Thermodynamic Lyophilization Control TLC® enables PAT compliance

During the lyophilization (freeze drying) process, the ice temperature is the important factor to monitor and control!

A safe, reliable, reproducible process is essential to pharmaceutical and biological production to achieve the specified properties and quality. In fact the FDA's PAT (Process Analytical Technology) initiative demands through process understanding, careful monitoring and control. This continuing trend towards more process automation (automatic loading and unloading systems as well as isolator technology being the relevant to lyophilization) to minimize contamination risks, meet sterile processing conditions, minimize the number of operators (human interference) and live up to the required validation regulations. This trend depends on increasingly sophisticated monitoring methods to control the lyophilization process.

Freeze Drying Cycle

Shelf temperature Product temperature measured with thermo probes      Ice temperature measured with TLC (or BTM)

TLC is a process automation tool for analyzing, monitoring and controlling the lyophilization process in research and development applications as well as for full-scale production.

The TLC has been developed as an integrated part of the complete automation infrastructure for:

• Monitoring the primary (main) drying (lyophilization)
• Determining the end of the main drying
• Monitoring the secondary drying
• Determining the end of the secondary drying

Lyophilizer Control System

TLC provides total control of the lyophilization process: minor variations such of the raw product or the filling height of the vials will automatically be identified and the process will be adjusted accordingly.

Principle
The TLC method is based on the relationship of ice temperature to vapor pressure *. The ice temperature is measured using pressure rise analysis BTM (Barometric Temperature Measurements) during main drying. The point at which to switch from main to secondary drying can be determined by tracking and analyzing the different BTM measurements. During secondary drying the process is monitored and the end point is determined by DRM (Desorption Rate Measurements).

Main Drying
TLC provides accurate temperatures control during the entire sublimation process without temperature probes, making the control of the drying process easy and reliable. Compared with other pressure rise methods, TLC needs only a short measuring time therefore prevents any warming influence on the product and the drying cycle. The end point of the sublimation ** process can be determined by monitoring the trend of the ice temperature. This makes the TLC method an ideal development tool and provides reliable data for the production process to help optimize the process cycle.

Secondary drying
The desorption rate is determined during secondary drying by measuring the pressure rise over a pre-determined period. The measuring time is longer than during the main drying process but has no impact on the product as only absorptively-bound water is present. The desorption rate is calculated using the chamber volume of the lyophilizer and the mass of the dry product.

Advantages:

• Applicable for all lyophilizer (freeze dryers)
• Ideal for sterile processing
• Ideal with automatic loading and unloading systems (ALUS)
• Ideal when isolator technology is used
• No need for mechanical modifications at the freeze dryer
• No risk of contamination
• Reproducible measurements
• Direct and accurate lyophilization monitoring and control
• Monitoring of the complete batch during the whole drying process
• Enables optimization of the lyophilization process cycle
• No impact on the product due to short measuring times
• Process data is easy to scale-up
• Delivers comprehensive data for better process understanding

*The vapor pressure of a liquid is the pressure exerted by its vapor when the liquid and vapor are in dynamic equilibrium.

**Sublimation is the transition of a substance from the solid phase directly to the vapor phase, or vice versa, without passing through an intermediate liquid phase. The process is known when ice or snow change directly to water vapor without first going through the liquid state. This phenomenon is obviously used in freeze drying (lyophilization) when the frozen product is slowly heated under a high vacuum.

A Link to a presentation titled "Advantages of PAT-Technologies for Cycle development of Freeze Drying Processes" given by Georg Frinke at PDA's Global PAT Conference.