Lyophiliser
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- 2. Seminar on Bharati Vidyapeeth College of Pharmacy, Kolhapur 2
- 3. Content Introduction. Importance of freeze drying. Freeze Drying Sequence. Calibration of Lyophilizer. Types of maintenance. Lyophilizer components system maintenance. Lyophilizer maintenance. Conclusion. References. 3
- 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. 4
- 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. 5
- 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 6
- 7. Type of Maintenance Reliability Preventive centered Maintenance Maintenance Corrective Maintenance 7
- 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. 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 System Instrumentation System Vacuum System Mechanical/Refrigeration System Product and Condenser Chambers 10
- 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 11
- 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. 12
- 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. 13
- 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. 14
- 15. Figure 1: Automated Leak Test on a PC control system. 15
- 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. 16
- 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. 17
- 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. 19
- 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. 20
- 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. 21
- 22. Vacuum leak Real vacuum Virtual leak vacuum leak Operating Gross leak leak Trivial leak 22
- 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. 23
- 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. 24
- 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. 25
- 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. 26
- 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. 27
- 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. 28
- 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. 29
- 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. 31
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