Intensification of a Perfusion Platform using Single-use XCell ATF Systems

Transcription

1 Intensification of a Perfusion Platform using Single-use XCell ATF Systems Olaf Mol Sr. Bioprocess Scientist The world leader in serving science

2 Global Footprint- Biologics Princeton, USA PD Center of Excellence Over 20 years of experience Track record for over 100 protein development programs Cell line & Process development Groningen, The Netherlands Clinical and Commercial Manufacturing >30 years experience Developed XD and Rhobust technology FDA Nov 2014 no observations Brisbane, Australia Clinical and Commercial manufacturing New state of the art facility, single use technology 2014 ISPE Facility of the year 2015 APAC CMO of the Year Award St. Louis, USA Greenville, USA Ferentino, Italy Monza, Italy PD Center of Excellence, clinical and commercial manufacturing Track record Commercial manufacturing (perfusion) Approved by all main regulatory authorities Drug Product Fill / Finish Drug Product Fill / Finish Drug Product Fill / Finish 2

3 Overview of Capabilities and Technologies Global Network for cgmp Manufacturing All plants are flexible, multi-product facilities, with quick expansion potential Site Bioreactor Scale Number of Bioreactors St Louis, MO, USA Manufacturing & Development Groningen, The Netherlands Manufacturing & Development Brisbane, Australia Manufacturing Princeton, NJ, USA Development Extensive Cell Culture Capacity 250L-2000L single-use disposable bioreactors available on all sites Xcellerex, HyClone, Sartorius production bioreactor systems Cell lines: suspension or attachment-dependent cell cultures Production modes: continuous perfusion, batch, fed-batch or XD Globally 11 x cell culture suites are available Flexible Downstream Capacity cgmp batch sizes of up to 10kg St Louis Groningen Brisbane 2000 L L L L L L L L L L 1 3

4 Patheon Biologics Groningen overview - Site History Site Established (BioIntermediair) Acquired by Gist-Brocades Acquired by DSM N.V. (DSM Biologics B.V.) Merger of DSM Pharmaceutical Products and Patheon Inc. (DPx) Jun 2014 Name change into Patheon Biologics B.V. Oct 2014 former Gallus acquired; expanding the biologics Patheon Network Acquired by Thermo Fisher Scientific Part of the Pharma Services Group 4

5 Patheon Biologics Groningen overview Clinical & Commercial Manufacturing EMA and FDA audited manufacturing facility >30 years experience and expertise in cgmp manufacturing of biologics products Phase I, II and phase III clinical production Commercial manufacturing Manufacturing support capabilities Fed-batch & perfusion 4 independent suites for mammalian cell lines 100% single use bioreactors 50L, 250L, 500L, 1000L, 2000L scale SUBs L Perfusion/XD Experienced tech transfer teams In-house QC and QA 5

6 Patheon has a proven Technology Transfer track record >50 programs have been transferred globally since 2014 ~ 30% are non-mab / non-fc-fusion ~ 25% are perfusion based cell culture processes ~ 50% were developed or characterized at Patheon ~ 50% of processes were transferred from a customer 8 programs have run in more than one manufacturing facility Mix of early and late Phase programs with over 10 programs scheduled to complete qualification batches by the end of

7 Introduction of Single-use XCell ATF Systems for last step of seed culture The world leader in serving science

8 extreme cell Density process (XD ) XD in short Perfusion based process Continues medium feed Filtration unit (e.g. ATF) to retain product and/or cells in the bioreactor Relatively simple media without the need for complex feeds Up to 4 VVD High titers Spent medium High cell density and high viability Robust and scalable 8

9 extreme cell Density process (XD ) Extensive knowhow on XD Process XD is a perfusion based process using a hollow fiber filter as a retention system (ATF) Example 1 9

10 extreme cell Density process (XD ) Example 2 10

11 Introduction of Single-use XCell ATF Systems for last step of seed culture Intensification of Fed-Batch Upstream Process: Increase inoculation density to 5-10 x 10 6 cells/ml Cell growth Product formation Challenge: N-1 seed culture step to deliver the necessary cells at a high enough cell count to allow for a minimal 1:3 dilution of the culture for inoculation of the production reactor 11

12 Design of N-1 mode of operation Use short perfusion / XD mode of operation to generate large amount of cells in a relatively short time Window for Using cells 12

13 Introduction XCell ATF Single-use System Traditionally Patheon has used Stainless steel ATF systems ATF-2 (GE-PS filters, 30 cm path length) ATF-6 ATF 10 For development, switch made to Single use ATF-2 system Benefits of Single use system: No cleaning, assembly, autoclaving Better model for scale up (hollow fiber length) Easy to use Performance comparable to previously used systems at small scale Picture: 13

14 Introduction XCell ATF Single-use System Philosophy, especially in Upstream processing, is Single use Multi product facility relatively easy change over to new product/client No cleaning of process equipment required No cleaning validations, CIP, SIP, etc. Stainless steel ATF not compatible with this Philosophy. Assembly of ATF is time consuming and relatively complex 14

15 Assembly of Stainless steel ATF-10 system 15

16 Pro s and Con s Pro s and con s for Stainless steel and Single use ATF systems Stainless steel ATF system Reusable Proven technology Time consuming assembly & setup Cleaning & Autoclaving SU Xcell ATF system Single use New technology, no track record. (limited track record for SU-ATF-2 and SU-ATF-6 but not for SU-ATF-10) 80% faster setup No cleaning & autoclaving required Preferred system for use at Patheon: XCell ATF-10 Single-use Pictures: 16

17 Introduction XCell ATF Single-use System Preferred system for use in our application: XCell ATF-10 Single-use System Unfortunately, Patheon timelines were not compatible with timelines for introduction of XCell ATF-10 Pilot in December 2016 while introduction of XCell ATF-10 SU System in Q Stainless steel system was purchased Challenges encountered with autoclaving cycle (related to Patheon Autoclave) Unfortunately / luckily a delay occurred in the Patheon time lines Delivery of first* beta-model for XCell ATF-10 SU System just in time for Pilot run possible Excellent technical on-site support by Repligen Successful Pilot at 250L scale (final process scale) First picture of ATF-10 SU system shared by Repligen (03FEB17) 17

18 Introduction XCell ATF Single-use System However, complete data package required for next batch middle of August. Regular updates on the qualification and validation progress for cgmp qualified version of XCell ATF-10 Single-use System were shared with Patheon Delivery of qualified XCell ATF-10 Single-use Systems in time for Engineering run. Successful run performed Next two systems are on stock at Patheon for next batches. 18

19 Conclusions Excellent support of Repligen during introduction of XCell ATF-10 Single use system Keeping timelines that were communicated Q Open communication Excellent on-site and on-line support for introduction of the XCell ATF-10 Single use system Comparable performance at small scale and 250L using XCell ATF-2 and ATF-10 Single use system Patheon / Thermo Fisher Scientific has the knowledge and expertise to help you develop an ATF based perfusion process 19

20 Thanks The team: Xi-En Yang Edith Olthof Sandra Wobma Mariska Vegter Douwe Westra Special thanks to: Repligen Thank You 20