Advantages of PAT-Technologies

Advantages of PAT-Technologies for Cycle development of Freeze Drying Processes

A presentation given by Georg Frinke at the PDA's Global PAT Conference on May 22, 2007. Please click here to download the complete presentation in a PDF format.

General data for cycle development

Investigation of product parameters

• Critical temperature of frozen product
  • t_Collapse / t_Glass / t_Eutectic (Thermo-resistance, DSC)
  • Effects freezing phase (thermal treatment)
• Vial Design / Stopper Design
• Product composition / filling volume
• Sorption Isotherm
• Required residual moisture for long-term storage

Time based Cycle Development

Statistic Crystallization

Development of freezing step

Estimation of freezing rate, freezing target temperature and hold time

There is no PAT-Tool available to control freezing of product (aseptic handling, product feedback, full batch)

Creating the recipe

• Estimation of required shelf temperature and chamber pressure for Primary Drying (PD)
• Estimation of required shelf temperature and chamber pressure for Secondary Drying (SD)
• Estimation of required cycle step duration

Comparison of 4 runs at PD

Reasons for deviations of Primary Drying time

• Manufacturing tolerances of vial format in connection with filling accuracy of whole filling system
• Variations of heat conductivity depending on vial surface at bottom
• Variations in Freezing
• Different environmental conditions of Freeze Dryer (FD) chamber
  (indefinite conditions at machine area / Edge effect etc.)
• Variation of vial quality due to supplier (long term)
  Variation of product composition (long term)

Schematic Sorption Isotherm

Time based Secondary Drying Step

Devices for external moisture evaluation

Sample Thief

Karl-Fischer (KF)-Titrator

Residual Moisture (KF) decrease during SD

Reasons for deviations of secondary drying time

• Impact of variations during Freezing Phase
• Indefinite Conditions at the end of Primary Drying

Conclusions

• Time based Cycle development allows robust cycles with sufficient reproducibility
• Time margins are always required, when pressure or shelf temperature is changed
• Time based developed Cycles do not need process feedback
• Variations in process conditions
• Recipe design always depends on the thermic & thermodynamic profile of the freeze dryer
• This impact needs to be considered for successful scale u
• Process results may vary due to deviations of input (Buffer ingredients)

Freeze Drying from PAT-Perspective

Basics of Freeze Drying for PAT

• Freeze Drying must be considered as a "multi-process" taking place in each vial in a variation range
• Freezing phase is mostly driven by statistic nucleation effects (Crystallization). Amorphous structure needs to be considered
• Ice temperature during sublimation depends on shelf temperature, chamber pressure and Freeze Dryer-design
• Desorption depends on product properties and previously accomplished cycle

Principles for Primary Drying (PD)

Principles for Secondary Drying (SD)

Parameters of Process & Product Feedback

• Ice temperature at sublimation front is the only direct product parameter, enabling full process control and full product protection ("True PAT")
  • No time margin required
  • Performance can be optimized in real time
• Measurement of Gas Velocity at the duct or Gas Moisture in the chamber determines the end points
  • No time margin required

Simplified temperature profile