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Ellab Recommends the following products for Lyophilization...

Wireless Solution

LYO Shuttle

LYO Shuttle

LYO 28

LYO 28

TSP Vacuum

TSP Vacuum

SKY Option

SKY Option

Prefer a wired solution? Click here to read about the E-Val Pro System

Lyophilization

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 using extremely low temperatures (typically –40 to –50°C), applying a vacuum and then slowly heating the product to ensure the ice turns into vapor. 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/Vacuum. 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, condenser cool down test, system evaluation test (Vacuum Pull-Down) to test Vacuum pumping system efficiency, and Vacuum integrity test to show quality of seals, as well as validation of steam supplies for the SIP system.

As freeze drying is a rather expensive process most products being processed are within the pharmaceutical and biotechnology industries. 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.


Lyophilization can also be performed in other industries like:

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 strains 

Conservation and preservation industry:

  • Flowers
  • Animals
  • Water damaged books and documents

Process

A freeze dryer consists of three main 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 an appropriate number of shelves which can be moved up and down if closing the vials is required. This is called the stoppering arrangement. There are essentially two categories of freeze-dryers: batch and continuous dryers.

Batch freeze dryers are designed for bulk drying where product is distributed onto trays or vial drying where product is dispensed into flasks (vials) using special rubber stoppers with vapor “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 Pro wired 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. Ellab offers a variety of data loggers that can withstand the lyophilization temperatures (Pro X, Pro XL, Compact Ultra X, Frigo).   A configuration of wireless loggers and low temperature multi-channel flexible sensors can be paired with SKY modules and the Access Point outside of a chamber for access to wireless real-time data. Due to the high vacuum (~ 0.005 hPa) only wireless loggers with the Ellab Vacuum Sensor can be used to monitor the Vacuum Level. 

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 fully automatic and sterile manufacturing with in-between batch sterilization (SIP) of the freeze dryer. This will exclude the use of cabled systems but again wireless loggers fitted with low temperature multi-channel flexible sensors are recommended. To cover the SIP part of the process, standard multi-channel flexible sensors are needed. The SKY option can be advantageous if transmission distances are not too far.

Challenges

Challenges

Product volume can be very small, so it is essential the sensor that measures the sample’s temperature can be introduced without jeopardizing the product integrity. To facilitate this process Ellab has developed a range of temperature flexible sensors (diameter 1.8mm) which can be easily inserted into the vial through the unique rubber stopper system. For chamber validation including shelf mapping, Ellab’s TPR contact puck is available to secure paramount contact between the shelf and sensor for accurate readings. Ellab’s “LYO Shuttle” fixture is also ideal when both the vial and contact puck need to be secured to the shelf and sensor.

The main challenges associated with validation freeze dryers 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, so only wireless loggers fitted with temperature and Vacuum sensors are recommended as vacuum is much more difficult to maintain than high pressure. Usually the low temperatures can make it difficult for data loggers to function but. Ellab offers a battery package that, when paired with an appropriate logger, can operate at low temperatures. The unique battery management system, the design of the logger and the flexible sensors make them suitable for most freeze dryer cycles, overcoming problems associated with the low pressure and temperatures.

Guidelines

The ISO 13408-3 standard describes Aseptic processing of healthcare products in regards to Lyophilization.  The freeze drying process is very delicate and complex so it is absolutely essential to be able to follow the process in real time. Ellab’s SKY system makes this possible. Ellab’s wide range of wireless loggers combined with PTFE flexible sensors and the vacuum sensor provide a unique solution.  The live transmission of data from all loggers placed inside of a chamber provides trouble free setup displaying accurate and instant process control along with documentation. The usual number of temperature measuring points during process monitoring could be as high as one sensor placed in a representative sample (vial or tray) per shelf. Often only one Vacuum sensor is required. 

For validation of the chamber, the usual number of temperature measuring points is five for each shelf – one in each corner plus one in center. Usually, the cross shelf stability (homogeneity) required is ±0.5°C to 1°C and shelf-to-shelf variation is 1°C to 2°C. As freeze dryers are often equipped with 10-15 shelves or more, it is essential that the logging hardware and analyzing software can handle data of that magnitude.  The loggers have a storage capacity of up to 60,000 data points per logger while the ValSuite™ Pro software can handle more than 100 channels in each session.

Method

Method

For pharmaceutical clients, most applications will require the use of advanced software such as ValSuite™ Pro with its 21 CFR Part 11 compliance and sophisticated reports/features. For process monitoring creating a Unit with exact positioning of each measuring point documented by pictures is mandatory when handling that number of sample points. Furthermore, adding it all into a Profile session including a Limit Report as well as a Statistical Report is useful and produces time savings.

For validation an even higher number of sampling points are required which is why using Sensor Grouping, Advanced Phase Statistics, Limit report and a Unit all setup in a Profileis recommended. When validating the SIP system, the Validation or the Advanced Validation Report is ideal.

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

Using the built-in calibration functionality, users can calibrate the Ellab sensors at regular intervals. The ValSuite™ Pro software generates an easy to read calibration report that includes all measurements and tolerances that are defined by the user. It is recommended that Ellab sensors and probes are sent in at least once a year for factory calibration (which includes a traceable calibration certificate).

ValSuite™ Software Reports | Lyophilization

Process Graph

Process Graph

Statistics

Statistics

Unit Report

Unit Report

Limit Report

Limit Report

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