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Freeze drying (lyophilisation) is a stabilisation method that is widely used in the pharmaceutical industry for drugs, vaccines, antibodies and other biological material. Freeze drying can be a complex process to manage effectively but despite improvements in analytical and process science a number of misconceptions persist.
This is part 2 / 2 in this series – click here for part one.
6. Lower chamber pressure means faster freeze drying
“A higher vacuum (lower pressure) will suck the water out faster and speed up processing”
The vacuum within a freeze drying chamber is intended only to create the necessary conditions for the moisture to sublime directly from ice to vapour. The moisture is not “sucked out” of the product and in fact chamber pressures that are unnecessarily low will slow freeze drying.
When moisture sublimes from ice to vapour, the product temperature will drop due to an effect known as “sublimation cooling”. As the product cools, sublimation will slow and the process will lengthen. In order to counter this effect energy (heat) needs to be continually added.
Heat enters the product by conduction and by radiation but also convection from the remaining air molecules. As the pressure in the chamber drops, the effect of convection decreases. Control of the pressure/vacuum in the chamber is therefore one way of influencing the overall speed of the process.
The driving force of freeze drying is the vapour pressure differential between condenser and the product in the drying chamber, not simply the pressure or the flow of gas created by a vacuum pump.
7. Condenser overloads
“Why does the condenser overload or by-pass when we’re processing far less than its stated overall capacity?”
If vapour is being created at a rate faster than the condenser can trap it, the vapour will bypass the condenser and exit to the vacuum pump. Known as an overload, this can cause vapour to condense in the pump, damage the pump and can also be an indication that there is a problem with the particular processing step or recipe.
Performance figures for freeze dryer condensers are most commonly given as overall capacity (at a particular ice thickness) and deposition rate over 24 or 48 hours – the latter being a particularly important figure. These figures are often quoted for comparison with other systems and it’s important to note that both of these measurements are based on a number of standardised parameters that may not be applicable to a particular scenario. Factors such as the processing temperature, the container type and the batch size can all affect the rate at which a quantity of vapour is generated and careful consideration of drying conditions is important.
Vapour will not be given off at an even rate throughout the cycle (see graph 1 above). Drying is often much faster at the start of primary drying, when there is less impedance to the migration of vapour. The condenser’s performance may match the requirements when they are taken as an average over 24 or 48 hours, but it may be that the majority of this vapour is being generated early on in too large a volume for the condenser to trap and the condenser will overload or by-pass.
Application of too much energy at the start of the drying process can lead to high vapour generation which in turn can lead to vacuum pump failure and risk a rise in condenser temperature as it tries to cope with condensing too much vapour. This is a particular design consideration when specifying benchtop or production systems and correctly sizing the condenser’s capacity and operating temperature to ensure the particular solvent will condense is important to long term reliability.
8. Shelf spacing requirements
“I have 10 ml vials with a height of 45mm plus stopper at 8mm for a total height of 53mm. Why can’t I specify a dryer with 55mm shelf spacing to maximise batch capacity?”
Shelf spacing calculations are made to ensure that not only can we easily load product onto shelves, but that there is also sufficient space above the drying vials ( or other container types ) to allow unhindered vapour escape. Vapour can leave the drying vials at a high rate and with insufficient space for that vapour to escape above the vials it is possible to set up local drying conditions in the centre of a shelf, for example, with different drying conditions than those vials nearer the edge of a shelf.
There are various formulas available for determining the shelf spacing required. In the example given above, our own calculations suggest that a spacing of 65mm (loaded with a removable bottom tray, so no extra allowance for tray thickness) would be more acceptable. In practice, we may also consider the dimensions of the shelf and vial shoulder design when making recommendations. It would be possible to complete drying at reduced spacing but it’s likely an extended cycle would be required to reduce possible vapour load and the risk of localised drying conditions.
On larger production dryers, it is increasingly common to employ automated loading and unloading systems (ALUS) and shelf spacing also needs to accommodate mechanisms of such equipment.
9. Vacuum pumps are all the same
“I have a vacuum in the lab that works fine, I’ll use that one”
“I’ll just connect the dryer to our house vacuum system”
“I want to put the vacuum pump at the other end of the bench”
“What is the gas ballast function?”
Many pumps often found in the lab – central vacuum systems, single stage pumps or diaphragm pumps – are not suited for freeze drying as they cannot achieve the required vacuum or maintain performance, having no pumping speed capability at typical freeze drying operating vacuum. The system must achieve a vacuum lower than the vapour pressure of ice at the frozen product temperature in order to begin the sublimation process.
Most commonly, a two stage, oil sealed, rotary vane vacuum pump is sufficient for most freeze drying applications. With the pump’s ultimate achievable vacuum typically of the order of <1mtorr (measured directly at the pump according to pump manufacturer data), this provides near 100% of the pumping speed performance across the typical working range of freeze drying vacuum requirements. If the freeze drying system is specified correctly then the condenser will trap all condensable vapours and the pump will provide initial pull down and maintain set vacuum in the case of minor vacuum fluctuations and control by gas bleed.
In all vacuum applications, it is useful to site the pump as close as possible to where performance is required as long length, small bore tubes have a significant effect on reducing vacuum pump performance.
Dry vacuum pump technology has improved in recent years and is more affordable. Dry pumps potentially offer reduced maintenance through no oil changes and certain designs can be more tolerant to agressive vapours, liquids and particulates. Although ultimate performance does not match “wet” oil sealed pumps, pumping speed characteristics have improved and such dry pumps are now successfully employed in freeze drying applications.
“Gas ballast” is normally a two position valve – on /off – that allows a small amount of air to be introduced at the final compression stage of the pump. The effect is to increase the pump’s tolerance to pumping water vapour and also to raise the pump’s operating temperature so degassing and cleaning up the oil of any solvent contamination. It is good practice to operate gas ballast for 10-15 minutes after a freeze drying run before switch off. Remember to turn the gas ballast off as oil carryover to the exhaust can be measured in significant cc/hr and will eventually drain the pump, potentially causing damage.
Vacuum pump maintenance is one of the more important day to day tasks that users can complete simply and easily to ensure the long term performance of the freeze dryer generally.
10. Freeze drying equipment doesn’t need maintenance
“No-one ever services my fridge/freezer.”
Freeze drying equipment can be very complicated, often operating daily at both high temperatures and very low temperatures in the same system as well working to negative and positive pressures. Changes in the batch quality, degradation in performance characteristics and system alarms may indicate that maintenance is required.
Problems in the refrigeration system can cause the shelf and/or condenser to cool more slowly or not to a low enough temperature. The amount of refrigerant in the system is important and both under- and over-charge can cause the system to function incorrectly. Other problems include moisture or air contamination and mechanical faults. Refrigeration problems should only ever be investigated by qualified engineers in accordance with EU legislation.
Refrigerating systems such as freeze dryers work best if they are run regularly as the refrigerants and system lubricants will pool and settle if left to stand even for a few months, so when bringing an old system out of storage or purchasing a second hand unit it’s important to consider that the system will not simply switch back on again and run as it used to. Freeze dryers should always be stored upright and should never be tilted or stored lying down.
As a vacuum system a freeze dryer is complicated and there are a lot of valves, gaskets and joints where leaks can develop. As well as reducing the vacuum that can be achieved this can also let moisture and contaminated air in to the chamber. However the most common cause of loss of vacuum is a problem with the vacuum pump which is relatively easy to service or even replace.
Control systems, CIP / SIP systems and instrumentation can also develop faults which will cause the freeze dryer to operate incorrectly or not at all.
Faultfinding can be time-consuming. Regular scheduled maintenance is the best way to ensure that the system continues to work as required with a minimum of downtime.
Links & More information
New to freeze drying? Request a free copy of our Introduction to Freeze Drying or learn about our Training Courses.