Frequently Asked Questions




CLEANROOM FAQs

The USP General Chapter 797 on compounding sterile preparations makes some specific recommendations regarding cleanliness and cleanrooms. While it does not specifically require a cleanroom for sterile compounding, the guideline does require that sterile compounding take place in a separate area that meets a defined level of cleanliness. Many pharmacists have expressed concern about cleanrooms and their requirements in an attempt to clarify the requirements for USP 797 compliance. These Frequently Asked Questions are intended to provide a general understanding of what cleanrooms are and how they are monitored.

What is a cleanroom?

ISO 14644, the internationally recognized cleanroom standard defines it as, "A room in which the concentration of airborne particles is controlled, and which is constructed and used in a manner to minimize the introduction, generation, and retention of particulates inside the room, and in which other relevant parameters, e.g., temperature, humidity, pressure, are controlled as necessary." The key word in this definition is "controlled." Personnel and housekeeping access, air quality, pressure, temperature, humidity and microbial contamination are all likely candidates for control in a cleanroom setting. Control in this context means that a selected parameter is governed by procedure and practice, is routinely measured, and prescribed action taken if that parameter exceeds predetermined limits.

What is a clean zone?

"A dedicated space in which the concentration of airborne particles is controlled, and which is constructed and used in a manner to minimize the introduction, generation, and retention of particles inside the zone, and in which other relevant parameters, e.g., temperature, humidity, pressure, are controlled as necessary." See ISO 14644.

How are cleanrooms and clean zones classified?

There are nine classes of cleanrooms specified in ISO 14644. These classifications are based upon particle counts within one cubic meter of room air. ISO Class 1 is the highest or cleanest rating. ISO Class 9 is the lowest possible rating.

In a hospital pharmacy context, USP 797 requires the maintenance of ISO Class 5 air quality. Below are the particle count requirements for ISO Class 5*:



What sorts of materials are used in cleanroom construction?

Floors may be constructed of standard sheet vinyl or 12" square material. They must be smooth and easy to clean. Cove bases - where the floor meets the wall - are critical and non-standard material. Special 12" rubber material can be used here. Whatever the material, these corners must be gradually rounded so they do not harbor debris and organisms and are easily cleaned.

Walls may be standard drywall construction, primed and sealed. At a minimum a good quality washable enamel paint is recommended. Anti-microbial paints are available and may be a worthwhile expenditure. Acoustic ceilings require special cleanroom ceiling tiles. These tiles are vinyl coated to prevent debris generation and can be wiped down. Cleanrooms are sealed areas. Doors and windows must be gasketed to prevent leaks.

There are a number of suppliers for modular cleanrooms, hoods and cleanroom supplies. One source is www.TerraUniversal.com.

How are particles counted?

Particle counts can be accomplished using air and surface test kits that are collected and sent for verification, or through automated particle counters. Firms that do the certification for laminar flow hoods and biological safety cabinets often have this capability as well. A number of firms provide environmental monitoring services. There are also a variety of equipment options. For background on particle counting, see http://www.particle.com/whitepapers_met/iaq.htm.

What are air turns or air changes?

Based on a calculation that includes the room size and the air volume pumped into the room over a unit of time, the number of times that the entire air volume in the room is exchanged can be calculated. Typically, this is expressed as air changes per hour. For example, at Baxa, our ISO Class 8 cleanroom does about 40 air changes per hour.

Why are particles a problem?

Airborne particles provide a ride for microorganisms, as well as food and surface area on which to reproduce. Outside of the microbial load, particulate that makes its way into IV solutions presents a challenge to the patient's organs and vascular system. Particulate undetectable by visual inspection can cause phlebitis or iatrogenic disease. People are the biggest contributors of particulate contamination.

What sort of monitoring is usually done in cleanrooms?

Typically, airborne particles, airborne viables, surface viables, pressure, and temperature are all monitored. The risk level of the compounded sterile product (CSP), the nature of the room, its history, people load, and other variables need to be taken into account when establishing the monitoring frequency.

What gives me the right to claim that my cleanroom meets ISO 14644 standards?

ISO 14644-4 specifies design construction and start-up. In order to classify a cleanroom, a qualification or validation must be done. There are three phases of qualification, which demonstrate that the cleanroom meets the requirements for the desired class. These three phases are: As Built, At Rest, and Operational. As Built is an empty room. At Rest is the room, plus tables and equipment etc. Operational is the room, the equipment and the people working at normal tasks. Note that USP 797 does not require a cleanroom that meets ISO Class 5 requirements. What it does require is that air quality to which CSPs are exposed be at least at the ISO Class 5 level.

Do I need procedures for a cleanroom?

Yes, typically you would find the following procedures helpful in an effective cleanroom program:
  • Cleanroom definition or specification document. This describes the room, how it will be used and why it is adequate for the intended use.
  • Cleanroom monitoring procedure. This indicates how and when you will perform environmental monitoring and includes a record of your monitoring activities.
  • Cleanroom entry procedure. The "rules" for authorized entry, gowning, hair covering, hand washing, what materials are and are not allowed.
  • Cleanroom housekeeping procedure. The guidelines for how you clean, approved cleaning agents, the frequency for cleaning, and a record of when it has been done.
  • Cleanroom alert and action limits should be established, as well as what to do in the event of a power outage or other shutdown.
  • An annual re-certification must be performed and documented.

What are HEPA Filters?

HEPA means High Efficiency Particulate Air. HEPA filters are disposable, extended-media, dry-type filters in a rigid frame, with a minimum particle-collection efficiency of 99.97% (that is, a maximum particle penetration of 0.03%) for 0.3 µm particles of thermally generated DOP or specified alternative aerosol.

How is cleanroom air filtration accomplished?

There are two common filtration methods. Both employ HEPA filters. Fan Powered HEPA Filtration uses motorized ceiling-mounted units that filter the air. The units fit neatly into an existing acoustic ceiling grid. This method does not pressurize the room and is the more inexpensive approach.

Alternately, banks of HEPA filters can be mounted in air-handling units outside of the cleanroom. Filtered air is pumped to the cleanroom and then returned and circulated through the filter banks. This method typically provides over-pressurization of the room.

References
  1. Control of Particulate Contamination in Healthcare Manufacturing, , Barber, Thomas A., Interpharm Press, ISBN 1-57491-072-8
  2. HEPA Corporation, www.hepa.com.
  3. ISO 14644 Cleanroom Standards (4 documents)
  4. Cleanroom Design, Whyte, W., ISBN 0471 942049.

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