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Help prevent contamination in a facility by zone.
The term “clean factory” was developed at the beginning of the 1970s with the birth of contamination control in the microelectronics industry, which introduced complex design manufacturing, defect control, and particle reduction. These demands grew beyond the cleanroom to utilities, equipment, and consumables. The late 1980s expanded contamination control beyond the manufacturing floor to the building and the parking lot.
Management of people, materials, processes, supplies, and utilities became a way of life for all types of cleanroom manufacturing, both industrial and healthcare. Additionally, in the early 1980s, the term “clean build” was initiated to promote controlled construction and reduce the risk of contamination from the design state until manufacturing.
Since then, decades of cleanroom technology brought about new tools and equipment, contained processes with isolators and mini-environments, increased contamination control standards and regulations, and increased customer demands for quality. The area concept established as part of the clean factory instituted protective barrier zones beginning with the process/product area and continued to the building exterior (1). The concept of defining seven zones for cleaning and sanitization worked well for years. The seven zones are:
Today, the pharmaceutical industry faces many challenges: quality for customers, international competition, costs, and changes in regulations. This article will augment the original seven zones of the clean factory by adding specific modifications for personnel and facility. “Clean factory system” is a more inclusive term that can be used for these enhancements and updated cleaning protocols.
Most programs begin at the controlled environment to reduce contamination that enters the cleanroom. The clean factory systems approach, however, addresses contamination from the parking lot to the critical zone. This article will focus on personnel, cleaning, and facility design and will also discuss clean construction protocols and facility start-up.
One of the key elements in the clean factory system is the selection of products for gowning and cleaning. The materials must support the contamination control program, reduce risk to quality in products, and meet the specifications for the class of cleanroom (i.e., particulate and if required, microbial levels). Additional gowning may be specific to product or process requirements. Other qualifiers, such as safety and electrostatic discharge (ESD), further define the selection process.
For gowning to be effective, the contamination from people must be addressed. Good sanitization and health habits are requirements of good manufacturing practices (GMP) (2). To help reduce particulate and microbial contamination, dedicated garments under cleanroom apparel are recommended. This type of garment replaces street clothing. Benefits to removing street clothing include:
Figure 1 represents a compilation of data from numerous companies over the past 30 years and shows the reduction in particles in a gownroom (3). Clean street clothing offers very little particle reduction when compared to specific restricted clothing: no heavy linting fabrics, no shorts. Building suits, which are controlled with laundry and fabrics, offer some reduction. Cleanroom scrubs made of low-lint fabrics and laundered in a cleanroom offer the best particle control for the gownroom.
Cleanroom gowning must follow the standard operation procedure (SOP) or protocols. Gowning materials and methods must be reviewed to ensure that the materials meet the following standards:
The zonal concept does not address separation as recommended today. If a company manufactures multiple products, there are specific protocols for the changeover of the cleanrooms that must be performed to reduce cross-contamination. Companies should consider the risk and address specific changeover protocols for personnel, cleaning and sanitization, and facility design.
In a GMP facility, manufacturers are expected to prevent or mitigate contamination from particulates and micro-organisms that could impact the safety and quality of products. All tools, equipment, and supplies used for maintaining the cleanliness of a cleanroom or controlled environment must be constructed of non-shedding materials that can be easily maintained. The methods and techniques of cleaning and sanitization of cleanrooms and controlled environments should follow IEST RP-18 (4) or in-house validated methods and techniques based on particulate and microbial removal efficiency.
The cleaning materials must be compatible to the finish of the surfaces to be cleaned. This will prevent particulate generation during the cleaning process. The cleaning agents and disinfectants must ensure compatibility with the product, process, cleanroom surface finishes, and environment (waste disposal handling).
Water used in the dilution of disinfectants or cleaning solutions must be equal to the process/product water. Additionally, the tools, equipment, supplies, and solutions for cleaning and sanitization of areas outside of controlled and classified areas must never create a risk to these areas. The selection process for these areas must consider the potential risk of cross-contamination from improper or incompatible chemicals. Tools, equipment, and supplies could create sources of contamination if inadequately cleaned, as could the use of unfiltered water and re-use of mops and contaminated mop materials. Although these areas are not controlled environments or classified cleanrooms, the methods and techniques used for the base building must be adequate to clean the surfaces.
Companies should review airlock procedures to institute more frequent cleaning, and sanitization of surfaces in the production. Surfaces that are contacted frequently, such as door handles, equipment latches, bench/counter tops, and control panels should also have a higher frequency of cleaning.
The recommendations for each zone address potential features to control contamination and cross-contamination.
This area requires the highest level of protection (facility design), cleanliness, and personnel protocols. The requirements must be specific to the class of cleanroom, product, process, and customer or patient requirements for quality, regulations, and standards. This zone could be a specific area within a cleanroom or an entire critical cleanroom.
People. Gowning must follow the SOP for the class of cleanroom. Critical apparel generally include: coveralls, hood, mask, boots, gloves, and eye protection.
Cleaning and sanitization. Protocols are based on classification of the cleanroom, the levels of particulate and microbial control, and the surface finishes. Tools must be compatible with surfaces and cleaning solutions. Mops should be a continuous filament microfiber material, sterile or non-sterile.
Critical equipment cleaning will require wipes (sterile or non-sterile) and tools that meet the process requirements for particle count, compatibility with cleaning agent or disinfectant, and extractables.
Facility design. Critical zones should have separate entrance and exit airlocks for personnel and materials.
The cleanrooms range in classification from ISO 1–8.
People. The gowning for this zone follows specific protocols for the quality of the product, process, classification of the cleanroom, contamination levels (particulate, microbial, electrostatic), standards, regulations, and any customer specifications. In selecting the proper gowning, you must consider first the classification of the cleanroom as the prerequisite.
Cleaning and sanitization. The protocols are based on classification of the cleanroom and the levels of particulate and microbial control and the surface finishes. Tools must be compatible with surfaces and cleaning solutions.
Facility design. The entrances into cleanrooms should be through personnel airlocks (gownrooms), corridor airlocks, or main traffic corridors that are the same classification.
People. Before entering a cleanroom or controlled environment, proceed to a locker room and wash hands. If required by protocol, remove street clothing and don building suits, plant uniforms, or scrubs.
Cleaning and sanitization. Garments can become contaminated if the gownroom is not adequately cleaned. Because of the traffic volume, these areas should be cleaned with a higher frequency than the manufacturing areas. This level of cleaning will reduce the risk of contamination to the garments, personnel, and the cleanroom itself.
Facility design. If the gowning requires the removal of street clothing as well as street shoes, extensive locker room space, shoe storage, and garment storage is required. Gownrooms must be designed to support the population density, gowning requirements, storage of garments (if reused), and exiting requirements.
People. Personnel should proceed to designated areas and store all personal items. Food items should not be contained in lockers that are adjacent to controlled corridors. Badges must be sanitized, and all personnel must wash hands. Some controlled environments have additional requirements, such as safety shoes, specific clothing (non-linting), no bare legs, no sleeveless tops, no jewelry, and no cosmetics.
Cleaning and sanitization. Dedicated low lint microfiber mops, filtered cleaning solutions, and dedicated tools are required for these areas.
Facility design. The surrounding environments will influence the cleanliness of the cleanroom. As people and materials are moved from Zone 5 to Zone 4, there is a risk of cross-contamination. It is important that separate airlocks are required for personnel and material entering or leaving controlled areas.
This area includes rest rooms, offices, cafeterias, lobbies, personal storage areas, and conference rooms.
People. Recommend hand sanitization stations throughout the building in public areas.
Cleaning and sanitization. Floors that are not maintained will create a risk of cross-contamination into the controlled environments. Cleaning should follow the protocols as outlined in Zone 6.
One of the biggest risks to the controlled environments from the base building is carpeted floors. Plants should consider the use of flooring materials that can be mopped daily.
People. At the entrance, all personnel should step on a mat to remove heavy debris from their shoes and use a shoe cleaner if available.
Cleaning and sanitization. Specific maintenance procedures should be established. All entrances must be cleaned at least once per shift to control the risk of contamination into the building. Entrance areas should be maintained free of visible debris and dirt and vacuumed, followed by wet cleaning. Warehouse areas should be free of all visible debris. Warehouse cleaning tools are dedicated to this area only.
Facility design. Entrance areas should contain local area mats that withstand heavy foot traffic and can be cleaned multiple times per day. Shoe cleaners should be considered as an additional method of contamination reduction. Warehouse design must consist of an airlock for the transfer of items from the warehouse to the base building. An airlock will control the risk of contamination from the exterior during transfer of transported items.
The outside appearance creates the mind-set for all personnel and visitors.
People. Clean clothing should be worn. If personnel will be working in controlled environments or classified cleanrooms, they should follow the protocols established for those areas.
Cleaning and sanitization. Seasonal outdoor maintenance must be performed (e.g., clearing of leaves, snow and ice, debris). Loading docks must be checked weekly and cleaned to prevent food debris.
Facility design. The entrances to the building (warehouse, visitor lobby, and employees) should have airlocks that will act as a buffer from the outside world. Entrance, exit, and emergency doors must have proper seals. The control of the building exterior should be reviewed for types and location of plants, pest control, drainage of water, grading, and snow removal, for example.
Clean build protocols should be considered to reduce the risk of contamination to the controlled environments and cleanrooms. The purpose is to establish and define the rules of entry, material transfer, construction activities, and personnel conduct. The specification delineates all procedures and requirements for all individuals gaining access to the areas and for entrance of all materials, equipment, and tools. As each phase of construction progresses, increasingly more stringent requirements are defined for personnel, material, equipment, tools, and cleaning. These requirements will provide appropriate levels of contamination control to the stage of construction and the intended designation for the area. All construction project personnel should follow the personnel guidelines as outlined for the clean factory system if transitioning from the exterior or through entrances.
Cleanrooms and controlled environments do not operate without careful consideration to their design, impact of contamination from the surrounding areas, personnel protocols, and specialized cleaning procedures. Cleanrooms and controlled environments must meet the specifications for particulate and, if required, microbial levels. These levels can only be achieved on a consistent basis by controlling the environments that surround these areas. SOPs are generally specific to an area and may not incorporate the entire facility system. The clean factory system concept, however, can be used as the foundation for analyzing gaps in contamination control for personnel, cleaning practices, and facility design, creating 360 degrees of cleanliness.
1. A. Dixon, “Chapter 11: Cleaning of Non-Product Contact Surfaces,” in Cleaning and Cleaning Validation, Paul L. Pluta, ed. (PDA, 2009).
2. 21 CFR 211.28(b).
3. A.Dixon, Data compilation from unpublished reports (2021).
4. IEST, IEST RP-18, Institute of Environmental Sciences and Technology Recommended Practice CC018.5, Cleanroom Cleaning and Sanitization: Operations and Monitoring Procedures (May 2020).
Anne Marie Dixon-Heathman, email@example.com, is principal of Cleanroom Management Associates, Inc.
Vol. 34, No. 7
When referring to this article, please cite it as A. Dixon-Heathman, “360 Degrees of Cleanliness,” BioPharm International 34 (7) 2021.