The most important consideration when choosing a freeze dryer is to ensure the system is fit for both today's applications and future needs. For the sake of this discussion, we will focus on freeze dryers with fluidfilled shelves, which does not include lowend manifold or heatonly shelf freeze dryers.
An understanding of the available features of a freeze dryer can facilitate the choice. The following are some considerations:
- shelf size (m2 )
- shelf style (bulk or stoppering)
- condensing rate (L/h)
- condensing capacity (L)
- condenser location (internal versus external)
- material (304 versus 316SS)
- 21 CFR Part 11 compliance.
The freeze dryer manufacturer will also want to know what space is available for the freeze dryer and what utilities, such as electrical, air, chilled water and air conditioning, are available.
- Cylindrical or rectangular product chambers — a cylindrical product chamber is less expensive than a rectangular chamber; however, it may occupy more floor space depending on the configuration of the shelf assembly.
- Internal or external condenser — an internal condenser is cheaper and provides unrestricted vapour flow. An external condenser is supplied with an isolation valve to separate the product from the condenser, which protects the product from reconstitution during power loss, and keeps the condensate out of the clean room environment.
- Pirani or capacitance manometer — piranis, the least expensive vacuum measurement device, read the relative vacuum inside a freeze dryer because they are affected by vapour. The more vapour present, the higher the pressure reading. A capacitance manometer reads the absolute vacuum level and the reading is unaffected by vapour pressure. Most production systems use a capacitance manometer for measurement and control of vacuum level. The best method for determining the 'end of primary drying' is to compare a pirani reading to a capacitance manometer reading. When they read the same, there is no vapour present and the product is dry. A quick test can be conducted by lowering the vacuum level to see if the pirani reading tracks the capacitance manometer. If water is present, the capacitance manometer will drop faster. If no water is present, they will drop at the same rate.
- Proportional vacuum control — the least expensive vacuum control system bleeds gas into the chamber using a solenoid valve, providing ±10 mT stability at 100 mT. For better stability, a proportional vacuum controller can be used that regulates the gas bleed through a proportional valve. The result is ±0.5 mT or better control.
Freeze dryer selection falls into two main categories: laboratory versus production, and non-sterile versus sterile.
Laboratory freeze dryers are used for a large variety of applications, including removal of solvent from a material, Phase I clinical trials and protocol development for scaleup production. A typical laboratory system will have a shelf area of 0.1–1 m2 and a condensing capacity of up to 30 L.
Laboratorystyle systems can be simple freeze dryers with only standard features, such as a pirani gauge for vacuum level measurement and thermocouples for temperature monitoring, or they can incorporate more advanced instrumentation:
- capacitance manometer for vacuum measurement
- proportional vacuum control for fine vacuum control
- isolation valve between the product chamber and condenser for pressure rise testing
- liquid nitrogen traps for organic solvent trapping
- additional product thermocouples for monitoring product temperature.
Pilot and production systems offer shelf areas from 1 m2 up to more than 40 m2 . Production systems are used for Phases II and III clinical trials, and tend to be used for the same or a limited number of products in high-volume production. Recently, there has been a shift from using 10–50-mL vials, to 2mL and 5mL vials for smaller volume, highpotency biotech and proteinrelated products. The result is smaller freeze dryers with expensive payloads.
The type of processing will determine whether stoppering is required. Bulk applications can have fixedinplace shelves, but vial applications require stoppering where the shelves move and are squeezed together to press the partially inserted stoppers into the vial.
Pharmaceutical and other applications may also need to be sterilised between cycles, which can add significant complications and costs to a freeze dryer. A freeze dryer is normally rated for vacuum and the most common method of sterilisation is pressurized steam, which requires the freezedryer chambers to be certified pressure vessels rated to 2 atm at 131 °C.
An alternative sterilisation technique, which is growing in popularity for laboratory and small production systems, uses hydrogen peroxide (H202). H202 does not require a pressurerated vessel, which helps to minimise costs.