Slide 1: Strategies to Evaluate CCI of Vial and Syringe Systems over Time and Temperature
Strategies to Evaluate CCI of Vial and Syringe Systems over Time and Temperature Amy Gindhart, Louis Brasten, Amy Kim, Jennifer Roark West Pharmaceutical Services, Inc.
Slide 2: Background / Strategy
Background / Strategy Aid pharmaceutical manufacturers to Determine if a system can meet the determine if a system is suitable for a maximum allowable leakage limit (MALL) drug product Proper characterization of container closure integrity (CCI) of vial and syringe systems is essential No single met
Slide 3: Techniques Used
Techniques Used Residual Seal Force Tracer Gas detection vacuum Laser-Based Gas Headspace Techniques combined (complementary method) mode with Helium (He Leak) Analysis (O2 & CO2) offer more complete • Quantifies compression of • Measures stopper/vial seal • Measures diffusion/effusion picture of CC
Slide 4: Residual Seal Force (RSF)
Residual Seal Force (RSF) Equipment: Genesis Model AWG RSF Tester RSF is a measurement of the seal tightness of the stopper against the vial in the stopper/seal/vial combination resulting from the sealing process Indirectly measures the force exerted by the stopper on a vial’s land surface Sealed vi
Slide 5: Helium Leak
Helium Leak Equipment: Leak Detection Associates (LDA)/Packaging Technologies and Inspection mass spectrometer (PTI) 1284+ Seal Integrity Monitoring System (SIMS) mass spectrometer 2 modes of operation • Standard (room temperature, -80°C and -180°C) vacuum • Continuous flow (room temperature) vacuum
Slide 6: Kirsch Limit
Kirsch Limit Often used as a valuation standard for CCI performance Hole Diameter (µ) He-Leak (cm3/s @ STP) - log (He-Leak) Microbial Ingress Rate (%) bacteria solution 2 1.0 x 10-3 3.0 70 0.7 2.0 x 10-4 3.7 65 0.4 9.0 x 10-6 5.0 11 --- 6 x 10-6 5.2 8 - 10 0.3 2.0 x 10-6 5.7 7 0.2 2.2 x 10-7 6.6 0 0
Slide 7: Headspace Analysis
Headspace Analysis Equipment: Oxygen Amount absorbed correlates Headspace Analyzer, FMS-760 to concentration by Lighthouse Instruments Uses near-IR radiation Advantages wavelength that is absorbed • Rapid testing time by gas of interest • Non-Destructive • Highly sensitive • No sample preparation λ
Slide 8: Glass Vial / Stopper / Seal Combinations
Glass Vial / Stopper / Seal Combinations Vial: size, blowback, supplier He leak and O2 headspace routinely used at West to quantify performance of Stopper: size, configuration/design, elastomer, post-treatment vial/stopper/seal combinations varying in: Assembly: compression level, seal 13 mm serum b
Slide 9: Residual Seal Force at Ambient Temperature
Residual Seal Force at Ambient Temperature 25 20 15 RSF (lbf) 10 5 0 18% Compression 25% Compression 30% Compression 13 mm Stopper 0M 3M 6M 12M 24M Reduces in value quickly at 3M 2R straight wall glass vial with Increases with compression and then remains constant over 13mm serum level as expected 2
Slide 10: Helium Leak at Ambient Temperature
Helium Leak at Ambient Temperature 8 40 35 -log (He Leak Rate) 7.5 30 7 RSF (lbf) 25 6.5 20 15 6 10 5.5 5 5 0 18% Compression 25% Compression 30% Compression 13 mm Stopper 0M 3M 6M 12M 24M Kirsch Limit Initial RSF Values correspond to 0% There was no change in helium Data demonstrates excellent micr
Slide 11: Helium Leak at Ambient Temperature (Low Compression)
Helium Leak at Ambient Temperature (Low Compression) 8 40 35 7.5 30 -log (He Leak Rate) 7 25 RSF (lbf) 6.5 20 Helium leak can indicate 15 compression levels that are 6 not optimal 10 • Including standard deviation 5.5 5 5 0 22% Compression 29% Compression 13 mm Stopper 0M 3M 6M 12M 24M Kirsch Limit
Slide 12: Headspace Analysis (O2) at Ambient Temperature
Headspace Analysis (O2) at Ambient Temperature 21.5 Oxygen Concentration (%) 21 20.5 20 19.5 19 18.5 N2 Air 18 17.5 17 18% Compression 25% Compression 30% Compression 13 mm Stopper 0M 3M 6M 12M 24M There was some egress of O2 and ingress of N2 over time not Rubber is known to be gas Egress was on av
Slide 13: Conclusion of Glass/Elastomer Vial Combinations
Conclusion of Glass/Elastomer Vial Combinations Combined He leak and O2 headspace analyses give a more complete view of CCI and better enables understanding if MALL can be met For the present example (13 mm stopper and 2R vial) • Seal integrity over 2 years is excellent • All He leak values are bett
Slide 14: Reason for Low Temp Interest in Polymer Vials
Reason for Low Temp Interest in Polymer Vials Gene and cell therapies require storage The vial/stopper/seal combinations Polymer-based vial/stopper/seal at -80oC (ultra-low) and below -130oC selected must be able to maintain combinations have lower risk of loss of (cryogenic). container closure inte
Slide 15: Polymer Vial-Stopper-Seal Combinations
Polymer Vial-Stopper-Seal Combinations 2005 Nobel Prize [ ] x Ring-Opening Metathesis Polymerization e.g., Ru[P2C3H2(C6H5)8]Cl2 R1 R2 R1 R2 [ ] x Mw ~ 7 x 104 Hydrogenation PD ~ 2 R1 R2 Daikyo Crystal Zenith® Cyclic Olefin Polymer (COP) J. Edwards, W. Wolf, R. Grubbs. The synthesis of cyclic polymer
Slide 16: Differences in Coefficient of Thermal Expansion
Differences in Coefficient of Thermal Expansion Polymer Vial Glass Vial -180°C -180°C Room Temperature polymer and rubber shrink at ~ same rate M. R. Gehrmann, et al. Long-Term Study of Container Closure Integrity of Rubber-Glass Vial Systems by Multiple methods. PDA Journal of Pharmaceutical Scienc
Slide 17: Differences in Coefficient of Thermal Expansion
Differences in Coefficient of Thermal Expansion Stopper Room Temperature Vial Coefficient of Thermal Expansion1 Volume Shrinkage (%) (10-6 cm / cm – K) (room temperature to -180°C) Glass 4 0.2 Rubber 77 4.5 COP 702 4.1 1 Thermal Expansion-Linear Expansion Coefficients: http://www.engineeringtoolbox.
Slide 18: Oxygen Headspace Room Temperature
Oxygen Headspace Room Temperature 18 Oxygen Concentration (%) 16 14 2 ml COP - RT 12 10 8 Air N2 6 4 2 0 0 50 100 150 200 250 Days 2 ml COP vial and 13 mm serum Expected –polymers are gas Significant permeation of O2 stopper permeable Ingress of Gases into Cyclic Olefin Polymer Vial-Based Container
Slide 19: Oxygen Headspace -80°C Storage
Oxygen Headspace -80°C Storage Oxygen Headspace for -80°C Storage (N₂ filled vials) 6.0 5.0 4.0 % atm O₂ 3.0 Air N2 2.0 1.0 0.0 13 mm Stopper 1 13 mm Stopper 2 2 mL COP vial Time 0 T12M T24M 2 ml COP vial and 13 mm serum Essentially no ingress of O2 over Low level of ingress of O2 over 24 stopper 12
Slide 20: Oxygen Headspace ≤-130°C Storage
Oxygen Headspace ≤-130°C Storage Oxygen Headspace for ≤-130°C Storage 22.00 20.00 18.00 16.00 14.00 % atm O₂ 12.00 liquid N2 vapor N2 10.00 8.00 6.00 4.00 2.00 0.00 13 mm Stopper 1 13 mm Stopper 2 2 mL COP vial Time 0 T12M T24M 2 ml COP vial and 13 mm serum stopper No ingress of N2 over 24 M Long-Te
Slide 21: CO2 Headspace at -78°C (Dry Ice Storage)
CO2 Headspace at -78°C (Dry Ice Storage) 4.5% 4.0% 3.5% Carbon Dioxide [%] 3.0% 2.5% 2.0% 1.5% 2R COP vial and 13 mm serum 1.0% stopper 0.5% 0.0% 1 Day 3 Days 7 Days 7 Days w/ Secondary Package Dry Ice Storage Interval T0 30 min post-storage 3 days post-storage 7 days post-storage 14 days post-stora
Slide 22: Conclusion of Polymer/Elastomer Vial Combinations
Conclusion of Polymer/Elastomer Vial Combinations For COP-based systems, gas permeation is For COP-based systems stored on dry ice: quantified: • Significant at room temperature • Small level of CO2 ingress occurs • Substantially reduced at -80°C • Can be addressed with a secondary package • Elimina
Slide 23: Summary
Summary Combining techniques (RSF, tracer gas analysis and headspace analysis) enables a more complete and quantified measure of CCI for vial and syringe combinations to enable judgement if MALL can be met 23
Slide 24: Acknowledgements / References
Acknowledgements / References Project Managers & Analytical Laboratory Staff: • V. Gupta, B. Jacobs, E. Crouch, G. O’deens, A. Chapman, A. McLean References: • L. E. Kirsch, et al. (University of Iowa) Pharmaceutical Container/Closure Integrity II: The Relationship between Microbial Ingress and Heli