Advances in pharmaceutical research and development have allowed increasingly selective compounds to be synthesized, better targeting disease with minimal side effects. Often, therapeutic doses are on the order of micrograms. And this increased specificity means that the compounds have increased potency.
But greater potency typically comes with higher toxicity--operating and maintenance staff must be protected from exposure, and the environment must be protected from discharge into the environment. Facility design and attendant heating, ventilating, and cooling (HVAC) system decisions play a critical role.
Exposure Limits Defined
The Occupational Exposure Limit (OEL) concept is used to quantify the toxic effects of compounds on workers (Table I).
Table I. Examples of Permissible Exposure Limits (8-hour time weighted average) (based on 115 50minute samples) Ethylene oxide 1 ppm 5 ppm 1910.1047 Methylene chloride 25 ppm 125 ppm 1910.1052 Methylene Dianiline 10 ppb 100 ppb 1910.105 Ethylene Oxide 0.75 ppm 2 ppm 1910.1048 Source: OSHA Standards 1901.1001-1052; Standard 1900, Limits for Air Contaminants, Table Z1
Compound Exposure Limit Short-Term Exposure Limit OSHA Standard
Table I. Examples of Permissible Exposure Limits
(8-hour time weighted average) (based on 115 50minute samples)
Ethylene oxide 1 ppm 5 ppm 1910.1047
Methylene chloride 25 ppm 125 ppm 1910.1052
Methylene Dianiline 10 ppb 100 ppb 1910.105
Ethylene Oxide 0.75 ppm 2 ppm 1910.1048
Source: OSHA Standards 1901.1001-1052; Standard 1900, Limits for Air Contaminants, Table Z1
The American Conference of Governmental Industrial Hygienists (ACGIH) has historically published occupational exposure limit (OEL) values for many commonly-used industrial chemicals and termed them threshold limit values (TLVs). When the U.S. Occupational Safety and Health Administration (OSHA) was formed, the ACGIH TLVs were adopted and codified as workplace standards.
The OEL is the maximum concentration of a chemical (in air) to which most workers can be exposed for an 8-hour work day, 40-hour work week over a 40-year lifespan without significant adverse health effects. The OEL is expressed in milligrams of substance per cubic meter of air (mg/m3), parts per million (ppm) or even parts per billion (ppb). A higher OEL value means that a compound is more benign, so a worker may be exposed to more of this substance without future risk.
The OEL measures the health effects of long-term occupational exposure to a compound. Short-term exposure limit values (STELs) have also been developed to define the health effects of more acute occupational exposures. Permissible exposure limit (PEL) values are published in OSHA Standards 1910.1001 through 1052. Table I identifies some sample permissible exposure limit values.
For any new compound or intermediate, the company's environmental safety and health group typically establishes TLV and STEL values through toxicological testing, after a drug candidate has advanced through the development process. Before that time, a toxicity level may be assigned based on extrapolation from other materials.
The process and facility must then be designed and operated to maintain the expected actual worker exposure below these TLV and STEL values. Table II identifies a typical exposure-control matrix, relating TLV to room design criteria.
Table II , Exposure Control Matrix, Potent Compound Classes Material, Effects Comments Minimum Dilution Rate Comments (air changes per hour) Non-toxic No special requirements 7 Dilution by room ventilation Low toxicity Local ventilation 7 Unidirectional supply air flow No migration to other areas (dedicated HVAC system) Short-term, reversible Limited open handling 10 HEPA filtration of exhaust Application of laminar flow booths Irreversible No open handling 12 Barrier/isolator technology Interlocked-door airlocks Life-Threatening Remote operations 12 Fully automated robotics
Table II , Exposure Control Matrix, Potent Compound Classes
Material, Effects Comments Minimum Dilution Rate Comments
(air changes per hour)
Non-toxic No special requirements 7 Dilution by room ventilation
Low toxicity Local ventilation 7 Unidirectional supply air flow
No migration to other areas
(dedicated HVAC system)
Short-term, reversible Limited open handling 10 HEPA filtration of exhaust
Application of laminar flow booths
Irreversible No open handling 12 Barrier/isolator technology
Life-Threatening Remote operations 12 Fully automated robotics
Potent compounds have low TLVs; so strategies must be developed in designing and operating facilities to handle these compounds and minimize worker exposure.
Labor-intensive unit operations, such as material transfer, are targets for applications of robotics. Barrier isolators, closed transfer systems and specialized connectors and valves contain potent compounds, thereby minimizing worker exposure. Secondary ways to limit exposure is by using personnel protective equipment such as gowns with breathing air or purified-air powered respirators.
The facilities housing potent compound processes provide a tertiary means of limiting occupational exposure and controlling environmental discharges.
Safety, Risk Drive HVAC Design
Facility design features are driven by the need to protect operating staff and the environment, comply with OSHA and FDA regulations, and are aligned with anticipated level of risk. This alignment must be based not only on the compound and process for which the facility is being constructed today, but also must include future flexibility. For example, clinical manufacturing facilities and contract manufacturers often produce several products simultaneously, and prevention of cross-contamination is critical.
What compounds should the facility be designed to handle in the future?
Design of potent compound facilities is governed by validation protocols, and proof of compliance also must be provided. Typically, critical utility parameters are trended to provide evidence that the compound is being produced consistent with cGMP requirements. For example, compliance documentation may indicate that a compound will be manufactured in a room having a certain temperature and relative humidity criteria. The room temperature and relative humidity should then be continuously monitored to ensure that room conditions are consistent with documentation.
Seven HVAC Design Considerations
Once acceptable exposure levels have been determined, an array of parameters will drive the design of the facility's HVAC systems.
Design indoor temperature determines the room airflow rate: as the indoor temperature decreases, more air must be supplied to a room to offset a given heat gain. Because compounds are generally stable over the range of typical room temperatures, the selection of the design point is most often a personnel comfort issue. Because potent compound suites are operated continuously, in order to maintain pressurization criteria, the room temperature must stay relatively constant. Workers in a potent compound facility will be heavily gowned and will start to experience discomfort above 68ºF.
Design outdoor temperature, which depends on where the facility is being built, will influence both the sizing of heat rejection equipment as well as wall construction methods, since heat will be conducted through any perimeter walls. If the potent compound facility receives chilled water for cooling purposes, there typically is no heat rejection equipment. However, if campus chilled water is unavailable, or the design indoor temperature drives the use of direct-expansion cooling equipment to depress the supply air temperature (and therefore the room temperature), then heat rejection equipment sizing is a function of design outdoor temperature.
The American Society of Heating, Refrigerating and Air-Conditioning Engineers (ASHRAE) identifies three outdoor temperatures for a given geographic area: the 0.4%, 1% and 2.5% conditions. For example, the most stringent 0.4% condition is exceeded in 0.4% of the hours in an average year (based on a 35-hour week). Selection of the design condition assumes that the indoor temperature will drift when the actual outdoor temperature exceeds the design outdoor temperature. If possible, selection of a lower outside air temperature provides a more economical design solution.
Design indoor relative humidity will be determined by the extent to which the compounds being processed in the facility are hygroscopic, or water-absorbing. If hygroscopic compounds are used, then the relative humidity needs to be low year-round (typically 30-35%). In temperate climates in the winter, this means that less moisture is injected into the dry outside air to maintain the design relative humidity. In the summer, this means that dehumidification provided by passing air over a cooling coil is inadequate: a desiccant dehumidification system is required. Because application of a desiccant dehumidification system has implications for construction and maintenance costs, the use of hygroscopic materials (either now or in the future) should be confirmed.
Room pressurization: The fundamental premise of industrial ventilation is that air should flow from clean toward dirty areas. In potent compound suites, this means that process rooms should be negatively pressurized with respect to adjacent areas, so that air flows from the adjacent room into the process room.
This criterion is met by transferring air from the clean room into the dirty room across the door. This air transfer can be performed either volumetrically or dynamically. In the volumetric method, the supply air flow rate into the process room is balanced to be less than its exhaust air flow rate (for example, by 150 cfm). The adjacent space is balanced so that its supply air flow rate exceeds its exhaust air flow rate by the same amount. Air then flows into the process room through the perimeter and undercut of the process room door.
In the dynamic method, the pressure difference between the process room and the adjacent area is measured, and a damper automatically changes the supply or exhaust air flows to maintain a pressure setpoint (relative to a datum point).
Using either method, when the process room door is open, the area across which air transfers is so large that no pressure difference exists between the process room and the adjacent room, which provides a potential path for contaminants to flow out of the process room. The solution to this potential problem is to install an airlock between the process room and the adjacent room. The airlock doors into the process room and into the adjacent room are interlocked so they cannot both open simultaneously, which allows the process room to be continuously negatively pressurized. The door interlock can be electrically or manually operated.
Air change rate is the rate at which filtered outside air is introduced into a room to dilute the concentration of compounds in that room. As the flow rate of air supplied to a suite increases, the compound concentration will be more diluted. However, this effect is nonlinear; the marginal effect of higher air change rates is small with high air change rates, as shown in Table III.
Supply air filtration is intended to prevent particles from the outside from contacting the product. Validation protocols establish the conditions under which the product is manufactured, including the filtration efficiency.
In oral solid dosage (OSD) manufacturing facilities, compounds are rarely exposed to room air, and supply air efficiency is typically not critical. In sterile filling facilities, however, a higher level of cleanliness mandates higher filter efficiency. Table III shows the correlation between cleanliness requirements and filter efficiency.
Air Changes per Hour % of Original Concentration 1 80 5 35 10 20 20 1 Greater than 20 1
Table III. Concentration of Gas Release After One Hour
Air Changes per Hour % of Original Concentration
Greater than 20 1
Exhaust air filtration is required so that the potent-compound discharge does not cause an environmental risk. As a minimum, exhaust air is routed through bag-type dust collectors. As an upgrade, exhaust air would be filtered additionally by HEPA filters to minimize the risk of discharge of this material into the environment.
The use of HEPA filters raises a number of logistical issues as well. Locating them at the exhaust fan exposes the return air ductwork to the potent compounds. Putting them in the room is a challenge as well; because the filters are 12-in. deep, they must be placed in a separate, adjacent mechanical space or the wall must be thickened to accommodate the filter depth. HEPA filters located within the suite require maintenance staff to gown and