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Jaume Vallet CEO, Pere Tapiolas Innovation Manager, Toni Sanz Automation Software Development at COMSER Pharma.
Introduction
In 2007 the ICH (International Conference of Harmonisation) guide Q8 defined the drug production processes development based on the introduction of quality in the process (Quality by Design). Since that, the industry has made an innovation effort to introduce PAT (Process Analytical Technology) tools in all critical processes to integrate the quality in the process.
The freeze-drying process is composed of three different sub-processes linked to each other, freezing, primary drying and secondary drying. Primary drying is the longest and most complex stage since it depends on three parameters that can be configured by the user (shelves temperature, chamber pressure and time). These three parameters should be configured to achieve the product critical quality attributes as fast as possible without exceeding the product collapse temperature (Tc).
Thanks to the studies carried out by the research team led by Dr. Michael J. Pickal of the University of Connecticut and the research team of Baxter led by Dr. Steven Nail, two key parameters were identified to define the primary drying design space.
1.- Heat transfer coefficient (Kv), which depends on the container to be used (type of vial, syringe, ampoule...) as well as the characteristics of the freeze dryer.
2.- Product resistance coefficient (Rp), which depends on the formulation, dosage volume and structure created during freezing.
Both parameters must be determined at different chamber pressure values. The calculation of these coefficients can be done based on mass and energy balances.
Where:
dq/dt = Heat flow.
Kv = Heat transfer coefficient.
Av = Vial base external surface.
Ts = Shelves temperature
Tb = Product temperature.
dm/dt = Vapour mass Flow.
Ap = Vial base interna Surface.
Pi = Vapour pressure of ice at sublimation front.
Pc= Chamber pressure
Rp = Product resistance coefficient.
ΔHs = Ice sublimation heat.
Solving the Kv and Rp coefficients from the balances, it is possible to identify the critical process parameters to be used for their calculation.
Those critical parameters can be classified between fixed parameters and variable parameters depending on whether they can vary during primary drying.
Both pilot and industrial freeze dryers incorporate PAT tools which allow knowing these variable parameters with certain precision, except for the vapour mass flow (dm/dt).
To develop, monitor and validate freeze-drying processes in QbD, a vapour mass flow sensor. It should be able to be installed on development freeze-dryers, but also on industrial manufacturing equipment.
Rp can be calculated in a development environment as it is product dependent, but Kv depends on the lyophilizer and therefore must be calculated in the manufacturing equipment.
Ways to Calculate Vapour Mass Flow
There are several techniques that allow vapour mass flow continuous monitoring, the most implemented are the following:
- Tunable Diode Laser Absorption (TDLAS). System to be installed in the chamber condenser duct. It measures the vapour mass flow of vapour by Near-Infrared (NIR) spectroscopy. This system has important limitations:
- Requires a special chamber condenser duct design.
- It can’t be installed in existing freeze dryers.
- Heat Flux Sensor (HFS). Thin plate installed between the vial and the lyophilizer shelf. The system can determine the heat flux between shelf and vial. From this value by energy balance equations, it is possible to determine the mass flow. This system has two important limitations:
- Estimates the mass flow from heat transfer by conduction but it does not consider the heat received by convection and radiation which can dramatically change depending on the chamber pressure.
- The measuring element must be installed between the shelf and the vial, modifying the conduction heat transfer conditions with respect to rest of vials in direct contact with the shelves.
COMSER LyoFLOW
LyoFlow is a disruptive and patented solution based on a new PAT tool for Real Time Mass Flow Rate measurement during primary drying of a lyophilisation process.
The system measures the vapour mass flow of all batches by gravimetry. The mass flow, product temperature, shelf temperatures and chamber pressure sensors are the inputs to the LyoFlow system brain. The system brain manages all this data to obtain:
- Real time the vapour mass flow rate (g/(hour·cm2)) or (g/(hour·vial).
- Real time product water contains (%).
- Dried product resistance coefficient (Rp f(time)) (Torr·hour·cm2·g-1)
- Heat transfer coefficient (Kv f(time)). (J/hour·cm2·K)
Based on these parameters the system can define the design space for a certain group of product, vial, and freeze dryer.
The system could be installed in a new and existing laboratory, pilot, and industrial freeze dryers. It ensures production freeze dryer Kv and Choke flow calculation.
The LyoFlow System opens a new step for development, scale up and process validation.
This new paradigm implementation follows the next steps:
In the Lyophilisation process development laboratory
- Characterisation of the product (Collapse temperature (Tc), glass transition temperature (Tg') and glass transition temperature of the dry product (Tg).
- Identification of the product related Rp parameter at different chamber pressure conditions.
In the production freeze dryer under GMP conditions:
- Identification of the lyophilizer plus vial related heat transfer coefficient (Kv) at different chamber pressure conditions.
- Identification of the lyophilizer choked Flow.
- Design Space Creation based on Rp, Kv, Choked flow and Collapse temperature.
- Lyophilization process monitoring and validation.
It is recommended to reverify the production freeze dryer Kv and choked Flow parameters as part of the equipment re-qualification as the freeze dryer cooling capacity may vary due to equipment wear.
Conclusion
LyoFlow aims to be the key to implement the development, scaling, and validation of freeze-drying processes according to ICHQ8 (Quality by Design) criteria.