergonomics is the key to successful use of a barrier isolator. Any workstation should have the ability to adjust height easily, good reach design, and angled viewing ports and should provide the operator with the option of sitting or standing. Ask vendors what level of technical support (documentation, procedures, and inservice training) they provide. Get a detailed written estimate.

Review each of the following items with the vendor: (1) installation without disruption in existing areas, (2) heat load and noise level created by the workstation, (3) cleaning and sanitizing recommendations, and methods and typical time required, (4) operating efficiency, and (5) costs of energy and disposable times. Ask for a list of references and follow up with calls or visits.

Conclusion

Having an understanding of the basic components of cleanroom and barrier isolator systems will help pharmacists define their needs and describe their needs to vendors.

REFERENCES

  1. American Society of Hospital Pharmacists. ASHP technical assistance bulletin on quality assurance for pharmacy-prepared sterile products. Am J Hosp Pharm. 1993; 50:2386-98.
  2. Sterile drug products for home use. Pharmacopeial Forum. 1995; 21:1587-602.
  3. 21CFR 10.90 Guideline on sterile drug products produced by aseptic processing 1987 (currently under revision). Washington, DC: Food and Drug Administration; 1987.
  4. Federal Standard 209E. Airborne particulate cleanliness classes in clean rooms and clean zones. Washington, DC: General Services Administration; 1992 Sep 11.
  5. Cleanrooms and associated cont4rolled environments. Part 4, design and construction. Geneva, Switzerland: International Organization and Standardization, 1998; TC 209.
  6. Avis KE. Assuring the quality of pharmacy-prepared sterile products. Pharmaguide Hospital Med. 1996; 9(2).
  7. 1999 ASHRAE handbook. Chap. 15. Clean spaces. Atlanta: American Society of Heating, Refrigerating, and Air-Conditioning Engineers; 1999.
  8. IES-RP-CC012.1. Considerations in cleanroom design. Section 5.6 Mount Prospect, IL: Institute of Environmental Sciences.
  9. Cleanroom basics. Cleanrooms. 1998; 12 (Dec suppl).
  10. ISPE Barrier Isolation Technology Conference wrap-up. Pharm Eng. 1995; 15 (Jan/Feb):58.
  11. Friedman RL. Compliance officer FDA. Design of barrier/isolators for aseptic processing a GMP perspective. Pharm Eng. 1998; 18 (Mar/Apr): 28-36.