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  • 1. 1
  • 2. Seminar onBharati Vidyapeeth College of Pharmacy, Kolhapur 2
  • 3. ContentIntroduction.Importance of freeze drying.Freeze Drying Sequence.Calibration of Lyophilizer.Types of maintenance.Lyophilizer components system maintenance.Lyophilizer maintenance.Conclusion.References. 3
  • 4. IntroductionFreeze drying is the removal of ice or other frozen solventsfrom a material through the process of sublimation and theremoval of bound water molecules through the process ofdesorption.Freeze drying is a batch process used for extracting dryproduct from an aqueous solution. 4
  • 5. Freeze drying leads to improved stability of the product andan extended shelf life.Accurate & sterile dosage adaptation is possible.Freeze drying can be operated in a more controlled environmentthan some other forms of drying, which means less chanceof contamination.As product are much lighter when they are dry, freeze dryingalso offers the benefit of reducing transportation costs. 5
  • 6. SteriliseLoadCool chamber to -50 CStabilise chamber at -50 CCool condenser to -50 CEvacuate to vacuum.Primary Drying.Secondary Drying.Pressure Rise Test to check drynessUnloadDefrost 6
  • 7. Type of Maintenance ReliabilityPreventive centeredMaintenance Maintenance Corrective Maintenance 7
  • 8. Calibration is reassurance that your pressure gauge, chart recorder,temperature display, or any other critical equipment that is reliedupon 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. 8
  • 9. Sr. no. Component Accuracy Accuracy Ratio 1 Vacuum Gauge 0.05% 4:1 Calibration 2 Thermometer Calibration 0.2 Degrees 4:1 Celsius 3 Thermocouple 0.2 Degrees 4:1 Calibration Celsius 4 power supply 0.025% 4:1 Table. 1- Calibration of Component 9
  • 10. Computer SystemInstrumentation System Vacuum SystemMechanical/Refrigeration System Product and Condenser Chambers 10
  • 11. The most overlooked aspect of dryer maintenance is thecomputer System on PC-based.It is important to keep the back-up or Archive data file ona 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 11
  • 12. The instrumentation system encompasses all of thetemperature and pressure sensors on a lyophilizer.Instrumentation systems that require calibration.Good manufacturing processes would suggest thatintervals of calibration.Capacitance manometer & pirani gauge convergencemethod are typically very stable once calibrated. 12
  • 13. Lyophilizer– components: vacuum pump, product chamber,and condensing chamber.The vacuum pump : “wet” pump with oil lubrication or anoil-free “dry” pump.Vacuum pump manufacturers recommend changing thepump oil between 2000-3000 hours.One method to verify the integrity of the oil is to visuallycheck the colour at the end of the cycle. 13
  • 14. Chamber door should be visually inspected before each cycle.High vacuum type grease should only be used in very smallamounts, and replaced between one and three years.Once a gasket has become cracked, split or damaged it shouldbe 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 theseals. 14
  • 15. Figure 1: Automated Leak Test on a PC control system. 15
  • 16. Periodic checks the overall operation consist of running aautomatic 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 berepeated and the measured temperatures & pressures recorded,checked against the set points.Compared to the previous data from running the same cycle. 16
  • 17. All internal chambers and surfaces should be clean after each run.Making sure to remove any spilled product, broken glass and vialstoppers 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 betaken to neutralize this by spraying a PH buffer into the chambers. 17
  • 18. Expansion Vacuum Noncondensable Valves Leak gasesVacuum Hydraulic Net Oil Pressure Pump Problem DischargeSuperheat Pressure Problem 18
  • 19. When changing the cage assembly match the spring tension fromthe old cage assembly to the new cage assembly. This shouldposition the new cage close to the old cage adjustment.Oil soak all the gaskets on the cage assembly with refrigerationoil before reassembly.Tighten the power assembly to body hold-down bolts evenly andtorque to the manufacturers specifications. 19
  • 20. Take a small sample from the pump drain and see if there is anycontamination 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 atleast 140 F to 160 F.The blank-off pressure should be at least 50 millitorr below thelowest required operating pressure. 20
  • 21. When a refrigerant is heated above its boiling point it is said to besuperheated.Ensure that the sensing bulb for the (TXV) clamped to the suctionline on a horizontal pipe.Securely attach your thermometer probe to the suction line bulb ofthe TXV.The correct superheat settings on a freeze dryer are between 5-degand 7-deg F in a no-load condition. 21
  • 22. Vacuum leakReal vacuum Virtual leak vacuum leak OperatingGross leak leak Trivial leak 22
  • 23. Real Vacuum Leaks These leaks are penetrations or passages through thefreeze dryer vessel or vacuum system the chamber, thecondenser, the vacuum lines, or the vacuum seals.Gross LeakThe leak is sufficient to prevent the vessel pressure fromreaching values that are within the operating range of thevacuum gauges.Operating LeakThe leak will allow the system to reach pressure withinthe operating range of the vacuum gauges. However, theultimate pressure obtainable by the system is significantlyhigher than the specification for the lyophilizer. 23
  • 24. Trivial LeakThe leak is small enough that the system can be pumped down toits low pressure specification. A trivial leak may be identified asa deviation from the normal rate-of-rise curve during the vacuumintegrity 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 systems interior. 24
  • 25. Symptoms Diagnosis Solution1. 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. 25
  • 26. Symptoms Diagnosis Solution3. 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. 26
  • 27. Symptoms Diagnosis Solution1. 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. 27
  • 28. Non-Condensable gases in a freeze dryer refrigeration systemcan degrade system performance and cause premature failureof 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 pressurewill be due to the amount of air trapped in the refrigerationsystem. This over-pressure can easily reach 40 to 50 psi. 28
  • 29. Net oil pressure (NOP), sometimes referred to as useful oilpressure, is the difference between the oil pump dischargepressure and the crankcase pressure.The oil pump picks up oil at crankcase pressure from thecompressors pump. The oil pumps rotating gear or eccentricthen adds pressure to the oil pumped through the crankshaft.The added pressure is considered "net" oil pressure. 29
  • 30. The freeze dryer is comprised of various componentsworking in harmony to provide the desired results.Keeping components of freeze dryer in good working orderhelps not only to assure the equipment itself but avoidsprocess failures or bad results.Routine maintenance and some simple rules help to provideuninterrupted freeze dryer for use.Routine maintenance on periodic bases help to assure goodresult in freeze drying. 30
  • 31. Dr. J. Jeff Schwegman "Basic Cycle Development Techniquesfor Lyophilized Products” 2009.Jennings, Thomas. “Lyophilisation: Introduction and BasicPrinciples”2002.John G, Day and Glyn Stacey, “Cryopreservation and Freeze-Drying Protocols”, Second Edition,2007.Matt Dellinger, “Basic lyophilizer maintenance assure goodresults”, S P Industries, 2nd April,2009,Review-I. 31
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