Lyophilization Process Validation

Freeze drying (or lyophilization) is a technique used to remove water from a solution to leave a dry ‘cake’ as an end product. The dry product is much more stable than a solution. The reduced weight and volume is a big advantage and the removal of the water does not change the activity of the product. This technique involves freezing the product on a shelf to very low temperatures, typically –40 to –50°C, applying a vacuum and then slowly heating the product to initiate the ice to turn into vapor and this removes the water content from product by a process called sublimation.

The critical parameters during freeze-drying are temperature (product and shelf) and pressure. These measurements are usually recorded with every cycle to determine when the product is dry. In addition to monitoring each cycle, freeze driers also require regular validation. This will generally involve temperature mapping of the shelves in the chamber as well as validation of steam supplies for SIP system.

As freeze drying is a rather expensive process most products being processed are within the pharmaceutical and biotechnology area where companies often use freeze-drying to increase the shelf life of products, such as vaccines and other injectables. By removing the water from the material and sealing the material in a vial, the material can be easily stored, shipped, and later reconstituted to its original form for injection.

You can still find lyophilization performed in other areas :

Food industry (example: freeze dried fruits, astronaut food supplies, instant coffee).

Technological industry:

  • In chemical synthesis to make them more stable, or easier to dissolve in water for subsequent use.
  • In bioseparations as a late-stage purification procedure to remove solvents.

In bacteriology to conserve special strain.

Conservation and preservation industry:

  • Flowers
  • Animals
  • Water damaged books and documents

PROCESS EQUIPMENT

A freeze dryer consist basically of 3 components: sample chamber, condenser and a vacuum pump system. Depending on what should be dried, the sample chamber that is directly connected to the condenser and vacuum pump is designed with appropriate number of shelves which can be moved up and down if closing of vials is requested. This is called the stoppering arrangement. There are essentially two categories of freeze-dryers: batch and continuous dryers.

Batch freeze dryers are designed either for bulk drying where product is distributed onto trays or vial drying where product is dispensed into flasks(vials) using special rubber stoppers with vapour “escape” holes (slots). The benefit of this container is that the product can be easily reconstituted by simply adding liquid. For both systems batch monitoring can be done either by using the E-Val Flex cabled system or TrackSense® wireless loggers. Due to the fact that maintaining a high vacuum is essential for all lyophilization processes, the use of wireless loggers is highly recommended. A configuration with Pro-X loggers, low temperature multi channel flex Teflon sensors in combination with the SKY module and Access Point outside chamber is an ideal solution. Due to the high vacuum (~ 0.005 hPa) none of the available commercial wireless loggers can be used to monitor pressure.

Continuous freeze dryers are designed for vial drying and complete filling, loading and unloading systems which are integrated in the freeze dryer design. This allows full automatic  and sterile manufacturing with in-between batch sterilization (SIP) of  the freeze dryer. This will exclude the use of cabled systems but again Pro-X loggers fitted with low temperature multi channel Teflon flex sensors is recommended. To cover the SIP part of the process, standard multi channel teflon flex sensors are needed. The SKY option can be advantageous if distances are not too big.

CHALLENGES

As product volume can be very small it is essential that the sensor that measures sample temperature during processes can be introduced without jeopardizing the integrity thus very slim temperature sensors are needed. Ellab has developed a range of low temperature Teflon flexible sensors with a diameter of only 1.2 mm which can be easily inserted in the vial through the rubber stopper. For chamber validation a contact puck made of brass is available to secure paramount contact between the shelf and sensor ensuring correct readings.

The main challenges associated with monitoring freeze driers are the low temperatures and the low pressures present. The low pressures (around 5 microbar) restrict the ability to introduce cables into the chamber while still maintaining a good (high) vacuum. The vacuum is much more difficult to maintain than high pressure. However, the low temperatures used can make it difficult for some data loggers to function. TrackSense® Pro and the Pro battery can be used in temperatures down to –30°C. With the TrackSense® Pro-X, the logger can even go as low as –80°C. The unique battery management system, the design of the logger and Teflon flexible sensors makes them suitable for almost all freeze drier cycles, overcoming problems associated with the low temperatures.

GUIDELINES

Freeze drying (or lyophilization) is a technique used to remove water from a solution to leave a dry ‘cake’ as an end product. The dry product is much more stable than a solution. The reduced weight and volume is a big advantage and the removal of the water does not change the activity of the product. This technique involves freezing the product on a shelf to very low temperatures, typically –40 to –50°C, applying a vacuum and then slowly heating the product to initiate the ice to turn into vapor and this removes the water content from product by a process called sublimation.

The critical parameters during freeze-drying are temperature (product and shelf) and pressure. These measurements are usually recorded with every cycle to determine when the product is dry. In addition to monitoring each cycle, freeze driers also require regular validation. This will generally involve temperature mapping of the shelves in the chamber as well as validation of steam supplies for SIP system.

As freeze drying is a rather expensive process most products being processed are within the pharmaceutical and biotechnology area where companies often use freeze-drying to increase the shelf life of products, such as vaccines and other injectables. By removing the water from the material and sealing the material in a vial, the material can be easily stored, shipped, and later reconstituted to its original form for injection.

You can still find lyophilization performed in other areas :

Food industry (example: freeze dried fruits, astronaut food supplies, instant coffee).

Technological industry:

  • In chemical synthesis to make them more stable, or easier to dissolve in water for subsequent use.
  • In bioseparations as a late-stage purification procedure to remove solvents.

In bacteriology to conserve special strain.

Conservation and preservation industry:

  • Flowers
  • Animals
  • Water damaged books and documents

PROCESS EQUIPMENT

A freeze dryer consist basically of 3 components: sample chamber, condenser and a vacuum pump system. Depending on what should be dried, the sample chamber that is directly connected to the condenser and vacuum pump is designed with appropriate number of shelves which can be moved up and down if closing of vials is requested. This is called the stoppering arrangement. There are essentially two categories of freeze-dryers: batch and continuous dryers.

Batch freeze dryers are designed either for bulk drying where product is distributed onto trays or vial drying where product is dispensed into flasks(vials) using special rubber stoppers with vapour “escape” holes (slots). The benefit of this container is that the product can be easily reconstituted by simply adding liquid. For both systems batch monitoring can be done either by using the E-Val Flex cabled system or TrackSense® wireless loggers. Due to the fact that maintaining a high vacuum is essential for all lyophilization processes, the use of wireless loggers is highly recommended. A configuration with Pro-X loggers, low temperature multi channel flex Teflon sensors in combination with the SKY module and Access Point outside chamber is an ideal solution. Due to the high vacuum (~ 0.005 hPa) none of the available commercial wireless loggers can be used to monitor pressure.

Continuous freeze dryers are designed for vial drying and complete filling, loading and unloading systems which are integrated in the freeze dryer design. This allows full automatic  and sterile manufacturing with in-between batch sterilization (SIP) of  the freeze dryer. This will exclude the use of cabled systems but again Pro-X loggers fitted with low temperature multi channel Teflon flex sensors is recommended. To cover the SIP part of the process, standard multi channel teflon flex sensors are needed. The SKY option can be advantageous if distances are not too big.

CHALLENGES

As product volume can be very small it is essential that the sensor that measures sample temperature during processes can be introduced without jeopardizing the integrity thus very slim temperature sensors are needed. Ellab has developed a range of low temperature Teflon flexible sensors with a diameter of only 1.2 mm which can be easily inserted in the vial through the rubber stopper. For chamber validation a contact puck made of brass is available to secure paramount contact between the shelf and sensor ensuring correct readings.

The main challenges associated with monitoring freeze driers are the low temperatures and the low pressures present. The low pressures (around 5 microbar) restrict the ability to introduce cables into the chamber while still maintaining a good (high) vacuum. The vacuum is much more difficult to maintain than high pressure. However, the low temperatures used can make it difficult for some data loggers to function. TrackSense® Pro and the Pro battery can be used in temperatures down to –30°C. With the TrackSense® Pro-X, the logger can even go as low as –80°C. The unique battery management system, the design of the logger and Teflon flexible sensors makes them suitable for almost all freeze drier cycles, overcoming problems associated with the low temperatures.

GUIDELINES

Because the freeze drying process is so delicate and complex it is absolutely essential to be able to follow the process in real time. With the recent introduction of SKY this is now possible. Using TrackSense® ProX loggers with Teflon flexible sensors is a unique solution and the live transmission of data from loggers placed inside to Access Point placed outside the chamber is a  trouble free setup providing accurate and instant process control and documentation. The usual number of measuring points during process monitoring could be as high as one sensor placed in a representative sample (vial or tray) per shelf.

For validation of the chamber the usual number of measuring points is 5 for each shelf – one in each corner plus one in center. As freeze dryers often are equipped with 10-15 shelves or more it is essential that the logging hardware and analyzing software can handle data of that magnitude. With a storage capacity of 60.000 data points in each logger and a ValSuite™ software which can handle in excess of 100 channels in each session this is easy to match.

METHOD

For mainly pharmaceutical clients most applications will require the use of advanced software i.e. ValSuite™ Pro with its 21 CFR Part 11 compliance and sophisticated reports and features.For process monitoring creating a Unit with exact positioning of each measuring point is mandatory when handling that many sample points. Further adding it all up in a Profile including a Limit Report as well as Statistical Report is useful and very time saving.

For validation an even higher number of sampling points is needed which is why using a Profile and a Unit is recommended. The same Limit Report and Statistical Report is required to analyze the data. When validating the SIP system, the Validation or even the Advanced Validation Report is perfect.

At the end of each study, report(s) can be signed by Electronic Signature(s) and stored, printed or distributed in secure and locked PDF format.

With regular intervals each probe or sensor can be calibrated or verified using the built in calibration functionality in the ValSuite™ Pro software which also issues a Calibration Report on demand and this ensures that all measurements are made within the tolerances required. A factory calibartion with a traceable calibration certificate is recommended every 12 months for all Ellab sensors.

Application at a glance …

  • Sky solves the need for online data.
  • Chamber integrity is secured by using TrackSense® loggers.
  • Teflon flexible sensors are ideal for measurements on shelves and in sample containers.
  • Large number of measuring points and extensive amount of data is matched by Access Point capacity and unique ValSuite™ Pro analyzing tool.


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