Mexico, DF, ID number: 299643
3 Design Considerations
3.15 Process Equipment Integration
There are specific requirements for process equipment. Specific aspects for the area containing process equipment should be considered in the design of HVAC systems.
3.15.1 Dust Extract Systems
Where there is a common dust extract system, aspects to consider in the HVAC system design include:
• What happens if the unit fails?
- Does the unit have a damper that closes, preventing air leaving the system? Is the pressure difference between the rooms served by the system adequate to obtain flow with a consequential risk of cross contamination?
• How does the dust collector clean itself?
- Some units are cleaned by a shaker mechanism; others use a pulse of compressed air. During this pulse, which is in the opposite direction to the normal airflow, the extract air flow can halt or even reverse for a short period, is this acceptable?
• It should be noted that one of the advantages of a remote system (regardless of whether it is a common or a dedicated system) is that the system heat gain is outside the room and the extract normally is located near an area where the equipment heat gain is high, so heat gains are extracted from the room, reducing the load on the area HVAC system. In addition, duct pressure is negative; keeping contaminants in the system should the duct develop a leak. Being remotely located, fan noise is not an issue.
3.15.2 Granulators/Coaters/Fluid Bed Dryers
These units typically have dedicated air-handling systems that are independent of the area HVAC. See the ISPE Baseline® Guide on Oral Solid Dosage Forms (Reference 13, Appendix 12). The design should consider what happens during periods of non-use and whether there is potential for moisture to migrate from an outside high-humidity environment into the system. Other aspects to consider include:
• Assess the risks of corrosion during use – what ductwork materials should be used?
• What areas of the duct are pressurized? What is the risk of drawing in untreated air? What is the risk of potentially contaminated (with product) air leaking out?
• If for multiple campaigned products, does the duct need Clean In Place (CIP)?
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Mexico, DF, ID number: 299643
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3.15.3 Glassware Depyrogenation Tunnels
Glassware depyrogenation tunnels generally are located between rooms with different area classifications (grades) and operate intermittently. They present a challenge to HVAC system designers. Area pressure differentials typically need to be held at a consistent level, usually requiring some type of active pressure control. (Risk analysis to determine areas of patient/product risk may present opportunities to reduce the room pressure differentials during periods of no production).
As tunnels are started up and the temperatures and volumes stabilize, there is a dynamic period in terms of changing airflow during which filling is not in operation. See the ISPE Baseline® Guide on Sterile Manufacturing Facilities (Reference 13, Appendix 12). Without a pressurized cool in-feed zone between the washer and the heat zone of the tunnel, held at the same pressure as the sterile filling line, extremely hot air can exit the front of the tunnel, creating a need for local exhaust to remove the excess heat and potentially creating a hazard.
Other issues with depyrogenation tunnels include the testing and integrity of high temperature HEPA filters and the monitoring of particle levels in the hot zone (sometimes over 325°C). These issues are discussed in the ISPE Baseline® Guide on Sterile Manufacturing Facilities (Reference 13, Appendix 12) and in online discussion groups such as the ISPE Sterile Processing COP.
3.15.4 Isolator Systems
Figure 3.16: Isolator System Schematic 1
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Mr. Gerardo Gutierrez, Sr.
Mexico, DF, ID number: 299643
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Figure 3.17: Isolator System Schematic 2
Where aseptic processing or containment of hazardous materials is required, barrier-isolator technology may be applied. Generally, when a closed isolator is used in aseptic processing and can be pressurized, room air class can be relieved by one or (often) two levels, requiring fewer air class zones, less gowning, and lower HVAC airflow.
When an isolator is used as containment for non-sterile products, potential for product release to the air and cross-contamination often is greatly reduced, lessening risk to product and operators and requiring less rigorous HVAC systems. See the appropriate ISPE Baseline® Guide (Reference 13, Appendix 12) for further information.
Considerable discussion on closed isolators (barriers) and open isolators (RABS) is provided in the ISPE Baseline® Guide on Sterile Manufacturing Facilities (Reference 13, Appendix 12).
Isolators are a microenvironment and the area of greatest risk, and therefore, greatest environmental control is minimized. This design makes isolators a “green” technology with lower energy consumption than conventional processing.
Isolator technology for aseptic processing or containment of hazardous material can reduce the exposure of
operators to product and the exposure of product to disinfection chemicals that may be used in a conventional aseptic processing suite.
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Mr. Gerardo Gutierrez, Sr.
Mexico, DF, ID number: 299643
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Isolators may be fed with room air (as shown in Figure 3.16 and Figure 3.17) or by dedicated air handlers. The use of dedicated air handlers decreases the risk of vapor phase hydrogen peroxide (VPHP) escape from the isolator and simplifies balancing of the room and enclosure. Use of room air is more energy efficient and potentially demonstrates less impact on isolator pressurization relative to the room because of changes in the isolator operating mode (or phase).
Depending on the source of makeup air to an isolator’s air handling system, there may be an effect on room pressure when an isolator is in use. When an isolator draws air from the room and returns it all to the room, there should be no effect during normal operation. If an isolator draws air from outside the room, air leaking from the isolator will further pressurize the room. Most isolators have multiple operating modes for open setup with unidirectional flow, CIP, closed-operation. The integration of an isolator to a processing room requires careful consideration of all operating phases and conditions. The effect of the transition between isolator operating modes on the surrounding room should be carefully considered, as it may impact the relationship of the processing room to surrounding spaces.
HVAC control designs for the room should account for planned isolator operating modes and transitions. Isolators decontaminated by VPHP and then aerated present additional challenges, as the air removed from the room is not returned during the aeration phase. VPHP sensors should monitor the room around the isolator and mechanical spaces outside the room as a further safety measure.
The air classification required for the background environment depends on the design of an isolator and the application. Room cooling loads should account for the heat generated by the isolator fan system(s).
3.15.5 Vial Capping
The 2008 revision to EU GMP Volume 4 Annex 1 provides specific requirements for finishing of sterile products, specifically for freeze drying vials:
“Partially stoppered freeze drying vials should be maintained under Grade A conditions at all times until the stopper is fully inserted.”
It also gives specific requirements for stoppering/crimping, to be implemented by 1 March 2010.
“As the equipment used to crimp vials can generate large quantities of non viable particulates, the equipment should be located at a separate station equipped with adequate air extraction.”
“Vial Capping can be undertaken as an aseptic process using sterilized caps or as a clean process outside the aseptic core. Where this latter approach is adopted, vials should be protected by Grade A conditions up to the point of leaving the aseptic filling area, and thereafter, stoppered vials should be protected with a Grade A supply until the cap has been crimped.”
Where facilities are being modified to comply with these regulations, the following factors should be considered:
• A UFH can be used to provide a robust Grade A (Grade 5) local airflow.
• The loss of air from an area due to an extract system for capper particles should be considered during balancing, unless the air is re-introduced into the room (in this case, via a HEPA filter in order to maintain environmental conditions).
• The heat gains from the fans of unidirectional flow and extract systems should be considered.
3.15.6 Lyophilizer
As the loading and unloading of a freeze dryer should be under Grade 5 (Grade A) conditions, it is usual to place a large UFH over the lyophilizer door. Smoke tests (with and without operator presence) may reveal poor air patterns near the bottom of the door opening. A low level return (with considerable airflow) below the lyophilizer door may help improve patterns.