3. Content
Introduction.
Importance of freeze drying.
Freeze Drying Sequence.
Calibration of Lyophilizer.
Types of maintenance.
Lyophilizer components system maintenance.
Lyophilizer maintenance.
Conclusion.
References.
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4. Introduction
Freeze drying is the removal of ice or other frozen solvents
from a material through the process of sublimation and the
removal of bound water molecules through the process of
desorption.
Freeze drying is a batch process used for extracting dry
product from an aqueous solution.
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5. Freeze drying leads to improved stability of the product and
an extended shelf life.
Accurate & sterile dosage adaptation is possible.
Freeze drying can be operated in a more controlled environment
than some other forms of drying, which means less chance
of contamination.
As product are much lighter when they are dry, freeze drying
also offers the benefit of reducing transportation costs.
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6. Sterilise
Load
Cool chamber to -50 C
Stabilise chamber at -50 C
Cool condenser to -50 C
Evacuate to vacuum.
Primary Drying.
Secondary Drying.
Pressure Rise Test to check dryness
Unload
Defrost
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7. Type of
Maintenance
Reliability
Preventive centered
Maintenance Maintenance
Corrective
Maintenance
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8. Calibration is reassurance that your pressure gauge, chart recorder,
temperature display, or any other critical equipment that is relied
upon daily is telling you the truth.
Calibration can be required when an instrument:
Has an elapsed calibration interval.
Has measurements that are questioned.
Has been serviced/repaired.
Has had a shock or vibration.
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11. The most overlooked aspect of dryer maintenance is the
computer System on PC-based.
It is important to keep the back-up or Archive data file on
a periodic basis as per an intensity created SOP.
A hard disk fragment can be run on computer system.
Minimize the number of other applications on the computer
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12. The instrumentation system encompasses all of the
temperature and pressure sensors on a lyophilizer.
Instrumentation systems that require calibration.
Good manufacturing processes would suggest that
intervals of calibration.
Capacitance manometer & pirani gauge convergence
method are typically very stable once calibrated.
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13. Lyophilizer– components: vacuum pump, product chamber,
and condensing chamber.
The vacuum pump : “wet” pump with oil lubrication or an
oil-free “dry” pump.
Vacuum pump manufacturers recommend changing the
pump oil between 2000-3000 hours.
One method to verify the integrity of the oil is to visually
check the colour at the end of the cycle.
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14. Chamber door should be visually inspected before each cycle.
High vacuum type grease should only be used in very small
amounts, and replaced between one and three years.
Once a gasket has become cracked, split or damaged it should
be replaced.
The valves should be inspected and cleaned on a periodic basis.
A leak rate test = to check integrity of the chamber and all of the
seals.
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16. Periodic checks the overall operation consist of running a
automatic system test cycle, also known as function test.
The function test - mechanical components, include compressors,
refrigerant valves, heat transfer systems, etc.
If the function test option is not available - Dry run could be
repeated and the measured temperatures & pressures recorded,
checked against the set points.
Compared to the previous data from running the same cycle.
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17. All internal chambers and surfaces should be clean after each run.
Making sure to remove any spilled product, broken glass and vial
stoppers and great care should be used around .
Stainless steel surfaces can be safely cleaned with most alcohols.
If acids have been lyophilized during the process, steps should be
taken to neutralize this by spraying a PH buffer into the chambers.
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18. Expansion Vacuum Noncondensable
Valves Leak gases
Vacuum Hydraulic
Net Oil Pressure
Pump Problem
Discharge
Superheat Pressure
Problem
18
19. When changing the cage assembly match the spring tension from
the old cage assembly to the new cage assembly. This should
position the new cage close to the old cage adjustment.
Oil soak all the gaskets on the cage assembly with refrigeration
oil before reassembly.
Tighten the power assembly to body hold-down bolts evenly and
torque to the manufacturer's specifications.
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20. Take a small sample from the pump drain and see if there is any
contamination such as metal particles or water.
Maintain a proper level of oil in the reservoir.
Before starting vacuum pump the pump should be preheated to at
least 140 F to 160 F.
The blank-off pressure should be at least 50 millitorr below the
lowest required operating pressure.
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21. When a refrigerant is heated above its boiling point it is said to be
superheated.
Ensure that the sensing bulb for the (TXV) clamped to the suction
line on a horizontal pipe.
Securely attach your thermometer probe to the suction line bulb of
the TXV.
The correct superheat settings on a freeze dryer are between 5-deg
and 7-deg F in a no-load condition.
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23. Real Vacuum Leaks
These leaks are penetrations or passages through the
freeze dryer vessel or vacuum system the chamber, the
condenser, the vacuum lines, or the vacuum seals.
Gross Leak
The leak is sufficient to prevent the vessel pressure from
reaching values that are within the operating range of the
vacuum gauges.
Operating Leak
The leak will allow the system to reach pressure within
the operating range of the vacuum gauges. However, the
ultimate pressure obtainable by the system is significantly
higher than the specification for the lyophilizer.
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24. Trivial Leak
The leak is small enough that the system can be pumped down to
its low pressure specification. A trivial leak may be identified as
a deviation from the normal rate-of-rise curve during the vacuum
integrity test.
Virtual Vacuum Leaks
A virtual leak is contained within the interior of the freeze dryer.
It can still be a difficult task to determine the source and location
of the out gassing.
Virtual leaks are generally harder to find than real leaks because
the source can be anywhere within the system's interior.
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25. Sr.no Symptoms Diagnosis Solution
1. Shelf lowering Shelf speed flow Open the shelf
operation too slow. control valve flow control valve
closed too much. for required speed.
2. Chattering During Shelf speed flow Close shelf flow
Shelf Lowering control opened too control valve for
Operation. much. smooth speed.
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26. Sr.no Symptoms Diagnosis Solution
3. Shelf Raising System pressure Adjust system
Operation Too set point too low. pressure.
Slow.
Low available Inspect reservoir
pressure from internally for pump
pump. or leaks, clogged
pump strainer.
Low on hydraulic 5 times completely
oil -possible air in up and down to
system. purge any air.
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27. Sr.no Symptoms Diagnosis Solution
1. Compressor Non- condensable Identify cause;
Discharge in system usually a leak to
Pressure Too High. (nitrogen, oxygen, atmosphere.
etc)
2. System Decrease the Remove excess
overcharged with efficiency of refrigerant.
refrigerant. cooling chamber.
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28. Non-Condensable gases in a freeze dryer refrigeration system
can degrade system performance and cause premature failure
of mechanical components.
Air is a mixture of approximately 78% Nitrogen, 21%,Oxygen,
1% Argon , and trace amounts of other gases.
Any pressure above the normal refrigerant condensing pressure
will be due to the amount of air trapped in the refrigeration
system. This over-pressure can easily reach 40 to 50 psi.
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29. Net oil pressure (NOP), sometimes referred to as useful oil
pressure, is the difference between the oil pump discharge
pressure and the crankcase pressure.
The oil pump picks up oil at crankcase pressure from the
compressor's pump. The oil pump's rotating gear or eccentric
then adds pressure to the oil pumped through the crankshaft.
The added pressure is considered "net" oil pressure.
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30. The freeze dryer is comprised of various components
working in harmony to provide the desired results.
Keeping components of freeze dryer in good working order
helps not only to assure the equipment itself but avoids
process failures or bad results.
Routine maintenance and some simple rules help to provide
uninterrupted freeze dryer for use.
Routine maintenance on periodic bases help to assure good
result in freeze drying.
30
31. Dr. J. Jeff Schwegman "Basic Cycle Development Techniques
for Lyophilized Products” 2009.
Jennings, Thomas. “Lyophilisation: Introduction and Basic
Principles”2002.
John G, Day and Glyn Stacey, “Cryopreservation and Freeze-
Drying Protocols”, Second Edition,2007.
Matt Dellinger, “Basic lyophilizer maintenance assure good
results”, S P Industries, 2nd April,2009,Review-I.
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