Continuous Processing Progress in Manufacturing

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1 Cell World Conference, San Francisco, May Dr. Berthold Boedeker, Bayer AG, Biological Development

2 Biologics at Bayer Regulatory support / drivers aof continuous processing Bayer s approach to continuous processing Agenda Most common perfusion systems Set-up, characteristics, cell retention system Integration of downstream processing Options and limits of continuous processing Technical feasibility, economics, plant design, validation Concept study: plant design standard fed batch vs. disposable continuous processing facility Conclusions and Outlook Page 2

3 Bayer Group Structure Board of Management Pharmaceuticals Consumer Health Crop Science Animal Health Corporate Functions & Business Services Currenta (60%) Covestro (around 64%) Slide 3

4 Pharmaceuticals Division One of the leading innovative companies in the healthcare industry Largest division of Bayer in terms of sales One of the fastest growing pharma companies worldwide Sales of billion Euro in 2016 Global headquarter in Berlin, Germany 40,100 employees worldwide in 2016 Largest German pharma company Focus on prescription products, especially for cardiology, oncology, hematology, women s healthcare, and ophthalmology Radiology franchise with contrast-enhanced diagnostic imaging equipment and contrast agents Page 4

5 Bayer Pharmaceuticals Betaferon /Betaseron Kogenate Eylea Product Indication Multiple sclerosis Hemophilia A Wet Age-related Macular Degeneration Market Worldwide Worldwide Ex-US Product presentation Volume Lyo-vial in kit Lyo-vial in kit Liquid-vial High (double digit million vials) Medium (one digit million vials) Growing Manufacture External In-house External Page 5

6 Regulatory support / drivers of continuous processing FDA encourages manufacturers to use continuous processing because of the perceived advantages: Improvement of product quality because of steady state operations (limiting processing variables) Improved patient access because of lower costs Indeed also industry expects pronounced advantages: Improved product quality Reduced CoGs Modular manufacturing in standardized plants using standard processes Less facility investment Easy site to site transfer Page 6

7 Preconditions to enable continuous processing Perfusion culture experience Advancement of disposable technologies Processing automation Continuous Processing Advancements in closed processing PAT Technologies On-line or in-line analytics Page 7

8 Bayer s approach to continuous processing Mainly within Bayer Engineering & Technology department Participation in German state funded consortium program Established a 10 L model processing unit for completely continuous processing from production fermenter to virus filtration (classical mab process) Disposable settlers or ATFs used for cell retention Multi-column chromatography systems Dual set-up for UF/DF/membrane operations no true continuous processing but continuous product flow in discontinuous individual systems --- unit is running and can be visited in Leverkusen Conclusion; doable, but very difficult to run and control Page 8

9 Bayer s experience with perfusion 30 + years of production of rec Factor VIII in perfusion Batch/fed-batch not suited because of fragility of the protein in culture short residence time of the product open cell retention system removing dead cells and debris (inclined plate settler) fermenter volumes/day yield in high volumetric production Extensive process validation efforts compared to batch BLA: 2-3 run of full length preparing several qualifying lots, duration 6-12 months, show seed to seed as well as early/mid/late fermentation consistency Page 9

10 Cell concentration [10 6 vc/ml] Viability [%] Long term continuous fermentation of rec FVIII 100 Viability Cell concentration 10 1 production of unstable protein q/v = 10 /d 1 Dr. Konstantinov, Bayer Corp., Dechema 2002, Frankfurt Time t [d] Page 10

11 Commonly used perfusion systems External filtration unit favorite ATF (alternate tangential filtration) Continuous centrifugation now also available as disposable unit All systems have a limited use time, therefore for continuous processing always 2 systems are set up in parallel: 1 in use, 1 to switch to Page 11

12 Commercial Perfusion System: ATF Perfusion System from Refine Technol. (presented at the Biomanufacturing Summit, San Diego, 2013 Page 12

13 Features of ATFs Limited scalability Easy to operate, but moving parts Clogging possible (2 systems in parallel) Low perfusion rates of max 2 fermenter volumes per day Accumulation of dead cells/debris may impact product quality over time Cell bleed adds another level of operational complexity No real steady state conditions possible Page 13

14 Integration of perfusion fermentation into continuous downstream operation Chromatographies Parallelized small disposable multi-columns operated batchwise in sequence without interrupting product flow Well established, several systems available Filtration / adsorption 2-systems-approach 1 in use, 1 to switch to ph inactivation Either continious via low ph elution or Batch-wise with 2 units Collect product upt to a certain volume, decouple, inactivate, continue with continuous operation Virus filtration See filtration Page 14

15 Technologies of the future to support continuous processing Disposable Flexible facilities Closed processing In-line dilution for large liquid volumes Ball-room facilities PAT tools Higher binding gels On-line monitoring Alternatives to chromatographies: membrane absorbers, precipitation Page 15

16 Ball-room plant design concept (1) Represents innovative concept to enable parallel processing of different products in the same low classification containment without upstream and downstream seggregation Concept addressed in the following paper: Simon Chalk et.al., Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug Substances, BioPharm International, Aug. 1, Based on the key assumptions that technological advances including single use sytems have continuously reduced the risk of environmental impact on processing. Most steps can be securely performed closed or functionally closed. The few remaining open processing steps have to be addressed independently (i.e. portable laminar flow hood, isolator technology) Page 16

17 Ball-room plant design concept (2) Basic thinking is that in a closed or functionally closed system, the process stream is isolated from the environment Remaining open operations (cell expansion, column packing, powder additions) have to be addressed separately, i.e. in small areas with classical containment set up, or closed solutions Potential breach of the closed system is the major risk, which has to be addressed: - prove no contamination or cross-contamination - intense microbial monitoring Maintaining the closed system status has to be addressed by a risk based approach with appropriate risk mitigation strategies considering each process step or operation Page 17

18 Facility of the future: Comparison of standard fed-batch to disposable based continous processing facility Most facilities nowadays are of hybrid design combining elements of classical hardpiped with single use elements. In order to evaluate differences of a closed systems, disposables and continuous processing based ballroom facility to such a fed-batch hybrid set-up, a concept study was performed by Bayer: Joergen Magnus, Bayer Technology Services at 12th Annual Biolog. Production Forum, Düsseldorf (2013) Page 18

19 Comparison to facility with traditional design and similar production capacity Cell culture pilot plant (Wuppertal) Purpose Produce material for phase 3 clinical trials Design Stainless steel equipment Functionally closed processing Fed-batch fermentation Operations are separated in different rooms Building concept 5 levels ~ 5000 m² total area ~ 1400 m² cleanroom (class D+C) Biofacility of the future Purpose Production for market Design 100 % single use process equipment Closed processing Continuous processing Ball-room production Building concept 2 levels ~ 1200 m² total area ~ 360 m² cleanroom (class D+C) Page 19

20 Design principle: 100 % single use technology Media bag Buffer bag Buffer bag Fermenter Filter UF/DF Chromatography Product bag Single use Bioreactor + single use tubings, bags, sensors, etc Single use filter cartridges Pre-packed columns No need for CIP or SIP Page 20

21 Design Principle: Continuous Processing Upstream Downstream Continuous fermentation with cell retention Continuous depth Continuous chromatography using simulated moving bed technology Continuous UF / DF Continuous virus inactivation Bioreactor performance depending on Cell specific productivity Cell density Perfusion rate Page 21

22 Closed processing in single-use systems Γ-sterilized Γ-sterilized Γ-sterilized Sterile tubing fuser or aseptic connector Page 22

23 Design Principle: Ball-room Production Ball-room includes: All process units All media and buffer containers All media and buffer preparation tanks But does not include Seed lab Bulk filling room (post viral area) Page 23

24 Benefits of continuous processing in a biofacility of the future concept Design Principles 100 % S.U. process equipment Continuous processing Closed processing Ball Room production in class D (except seed lab and final filling) Benefits Shorter engineering, construction, commissioning, qualification and validation times Decoupling of equipment from building Smaller building footprint Energy and water saving Reduced investment and production cost Reduced complexity Page 24

25 Pro s and Con s of continuous processing individual unit operations difficult to get lower plant footprint lab-like infrastructure easier to build and validate easy to operate, if fully automated easy site to site transfer lower CoGs continuous risk of product quality issues because of perfusion operation glycosylation depends on specific perfusion rate glycosylation different to fed-batch (transition issues) no real steady state possible same quality over complete run length needed titer dilution (harvest) batch definition increased process validation effort Page 25

26 Bottlenecks of continuous processing immature technologies yet (especially in DSP) scalability problematic process characterization problematic scale down models upstream extended validation effort development/operations/facilities in-house infrastructure for fed-batch lack of automation on-line monitoring and control complex biological systems regulatory acceptance and experience maintaining microbial control cell lines/culture media optimized for long fedbatch process with cells in stationary phase Page 26

27 Currently preferred processing strategy Integrate disposables use, closed systems operation and parts of continuous processing to obtain a flexible, easy to validate and operate facility using lowered containment classification than current standard Fermentation preferred fed-batch, in few cases perfusion (molecule dependent) DSP could be done partly continuous, if technologies advance correspondingly - chromatographies via multi-column units - membrane adsorbers instead of chromatographies - filtration in parallel mode Page 27

28 Forward-Looking Statements This website/release/presentation may contain forward-looking statements based on current assumptions and forecasts made by Bayer management. Various known and unknown risks, uncertainties and other factors could lead to material differences between the actual future results, financial situation, development or performance of the company and the estimates given here. These factors include those discussed in Bayer s public reports which are available on the Bayer website at The company assumes no liability whatsoever to update these forward-looking statements or to conform them to future events or developments. Page 28