Technical Brief 2010 Volume 9
Cleanroom Operations Background Cleanrooms are defined as a room or suite of rooms, in which the concentration of airborne particles is maintained within established parameters and where other factors are controlled to within specified limits. These rooms are designed to provide control of environmental factors including: • Viable and non-viable airborne particles • Air flow patterns • Temperature and humidity • Air pressure differential • Containment of hazardous aerosols Applications include the manufacture of sterile and non-sterile pharmaceutical and biotech products, medical devices, and implants. These rooms are also used to manufacture sensitive electronics. However, the requirements for these latter applications are not the objective of this article. GMP requirements from the different Boards of Health, including the US Food and Drug Administration (FDA), for sterile pharmaceutical, biotech, medical devices and implants require the manufacture of these products are performed in clean environments that meet the requirements of standards such as ISO EN146441. Compliance Requirements: • FDA Guideline Sterile Drug Products Produced by Aseptic Processing2 • European Union (EU) GMP Annex 13 Manufacture of Sterile Medicinal Products Other Helpful Documents: • ISO EN14644-1, -2 • International Society for Pharmaceutical Engineering (ISPE4)
more restricted the air flow, the In order to control contamination, more turbulence and this can operators and those in charge of a cause undesireable particle cleanroom need to be cognizant of movement. sources of contamination. These • Filtration – In addition to the HEPA filters commonly used in include: 1. Facilities: walls, floors and cleanrooms, there are a number ceilings; paint and coatings; spills of other filtration mechanisms used to remove particles from and leaks gases and liquids used in the 2. People: skin flakes and oil; manufacture of pharmaceutical cosmetics and perfume; spittle; products. These filters are clothing debris (lint, fibers, etc.); essential for providing effective hair contamination control. 3. Tool-generated: friction and • Cleanroom Garments – The wear particles; lubricants and requirements for cleanroom emissions; vibrations; brooms, garments will vary from location mops, and dusters to location. It is important 4. Fluids: particulates floating in air; to know the local cleanroom bacteria, organics, and moisture; garment requirements. Gloves, floor finishes or coatings; face masks and head covers cleaning chemicals; plasticizers are standard in nearly every (outgasses); water cleanroom environment as well 5. Product-generated: glass flakes; as coveralls. cleanroom debris; aluminum • Personnel - There are both particles from vial caps physical and psychological when humans Key Elements of Contamination Control concerns are present in cleanrooms. • Cleanroom Architecture – Physical behavior like fast Cleanrooms are designed to motion and horseplay can achieve and maintain an airflow increase contamination. in which essentially the entire Psychological concerns like body of air within a confined comfort, claustrophobia, strong area moves with uniform velocity odors, and workplace attitude along parallel flow lines. This air are important. Below are flow is called laminar flow. The several ways people produce contamination: Table 1 ◊ Behavior-- Rate of moveParticles/Minute (≥0.3 μ) ment, sneezing and coughing
supplied in accordance with ventilation codes, to balance exhaust air and to maintain specified pressures. Unless, otherwise specified, typical temperature range for this kind of room is within the range of 16 to 19 °C and relative humidity of approximately 50% is maintained. The type of equipment and number of people in the room may dictate where in the range you need to be to assure that during production the operations area is maintained at the right temperature and humidity levels. Only HEPA filtered air should enter the cleanroom and the gowning areas. These modules are available in fan assisted with fan speed control and should operate at a velocity of 90 ± 10 fpm or 0.45 ± 0.05 m/s. The location of the HEPA filters and air return grilles should create air movement from the designated ‘clean zone’ to the ‘less clean’ zones. Return air grilles should be at a lower level to aid in laminar flow requirements. Air supply to the cleanroom should provide a room air change rate of >20 per hour. Air cleanliness will be enhanced by higher air change rates. When the doors are opened the supply air volume should maintain an outward flow of air.
People Activity
Sources of Contamination
Motionless (Standing or Seated)
100,000
Walking about 2 mph
5,000,000
Horseplay
100,000,000 Table 2
Maximum permitted Old Fed Std 209E ISO EN14644 EU GMP Annex 1 particles per m3 equal to or greater than tabulated size
Air Handling Requirements Room air should be supplied by an external air conditioning system, preferably dedicated to the facility. Partial recirculation of room air is appropriate and this allows for optimal energy utilization. Sufficient fresh air should be
◊ Attitude-- Work habits and communication between workers People are a major source of contamination in the cleanroom
At rest
In operation
0.5 µ
0.5 µ
Maximum Microbiological Active Air Action Levels (cfu/m3)
100
ISO 5
Class A & B*
3,520
3,520
1
1,000
ISO 6
---
35,200
---
7
10,000
ISO 7
Class C
352,000
3,520,000
10
100,000
ISO 8
Class D
3,520,000 Not defined
100
*Requirements for particle counts during operation are different from class A, 35,200 particles at 0.5 µ ©2010 Particle Sciences, Inc. All rights reserved.
(Table 1). Notice the number of particles produced per minute during these activities. Cleanroom Classifications Cleanroom Classifications as specified by different standards are shown in Table 2. Non-sterile products are typically produced in an ISO 8 or EU Class D environment. Sterile products are required to be filled and stoppered in an ISO 5 or EU Class A environment. Cleanroom Cleaning As an example, here are some recommended procedures for cleaning a Class C or ISO 7 Area cleanroom. These procedures are simply guidelines, not standards or rules. It is important to review all cleaning procedures to be used in a cleanroom with responsible management. A detailed cleaning schedule should be prepared for every cleanroom. Procedure Good housekeeping and maintenance of the cleanroom and the associated restricted areas are essential to assure quality. Cleaning of an active cleanroom should be performed daily. However, if the room is not used daily, a different schedule may be implemented, but it should be cleaned after every use. Improper cleaning of the cleanroom can lead to contamination and compromise product quality. Proper selection of equipment, cleaning agents and cleaning materials is important for proper cleaning. Only products that have proven cleanroom performance records should be considered for use. These products should be listed in appropriate policies or procedures and all vendors should be informed about the strict policies of how products are qualified. All procedures should be strictly enforced. Below are some examples of how to organize cleanroom cleaning. These are guidelines for preparing work procedures and schedules. Local requirements must be included in any cleaning program. Equipment and Supplies – all supplies must meet the Class C or ISO 7 Area minimum requirements • Cleaning and disinfecting solutions
• Only garments approved for • Cleanroom mops the cleanroom should be worn • Cleanroom vacuum cleaner when entering. (if allowed) • No cosmetics shall be worn in • Cleanroom wipers the cleanrooms. This includes: • Cleanroom mop bucket and rouge, lipstick, eye shadow, wringer eyebrow pencil, mascara, eye Cleaning Tasks – frequency may liner, false eye lashes, fingernail vary depending upon local requirepolish, hair spray, mousse, or ments the heavy use of aerosols, after • Cleaning of all work surfaces in shaves and perfumes. the controlled environment • Only approved cleanroom • Vacuuming (if allowed) of the paper shall be allowed in the floors and work surfaces cleanroom. • Emptying of appropriate trash • Gloves should not be allowed and waste receptacles to touch any item or surface that has not been thoroughly • Cleaning of the doors, door cleaned. frames and lockers in the prestaging area and gowning areas • Only approved gloves, pliers, using the approved cleaning tweezers should be used to solution handle product. • Mop gowning area and cleanroom • All tools, containers and fixtures floors used in the cleaning process should be cleaned to the General Cleanroom Requirements same degree as the cleanroom Here is a list of general requiresurfaces. ments recommended as a mini• No tool should be allowed to mum for the successful operation rest on the surface of a bench of a cleanroom. All cleanroom peror table. It should be placed on sonnel should be aware and follow a cleanroom wiper. these requirements at all times. • Only cleanroom approved • All personal items such as keys, wipers are allowed to be used. watches, rings, matches, lighters The wipers must be approved and cigarettes should be stored for the class of cleanroom being in the personal locker outside the cleaned. gowning room. • All equipment, materials and • Valuable personal Items such containers introduced into a as wallets may be permitted in sterile facility must be subjected the cleanroom provided they are to stringent sterilization prior to never removed from beneath the entrance. cleanroom garments. • No one who is physically ill, • No eating, smoking or gum especially with respiratory or chewing is allowed inside the stomach disorders, may enter a cleanroom. sterile room. Figure 1
NEGATIVE PRESSURE CLEANROOM FOR HANDLING POTENT COMPOUNDS Cleanroom Z = P1
= Air Flow Z = HEPA Filtered Air
Gowning Area Z = P2
3894 Courtney St., Bethlehem, PA 18017-8920, USA
Definitions HEPA Filter - High Efficiency Particulate Air Filter Viable - a particle capable of living, developing, or germinating under favorable conditions, i.e., bacteria. Non-viable - typically dust or liquid particles Airborne - carried by or through the air Cleanrooms for Handling Potent Compounds For handling potent compounds, i.e., toxic materials, in addition to the requirements described for a cleanroom, precautions need to be taken to avoid spreading the toxic material to adjacent areas. This may be achieved by maintaining a negative pressure differential between the cleanroom and adjacent area so any hazardous powder or aerosol is contained within the cleanroom, i.e., P3 ~ P2 > P1 (Figure 1). This is accomplished by designing the facility with HEPA filtered incoming air and providing HEPA filtration at the exhaust. Also providing a higher flow through the exhaust filters to assure proper flow, pressure differential and sufficient air changes in order to meet the required room classification; this setup does not allow air from the cleanroom to enter into adjacent areas. Additionally, by providing localized exhaust or incorporating isolators onto manufacturing equipment, the control of aerosols and dust from handling powders is increased. Note that personnel enter the cleanroom through the gowning area whereas equipment and materials are brought through the air lock. References 1. ISO EN 14644-1, -2, -5, -9 International Standards Organization Cleanroom Standards 2. FDA Guidance for Industry – Sterile Drug Products produced by Aseptic Processing – CGMP September 2004 3. EU GMP Annex 1- Manufacture of Sterile Medicinal Products
Air Lock Z=P3
4. ISPE – International Society for Pharmaceutical Engineers Particle Sciences Phone: +1 610 861 4701 Fax: + 1 610 861 4702 Email:
[email protected] www.particlesciences.com
Particle Sciences is a leading integrated provider of formulation and analytic services and both standard and nanotechnology approaches to drug development and delivery.
