» LYOPHILIZATION
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Table 3. Techniques for Characterization of Frozen, Dried, and Freeze-Dried Product
Step
Freezing (frozen)
Primary drying (partially frozen/ partially dried)
Secondary drying (dried)
Figure 4. Minimum Achievable Chamber Pressure as a Function of Sublimation Rate
Physical Property PAT Tools
Ice nucleation crystallization
DSC FDM FD-XRD
Tg’, Tc ice sublimation
Tg, water sorption/ desorption
Freeze- dried product
Tg residual water specifi c surface area crystallinity cake morphology water sorption rate mobility (α and β relaxation) density
DSC FDM
NIR (in-situ) Raman (in-situ)
DSC DVS
DSC KF NIR BET
XRPD SEM DVS TAM Neutron Scattering Helium pcynometer
BET = Brauner-Emmett-Teller; DSC = diff erential scanning calorimetry; DVS = dynamic vapor sorption; FDM = freeze-drying microscopy; KF = Karl Fischer; NIR = near infrared; PAT = process analytical technologies; SEM = scanning electron microscopy; Tc = collapse temperature; Tg/Tg’ = glass transition temperature; XRPD = X-ray powder diff raction; TAM = thermal activity monitor
Summary
Figure 5. Design and Control Space, with Set Point, for the Primary Drying Step of the Freeze-Drying Process
an appropriate safety margin to prevent a run-away process (i.e., loss of process control) due to choked fl ow or condenser overload.
Step 4: Post-lyophilization Product Characterization
Extensive characterization of the freeze-dried cake is critical for understanding the impact of formulation and process on drug product quality. Several techniques that are widely used to characterize both the freeze-dried cake and the diff erent physical states of the formulation matrix during freezing and drying are listed in Table 3. These techniques can be used to monitor the critical physical properties as the formulation matrix changes physical state from frozen to partially frozen and partially dried to dried and, fi nally, completely freeze-dried [33]. These physical properties have been shown to potentially impact product quality attributes such as residual water, reconstitution time, cake appearance, and physical stability.
82 | | September/October 2013 - 15TH ANNIVERSARY ISSUE
Formulation and process development challenges need to be considered during early development to ensure product quality. Formulation characterization tools provide a macroscopic and microscopic comparative analysis to determine if any physical change occurred in the freeze-dried drug product. These tools are also valuable for comparative studies of freeze-dried products when changes are made to site, scale, process parameters, and drug product presentation. Lastly, PAT and design space are integral elements of QbD. PAT tools help confi rm that the lyophilization process is performing as expected, thereby assuring desired product quality.
Acknowledgements
The authors would like to acknowledge Nancy Craighead (Scientifi c Writing, MedImmune) for all her help with editing the manuscript.
Author Biographies
Dr. Sajal Manubhai Patel is currently working as a scientist at MedImmune in the department of Formulation Sciences. In his current role, Dr. Patel is responsible for formulation and drug product process development for both liquid and freeze-dried
biologics. He is also in charge of developing strategy for freeze-dried drug product development and manufacturing. He received his M.S. in
Residual water cake appearance reconstitution time physical stability
Potential Product Quality Impact
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