Stainless steel or plastic? The Rentschler decision process

Transcription

1 Stainless steel or plastic? The Rentschler decision process BPI West, March 1, 2017

2 Content 1 Introduction 2 Cost 3 Scale 4 Safety 5 Outlook BPI West, San Francisco February/March

3 Location of the Company Rentschler Laupheim in the South of Germany Frankfurt Airport 2.5 h Munich Airport 2 h Stuttgart Airport 1 h Laupheim BPI West, San Francisco February/March

4 Full-Service Concept of Rentschler Bioprocess Development Cell Lines Processes Analytical Methods Formulations Biomanufacturing Upstream Downstream Fill & Finish Quality Control Consulting Services Consulting and Planning Project Management Regulatory Support BPI West, San Francisco February/March

5 Outstanding Single-use Experience Pioneer in mid scale single-use manufacturing More than 100 batches in fed-batch and perfusion mode Majority of the products in phase I/II and some in phase III in single-use bioreactors Upstream L HyClone TM bioreactor L Xcellerex TM bioreactor L Xcellerex TM bioreactor 2 nd L Xcellerex TM bioreactor st ÄKTA TM ready system Single-use tangential flow filtration Single-use virus filtration ReadyToProcess 20 cm columns 2 nd ÄKTA TM ready system OPUS 45 cm pre-packed columns Planned expansion Downstream BPI West, San Francisco February/March

6 Utilization of Single-use equipment Single-use Technology R&D, clinical production Small scale Production < 2,000 L Large scale production, Dedicated facility Stainless Steel [USP]100 % Is this really true? Hybrid Shire L Single-use bioreactor facility for Gaucher s disease drug VIPRV 0 % 0 % Hybrid 100 % [DSP] BPI West, San Francisco February/March

7 Fully Disposable Process USP Bags DSP Filtration Chromatography Shukla, TIBT, 2013 BPI West, San Francisco February/March

8 Comparison: Single Use vs. Stainless Steel Parameter SU SS Comments Energy Less steam, less heating, ventilation, and air conditioning Labour +/- +/- No clean in place (CIP), no sterilize in place (SIP) but a lot of manual activities for preparation of manifolds (less automation) Material + - Less CIP media, fewer spare parts Consumables - + Higher cost for single-use material Maintenance ++ - Less complex equipment, lower effort for preventive maintenance Turnover time + - Much faster, no CIP/SIP of unit operation systems Supply chain -- + Some items with long lead time, higher dependency on certain suppliers Quality + + Extractables and leachables to be addressed, lower risk of cross contamination Success rate + + Applicability of SU 98 %, 1-2 % failure rate (mostly due to leaks) Risk of microbial contamination + - Closed systems are much easier to generate (e.g. weldings of tubings) BPI West, San Francisco February/March

9 Benefits and Limits of Disposables (CDMO Perspective) Lower maintenance Repetitive consumables Lower investment Smaller footprint Storage space Inventory Reduced complexity Cost Supplier monopoly Waste management Customization Fully closed process Flexibility Lower cross contamination Supplier qualification Leachables & extractables Safety Quality Scale limitation Leakage Transportation risk Particulates Standardization Sterilization Time Supplier dependency Logistics Shelf live Delivery lead times Faster installation Faster changeover Faster time to market Schmidt, Am Pharm Rev, 2016 BPI West, San Francisco February/March

10 Content 1 Introduction 2 Cost 3 Scale 4 Safety 5 Outlook BPI West, San Francisco February/March

11 Cost of Goods (COGs) Capital Process equipment Buildings Utilities Labour Process Indirect Quality (QC/QA/RA) Materials/consumables CIP/SIP media Buffers, Water Raw materials Resins Filters Tubing/manifolds/connectors Bags Other Waste management Utilities Insurance Maintenance BPI West, San Francisco February/March

12 COGS Comparison 2,000 L SU vs. 3,000 L SS for 100 kg/yr 2,000-L SU: 36 batches; 3,000 L SS: 24 batches Assumptions: titer 2 g/l, yield 70 %, fed batch Overall COGS difference (+20 % for 2,000 L variant) BPI West, San Francisco February/March

13 Process Economics Single-use Virus Filtration (15 b/yr) Quattroflow pump (disposable pump head) Up to 4 m² filters Details: 98 % less water usage (m3/batch) 85 % more plastic waste (kg/batch) appr. 15 kg BPI West, San Francisco February/March

14 Comparison of Facility Types Based on Net Present Cost (NPC) Additional facility NPC recognizes total cost associated with facility (construction, capital, operating costs) Jeff Johnson, Merck & Co, Bioprocessing Summit 2015 BPI West, San Francisco February/March

15 Content 1 Introduction 2 Cost 3 Scale 4 Safety 5 Outlook BPI West, San Francisco February/March

16 Scale Limits of Single-use Equipment Step Max. Limit Cause USP DSP Reactor volume 2,000 L (3500 L ABEC Nov 2015) Pressure stability of polymer material Low power input through stirrers Low O 2 / heat transfer rates Cell retention 1,000 L Size of hollow fiber (ATF10) Centrifuge 1,000 L Comparatively high investment costs Low flow rates / g-forces Chromatography column Chromatography systems 60 cm (56 L) diameter (2,000 L) 510 L/h (1,000 L) Stability of material Ease of packing Tubing and pump BPI West, San Francisco February/March

17 Cell Removal/Retention with Single-use Systems Dynamic Body Feed Filtration Single-use centrifuges o Unifuge Pneumatic Scale Angelus (up to 4000 g / 240 L/h) o ksep-systems (up to 2000 g / 720 L/h) o Comparatively high investment costs o Low flow rates/g-forces Pictures are courtesy of PSA and ksep Systems BPI West, San Francisco February/March

18 Single-use Chromatography Classical packed column Scale limitation (60 cm dia) Resin selection 3D macroporous hydrogel High capacity High flowrate High salt tolerance Scale limitation (0.5 L) Only AIEX (and CIEX) Monolithic column Ideal for large molecules High flowrate High resolution Fixed bedheight Scale limitation 128 L CV Charged membrane High flowrate IEX and HIC Ideal for FT mode Scale limitation 5 L BPI West, San Francisco February/March

19 Single-use Pumps and Chromatography Systems ÄKTA Ready HF 510 L/h Mobius FlexReady 480 L/h QuattroFlow qf5050su 5000 L/h BPI West, San Francisco February/March

20 Content 1 Introduction 2 Cost 3 Scale 4 Safety 5 Outlook BPI West, San Francisco February/March

21 Safety/Risk Assessments Single-use Technologies BPI West, San Francisco February/March

22 Issues with Disposables: L&E Extractables: Compounds that originate from a component (or a system) in solution after exposure of the material at conditions that are more extreme than typical operation conditions o Temperature o ph o Polarity o Time o Contact surface Leachables: Compounds that originate from a component (or a system) in solution under typical operation (or storage) conditions Expected to be a subset of extractables Extractables Leachables BPI West, San Francisco February/March

23 Summary on Overall Risk Assessment BPI West, San Francisco February/March

24 Increasing costs and effort Leachables & Extractables - Modules of Process Specific RA Module 1 Overall risk assessment, identification of relevant materials Module 2 * Module 1 + Manufacturer documentation Module 3A * Module 2 + Material-specific risk assessment Qualitative evaluation of extractables data (data representative/worst case) Module 3B * Material-specific risk assessment, Module 3 A + Quantitative evaluation of extractables data Module 4 Support of extractables / leachables studies (e.g. supply materials, support study design) * May require a 3-way Confidentiality Agreement BPI West, San Francisco February/March

25 Rejected qty Quality Issues with Disposables Bioreactor Bags 6 Timeline Complaints Bioreactor Bags in total Jan 15 Feb 15 March 15 Apr 15 Mai 15 Jun 15 July 15 Aug 15 Sep 15 Okt 15 Nov 15 Dec 15 Jan 16 Feb 16 Mar 16 Apr 16 May 16 Timeline BPI West, San Francisco February/March

26 Quality Issues with Disposables Bioreactor Bags Separation of film layers Incomplete welding seams Punctures, holes From September 15 until May 16, 14 % of reactor bags were faulty! Current failure rate <1 % BPI West, San Francisco February/March

27 Quality Issues with Disposables Check Valve Specification Current polypropylene used in gas filters housings is somewhat prone to cracking during handling (<1.0 %). An alternative polypropylene formulation is now available from Meissner that mitigates this issue. Change will be implemented through CCN. Question whether this spacing is within specification No failures related to the sparge line check valve have been reported to date (supplier information) Experienced and mindful operators combined with a comprehensive documentation. BPI West, San Francisco February/March

28 Quality Issues with Disposables Chemical compatibility Mechanical stability Packaging changes BPI West, San Francisco February/March

29 Content 1 Introduction 2 Cost 3 Scale 4 Safety 5 Outlook BPI West, San Francisco February/March

30 Decision Tree Verification of feasibility (Technical, economical) Assessment of risks (Product, process) Future strategies (Implementation, process and logistics continuity) BPI West, San Francisco February/March

31 Conclusion To date, the decision-making on whether and when to use single-use (SU) devices or stainless steel (SS) equipment for biopharmaceutical manufacturing is ambiguous. None of the arguments in terms of safety, cost-effectiveness, or operational efficiency is fully convincing to choose one technology platform or the other. The service provider business model particularly forces CDMOs to look for more flexible production capacity, fast campaign change-overs and rapid production at varying scales. These demands are nicely fulfilled by single-use equipment which made CDMOs the early adopter of that technology. BPI West, San Francisco February/March

32 References Rogge, Pharma Bio World, 2012 Shukla, TIBT, 2013 van der Meer, BioProcess Int, 2014 Martin, BioProcess Int, 2014 Rios, BioProcess Int, 2014 Ding, Pharm Eng, 2014 Rogge, BioProcess Int, 2015 Schmidt, Am Pharm Rev, 2016 BPI West, San Francisco February/March

33 Contact Dr. Frank Gießelmann, Director USP Production Tel.: Fax: Rentschler Biotechnologie GmbH Erwin-Rentschler-Str Laupheim Germany Rentschler Inc. 400 Oser Ave., Suite 1850 Hauppauge, NY USA BPI West, San Francisco February/March