GORE ImproJect Plunger: A New Option for Delivery of Sensitive Biologics in Pre-Filled Syringes

Transcription

1 GORE ImproJect Plunger: A New Option for Delivery of Sensitive Biologics in Pre-Filled Syringes Russ Hornung, Business Development,, Inc.

2 Overview Industry trends / environment Traditional role of silicone Current / emerging issues related to sensitive biologic packaging New option to address silicone in pre-filled syringes Computer Artwork depicting Alzheimer's Treatment C

3 Molecule Trends Biopharmaceuticals development: mabs, conjugate vaccines, ADCs, hormone / gene therapy, etc. Higher sensitivity of biologics to stability Higher complexity of Biologics Higher viscosities create stability challenges Higher concentrations can potentially lead to aggregation Sources: PhD, Nilanjana Das. Commercializing High-Concentration MAbs. BioPharm Home, Biopharm International, 28 Sept. 2017, Wang, Wei. Advanced Protein Formulations. Protein Science, Wiley, 1 May 2015

4 Patient-Centric Trends Minimize burden of frequent injections and maintain stability with next-generation biologics Desire for higher purity, simplified formulations and reduced excipients * Injection site irritation / local reactions / pain management Increased use of self injection with auto-injector Drives need for higher degree of break loose / glide force consistency (predicatable, repeatable drives comfort to facilitate patient adherence) Source: Overcoming Formulation Challenges for Biopharmaceutical Development: CHI Ninth Annual The Bioprocessing Summit August 21-22, 2017 Andrea Hawe, Ph.D.

5 Economic Trends First to market advantage Average market-share advantage (10 years after launch): 9% for injectables Opportunity to estabilish packaging differentiation Time to market even more crucial Reformulation (vial to syringe) can extend timeline 1-3 years Revenue loss Reformulation costs - can exceed millions of $ or Erosion of market window position - competition entry Patent life Manufacturing costs Single-dose vial: 10-20% overfill, pre-filled syringe savings Other costs related to quality issues (particles), inspection yields, recalls, complaints, etc. Source: The Therapeutic Monoclonal Antibody Market, Ecker DM, Jones SD, Levine HL.MAbs Jan-Feb; 7(1): 9 14.

6 FDA Guidance for Industry Aggregates & Immunogenicity Interactions between therapeutic protein products and the container closure may negatively affect product quality and immunogenicity. Silicone oil-coated syringe components produce a chemical and structural environment on which proteins can denature and aggregate. Leached materials from the container closure system may be a source of materials that enhance immunogenicity,, including the following: Organic compounds with immunoglobular activity maybe eluted from container closure materials by polysorbate-containing formulations Metals that oxidize and aggregate therapeutic protein products... have been found in various products contained in pre-filled syringes and vials. FDA Guidance for Industry: Immunogenicity Assessment for Therapeutic Protein Products; US Dept. of Health and Human Services; FDA, CDER, CBER; Aug 2014 Summarized by Prof. Robert Langer and Dr. Christopher Weikart for 2016 PDA/FDA Joint Regulatory Conference

7 Ongoing Article Topics Silicone Oil-Induced Aggregates We found that the presence of silicone oil microdroplets in OVA formulations caused structural perturbations in the protein which were detected after only relatively short periods of exposure to silicone oil-water interfaces. In Vivo Analysis of the Potency of Silicone Oil Microdroplets as Immunological Adjuvants in Protein Formulations: Chisholm et. Al., J. Pharma. Sci., 104, (2015). [Silicone oil] may be responsible for the phenomenon of soluble-protein loss and the irreversible adsorption of protein may be associated with protein denaturation/aggregation. Mechanistic Understanding of Protein-Silicone Oil Interactions: Li et. al., Pharm. Res., 29, (2012) The most probable explanation for silicone oil induced aggregation is that the oil has direct effects on intermolecular interactions responsible for protein association through interaction with protein surfaces or indirectly through the effects of the solvents. Silicone Oil Induced Aggregation of Proteins: Jones et. al., J. Pharma. Sci. 94, 4, (2005) Acknowledgment: Previously presented by Prof. Robert Langer and Dr. Christopher Weikart, Advanced In-Process Monitoring & Traceability for Primary Container Manufacturing, 2016 PDA/FDA Joint Regulatory Conference

8 Topics: Regulatory / Professional Associations Increased scrunity of sub-visible / visible particles from authorities Even lower particulate matter in ophthalmic solutions, Reference USP <789> Continued trend to further decrease particles Particle characterization and more effective techniques are reconized by Regulatory and Industry Experts

9 Role of Silicone in Pre-Filled Syringe Lubrication for handling / processing during filling Helps provide seal between syringe / plunger Can provide hydrophobic protective barrier between biologic / bare glass Lubrication on needle for improved comfort during insertion Lubricant between plunger / syringe during drug adminstration Image courtesy of SCHOTT AG

10 Challenges of Syringe Lubricants Potential interaction with sensitive biologics may cause stability issues Estimated between 10-15% of large molecules* Commercial : 231 (BioTrak database), 138 (FDA Purple Book) ~1,500 large molecules in pipeline (The Pharma Letter, McKinsey) Particulation / aggregation Drug packaging / manufacturing Formulation time Contamination / containment in fill and finish Consistency at start up / lubrication accumulation Impact on inspection / yields (lost value of expensive API) Consistency of Delivery Break / glide force changes over time, impact on shelf life, etc. Pre-Filled Syringes West Coast 2016, Kevin Constable, Terumo and Prefilled Syringes - Issue 55 ONdrugDelivery, Feb 8, 2015, Issue 55, Pg 41. Alessandro Morandotti - Ompi

11 Potential Infuences of Silicone on Protein Aggregation Interference with particle characterization Addition of particles to drug product AR >0.8, ISTD >140 (Pass filter) SO Non-SO Promotion of protein aggregation Source: Protein Aggregation: Formulating a Problem, J. Bryan, The Pharmaceutical Journal, Vol. 293, n 7826 Source: Evaluation of Incremental Siliconization Levels on Soluble Aggregates, Submicron, Subvisible Particles in a Prefilled Product S. Bai, P.Landsman, A. Spencer & coll., J.Pharm.Sci., Jan 2016, Vol.105, p

12 Need for Improved Glide Force Consistency Increased use of auto-injectors in home care setting / trends toward more viscous drugs dictates solution that minimizes glide force increase over time Traditional siliconization process leads to silicone migration / increased glide force over time Current efforts focused on maintaining consistent silicone layer to mitigate risk of incomplete injection After Sterilization Images courtesy of SCHOTT AG After 2 years of storage

13 Challenges of Auto-Injection Injection Time Examples Example: Stalling after Triggering (Siliconized-commercial product: Company A) n = 10 n= 11 Example: High Variability after Aging (Siliconized-commercial product: Company B) n= 10 n = 1 out of 11 n = 1 out of 2 n = 1 out of 2 Test Setup Initial Spring Force: 20 N Spring Constant: 358 N/m Final Spring Force: 8.5 N Fill: 960µL, 1cP Solution Needle: 25g SW 5/8 in.

14 Addressing Silicone in Pre-Filled Syringe Minimize silicone quantity Stabilize silicone layer What about a strategy to eliminate silicone from plunger AND barrel? Replace alternate lubricant

15 Proven Strategy to Eliminate Silicone in Pre-Filled Syringe NO silicone No silicone oil No cross-linked silicone No baked-on silicone No resin-enhanced silicone Using a BARE glass barrel for vial-like performance Lubricant-free barrel Silicone lubricant-free plunger with fluoropolymer barrier Only plunger that enables low particulate and consistent glide force in bare glass pre-filled syringes

16 Exceptionally Low Sub-Visible Particulates Avastin -Filled Syringe Tested via MFI (Micro-Flow Imaging) 30 plungers per lot were tested in in 30mL of Particle-Free Water Tested via Light Obscuration per USP <788> Chart Source: Teska et al., J Pharm Sci. 2016, 105 (7), Avastin is a registered trademark of Genentech U.S., Inc. Order of magnitude reduction in particle concentration

17 Significantly Reduced Extractable Profile in Glass PFS Plungers in barrel: 100% IPA at 55 C for 72 hours Full immersion of elastomer only Performed in exhaustive extraction conditions Showed compounds typical of those observed in commercial rubber plungers Abundance Gore Fluoropolymer Barrier Clean Butyl Rubber Example In-barrel extractions of plunger fluid contact surfaces Extraction profile comparable to full immersion when using elastomer only Showed no significant extractable compounds with Gore s fluoropolymer surface Elution Time

18 GORE TM ImproJect TM Plunger - Consistent Slide Behavior After Aging Filled with 1 ml water for injection (WFI) Tested at 250 mm / minute SCHOTT Silicone-Free SyriQ 1 ml Long Staked Needle Syringe (27G TW) Force (N) Break Glide Error bars are 1 standard deviation 1 Week 2 Years * Real time 2-year aging available in late-october 2018 (accelerated at 40C for 65 days) Maintains consistent delivery throughout injection and after aging

19 GORE TM ImproJect TM Plunger - Consistent Injection Time 15cP surrogate 20N Spring Injection Time (s) Week 2 Years Fill: ~1mL, 15cP Glycerol/WFI, Schott 27G TW staked needle, Flat Plunger Rod

20 Proven Strategy to Eliminate Silicone in Glass PFS Eliminate silicone from plunger AND barrel Only plunger enabling low particulate / consistent glide force in BARE glass PFS

21 THANK YOU! Russ Hornung Rob Gelissen W. W. L. L. Gore Gore & & Associates

22 Gore - Who we Are Est.1958 US UK Germany 10,000+ associates China Japan 45+ manufacturing & sales locations Sales of >$3.0b Lattice organization Improving lives though advanced materials W. W. L. L. Gore Gore & & Associates

23 Gore products are implanted extensively in human tissue W. W. L. L. Gore Gore & & Associates We make vascular grafts, endovascular and interventional devices, and surgical meshes used by healthcare professionals to improve the lives of patients worldwide

24 Gore PharmBIO Business Unit Products that support pharma and biotech processing and drug delivery devices: Drug Delivery components (syringe plungers), Implantable cell therapy delivery device technologies GORE Protein Capture Device with Protein A, GORE STA-PURE Flexible Freeze Containers, GORE LYOGUARD Freeze-Drying Trays, STA-PURE Pump Tubing Dedicated clean facility and cgmp Quality System ISO 15378, ISO W. W. L. L. Gore Gore & & Associates