Case Study Lonza: Manufacturing of Antibody Drug Conjugates using Single Use Equipment Frankfurt 8. November 2018

Transcription

1 Case Study Lonza: Manufacturing of Antibody Drug Conjugates using Single Use Equipment Frankfurt 8. November 2018 Lonza Pharma & Biotech Fabian Studer 2018

2 Disclaimer The information contained herein are believed to be correct. However, no warranty is made, either expressed or implied, regarding its accuracy or the results to be obtained from the use of such information. Lonza disclaims any liability for the use of this presentation and the use of the information contained herein is at your own risk. All other trademarks belong to Lonza or its affiliates or to their respective third party owners Lonza All rights reserved. Lonza Pharma & Biotech Overview

3 Corporate Communications Visp

4 Lonza Visp Corporate Visp 2018

5 Visp key figures and outlook 111 facilities 90 hectares area Ibex Solutions 30 operations Corporate Visp 2018

6 Our offer spans across broad range of technologies Drug substance Chemical technologies small molecules, HAPI, cytoxics, intermediates Bioconjugates Biologics in mammalian and microbial expression systems, cell, gene and viral therapy Drug product Oral dosage forms & delivery systems Hard capsules Soft capsules Parenteral drug product services Lonza Pharma & Biotech Overview

7 Bioconjugation Facilities PCP Visp * Operated 24/7 to support: 2 commercial ADCs 6 late stage ADCs > 20 phase I/II ADCs A few characteristics of ADCs How are ADCs produced - Key Step and Process General challenges related to ADC manufacture Lonza s AHSK classification Substances handled and their OELs Operational hygiene (surrogate study) Benefits of utilizing SU equipment Considerations in individual unit operations Overview and Conclusion * protein conjugation production Pharma & Biotech Antibody Drug Conjugates 7

8 Antibody-drug conjugates (ADCs) Some characteristics, mode of action Sub-class of bioconjugate products ADCs combine the selectivity of mabs with the potency of cytotoxic molecules to generate high potent but selective anti-cancer agents. The payload (toxin) is typically covalently bound to the mab through a stable chemical linker Internalization through receptor mediated endocytosis is key to the mechanism of action From: biooncology.com (Roche/Genentech) Jaracz et al. Bioorg Med Chem. 2005;13: Chari. Acc Chem Res. 2008;41: Erickson et al. Cancer Res. 2006;66: Pharma & Biotech Antibody Drug Conjugates 8

9 ADC production process overview Example: Cysteine conjugation Unit Operations: Reaction: Modification Conjugation Formulation Pharma & Biotech Antibody Drug Conjugates 9

10 A brief history of the single used technologies within PCP Standardize Outsourcing Manifolds / tube sets designing 2018 our own TFF skid Lonza Pharma & Biotech Overview

11 General challenges in ADC manufacturing Focus is on GMP and SHE Patient Safety Organic Solvents Environment Operator Protection Ever increasing druglinker toxicity (OEL down to 1ng/m3) > cross contamination Increased leachables risk and potential impact on stability of production equipment Toxic waste streams Highly potent, cytotoxic molecules with at 1 ng/m3 Dedicated Equipment Validate our cleaning processes Capability of analytical methods (LOQ) Pressure cascade (in-out) Ensure stability (seals and other synthetic materials) Leachables risk assessment Extractables studies Collection of all waste streams (liquid and solid) Decomposable (e.g. chlorine, caustic)? Incident management (procedures by hand) Safe disposal (transport and incineration) Closed operation Protecting cloths Environmental monitoring (surrogate studies) Pressure cascade (out-in) Pharma & Biotech Antibody Drug Conjugates 11

12 Lonza AHSK classification Operational exposure limits and related working standards Lonza AHSK classification OEL Toxicity and potency Typicale dosage [mg/kg] class 1 class 2 class 3 class 4 class 5 class 6 1 mg/m g/m 3 10 g/m ng/m 3 1 ng/m 3 low moderate potent highly potent > < 0.01 Impact on health irritation, no systemic organ effects, no permanent or genic effects moderate to high acute effects, no genic1) effects, reversible systemic toxicity carcinogenic, mutagenic, sensitizing, severe health effects carcinogenic, mutagenic, developmental and/or reproductive toxicity, permanent severe effects Working standard in production Working standard in (QC ) labs Manufacturing out of standard production trains HAPI trains Cyto / ADC trains Execution of work in standard labs / hoods HAPI hoods / labs Isolators SafeBridge classes / recommendation good manufactering practice with localized exeptions good manufacturing practice with ventilation extractions contained production no open handling, closed system mab g/m 3 payloads 20 1 ng/m 3 ADCs ng/m 3 Ader AW, Kimmel TA, Sussman RG. (2009). Applying health based risk assessments to worker and product safety for potent pharmaceuticals in contract manufacturing operations. Pharmaceutical Outsourcing. Vol 10, Issue 4; Hensgen MI, Stump B (2013). Safe handling of cytotoxic compounds in a biopharmaceutical environment. In L Ducry (ed), Antibody Drug Conjugates, Methods in Molecular Biology. Vol 1045, DOI / _8. New York, Heidelberg: Springer; pp Harris RH (2012). Formulating high potency drugs. Available: issues/ /view features/formulating high potency drugs. Accessed on August 27, Pharma & Biotech Antibody Drug Conjugates 12

13 Operational Hygiene (with a focus on SU equipment) Understanding the risk avoid leakage (FMEA) Risk Factors (causing leakage) Physical process conditions (temperature, pressure, mechanical impacts), Duration of exposure Chemical process conditions (organic solvents, ph extremes) Welding seams Sensor ports Connections (tubing assemblies, samplings sets, connectors) Cassette stacks Equipment Level Surrogate Study (Naproxen) Hazard Scenario Measures Pre-use visual inspection Adjust SU equipment (pressure, closed) SOP Demo of Equipment capability Process steps under real conditions Mimicking worst case scenario (concentration, volumes) Multiple runs with different operators Airborne samples and Surface swaps Standardized spillage handling Spillage fighting kits on site Drip pans, bench paper EXTENSIVE TRAINING OF STAFF - for process execution and for incident handling Pharma & Biotech Antibody Drug Conjugates 13

14 Processing Solutions in Use Unit Operations, Purpose, Specific Considerations Toxin Compounding Toxin powder handling, Dissolution in 100% solvent Mixing Reduction, Selective Oxidation, Conjugation, Quench excess drug-linker, Formulation, TFF recirculation bag Filtration, Transfers, Sampling Dosing into SUMs, Filtration (bioburden control and particulates removal), Final BDS Fill, Aseptic-closed sampling Isolator Toxin in solid state (weighing) 100% solvent Careful choice of disposables (container and transfer tube) Reactions under N2 (5 mbar) requiring head pressure control in the bag In-situ integrity testing (50 mbar) Option for subsurface addition Control of filtration backpressure (emergency stop) Transfers partially pressure (N2) mediated Selection of tubing materials Selection of connectors Pharma & Biotech Antibody Drug Conjugates 14

15 Processing Solutions in Use Unit Operations, Purpose, Specific Considerations Tangential Flow Filtration Concentration, Clearance of excess drug linker, solvent, other reaction agents, Buffer exchange - Diafiltration Chromatography Purification, Removal of aggregates and by-products Endfill, Freezing Endfill into Bottles and 2D bags, freezing High inlet pressure 4.5 bar (flowset design with vendor) - due to viscosity issues Disposable stainless steel dip tube design Use of pre-packed columns (disposed off together with the disposable chromatography flow set) Bottles filled in crabs* Bags filled in a closed manner through sterile manifolds Best in class protecting shells (RoSS) for bags * Closed Restricted Access Bariere System (laminar air flow, UV lamp, transfer lock) Pharma & Biotech Antibody Drug Conjugates 15

16 Processing Solutions in Use Unit Operations, Chromatography Pharma & Biotech Antibody Drug Conjugates 16

17 Start cooperation with Repligen Why prepacked columns? Payload (Toxin) is very toxic Leader in pre-packed chromatography column No columns (stainless steel/glass) technology available 20 of the top 25 Pharma companies use Repligen No packing equipment available products Investments needed ISO 9001 certified manufacturing Column packing has to be Secure supply chains performed within the production Complete regulatory support packages available suites, no separate packing suite The packing facility in Waltham was audited by available Lonza Stainless steel production equipment (TW Supplier Master Record ) is toxin dedicated They provide a warranty of the packing services Column packing is not a routine Great customer service operation for the operators within the conjugates production Pharma & Biotech Antibody Drug Conjugates 17

18 Summary Advantage and Weakness of using SU Technology for ADC production Advantages Control over cross-contamination Cleaning of processing equipment is obsolete No cleaning risk assessment related activities (cleaning process development) Reduced analytical effort Increased flexibility through quick change-over (more batches of different products p.a.) Reduced toxic waste streams (from cleaning) Reduced maintenance cost Reduced CapEx (equipment is not dedicated and no CIP stations needed) reduced stainless steel equipment Disadvantages Solvent handling, at high concentration, needs specific solutions L&E risk assessment and studies are coming at a cost Higher OpEx driven by higher consumables cost Implementation of integrated automation (DCS type) is more challenging for SUT based lines Dependency of different manufacturer could be very challenging Vendor change notification Pharma & Biotech Antibody Drug Conjugates 18

19 Conclusion Production of ADCs is highly demanding: patient safety and safe working conditions: high requirements for using single use equipment Organic solvents used in the ADC Processes could be challenging In our experience, utilization of single use technology in ADC production can be equivalent or superior in terms of Safety Equipment functionality Time for Tech Transfer Overall project cost Acknowledgement Schmidhalter Diego, Stephan Elzner, Romeo Schmid, Laurent Ducry Pharma & Biotech Antibody Drug Conjugates 19

20 Visp Delivering the medicines of tomorrow, today