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LYOPHILIZER MAINTENANCE HELPS ASSURE GOOD RESULTS

Presenter:Avinash A. ManeM.Pharm (Sem.- II), Dept. of Quality Assurance.

Guide :Prof. A. A. HajareProf. and Head Dept. of Pharm. Tech.

Bharati Vidyapeeth College of Pharmacy, Kolhapur

Date – 29-03-2012

Seminar on

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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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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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Importance of freeze drying

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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Freeze drying Sequence 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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Type of Maintenance

Preventive Maintenance

Corrective Maintenance

Reliability centeredMaintenance

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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.

Calibration of Lyophilizer

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Sr. no. Component Accuracy Accuracy Ratio

1 Vacuum Gauge Calibration

0.05% 4:1

2 Thermometer Calibration 0.2 Degrees Celsius

4:1

3 Thermocouple Calibration

0.2 Degrees Celsius

4:1

4 power supply 0.025% 4:1

9Table. 1- Calibration of Component

Lyophilize components systemmaintenance

Computer System

Instrumentation System

Vacuum System

Mechanical/Refrigeration System

Product and Condenser Chambers

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Computer system

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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Instrumentation system

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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Vacuum system 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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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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Figure 1: Automated Leak Test on a PC control system.15

Mechanical/Refrigeration system

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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Product and condenser chamber

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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Lyophilizer maintenance

Expansion Valves

Vacuum Pump

SuperheatDischarge Pressure Problem

Hydraulic Problem

Vacuum Leak Noncondensable gases

Net Oil Pressure

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Expansion Valves

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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Vacuum PumpsTake 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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Measuring Superheat

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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Vacuum leak

Real vacuum leak

Gross leak Trivial leak

Virtual vacuum leak

Operating leak

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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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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

Shelf Hydraulics Problems

Sr.no Symptoms Diagnosis Solution

1. Shelf lowering operation too slow.

Shelf speed flow control valve closed too much.

Open the shelf flow control valve for required speed.

2. Chattering During Shelf Lowering Operation.

Shelf speed flow control opened too much.

Close shelf flow control valve for smooth speed.

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Sr.no Symptoms Diagnosis Solution

3. Shelf Raising Operation Too Slow.

System pressure set point too low.

Adjust system pressure.

Low available pressure from pump.

Inspect reservoir internally for pump or leaks, clogged pump strainer.

Low on hydraulic oil -possible air in system.

5 times completely up and down to purge any air.

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Compressor Discharge PressureSr.no Symptoms Diagnosis Solution

1. Compressor Discharge Pressure Too High.

Non- condensable in system (nitrogen, oxygen, etc)

Identify cause; usually a leak to atmosphere.

2. System overcharged with refrigerant.

Decrease the efficiency of cooling chamber.

Remove excess refrigerant.

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Noncondensable Gases in Refrigeration Circuits

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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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.

Net oil Pressure

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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.

CONCLUSION

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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.

References

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Thank You...

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Any Question

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