Like most scientific equipment, the freeze dryer (lyophilizer) is made up of different components that work in unison to deliver the desired scientific results. Keeping those subcomponents in good shape helps to guarantee that the equipment itself does not cause process failures or incorrect results. Regular maintenance and a few simple housekeeping rules that can aid continuous freeze dryer use are explored in this article.
Lyophilizer components typically include the following:
- Computer System
- Instrumentation System
- Vacuum System
- Mechanical/Refrigeration System
- Product and Condenser Chambers
The most overlooked aspect of dryer maintenance is often the computer system on PC-based PLC controllers. It is crucial to keep the computer unit operating at peak efficiency and to archive or backup data files in a systematic manner, according to an internally created SOP. It is recommended that data files be backed up no less than once a month, if not more frequently, so that data can always be recovered in the event of computer-network malfunctions.
A hard disk defragmentation can be carried out on computer systems that are working sluggishly. However, this should not concur with an active lyophilization cycle. This check can be done by the user or by an internal IT team, if possible.
When using a standalone computer on an essential piece of research equipment, such as a lyophilizer, it is good practice to reduce the number of other applications being used on the computer.
The instrumentation system includes all of the pressure and temperature sensors on a lyophilizer. In a majority of freeze dryers, there is most typically a minimum of two or three types of instrumentation systems that need calibration.
These normally include different types of pressure and temperature sensors. Usually, “T” type thermocouples are used to measure both product temperatures and the temperature of the shelf heat transfer fluid and the condenser temperature. Vacuum sensors may be any mishmash of Pirani and/or Capacitance Manometer-type gauges on larger freeze dryers or just a simple thermal conductivity gauge on bench-top units.
Depending on whether the freeze dryer is a GMP production dryer or a non-GMP lab scale dryer, the calibration interval will differ, and this should be stated in an internal SOP. The need for calibration intervals may be varied for various lyophilizers based on where the lyophilizer is being used and whether or not it is part of the serious path for the development of a freeze-dried product.
Good manufacturing processes would indicate that intervals of calibration should preferably start out with a comparatively short interval, such as monthly or weekly calibrations. If the calibration process specifies that the system calibration is moderately stable, the interval between calibrations can be increased.
Theoretically, there will be an interval at which the system seems to be repeatedly out of calibration. In this situation, the ideal approach is to back up one calibration interval and utilize that at the time interval for calibration moving in the future. In this manner, the user has a comparatively high degree of assurance that the system is in calibration during every single run. At a minimum, it is suggested that calibration of the lyophilizer sensors be performed on a yearly basis.
Maximum calibration routines can be conducted in-situ in many different ways. A crushed de-ionized ice bath - to assess product probe thermocouples at 0° Celsius - is one such way. Certain temperature sensors can only be calibrated using an electronic temperature simulator. It is suggested that the manufacturer of the system be consulted for the ideal method to use.
In a system with both a Pirani gauge and a Capacitance Manometer, a basic check of the vacuum gauges can be done by operating the freeze dryer dry and empty, with a set point of 0 mT. Pirani gauges, despite reading inaccurately high in the presence of water vapor, are normally highly stable once they are calibrated.
After the freeze dryer is allowed to stabilize at a moderately low pressure, the Capacitance Manometer and the Pirani gauge should be compatible. If these gauges are not compatible, and if there is a high degree of certainty that the system is fully dry and it has been completely evacuated and pulled down to its maximum low pressure, then it can be safely assumed that the system is not in calibration.
When a more detailed check is required, a vacuum transfer standard should be used to confirm that the vacuum zero modification is within tolerance. Calibration may be provided by an outside service, or developed and implemented within one’s own company. Vacuum gauge manufacturers mostly provide calibration information that may turn out to be valuable when users are developing their own calibration processes.
Every lyophilizer includes a vacuum system that encompasses a vacuum pump and a product/condensing chamber(s). The vacuum pump can be either an oil-free “dry” pump or a “wet” two-stage direct drive pump with oil lubrication. Wet pumps can attain very low vacuum levels (<10 mT) and are comparatively inexpensive, rendering them the most frequently used vacuum pump in freeze drying.
The majority of wet vacuum pump manufacturers recommend that the pump oil be changed between 2000 and 3000 hours. However, in certain freeze drying applications, the time between oil changes should be more frequent. These applications would include freeze drying using any solvents other than water.
One technique used to confirm the reliability of the oil is to visually check the color at the end of the cycle. In case the color has darkened to a noticeable degree, it is suggested that the oil be changed at the end of the cycle, while the oil is still warm.
A few vacuum pump manufacturers separate the vacuum pump oil level sight glass from the central working oil in the pump itself. If this is the case, then the sight glass cannot be used to identify vacuum pump oil degradation. Wet pumps also contain an oil mist eliminator (OME) filter that must be swapped at regular intervals, usually once per year.
Although oil-free vacuum pumps do not need oil changes and do not add to vacuum pump oil back-streaming, they do require regularized rebuilding due to the lack of lubrication. Furthermore, they normally are not able to attain as low of a vacuum level as a wet pump. Users will have to consult the pump manufacturer for the proposed interval for the upkeep of this type of pump.
Chamber door and/or manifold gaskets are another crucial part of the overall vacuum system on a lyophilizer and they should be visually checked before each cycle. The freeze dryer could have one or more gaskets, as per the design of the system.
Most rubber or silicon door gaskets do not necessitate lubrication except if they have become dry—new gaskets are usually impregnated with oils from their manufacturing process.
A common mistake is applying a heavy coat of vacuum grease to the gasket. This will basically attract dirt and contaminants to the grease, thus ruining any advantage of the vacuum grease. High vacuum type grease should only be used in very small quantities to lubricate the gasket. It must never be used to fill splits or cracks on a worn gasket. Once a gasket has become split, cracked, or damaged, it should be changed. The time interval will differ according to system usage. Gaskets are usually switched between one and three years.
Bench-top freeze dryers will usually comprise of an adaptor plate, manifold, and quick-seal valves for attaching flasks. All of these parts should be leak-free for the system to attain a satisfactory vacuum level.
Acrylic manifolds and adaptors plates should be checked at regular intervals for cracks and etching, particularly if organic solvents have been employed (many organic solvents necessitate the use of stainless manifolds). The valves should be examined and cleaned on a regular basis.
Even a small scratch could make a flask implode when exposed to the pressure differential of a vacuum; therefore, all glassware should be scrutinized for scratches and cracks.
A basic check of the whole vacuum system is done to confirm the ultimate low pressure (0 mTorr set point) in a clean dry system with the condenser switched on. If the vacuum level does not meet factory specifications, there is either a leak at some portion in the system, or the vacuum pump needs maintenance. (Note: This assumes the pressure gauge has been calibrated and is reading precisely. Furthermore, any filter trap cartridges should be taken out before testing as out-gassing may influence the ability of the pump to totally evacuate this system).
A leak-rate test can be carried out on the system to validate the integrity of the chamber(s) and all of the seals. This can be as basic as manually operating the system down to a low vacuum set point and then switching off the vacuum pump for a definite period of time, such as one hour.
A leak rate, usually expressed in mTorr/hour, can then be calculated based on the change in vacuum level. Acceptable leak rates are set according to the volume of the vacuum chamber. General leak-rate specifications are below 60 mTorr/hour for bench-top units, 30 mTorr/hour for pilot-sized freeze-dryers, and 15 mTorr/hour for larger production units.
Leak rates can also be identified in units of mTorr∗L/second, if the total volume of the system is identified. PC-based control systems will mostly include an automated leak-rate test cycle. Leak-rate tests should be carried out regularly, as defined in an internal SOP.
Since a leak-rate test can be done quite quickly, it is frequently done on a regular basis, particularly in a production environment.
Note: One must be cautious when running a leak test on older systems, particularly those that do not have an individual vacuum brake solenoid (VBS) anti-suck back valve integrated into the vacuum system. Although the majority of vacuum pumps do contain a basic integrated anti-suck back check valve, this valve may often not be completely functioning. If this is the case, and the lyophilizer is left in a deep vacuum while the pump is switched off, the user runs the hazard of sucking vacuum pump oil back into the freeze dryer.
Systematic checks of the overall operation of the freeze dryer should be carried out at regular intervals. This may include carrying out a built-in automatic system test cycle, also known as a function test. The function test should be done at least once per year, although quarterly or semi-annual checks are suggested for production systems to reveal system deficiencies that may be emerging slowly and not spotted during a standard process run.
These deficiencies could turn out to be harmful to the processing of a product during future cycles. The function test will check that all of the mechanical and refrigeration parts, including compressors, valves, refrigerant charge, heat transfer systems, etc., are functioning well.
If there is no automated function test option, a basic recipe (dry run) could be repeated at regular intervals, and the measured pressures and temperatures could be noted alonside the set points and compared with the earlier data from the same cycle. For standard bench-top lyophilizers, the lowest condenser temperature can act as a check of the whole refrigeration system.
Typical equipment problems that may crop up are electrical relay failures, refrigerant leaks, and valve failures. Conducting regular checks on these components can expose potential issues. It is suggested that someone who is acquainted with the mechanical and refrigeration systems on the lyophilizer check these areas if the results of the function test are out of factory specifications. Having preventative maintenance performed on the lyophilizer at periodic intervals can decrease the number of issues encountered with product runs by revealing potential problems early on. Leading freeze dryer manufacturers have service staff who are qualified to undertake this type of maintenance.
Refrigeration systems comprised of air-cooled condensers need periodic cleaning of the fins to remove dust and dirt. A vacuum with a nozzle brush can be employed, taking precaution not to damage or bend the fins.
The internal chambers and shelf surfaces must be maintained in a clean manner. After each run, they must be cleaned, making sure to get rid of any spilled product, vial stoppers, and broken glass. A lot of care should be taken around thermocouple wires and jacks. It is good practice to make sure that the unit is clean before the start of every cycle, particularly when there are a number of users in a laboratory environment.
Stainless steel surfaces can be securely cleaned using most alcohols, but care should be taken around clear acrylic doors, as some cleaning solvents can etch and craze this type of door. If organic solvents are used in the product, additional care must be taken to stop the melted condensate from resting against the condenser door after a cycle.
It should be drained instantly and appropriate steps must be taken to get rid of the condensate. If acids have been lyophilized during the process, neutralization steps need to be carried out by spraying a PH buffer into the chambers.
Other Maintenance Items
Adhering to the recommendations in the operations manual is the best way to ensure the precise interval for system maintenance. General housekeeping should be used to maintain the inside as well as the outside of the lyophilizer clean. Basic housekeeping procedures and a calibration schedule should be integrated into the SOP.
A few maintenance items not discussed in this article should only be performed by qualified service personnel. These are:
- Checking static pressure in the refrigeration system
- Checking for heat transfer fluid leaks
- Checking the refrigeration system for leaks
- Solid State Relay Test on microprocessor type controllers
- Repairing/rebuilding vacuum pump
All queries can be directed to the service department of the equipment manufacturer. A preventative maintenance plan can help guarantee that all regular maintenance items are done as per the proposed schedule. This will help keep the freeze dryer running at highest performance.
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