BR2 – Effective and Efficient Delivery of Parenterals: Injection Practice and Technology Presented By: Joumana Zeid Injection Site Leakage (SC Injections): How Much Does it Impact your Delivered Dose? October 7, 2014 Joumana Zeid Device Development Genentech / Roche Diversity in Biopharmaceutical Landscape Worldwide (WW) Launched Injectables: By Route of Administration* WW Subcutaneous (SC) Launched Products Source: Health Advances analysis, Citeline Pipeline. SC = Subcutaneous 2014 PDA Universe of Prefilled Syringes and Injection Devices 2 BR2 – Effective and Efficient Delivery of Parenterals: Injection Practice and Technology Increased SC Doses for Biopharmaceuticals Molecule Indication Company Dose Enbrel RA Amgen 50 mg Kineret RA Amgen 100 mg per day Humira RA AbbVie 40 mg Xolair Asthma Roche 150 - 375 mg Novartis Cimzia RA UCB Lebrikizumab Asthma Roche 75 – 600 mg 200 mg / 2 weeks, or 400 mg / 4 weeks*. 125 - 500 mg evolocumabÊ (AMG 145) Lowering LDL-c Amgen 140 mg / two weeks or 420 mg monthly MPSK3169A Lowering LDL-c Roche up to 800 mg *200 mg per injection Impact of Doses (SC Administration) Increasing Drug Concentration (g/L) Limitations on maximum concentration Maximum based on spatial distribution Increased viscosity1 Increased protein aggregation2 1J. Liu, M.D. Nguyen, J.D. Andya, S.J. Shire, Reversible self-association increases the viscosity of a concentrated monoclonal antibody in aqueous solution, J. Pharm. Sci. 94 (2005) 1928–1940. B, Platz R, Tzannis ST. 2007. High concentration formulation feasibility of human immunoglubulin G for subcutaneous administration. J. Pharm. Sci. 96:1504–17 2Dani 2014 PDA Universe of Prefilled Syringes and Injection Devices Presented By: Joumana Zeid BR2 – Effective and Efficient Delivery of Parenterals: Injection Practice and Technology Impact of Doses (SC Administration) Increasing Drug Concentration (g/L) Limitation on maximum concentration: • Maximum based on spatial distribution • Increased protein aggregation • Increased viscosity OR Increasing Injection Volume Not well understood / characterized Today: Dose Delivered Factors Impacting Dose Delivered Factors Typically Considered Addressed via technical assessments Filling Accuracy Device Delivery Accuracy Drug Substance Concentration Potential Additional Factor for High Volume SC Injections Addressed via clinical assessment Injection Site Leakage ? 2014 PDA Universe of Prefilled Syringes and Injection Devices Presented By: Joumana Zeid BR2 – Effective and Efficient Delivery of Parenterals: Injection Practice and Technology Presented By: Joumana Zeid Approach: Assessing Injection Site Leakage • Survey of SC injection volumes of marketed biologics • 25+ therapeutics in prefilled syringe presentation • Volume range = 0.2 – 2 mL • Chose nominal volume Referred to as Standard Prolia Kineret Copaxone Aranesp DuoDote Humira Neulasta Avonex Fluzone Arcalyst Rebif Pegasys Mircera Afluria Enbrel Actemra Neupogen M-Enoxaparin Simponi Somatuline Depot Cimzia Lovenox Extavia Ovidrel Orencia Saizen Approach: Assessing Injection Site Leakage • Designed clinical studies to understand injection site leakage of higher volume injections • Volumes to simulate two scenarios: • Large Bolus SC Injection (~2x standard) • Large Infusion SC Injection (~4x standard) • Varied viscosity and injection duration: Based on pipeline needs & device technologies 2014 PDA Universe of Prefilled Syringes and Injection Devices BR2 – Effective and Efficient Delivery of Parenterals: Injection Practice and Technology Study Design: Large Bolus SC Injection 15 5 Viscosity (cP)* Injection rates comparable to bolus injection (e.g. autoinjector) 7 14 21 Duration (seconds) *Achieved via active drug and/or surrogate N=24 subjects / cohort Study Design: Large Infusion SC Injection 8 1 Viscosity (cP)* Injection rates comparable to infusion injection (e.g. patch injector) 80 sec 4 min 8min Duration N=24 subjects / cohort *Achieved via active drug and/or surrogate 2014 PDA Universe of Prefilled Syringes and Injection Devices Presented By: Joumana Zeid BR2 – Effective and Efficient Delivery of Parenterals: Injection Practice and Technology Critical Study Design Considerations Delivery Set-up • Accurate volumes and injection rates • Delivers across range on interest • Needle ID and Length comparable to actual injection Attach infusion set to deliver SC injection Critical Study Design Considerations • Representative Demographics (example below) Age in years Mean (Range) 42 (18 – 75) BMI in kg/m2 Mean (Range) 26 (21 – 32) Gender n (%) Male 31 (43%) Female 41 (57%) • Injection site = Abdomen 2014 PDA Universe of Prefilled Syringes and Injection Devices Presented By: Joumana Zeid BR2 – Effective and Efficient Delivery of Parenterals: Injection Practice and Technology Presented By: Joumana Zeid Injection Site Leakage Assessment • Injection Site Leakage: Volume wiped with a preweighed cotton swab • Minimum wait time (e.g. 30 second) post catheter removal to allow for any liquid to come back to surface Large Bolus Injection: Low Injection Site Leakage Ref Inj A Inj B Standard 5 cP 7 sec Inj C Inj D Inj E Inj F 15 cP 14 sec 15 cP 21 sec High Bolus 5 cP 7 sec 5 cP 14 sec 5 cP 21 sec 15 cP 7 sec 2014 PDA Universe of Prefilled Syringes and Injection Devices BR2 – Effective and Efficient Delivery of Parenterals: Injection Practice and Technology Presented By: Joumana Zeid Large Bolus Injection: Low Injection Site Leakage Results consistent across design space tested Ref Inj A Inj B Standard 5 cP 7 sec Inj C Inj D Inj E Inj F 15 cP 14 sec 15 cP 21 sec High Bolus 5 cP 7 sec 5 cP 14 sec 5 cP 21 sec 15 cP 7 sec Large Bolus Injection: Low Injection Site Leakage All injection site leakage was < 5% Ref Inj A Inj B Standard 5 cP 7 sec Inj C Inj D Inj E Inj F 15 cP 14 sec 15 cP 21 sec High Bolus 5 cP 7 sec 5 cP 14 sec 5 cP 21 sec 15 cP 7 sec 2014 PDA Universe of Prefilled Syringes and Injection Devices BR2 – Effective and Efficient Delivery of Parenterals: Injection Practice and Technology Presented By: Joumana Zeid Large Infusion Injection: Low Injection Site Leakage Site Leakage (%) Similar findings with large infusion injections Inj A Inj B Inj C Inj D Inj E Inj F Large Infusion 8 cP 8 min 1 cP 8 min 8 cP 4 min 1 cP 4 min Ref Large Bolus 8 cP 80 sec 1 cP 80 sec 1 cP 7 sec So what did we learn? • Design Clinical Assessments to better assess high volume SC Injections • Injection site leakage < 5% for all injections tested • Large Bolus SC Injection • Large Infusion SC Injection • Identified robust design space (injection time & viscosity) Minimal impact on Delivered Dose 2014 PDA Universe of Prefilled Syringes and Injection Devices BR2 – Effective and Efficient Delivery of Parenterals: Injection Practice and Technology Further Considerations • Device design & interaction with injection site may influence results Initial Study: Proof of Concept Confirmatory Studies: Actual Device Example devices for High Volume SC Infusion Delivery • Other aspects need to be considered to address tolerability : Injection Pain, Injection Site Reaction Acknowledgments • Device Development • Formulation Development • Biostatistics • Clinical Pharmacology • Clinical Safety • Clinical Operations • Technical Regulatory 2014 PDA Universe of Prefilled Syringes and Injection Devices Presented By: Joumana Zeid BR2 – Effective and Efficient Delivery of Parenterals: Injection Practice and Technology Presented By: Joumana Zeid Appendix Diversity in Biopharmaceutical Landscape WW Subcutaneous Launched Products By Therapeutic Area (As of January 2014) Note: Oncology includes all cancer types; Endocrinology includes diabetes injectables; Autoimmune includes RA, MS, lupus, psoriasis, psoriatic arthritis, Celiac, and Crohn’s/IBD; Infection includes HCV, other Hepatitis, HIV, Flu Vaccines and others. Numbers are directional. Primary Indication reflects the indication with the highest phase of development Source: Health Advances analysis, Citeline Pipeline. 22 2014 PDA Universe of Prefilled Syringes and Injection Devices
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