Considerations for establishing a single use technology-based biological plant: Case Study

Transcription

1 Considerations for establishing a single use technology-based biological plant: Case Study PDA Israel Single Use Equipment Tel Aviv, 7th May 2018 Nitzan Levy, Ph.D

2 Tarom Applied Technologies The Israeli pioneer in SUT Tarom - the 1 st to introduce single use equipment to the Israeli Biopharmaceutical Sector (since 2007) SUT main Suppliers SUT major Customers 2

3 More than 10 years in the Biopharmaceutical industry Head of Bioreactors Unit Scale-Up (Pilot) Manager Production Manager Head of R&D Team member in designing, implementing, supervising and operating InSight s production facility which is based on a single use technology 3

4 InSight Biopharmaceutical Ltd. Established in 1995, Privately held 150 employees Focus on biosimilars (API) Development of biological products Technology transfer to partners Development needs: Parallel (multi-product) Fast (time to market) Robust and Reliable Scalable Cost effective Small scale (perfusion hormones, cytokines) / Large scale (batch mabs) 4

5 When is it worth using single use products? Goals Price Number of Items Number of repeats Scale Amount of labor Operational complexity Workers skills Special Situations 5

6 Considerations Technical aspects Quality Regulatory aspects Operational flexibility Cost 6

7 Basis of Design (BOD) Production of mabs & hormones First production facility, no experience No skilled workers (production, QA, engeneering) Biologics (strict quality) New and unknown 4 products in the same production suite Multi-product Limited space GMP compliance Minimum down time Minimum need for sterilization / cleaning Batch size (SUB limitations) Seed train design 1:4 ratio / 1:10? / 1:20? Infrastructure limitations Compliance Operation Scalability Process 7

8 Single Use Components USP or DSP? mainly in the USP SUB s and clarification Buffers / media storage Seed train USP Clarification Intermadiate steps storage Drug substance final storage 8

9 InSight - R&D USP 1-3L Applikon glass bioreactors 10L Celligen glass bioreactors 10L Wave 100L SS Applikon bioreactor 9

10 A Major Threat: Contamination Bioreactor runs bioreactor runs (~83 runs/ year) 234 small scale 28 pilot scale Contaminations 3 small scale (1.3%) 13 pilot scale (46%) Contamination investigation Damaged seal in 100L bioreactor 10

11 What is the Best Decision Point? Should we only establish a single use technology for new equipment or is it worth swiching existing equipment to single use? 11

12 InSight s decisions Hyclone Finess Tarom (Support by InSight s former team members) Logistic control partnership between supplier and end user Technical support Quality Regulatory Software flexibility Remote access Backup 12

13 Scale up: from R&D to Commercial Scale Would scale up be linear? Would the product maintain its physicochemical characteristics? Would it stay cost effective? 13

14 Cell density [10^6 mg/ml] Cell viability [%] Bioreactors Scale Up - Cells profile (1) Cells viability Cell density and viability L Scale 100.0% 98.0% % L AVG 94.0% % 90.0% % Time [Day] 86.0% 14

15 Protein Similarity: Commercial Scale vs. RLD Titer, Commercial scale vs. pilot scale ~1:1 U16sP-1.0 MS load A B C MS and VI RS Remicade (lot # CFD46046) 1.4 MS elution 2.1 VI P-3.0 ES load ES, CA and UF steps 3.3 ES elution 4.0 CA load 4.1a CA collected 5.2 UF ret. 5.3 UF wash Remicade NR SDS-PAGE gel of in-process samples of InSight-Infliximab 15

16 Cell density [x10^6 cells/ml] Scale Up: Cell Growth (2) 6.0 Cell density of pilot and commercial scale batches Time [Days] AVG Pilot scale U18Eng1 AVG Pilot scale low iron + B3 addition U18Eng2 16

17 Cell viability [%] Scale Up: Cell viability (2) 100 Cell viability of pilot and commercial scale batches Time [Days] AVG Pilot scale U18Eng1 AVG Pilot scale low iron + B3 addition U18Eng2 17

18 Titer : Commercial Scale vs. Pilot Scale ~1:1 NR SDS-PAGE gel of in-process samples of InSight-Adalimumab 18

19 Implementation Scale up issues with SUBs Before antifoam 10 min after antifoam addition 19

20 Extractables and Leachables Thaw Contact with the product Long term or short term storage 100% SFM 100% SFM + MTX Propagation in SF Ex-Cell 325X100 Propagation Wave Anti foam S. Bicar bonat e Propagation in 100L Sub Glucose 90% SFM + Se Production in 1000L Sub CB4 + YE+ Glu gln DPBS Clarification 20

21 Flexibility of changes Probes Inlets Outlets Filters Sampling 21

22 Clarification 1000L Sub Pressure Switch Sterile filtration Depth filtration Waste Pump 2x 500L bag Clarified harvest 22

23 Conclusions Single use technology was successfully implemented in Insight Implementation was fast and relatively simple Technology was found to be robust and reliable Technology was found to be scalable There were no major scale up issues In retrospect, single use technology was good for the pilot as well 23

24 Thank you Nitzan