Written by Rob Smith - from an article published in A2 C2 Magazine
The need for biotech companies to design purification cold rooms and tissue culture warm/clean rooms at classified conditions to meet CGMP standards, and allowing for proper validation is critical to future growth and product development. However, the excessive cost of design standards often practiced with the larger pharmaceutical companies necessitates a need for a change in the design philosophy without an appreciable change in performance. This paper provides alternatives, time tested in the field, and completely validated to maintain Class 10,000 and Class 1,000 conditions with Class 100 zones for applications at 4 °C and +37 °C.
Prior to the early 1990’s, institutional cold rooms and pharmaceutical cold rooms were typically at 4 °C with no attempt at clean room classification. Although uniformities at the working plane were often at ±.5 °C, to prevent protein denaturing, process contamination, clean room classification and ultimate validation were not variables often considered. Although the majority of vendors in the environmental room industry have been providing strip chart test recording for many years, complete IQ and OQ validation were strictly in the hands of the client, with little pressure from external sources.
With the advent and growth of biotechnology products in the 80’s and 90’s, the need for purification cold/clean rooms and tissue culture warm/clean rooms, typically at Class 1,000 or Class 10,000 conditions, intensified. Recognizing that biotech companies operate in an extremely cost conscious environment to reduce the burn-rate on the company’s cash flow, alternative strategies to achieve these conditions at reduced costs needed to be developed. The traditional clean room approach with remote air handlers and recirculating fan units were excessive in cost due to the amount of insulation required at 4 °C applications as well as the integrity of the ductwork for these cold rooms needed to be welded ductwork to prevent condensation at critical joints. Although skidded air handlers, often with dehumidification systems, had been provided to pharmaceutical companies, the excessive cost of these cold/clean rooms was beyond the means of many biotech companies. Working with companies such as Genetics Institute, Genzyme, and BASF Bio Research, Harris Environmental Systems embarked on a patch to create cost efficient cold/clean rooms for the biotech industry.
Fundamental Design Criteria
In general terms, the design criteria for cold/clean rooms for purification applications in a pilot plant or production suite are as follows:
|Temperature||4 °C to ambient|
|Temperature Uniformity||±.5 °C|
|Temperature Gradient||(point to point control) ±1 °C|
|Classification||Class 1,000 or Class 10,000 with Class 100 zones|
|Humidity Control||Not always applicable, but limited defrost cycles if an at all, were requested|
|Validation||All systems must meet validation, IQ and OQ protocols|
Solutions To Meet Design Criteria:
Figure 1 shows the typical pharmaceutical cold/clean room utilizing a remote double wall conditioning system, complete with a desiccant dehumidifier ducted to HEPA filters within the cold/clean room. There are many advantages to this system including complete service access remote from the space, uniform architectural finishes with HEPA filters cut into the roof panels, which eliminates any potential ceiling leakage, and an extremely quiet system due to the ability to install large sound attenuators. Additionally, air balancing is provided by using flow hoods directly in the room during certification process or at a separate time. By installing desiccant dryer integral to the air handling system, the dewpoint can be maintained below the coldest surfaces, which are the evaporator temperatures, and thus no defrost cycles are required. This allows for uniform temperature at all times, with the additional benefit of preventing any potential mold or mildew growth due to higher relative humidities. Although these systems are by far the most preferred, and are typically done for large production pharmaceutical operations, the expense involving these systems is quite high. Double wall air handlers with completely clean in place finishes are extremely expensive. The utilization of expensive welded stainless steel ducting with 2” isocyanurate duct insulation due to the low temperatures is another increased cost. Furthermore the additional power and control runs from the remote air handler to the room bring an additional cost to these projects. All in all these systems are wonderfully designed and perform extremely well, easily meeting all IQ/OQ requirements, but at am extremely high cost, beyond the means of most new and/or even established biotech companies.
|Figure 1. Typical pharmaceutical cold/clean room|
What to Do:
In looking at the solutions to this problem, there are certain aspects of the design criteria that cannot be changed or sacrificed. Room temperature control, temperature uniformity, room gradients and air changes per hour based on the classification must all be maintained. Additionally, any pressurization, if applicable, must be maintained. Furthermore, the possibility of utilizing desiccant dryers may, in fact, still be required if the client does not allow any defrost cycles. The solution proposed by Harris Environmental Systems and validated at many facilities, as shown on the attached Fig. 2, utilizes fan/coil plenum air handlers with fan/filter modules. With this design, first we calculate the required air volume based on the required gradient and the expected internal heat load. This total air volume is then matched with the air volume required to maintain the classification. Whichever air volume is greater is utilized and all air is then passed up a return wall with pre-filters, through fan/coil units, and into fan/filter modules, down through plenum ceilings. The result is a truly modular room with everything completely enclosed within the room with the exception of the condensing unit, which would be remote in all cases, and a small desiccant dryer that can be installed directly above the roof panels of the insulated environmental room.
Advantages that the biotech company realizes are as follows:
- FDA validation for IQ and OQ is obtainable as is proven by installation Harris has completed at BASF Bio Research, Genetics Institute, Genzyme and others.
- This is a cost-effective design since no external ducting outside of that to the dehumidifier is required.
- The plenum after the fan/coil units is at a negative pressure due to the installation of fan/filter modules, which eliminates any potential ceiling grid leakage.
- The installation time and labor requirement is simplified greatly due to everything being close-coupled to the plenum ceiling.
Years ago, the disadvantage of this type of system resulted from the fact that servicing had to be required from within the cold/clean room and that the sound levels remained quite high. With the newer, high energy efficient and extremely quiet fan/filter modules, sound levels typically at 60 to 65 dB can easily be attained, even with over 50% filter ceiling coverage. Although coils, valves, and other components must still be serviced in the room, the utilization of room side replaceable HEPA filters makes this a fairly simple matter for the filtration side. If redundant air handlers are utilized, we have found maintenance to be extremely low for refrigeration and air moving devices. Finally, complete certification and validation is attainable as long as PID or microprocessor based discrete controls are utilized. The end result for the biotech company is that rooms of any size, completely modular, which can in fact be relocated in the future, can be installed with this design.
|Figure 2. Typical biotech purification cold/clean room|
To Dehumidify or not to Dehumidify:
With ventilation requirements for laboratory spaces at 20 CFM per person as a minimum, in most cases larger purification cold/clean rooms have in the vicinity of 50 to 100 CFM of make up air. Harris Environmental Systems experience, as well as basic physical laws, indicate that excessive defrost cycles will occur with cold, wet make up air unless desiccant dehumidification is utilized on this make up air to maintain the dewpoint below the coldest surface temperatures. Other various means such as refrigeration stripper coils operating continuously at a low suction temperature from the refrigeration system have been employed in an attempt to dehumidify make up air volumes. These methods at best can be described as secondary in the end result due to the fact that make up air coils at low temperatures can easily freeze up, causing additional defrost problems. Therefore, if the client is requiring no defrost cycles at any time, it is highly recommended that a small desiccant dryer be installed directly remote from the room and ducted to the return-side of the air handling system within the plenum.
Purification cold/clean rooms and tissue culture warm/clean rooms have been installed for almost 20 years by Harris Environmental Systems throughout North America. The proposed design utilizing fan/filter modules, small desiccant dehumidifiers, and internal fan/coil units is predominantly what has been chosen by both the biotech industry, and in some cases by the larger pharmaceutical clients. Pilot plant and production facilities have met IQ and OQ validation procedures now and in the near future with this design procedure. Redundant refrigeration systems can easily be employed when the room is large enough to fit another secondary internal air handler within the plenum. Cost saving in the order of 40 to 50% over remote skidded dehumidification/air handling systems can be expected with the proposed fan/filter fan/coil arrangement.