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 CriteriaIn 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
- 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.
|Figure 2. Typical biotech purification cold/clean room|