In the past, many biotech companies chose the traditional approach of building a dedicated facility for the purpose of manufacturing a single product. This approach has some advantages from a cGMP/regulatory compliance, staffing and production control standpoint. However, this approach could put a heavy financial burden on established companies, as well as those start up companies with several products in the development pipeline who lack enough capital to support expenditure and investment in the construction of a new facility.
For several years it has become increasingly common for companies to develop multi-use manufacturing facilities capable of producing two or more products simultaneously. The multi-product or multi-use manufacturing nomenclature refers to a situation where a manufacturer of medicinal products produces two or more products within the same facility either concurrently or on a campaigned basis. Note that facility design for working with live cells vs. inactivated products needs to address strict containment issues for both personnel safety and cross contamination between areas and products.
In such facilities the following key factors are considered to minimize the chance of cross contamination between different production areas, and consequently the product:
- The engineering design
- Use of functionally closed process systems
- Air handling systems segregation
- Procedural separation of production activities
- Personnel flow, product flow, clean/dirty equipment flow
- Gowning regime
- Validated cleaning and changeover procedures
One of the key elements in a multi-product facility is the cleanroom design and its associated heating, ventilation and air conditioning (HVAC) system. A properly designed HVAC system will provide comfort, cleanliness, area segregation/containment, as well as personnel and product safety, which is essential for the successful operation of a multi-product biopharmaceutical manufacturing facility.
HVAC Design Considerations
The HVAC design of a multi-product manufacturing facility requires close interaction of the HVAC engineer, process engineer and the process architect (facility planner) from the start of the concept design throughout the completion of design documents. This will ensure implementation of an HVAC system in harmony with all elements of the facility as required for producing different products concurrently or on campaign basis.
This article will address the following key design considerations using an example of a multi-product facility, which was designed and validated successfully to produce multiple products with a campaigned manufacturing approach. The following requirements are defined during the project conceptualization phase.
- Area segregation and containment
- Product and personnel safety
- Temperature and humidity
- Area classification and pressurization
- Building automation system and environmental monitoring
- Regulatory requirements as it pertains to HVAC design
Area Segregation and Containment
An effective way to minimize cross contamination between different areas of processing operation is through area segregation of both process and cleanroom ventilation systems.
For cleanroom HVAC design, the area segregation is normally accomplished by using a separate air handling system dedicated to each area of the process operation including the inoculation suite, fermentation area, purification area (pre and post viral inactivation), and the bulk fill area. (See Figure 1)
Note that in this article, an air handling system consists of: air conditioning devices; air distribution ductwork and devices; supply; return; exhaust fans; and associated control systems.
The air handling system serving these areas could be a recirculating type or a once-through air design. The type of air handling system design and selection should be based on the type of product and process operation, as well as process equipment design (open vs. closed systems), product manipulation and toxicity of the product being produced.
As an example, when the potential of releasing dust or aerosolized materials from toxic substances and/or infectious agents into the room exists, utilization of a once-through HVAC system is recommended. This will protect the ventilation system serving the multi-use production area, and ultimately prevents cross contamination between products manufactured within the area by the ventilation system.
A dedicated air handling system for each area needs to be combined with airlock systems and a sound pressurization strategy to effectively control contaminated air from migrating into the adjacent zones housing different process operations.
In general, there are three basic airlock designs that can be combined or used individually to protect the cleanroom and/or prevent cross contamination between two adjacent areas of different process operations served by two different HVAC systems. These three airlock systems are:
- The cascading pressure airlock
- The pressure bubble
- The pressure sink
The cascading pressure airlock is used to protect clean areas from adjacent areas with lower required cleanliness. Normally, in this type of airlock, the transfer from the cleaner area, which does not pose any issue with cross contamination, is pushed into an access hallway. (See Figure 3)
The pressure bubble airlock is used to create a barrier between the cleanroom where the process resides and the adjacent area or access hallway. As the name implies, this type of airlock is a pressurized space that pushes the air out and into both the areas it protects. This type of airlock creates a barrier between the two spaces it serves, thus preventing cross contamination. (See Figure 4)
The pressure sink airlock is used to create a barrier between the cleanroom where the process resides and the adjacent area or access hallway. This type of airlock is a negatively pressurized space that pulls the air in from both the process area and the adjacent space thus creating a barrier between the two spaces it serves. (See Figure 4)
A combination of sink and bubble air lock design is also used for creating a barrier between potent compound or biocontained clean areas and the adjacent space.
Figures 1 and 2 show a facility designed and configured to manufacture the two different products ìAî and ìBî on a campaigned basis. By having HVAC and process systems segregated and dedicated to each stage of the process, the manufacturer was able to implement cleaning and changeover procedures to prepare the upstream manufacturing area for product ìB,î while maintaining the integrity and cleanliness required for downstream unit operations processing product ìA.î Note that this applies for segregation between live/dead cells and pre/post viral inactivation throughout the process operation.
As mentioned earlier, airlock and pass-through systems are utilized to segregate different production areas to achieve containment and reduce the chance of cross contamination between manufacturing areas.
Product and Personnel Safety
An appropriate cleanroom design addresses product safety by controlling both the number of viable and the non-viable airborne particles to an acceptable level for the process operation and associated cleanroom classification, as defined in the basis of the design during the project conceptualization phase. To protect the product from contamination, conventional cleanrooms are typically supplied with HEPA filtered air and local unidirectional hoods above areas where the product is exposed to the environment. Area segregation, as discussed earlier, would prevent cross contamination between two different products or product processing operations.
The personnel safety in areas handling raw material and/or working with live cells is achieved using containment hoods, isolators, masks and SOPs, combined with proper facility design and layout. The containment device, custom or pre-fabricated, should be designed to minimize the chance of operator error in the handling of product, and the location should be incorporated into the cleanroom layout design such that the airflow patterns do not affect the containment deviceís performance and integrity.
Temperature and Humidity
The control of temperature and humidity within process areas is based on area cleanliness, product requirements and occupant comfort. These parameters should be defined and included in the basis of design at the early stages of the conceptualization phase.
For space temperature maintenance, reheat coils must be installed in the supply ductwork serving the space or cluster of spaces. The thermostat should be located within any areas having critical process operations and temperature requirements.
The temperature set point for comfort is usually 68ƒF or less depending on the required level of gowning for the personnel working in the process area.
Space relative humidity (RH) affects personnel particulate shedding (space cleanliness) if the RH is too low, and promotes the growth of toxic molds and other forms of biological contaminants when too high. RH could also be detrimental to hydroscopic powder materials that are sensitive to high moisture content in the ventilation air, which causes clogging of powders used in buffer and media preparation.
For products and processes that require a specific range of relative humidity, the HVAC system should have the capability of providing both humidification and dehumidification to maintain the space RH within the pre-determined range. A relative humidity range of 30% to 60% would work with most products and provide a comfortable working environment for gowned personnel.
For humidification, a clean steam humidifier is recommended. The steam humidifier can be installed at the AHU to maintain an average humidity setpoint for areas served by the air handling system. However, if humidification control for a specific processing area is required, then a duct-mounted humidifier should be used to maintain that space humidity requirement.
Dehumidification can also be accomplished by using the air handling unit cooling coil if the plantís chilled water temperature is low enough (40-42ƒF) to extract moisture from the supply air. Note that the cooling coil face velocity should be between 400 to 450 ft/min to improve the cooling coil moisture extraction. If the process operation requires a higher level of dehumidification that cannot be attained with cooling coil dehumidification, then a dry or wet type dehumidifier should be used.
Selecting an appropriate location for the humidistat is important for maintaining the design setpoint. Designers working with end users should determine the level of average RH for an area served by the air handling unit vs. one specific space or area. To maintain RH for process areas served by an AHU, the RH sensor can be located in the supply main or return main of the AHU. But for individual space RH control, the sensor should be located in the space or the common return/ exhaust duct serving that space.
Area Classification and Pressurization
The process operation dictates the area classification or cleanliness of the environment in which the product is produced, purified and filled. Normally, upstream processes require lower area classification while the processes are exposed to the surrounding environment; down stream manufacturing steps require a higher area classification in order to protect the integrity of the bulk product that is in the final state ready for shipping to the fill and finish facility. All classified area ventilation should be supplied through terminal HEPAs and returned/exhausted through low wall grilles. The HEPA filtration for ISO9/Grade D areas could be installed inside the air handling unit and the return/exhaust grilles could be ceiling mounted. (See Figure 2)
The various classifications require a different number of air changes per hour (ACH) to achieve the required cleanliness associated with the class or grade designation. Typically, 20 air changes per hour is the starting point for ISO 8/Class 100,000 process areas. This ventilation rate (ACH) could be higher depending on the nature of the process and number of personnel present. Higher classifications require higher ACH and the ISO5/Class 100 is defined based on air velocity of 90 (+/-20%) feet per minute.
The area classifications most commonly used in the biotech industry are shown in Table 1. Some companies use ISO6/Class 1000 for the background in the critical areas with local ISO5/Class 100. The first column in Table 1 is a cross reference to the old standards 209E. Note that on November 29, 2001 Federal Standard 209E was canceled and superseded by ISO 14644-1 and 14644-2.
Rooms where the most critical processing takes place should have the highest differential pressure with respect to the areas surrounding the process suite. Overall the designer should maintain the building positive with respect to the outside of the building.
The pressure cascade should be designed such that the areas with the most critical processing have the highest pressure and the less critical areas have lower pressurization by a pre-determined pressure differential in the order of cleanliness required for each stage of process operation. Pressure drop across the airlocks separating two different classifications should be 0.05î of Water Column (W.C.) for US and between 10 to 15 Pascal (0.04î to 0.05î W.C.) in compliance with EU requirements. The least critical areas, like common corridors and staging areas, should have the lowest pressurization while maintaining the positive pressurization with respect to the outdoor environment. Determining the required space pressurization for cascading and/or regulatory requirements, the designer should carefully consider the pressure levels in the adjacent rooms to prevent possible problems with the door opening/closing due to excessive pressure differential across the doors.
Building Automation System and Environmental Monitoring
The facilityís building automation system (BAS) requires the ability to monitor and control the setpoints as determined by the design team and documented in the project basis of design. The BAS must be capable of indicating and recording alerts and alarms when the critical processing spaceís temperature/humidity/pressurization is not to specification.
Note that data recording by BAS and or other means should be in accordance to cGMP requirements and of a methodology acceptable by the regulatory agencies.
Temperature and RH sensors should be installed in the critical processing rooms, cold rooms, warm rooms and in the HVAC equipment serving the critical manufacturing areas to monitor the systemís performance as required in the basis of design and validation documents.
Regulatory Requirements As It Pertains To HVAC Design
The design and construction of multi-product manufacturing facilities shall meet cGMP in compliance with the FDA and, if exported, the regulations for the country in which the product is marketed and sold to the consumer.
The basic requirements for US regulations are found in the Code of Federal Regulations (CFR), Title 21, Part 210, 211, 606-680 and 820.
Part 210 covers cGMP in manufacturing, processing, packaging, or holding of drug products and Part 211 covers cGMPs for finished pharmaceuticals.
˜n November 29, 2001, the General Service Administration issued a notice that ìFederal Standard 209E dated September 11, 1992 is hereby cancelled and superseded by International Organization for Standardization (ISO) standards for cleanrooms and associated controlled environments.
ï ISO 14644-1 Part 1 (Classification of Air Cleanliness)
ï ISO 14644-2 Part 2 (Specifications for testing and monitoring to prove continued compliance with ISO 14644-1).î
European Community GMPs could be found in the ìRules and Guidance for Pharmaceutical Manufacturers and Distributors, 2002.î
The material covered in this article establishes the fact that a successful design, construction and operation of a multi-product facility depends on the interrelation of the manufacturing procedures, process and process equipment design, cleanroom and associated HVAC design, equipment flow, material flow, personnel flow, building design, validated cleaning and changeover procedures.
Several key factors for design of HVAC systems for a multi-product manufacturing facility were discussed. The implementation of these design considerations, and the adherence to cGMP regulations with a well-designed building layout will serve as basis for a successful multi-product facility.