AMC and its many sources can present formidable contamination issues for biotech cleanrooms.
HVAC systems serving biotechnology, pharmaceutical, and life science cleanrooms are designed to provide and maintain environments sufficiently well-controlled as to minimize process defects, assure product quality, and to provide for worker safety and health. They are an attempt to maximize production rates and yields for environmentally-sensitive materials and products.
The large majority of cleanrooms are designed to provide contaminant-free manufacturing environments by (primarily) maximizing the control of airborne particulates—both viable and non-viable. However, there is another important type of airborne contamination that is not controlled with traditional cleanroom filtration technology. This is non-particulate, or molecular, contamination.
Molecular Contamination Sources and Types
The term airborne molecular contamination (AMC) covers a wide range of chemical contaminants that can be present in cleanroom air. AMC can be in the form of gases, vapors or aerosols and their chemical nature can be organic or inorganic. AMC includes acids, bases, condensables, organic chemicals, polymer additives and organometallic compounds.
Outdoor air, manufacturing processes, fugitive emissions from process equipment and chemical supply lines, cross-contamination between manufacturing areas, chemical storage areas, off-gassing from building and construction materials, accidental spills, and bioeffluents from cleanroom personnel can all contribute to the overall AMC load in the cleanroom. AMC can be detrimental to many processes and products and also can represent considerable health hazards to personnel.
There are a variety of ways by which AMC may be classified. None are definitive, but the following classifications have relevance in biotechnology/life sciences cleanrooms:
Toxic: A substance is said to be toxic if it exhibits the ability to cause damage to living tissue, impairment of the central nervous system, or in extreme cases, death when ingested, inhaled, or absorbed through the skin.
Corrosive: Those compounds which are likely to cause deterioration or damage to the interior of a building or its contents are considered corrosive. They may also have a detrimental effect on human occupants as well.
Irritant: Chemicals that can be said to cause discomfort, and potentially permanent damage, to an exposed person may be considered irritating. Many of the gases considered to be irritants produce symptoms of pain or discomfort to the eyes, skin, mucous membranes, or respiratory system.
Odorous: Materials that primarily affect the olfactory senses are considered odorous and usually carry negative connotations.
AMC Concerns in Biotechnology/ Pharmaceuticals/Life Sciences
AMC has long been recognized by leading-edge microelectronics manufacturers as a critical environmental parameter that must be controlled. AMC effects on materials and processes are well-documented and acceptable levels of AMC in the cleanroom are only expected to decrease with future device generations.
To date, AMC control has not been a major issue with biotech firms and pharmaceutical manufacturers. Odor complaints are probably the biggest AMC issue for these cleanrooms. Odor episodes in cleanroom applications are typically considered as transient events and, as such, can be difficult to resolve and have the potential to disrupt manufacturing operations.
Most odor control applications are based on what are considered to be “nuisance levels” of various chemicals from process emissions. Emission control has been mostly voluntary although there are an increasing number of various local, state, and federal regulations based on the health concerns from exposure to these materials.
Outdoor air quality has become much more important for advanced biotechnology processing (e.g., DNA-chips, gene chips). Ozone levels as low as 5-10 parts per billion (ppb) have been reported to cause dramatic decreases in yields1 . Fertilization clinics have developed stringent air quality guidelines to improve their success rates. Formaldehyde and other organic chemicals are known to affect the viability of eggs during fertilization and implantation.
There is also concern with cross-contamination from one production/process area to another and the potential for “tainted” product or a problem with the integrity of packaging for drugs and medical devices. Fugitive emissions migrating from one area into the general cleanroom airstream and being distributed throughout have become a cause for concern for many manufacturers.
Sterilization processes and waste disposal pose their own specific concerns with regards to AMC control. Odor control is always an issue here—especially with autoclaves and incinerators. However, there could also be concerns with toxic gases depending on the sterilization procedures and sterilants being used.
AMC Control Considerations
In much of the world today, ambient (outdoor) air contains levels of ozone, sulfur, nitrogen oxides, and volatile organic compounds (VOCs) high enough to cause problems in cleanrooms. Many production and research facilities are located in non-attainment areas for one or more of these contaminants2 (Figure 1). Non-attainment areas are those where EPA-monitored pollutant concentrations exceed the standard a certain number of times over a three-year period, even if at only one monitor in an area. There are elevated levels of sulfur and nitrogen oxides from automobile exhaust and combustion processes in urban areas. Atmospheric chlorine and boron can be found in coastal locations. Ammonia and amines may be present from agricultural activities.
Major considerations are:
1.Makeup air systems will see primarily atmospheric contaminants if the outside air intake locations are chosen carefully. Zero downtime systems should be considered for makeup air handlers. A balance should be struck between the desired level of AMC control versus pressure drop versus service life.
2.Recirculation air systems require that AMC control be chosen based on functional area requirements.
3.Exhaust air systems generate a significant number of complaints from neighboring facilities due to nuisance odors from exhaust abatement equipment. Continuous monitoring and regular maintenance are called for. Careful location of exhaust stacks, compliance with environmental regulations, and dispersion modeling are required for all production facilities.
4.Minienvironments with self-contained chemical contaminant control systems can significantly reduce the occurrence of odors related to production processes. Added benefits include increased protection for the product and the reduction of the total exhaust requirements.
Air Cleaning: Air cleaning is one of three methods of removing AMC from the cleanroom. In order of effectiveness, the three methods are:
• Removal of the contaminant source or control of its emissions
• Ventilation with clean dilution air
• Air cleaning—for either particles or gases, or both
Source control for outdoor air contaminants is often not feasible or practical, therefore, ventilation control should be the next option. However, this may not prove viable in all cases either as the use of large amounts of outdoor dilution air is neither cost-effective nor energy-efficient. Further, bringing in additional quantities of outside air could result in substituting one group of contaminants for another— those with sources outside the cleanroom for those internally generated. In areas with poor outdoor air quality, neither source or ventilation control can prevent the introduction of contaminants into a facility, therefore, air cleaning must be employed.
Air cleaning is often used as an adjunct to source control and ventilation. A gas-phase air filtration system as an integral part of a cleanroom HVAC system can effectively reduce AMC to levels that are at or below the level of detection for the monitoring techniques employed. Properly applied, gas-phase air filtration also has the potential for energy savings3 .
Makeup air systems must typically be designed to control SOx, NOx, ozone, VOCs, and some site-specific contaminants such as chlorine, organophosphates, and ammonia. Chemical filtration equipment in recirculation systems must be designed to remove a wide array of acids, bases, hydrocarbons, and other VOCs. As a rule, organic compounds—although perhaps not the most damaging—are the most abundant types of AMC found in these facilities.
An example of an air quality survey performed at one facility is shown in Table 1. It shows the types and amounts of AMC being introduced from the outside, the effect of dilution (if any) with ventilation air, as well as the contamination being introduced from inside the facility.
Control Technology: As biotechnology and the pharmaceutical industry has progressed, so too, has AMC control technology. This progress presents itself in the form of:
• Dry-scrubbing (gas-phase) air filtration media, filters, and systems that can address essentially any AMC issue—from emergency gas scrubbers for toxic gas control to cleaning the outdoor air being used for ventilation to general odor control
• Filtration systems that can be easily integrated into existing air handling equipment
• Development of AMC standards and guidelines for environmental assessment and monitoring
• Real-time and passive air monitoring devices such that can provide accurate environmental assessments
• Technical competence of AMC control system manufacturers to work with facility engineers and cleanroom personnel to provide effective and economical solutions
AMC Control: Toxic and corrosive materials, by definition, will require absolute control. Substances classified as irritants may warrant special attention considering that exposure to many of these materials can have long-term health effects in addition to the short-term irritant effects. Odor control applications may also require tight control in order to reduce odors below levels that would be considered objectionable by cleanroom personnel and/or to meet regulatory requirements.
It is well-known that a single adsorbent or chemisorbent media may not adequately control all classes of AMC or multiple contaminants. The types and numbers of AMC one would encounter make it likely that air cleaning systems need to be equipped with multiple specialized media. The preferred system would contain these media in discreet filter beds.
It is not always feasible to incorporate an AMC control system with two or more filter beds. Retrofit applications in particular, present challenges to the HVAC engineer who is often limited by lack of physical space for the system, sufficient static pressure in the air handling system, or budgetary constraints. In these cases, two media may be blended and used as a single stage to reduce the size and/or cost of the system. Properly applied, blended media should not affect the efficiency of the AMC control system, however, the service life will be reduced.
Physical limitations placed on AMC control systems and constant budgetary constraints have spurred the development of many new chemical filtration products. A few manufacturers are applying dry-scrubbing media to various filter substrates, but most processes cause the adsorbent materials to become “blinded” or essentially spent, through the use of and reaction with various binders and adhesives, and the manufacturing techniques employed. Recent advances in filter manufacturing technology, however, have eliminated these deficiencies.
One manufacturer has developed a new chemical filter using a patented technology that can allows for the application of multiple plain and chemically-active sorbents to a non-woven bi-component fiber matrix (Figure 2). The resulting product is a robust, pleatable roll good with many advantages over existing alternatives. It provides for flexible filter design allowing easy application into new or existing HVAC systems4.
Perhaps the most important feature of this product is that it can also be produced with an integral particulate filter that practically eliminates retrofit costs. The result is a unique and effective combination filter material that can be pleated into essentially any standard filter size for the removal of both gaseous and particulate contaminants. (Figure 3).
The control of molecular (chemical) contaminants is becoming crucial to providing a truly “clean” manufacturing environment. Their control requires a specific knowledge and understanding of the problem and each application may require a new solution involving one or more different control technologies.
In contrast to particulate filtration, AMC control is used in only a small minority of biotech/life science cleanroom facilities due to a lack of regulatory or process-specific requirements, the associated higher operating and maintenance costs and a general lack of perceived benefits in doing so.
AMC control can be applied a couple of ways in a cleanroom HVAC system for best effectiveness. The first would be to treat only the outdoor air—typically 10-20% of the total HVAC air volume. The second application would be to treat the mixed air stream (outdoor + recirculation air). Initial costs would for the latter would be higher, but overall operating and maintenance costs could be lower if energy conservation measures were applied.
As a minimum, the broad guidelines for applying AMC control are in all makeup air units serving process and production areas, and all recirculation systems serving areas where environmentally-sensitive materials are processed, stored, or handled. In addition, AMC control should be considered for all makeup air handlers serving Class 100 or better cleanroom areas.
A properly designed, installed, and maintained gaseous air cleaning system will be able to effectively and economically remove essentially all chemical contaminants of concern from the cleanroom environment. When AMC control is employed in biotech cleanrooms, one gains the dual benefits of process/product protection from chemical contamination as well as overall improved air quality. Both can benefit the bottom-line, however, the latter can have even more far-reaching implications when worker satisfaction and productivity are factored in.
1 Muller, Chris. 2002, pers. comm.
2 Air Facility Subsystem (AFS). 2003, U.S. Environmental Protection Agency, Washington, D.C.
3 ANSI/ASHRAE Std. 62-2001, “Ventilation for Acceptable Indoor Air Quality,” American Society of Heating, Refrigerating and Air-Conditioning Engineers, Atlanta.
4 Middlebrooks, M.C. and Muller, C.O., Development and Evaluation of a New Dry-Scrubbing Chemical Filtration Medium, In Proceedings of the Air & Waste Management Association 94th Annual Meeting and Exhibition, June 24-28, 2001, Orlando, FL.