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Strategies for Induced Nucleation
A Review and Scale-up Case-Study for a 56 m2
Freeze-Dryer with 195,960 Vials using VERISEQ® Nucleation
April 22nd, 2016
VERISEQ® Nucleation is a registered trade mark of The Linde Group
Motivation for Controlled Nucleation
Introduction to VERISEQ® Nucleation
VERISEQ® Nucleation on freeze dryers of varying sizes:
15m2 shelf area – Test at IMA Life Tonawanda
39m2 shelf area – 45,540 vials at customer site
56m2 shelf area – 195,960 vials at customer site
IMA Life and THE LINDE GROUP – a strong partnership
Process by which ice crystals (seed crystals) are formed from originating sites (nuclei) under proper temperature conditions (super-cooling)
Naturally, suspended particles or container defects provide nucleation sites
In production settings, nuclei form from water, but only after significant super-cooling
Because nucleation is an exothermic event, it can be detected with temperature measuring devices
Natural (uncontrolled) Nucleation:
Occurs randomly, once nuclei
Over extended period of time
Within extended temperature range
Without Nucleation Control:
Larger degree of super-cooling = smaller ice crystals
Smaller ice crystals = higher resistance to vapor flow
High resistance to vapor flow = longer cycles, possible vial breakage
Larger vial to vial variability
With Nucleation Control:
Reduced vial to vial variance – scale-up prediction
Better prediction of product stability
Quite often leads to reduced reconstitution time
Regulatory bodies are putting pressure on manufacturers to better control and understand their processes. Until now, control of the nucleation step has not been
WHY CONTROLLED NUCLEATION?
“…determine the influence of ice nucleation temperature on the primary drying rate during lyophilization for samples in vials that were frozen on a lyophilizer…”
James A. Searles, John F. Carpenter, Theodore W. Randolph
Higher nucleation temperature faster drying
Nucleation temperature affects drying rate:
“[…] effect of the ice nucleation temperature on the primary drying process using an ice fog technique for temperature-
controlled nucleation. In order to facilitate scale up of the freeze-drying process, this research seeks to find a correlation of the
product resistance and the degree of supercooling with the specific surface area
of the product.”
Abstract from “Heat and Mass Transfer Scale-Up Issues during Freeze Drying: II. Control and
Characterization of the degree of Supercooling” AAPS PharmSciTech 2004 (S. Rambhatla, R.
Ramot, C. Bhugra, M. J. Pikal)
Nucleation temperature affects product mass transfer resistance:
Higher nucleation temperature lower product resistance to water vapor
“…fundamentals of ice nucleation in the field of freeze-drying are presented. Furthermore, the impact of
controlled ice nucleation on product qualities is discussed, and methods to achieve controlled ice
nucleation are presented…”
R. Geidobler, G. Winter (European Journal of Pharmaceutics
and Biopharmaceutics, May 2013)
Importance of controlled nucleation is emphasized by various researchers
Partially seated stopper
VERISEQ® NUCLEATION REVIEW
1. VERISEQ® Nucleation uses liquid nitrogen and water vapor (steam) to create a cryogenic fog or “ice fog”.
2. This fog permeates the product chamber and enters the vials.
3. Ice crystals contact (seed) the surface of the product, nucleation proceeds rapidly from the top downwards in the vial.
VERISEQ® NUCLEATION REVIEW
*Note: same product, same magnification
Advantages of VERISEQ® nucleation:
Ability to induce nucleation at a fixed (reduced) degree of super-cooling (higher product temperature)
Increased robustness Laboratory (non-aseptic, stand-alone) and production scale (aseptic, fully
integrated) versions No pressure rating requirement Scalability Ability to retrofit practically any freeze dryer
Natural nucleation* VERISEQ® Nucleation*
Lab-scale (non-aseptic) units Designed for use with laboratory
Stand alone device that operates at or below atmospheric pressure using its own PLC for system control.
The system is designed to work on pressure rated as well as non-pressure rated freeze dryers.
Production scale (aseptic) units Sterile liquid nitrogen is obtained
from condensing filtered gaseous nitrogen.
The aseptic system uses clean steam normally used to sterilize the freeze dryer.
The VERISEQ® Nucleation system is sterilized prior to use.
This system is fully integrated into the freeze dryer control system.
SUMMARY OF LAB-SCALE TESTING
Uniformity of ice-fog distribution.
Ensuring that every vial is seeded.
Duration of ice-fog injection.
Product temperature control. Nucleation is based on two factors: presence of nucleation sites (nuclei), and proper degree of super-cooling. If the product is too warm, nucleation will not occur even if nuclei are present.
Larger heat transfer on top shelves (vials run warmer)
Optimization Study on 15 m2 Freeze Dryer
IMA Life, Tonawanda
OUTLET: 2” MAIN DOOR
SINGLE INLET – SINGLE OUTLET
SHELF 4 (S4)
SHELF 8 (S8)
SHELF 1 (S1)
S4, BR S4, FR
S8, FL S8, FR
15 m2 shelf area Cluster of 8-10 vials in each location Each pack mounted with 1 internal thermocouple and 1 external thermocouple
LAYOUT: VIAL FROM MAIN DOOR
1 vial nucleates during ramp down on shelf 1 (directly facing chamber wall)
VIAL ON SHELF 1 DOES NOT NUCLEATE
WALL TEMPERATURE: ~16 ˚C
POSITION DEPENDENCE: 2˚C SPREAD IN PRODUCT
100% nucleation on all shelves Wall temperature can be a crucial factor in success of inducing nucleation
WALL TEMPERATURE: ~10 ˚C
WITH CHAMBER WALL COOLING
~150 vials with 1 ml water fill in 3 ml vials, used in cluster of ~10 vials each,
1 external and 1 internal thermocouple in each cluster
Shelf 1,4,8 used with clusters located in 4 corners and center, Tsh hold time
Successful run (no nucleation during ramp down) obtained with chamber wall
cooling for reduced radiation (65%)
Optimized process and injection configuration successfully tested with
placebo in dryer
SUMMARY AND LEARNINGS
Thermal gradients in large production freeze dryers should be considered when designing the freezing protocol
Full Scale Test Without Jacketed Cooling 45,540 vials in a 39m2 machine at
Shelf area=39 m2,
Chamber volume=9 m3
Machine has no jacket cooling
Number of vials: 45,540 including:
15,840 vials of 20x dose
29,700 vials of 1x dose
SUMMARY OF SETUP
ICE-FOG INLET (2 IN)
OUTLET (3 IN)
Nucleation time in probed vials reduced from 118 min to < 2min (see plot)
Nucleation time in wireless probed vials reduced from 152 min to <2 min (not included in plot)
Nucleation temperature range reduced from 9°C to <0.8°C
CYCLE DURATION COMPARISON
Point of reduced sublimation rate reduced by 12.4 hr. Primary Drying time reduced by 5.4 hr. at same process conditions
VERISEQ® Ice Fog demonstrated on a 39m2 shelf area freeze dryer
(9 m3) with no silicone jacket cooling with 45,540 vials (35% of 20x
Nucleation time in probed vials reduced from 152 min to < 2min
(Wireless probes not included in nucleation plot)
Nucleation temperature range in probed vials reduced from 9 °C to
< 0.8 °C
Point of reduced sublimation rate reduced by 10% (12.4 hr.)
Primary Drying time reduced by 5% (5.4 hr.) at same process
Full Scale Test: 195,960 vials in a 56m2 Freeze Dryer at Client Site
ICE-FOG INLET (3 IN)
OUTLET (3 IN)
Shelf area=56 m2,
Chamber volume=17.5 m3
20+1 shelves Walls cooled with cooling
jacket during ramp 195,960 vials:
1.2 ml fill in 3 ml vials
SUMMARY OF SETUP
• Nucleation time in probed vials reduced to < 2.5 min • Nucleation temperature range in probed vials reduced to 0.6 °C
Summary of setup
195,960 vials: 1.2 ml fill in 3 ml vials
Shelf load: 5 ˚C Ramp to -7 ˚ C Walls cooled with cooling
jacket during ramp Hold: 90 min
Primary Drying time reduced by 812 (19%) minutes, can be further reduced by increasing primary drying temperature
Dotted line indicates original primary drying duration
Parameter Without Ice Fog With Ice Fog
Loading temperature, ˚C -45 ˚C
Nucleation temperature, ˚C 0 to -45 ˚C
-6 to -6.6 ˚C
Total variation in nucleation
time between vials
~10 hours (theoretical) 2.5 min
Nucleation completed in < 80 min (variable for vials) 140 min (all during ice fog injection ~ 2.5
min), some with probes inside nucleate early
Primary drying time (time
from Tsh=-9 ˚C to time for
TC to reach shelf temp.)
1001 min 812 min (*not optimized) -19% reduction in
primary drying time, can be reduced further
by increasing shelf temp.
Total time to end
1514 min 1854 min (*not optimized)
Product uniformity 0% (Control) 40% reduction in range of activity values
By using VERISEQ® Nucleation technology, a 40% improvement has been achieved
All times are from time of loading complete (t=0) CYCLE IS NOT OPTIMIZED WITH ICE FOG
Comparison of product uniformity with and without controlled nucleation
Scalability of VERISEQ® Nucleation technology was demonstrated and the following observations were made Overall benefits of VERISEQ® nucleation:
Nucleation time in probed vials reduced from 152 min to < 2min (from 39m2 test) Nucleation temperature range in probed vials reduced from 9 °C to < 0.8 °C (from 39m2
test) Improvement in product uniformity: 40% (from 56m2 test) ~19% reduction in primary drying time even at the same shelf temperature (from 56m2
test) Learning from the scale-up tests:
Ice-fog distribution: robust, not affected by scale of freeze dryer (batch size) The technology is capable of ensuring effective ice fog circulation throughout the
entire chamber volume
Temperature conditions – Critical requirement! The product must be at the right temperature across the entire batch in order to
Duration of ice-fog injection: does not noticeably affect the nucleation temperature and, therefore, uniformity of product attributes Ice fog injection was completed in < 2.5 min (can be less if optimized)
Wexler, E., Brower, J., Controlled Nucleation for a Monoclonal Antibody
Formulation – A Case Study, Pharm. Tech. Bioprocessing and Sterile
Manufacturing, pp. 31-34, May 2015.
Wexler, E., Brower, J., New Developments in Controlled Nucleation, Pharm.
Manufacturing, pp. 26-29, October 2015.
Brower, J., Lee, R., Wexler, E., Finley, S., Caldwell, M., & Studer, P. (2015).
New Developments in Controlled Nucleation: Commercializing VERISEQ®
Nucleation Technology. In Lyophilized Biologics and Vaccines (pp. 73-90).
Springer New York.
DeMarco, F., Renzi, E., Lee, R., Chakravarty, P, Ice Fog as a Means to Induce
Uniform Ice Nucleation During Lyophilization, BioPharm International, vol, 25
(1), January 1, 2012
A STRONG PARTNERSHIP
THE LINDE GROUP
Linde has developed the VERISEQ® Nucleation Technology and the CUMULUS LF Technology (cryogenic cooling of freeze dryer shelves and condenser) in cooperation with IMA Life.
Linde also provides for the pharma industry:
VERISEQ process-grade gases featuring high-purity, traceable N2, O2, CO2, Ar, He & synthetic air
HiQ - specialty gases for calibrating gas monitoring equipment
Process chemicals for applications like for example amination, catalysis or fluorination
Gas applications for ozonolysis, inerting, purging, charging, mixing
Gas applications for Reactor Cooling, cryogenic storage and transport, freezing.
Exclusive rights to market VERISEQ® Nucleation technology.
World leader in the design and manufacture of aseptic processing and freeze-drying equipment.
5 manufacturing sites in Italy, US and China, and 3 service centers in Italy, Netherlands and Japan.
Worldwide networking covering more than 80 countries.
Access to freeze-drying laboratory for development work with 1 laboratory scale, 1 pilot scale freeze-dryer and other analytical tools including tunable diode laser absorption spectroscopy (TDLAS) instrumentation, residual gas analyzer and other re-configurable instrumentation ports.
Joe Azzarella (Technical Product Manager, Ice Fog) - [email protected]
Arnab Ganguly (Technology Manager) - [email protected]
Frank DeMarco (US Sales, Technical Product Manager, Freeze Drying) - [email protected]
Geoffrey Sortais (Asia Sales) - [email protected]
Christophe DeStLeger (Europe Sales) - [email protected]
Eugene Wexler (Product Manager and Global Technical Support) - [email protected]
Peter Studer (Americas) – [email protected]
Rolf Heninger (Europe) – [email protected]
Arthur Zhang (Asia Pacific) – [email protected]
Ulrich Hanke (Marketing) – [email protected]