Primary Packaging change: Switch from a lyophilisate in vial to a lyophilisate in double chamber cartridge

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1 Primary Packaging change: Switch from a lyophilisate in vial to a lyophilisate in double chamber cartridge Christoph Stark Head Pharmaceutical Development Novartis Pharma AG, Novartis Biologics CASSS CMC Strategy Forum Vienna, May 27, 2010

2 Background what is a Double Chamber Cartridge? + Lyophilizate Diluent Dosing soluton administered via syringe rubber stoppers (different geometries) bypass in glass barrel Lyophilizate and Diluent Dosing solution administered in double chamber cartridge via double chamber cartridge (DCC) operated in pen (DCC) operated in pen 2 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

3 Underlying rationale on how to assess a change of an existing product The change from vial to double chamber cartridge system will typically happen before or during PhIII or as a LCM, where already comprehensive safety and efficacy data are available. Therefore the right question at this time is: How does the change influence the safety and efficacy of the product? rather than starting from scratch and asking: Is the new (changed) product safe and efficacious? 3 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

4 Agenda 1. Compatibility and safety 2. Protection (container closure integrity) 3. Manufacturing process changes 4. Summary 4 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

5 Compatibility and Safety Aspects of a change in primary packaging New packaging material, new leachables Compatibility Accelerated or modified degradation Adsorption Precipitation Loss of biological activity Others Accelerated stability and stress testing to demonstrate same degradation pathways. Individually extended analytical program beyond standard release analytics. Real time stability to demonstrate same degradation kinetics ( 6M data for BLA) and confirm absence of adsorption and precipitation 5 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010 Safety Toxicity Extractables and Leachables testing, assessment according ICH Q6A or individual specification setting considering PQRI Safety Concern Threshold (SCT) and Qualification Threshold (QT) concepts. Risk based approaches.

6 Compatibility and Safety (cont.) Linking old and new packaging components Rubber stopper polymer type and coating Lyophilizate Diluent Glass: typically Type I, but even if vial/dcc is manufactured from same glass cane differences due to differences in glass forming process might occur DCC Setting up early on in development a change strategy for the primary packaging will minimize the risk of non-comparability in later phases 6 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

7 Compatibility and Safety (cont.) Strategy for compatibility and safety assessment No direct contact to stopper Direct contact to glass Lyophilizate Diluent Direct contact to silicone oil Contact liquid-stopper ~ 15hrs solid -stopper for shelf life Direct contact to stopper(s) Direct contact to glass Direct contact to silicone oil DCC risk based assessment should be possible, e.g. discussing changed surface/volume ratio Full assessment necessary 7 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

8 Compatibility and Safety (cont.) Silicone oil as leachable Coating of syringe barrel with silicone oil (dimeticon) is required to allow low injection forces Free silicone oil needed for lubrication Force [N] Not siliconized Siliconized, all free silicone oil removed During long term storage, silicone oil is partly solubilized by amphiphilic protein and stabilizers (surfactants) 10 0 Siliconized Displacement of plunger [mm] Favorable TOX package, ADI 140mg >>> free silicone oil in cartridge 8 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

9 Compatibility and Safety (cont.) Silicone oil forcing to switch analytical methods Might lead to failure in USP <788> and Ph.Eur subvisible particulate matter testing by light obscuration; requiring switch to microscopic method. Might require a change from A 280 assay to LC assay Proof of root cause e.g. by Micro Flow Imaging (MFI) and statistical analysis of differences between active and placebo (turbidity, sub-visual particle counts) MFI: Silicone oil droplets Protein particles 9 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

10 Compatibility and Safety (cont.) Drug product compatibility studies with silicone oil As silicone oil levels in syringes/dccs variable in amount/device, distribution over device surface and potential solubilization over time a rich understanding on the compatibility of the protein formulation with silicone oil should be created. Effect of silicon oil on protein stability to be demonstrated by forced degradation and stability testing For initial assessment testing in presence of silicon oil emulsion (control of emulsion stability!) Detailed assessment with over-siliconized (2-3 x) packaging material; bracketing approach. Consider shaking and multi-factorial root cause for aggregate/particle formation of protein formulations 10 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

11 Agenda 1. Compatibility and safety 2. Protection (container closure integrity) 3. Manufacturing process changes 4. Summary 11 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

12 Container Closure Integrity Test (CCIT) as part of pre- or post approval stability testing Microbiological Container Closure Integrity Test for qualification of primary packaging combination, not drug product specific hence not seen as sufficient for preservative free, sterile products (FDA Guidance for Industry: Container and Closure System Integrity Testing in Lieu of Sterility Testing as a Component of the Stability Protocol for Sterile Products, 2008) However is an important tool during the product development phase and shall be applied in parallel to physical testing methods (eg. vacuum decay, helium leak, high voltage, dye immersion, package headspace ) 12 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

13 Container Closure Integrity Test (CCIT) as part of pre- or post approval stability testing Physical CCIT per dye ingress: is product specific to be validated against microbiological CCIT (simulation of micro defects in container closure by artificial defects; micro wires between stopper and glass barrel, capillaries, laser drilling, ) immersion of containers in e.g. methylene blue bath, application of approx. 500mbar (and 1500mbar) under(/overpressure) for a defined time (ASTM D feeder aircraft transportation conditions); visual or UV meter evaluation of samples USP<1207>: Testing should also validate the integrity of the design when exposed to anticipated extreme conditions of storage, shipment, and distribution. 13 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

14 CCIT per dye ingress some practical considerations 1. Vials: In practical application no problem at all. Dye ingress testing turned out to be slightly more sensitive than microbiological CCIT in cross-validation 2. Syringes: Test protocols usually comparable to vials, under-pressure might be adapted if required due to movement of plunger stopper 14 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

Double chamber cartridges: Due to large headspace in both

differential 1 2 1 2 Adaptation of test pressure

Note: After assembly in the pen the back stopper of the

15 CCIT per dye ingress (cont.) some practical considerations 3. Double chamber cartridges: Due to large headspace in both chambers the system is more sensitive to pressure differential Adaptation of test pressure differential is necessary for testing the bulk cartridge. Note: After assembly in the pen the back stopper of the cartridge is fixed and withstands ASTM D test conditions 15 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

16 Agenda 1. Compatibility and safety 2. Protection (container closure integrity) 3. Manufacturing process changes 4. Summary 16 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

17 Manufacturing process changes Comparison of vial and DCC lyophilization Thermal radiation conduction shelf convection Thermal radiation and thermal cooling effects from multi tons of lyophilizer steel have significant and position specific impact on effective drug product temperature during lyophilization. Vial is predominantly controlled by conduction from shelf DCC is controlled by equilibrium of convection and thermal radiation 17 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

18 Manufacturing process changes (cont.) Comparison of vial and DCC lyophilization Temperature Shelf Vial Cartridge Time Compared to vials DP temperatures of cartridges typically show: lower slopes in cooling and heating gradients greater deviation from shelf temperature in equilibrium, warmer in the freezing steps, cooler in the drying steps greater intra- and inter shelf variances due to positional effects 18 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

19 Manufacturing process changes (cont.) Constant product quality by process understanding and control 1. Robust lyophilizate formulation with high collapse temperature as pre-requisite 2. Broad knowledge and design space by extensive thermal characterization of the formulation and broad range DoE lyocycle development 3. Temperature mapping of lyophilizer under full load production conditions; characterization of positional effects/trends 4. Verify design space at full scale and gather ample commercial scale production experience 19 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

20 Agenda 1. Compatibility and safety 2. Protection (container closure integrity) 3. Manufacturing process changes 4. Summary 20 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

21 Summary 1. Consider potential future changes in primary closure early in development strategy of your product 2. If you performed a change ask the right question: How does the change affect my product s...? 3. Use risk based approaches to assess impact of change 21 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

22 Acknowledgements Michael Soukenik Marie Picci Rolf Buergi Dieter Witthauer Jürgen Sigg Kurt Forrer Atanas Koulov Tom Spitznagel Melissa Perkins James Colandene Angela Blake-Haskins Tesfu Mezghebe 22 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010

23 23 Christoph Stark, CASSS CMC Strategy Forum Vienna, May27, 2010 THANK YOU!

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