Towards Flexible Single-use Biomanufacturing: Key Technologies Needed and Lessons Learned

Transcription

1 Case studies in process intensification Towards Flexible Single-use Biomanufacturing: Key Technologies Needed and Lessons Learned March 14, 2017 San Diego, California Adam Goldstein, Oliver Molina, Michelle Wong Global Manufacturing Sciences and Technology Genentech Inc, A Member of the Roche Group

2 Introduction Single-use technologies (SUTs) are being rapidly adopted by the biopharmaceutical industry This talk will provide an overview of single-use technology implementation at Genentech and Roche Emphasize challenges of SUT flexible facilities and emerging markets

3 Agenda 1. Roche at a Glance 2. Intro to Single-Use Technologies (SUT) 3. Current SUT Uses in the Industry 4. Vendor Expectations 5. Challenges and Opportunities 6. What is next for SUT Facilities 7. Design Concepts

4 ROCHE AT A GLANCE

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10 SINGLE-USE TECHNOLOGY INTRO

11 Background Early Adoptions Pictured above: blood bags, IV bags, eyedroppers, beverage bottles, gloves, syringes

12 Reasons for Increasing Use of Disposable A recent 2015 industry survey by BioPlan Associates has explored trends associated with the increasing use of disposables, the following figures and examples will provide information regarding these trends associated with Single-Use Technology The survey identified the Top Concerns for why biopharmaceutical manufacturers are choosing to increase their use of disposables: 1. Eliminating cleaning requirements 88.9% 2. Reduce time to get facility up and running 87.5% 3. Reduce capital investment in facility & equipment 86.3% 4. Faster campaign turnaround time 83.2% 5. Decrease risk of product cross-contamination 80.6% 6. Flexibility of a modular approach 78.6% SOURCE: BioPlan Report and Survey of Biomanufacturing Capacity and Production, 2015

13 Single Most Important Biopharma Trends Pictured Left: Single most important biomanufacturing trends or operational areas on which the industry must focus its efforts, Note: Single-Use Systems: Implementation and Integration, was noted as one of the top 5 most important biopharma trends for SOURCE: BioPlan Report and Survey of Biomanufacturing Capacity and Production, 2017, Preliminary Results

14 Unit Operational Use of Disposables Pictured Left: Applications in Biopharmaceutical Manufacturing: % Using Single-Use Products (including all stages of R&D or Manufacture, 2017). Note: quantities for these products were not indicated in the survey question, only any incidence of usage at any stage. Thus, while any usage and the number of purchasers for these products may be increasing substantially, these data do not provide information on the volume of sales increases. SOURCE: BioPlan Report and Survey of Biomanufacturing Capacity and Production, 2017, Preliminary Results

15 Capacity and Industry Trends - Volume Overall, the industry currently considers 2,000L to generally be an optimal size, in terms of cost-effectiveness for mammalian cell culture bioreactors Stainless steel bioreactor-based systems at the 1,000L scale are becoming costly and too much work in terms of upfront investment and infrastructure, compared to single-use systems Single-use systems are already significantly beating out fixed stainless steel-based systems on economics and flexibility, particularly for manufacture of R&D and clinical supplies The trend going forward is to use multiple disposable 2,000L bioreactors SOURCE: BioPlan Report and Survey of Biomanufacturing Capacity and Production, 2015

16 Capacity and Industry Trends - Titer Current industry yields are trending at >3 g/l Most mab commercial manufacturers will likely be rather satisfied consistently attaining production yields on the order of 3 g/l; at least until downstream operations improve to better handle higher-yield bioreactor output, including resolving aggregation and other problems associated with higher titers This 3 g/l is currently becoming a reference standard for single-use system-based mab manufacture at 1,000-2,000 L scale At this rate, a single 1,000 L bioreactor (fed-batch or equivalent more continuous culture) production run can provide ~3,000 g of protein per run Even at a low potency of 100 mg/dose, this provides about 30,000 doses Presuming this is a relatively inexpensive antibody, selling for only ~$1,000/dose, this provides $30, revenue. SOURCE: BioPlan Report and Survey of Biomanufacturing Capacity and Production, 2015

17 CURRENT SUT USES IN THE INDUSTRY

18 Examples of Current Uses in the Industry (GMP) Spinners Disposable Bags Columns Sampling Containers Mixers Images Courtesy of: Sartorius Stedim, Millipore, and Corning

19 Examples of Current Uses in the Industry (GMP) Hydration Media Prep Buffer Prep Mixing Transportation, Storage & Shipping Substantial savings in Labor, Water, turn around time for set up break down. May aid in major debottlenecking efforts Courtesy Thermo / Millipore

20 Examples of Current Uses in the Industry (Development Downstream Processing) Coriolis Flow Meter GEHC Akta Ready AlphaBio ABS0333

21 Examples of Current Uses in the Industry (Development Downstream Processing) Repligen OPUS (20mL 60cm) GE ReadyToProcess (1L 20L) Life Technologies GoPure (5mL 6.3L) Images courtesy of: RepliGen, GE, and Life Technologies

22 VENDORS EXPECTATIONS

23 Supplier Expectation Hierarchy Basic Fundamentals Differentiators Innovation Total Cost of Ownership Service Quality/ Regulatory Compliance Assurance of Supply

24 Strategic Relationships Expectations of a Strategic Supplier Right First Time Reliability of Supply Predictability in processes and results Business continuity, effective management of inherent risks Year-over-year productivity improvements Innovation

25 CHALLENGES AND OPPORTUNITIES

26 New technologies are great, but it takes time and resources to implement them A coordinated and strategic approach across the company towards is key in order to set guidelines for the implementation of disposables SUT Bulk Freeze Applications are no Exception

27 Critical Aspects and Challenges Managing and Harmonizing Single-Use Technologies Single-use technologies have become a complex component of operations Requires coordination of many factors such as: Raw material attributes, COA qualifications Film design / composition, Testing and verification of the raw material and final film, Functional performance of the assemblies Large Companies need the ability to focus on strategy and network Globally harmonize sites that may be operating independently Coordination, management, and harmonization of Single-Use Technology (SUT) practices across company sites requires a global strategy: Adoption of SUT is often done without a Network Strategy - can lead to: Duplication, missing out on lessons learned, and without a strategic purpose. Some SUT projects being implemented in a non-coordinated manner from Site to Site and between PD and Operation Site-specific adoptions are done in isolation from the network

28 Single-Use Materials are Complex Example: Film Composition Requires understanding of many factors such as: Film design and composition Outer Layer, e.g. EVA, ULDPE Inner Layer, e.g. PE, EVA Testing of raw materials and final film Outer layers may also impact compatibility and E/L of final film Images Courtesy of: Sartorius Stedim

29 Single-Use Materials are Complex Example: Film Extrusion Image Courtesy of: Eastman Chemical Company

30 Critical Aspects / Challenges Film Quality Particle Risk Potential to contaminate final dosage Process w/out final filters Final fill Film Extrusion / Clean room assembly ISO 7 ( class 10,000 / Grade C) Additives Polymers, stabilizers, antioxidants, anti-static agents Extrusion mold release agents Leachables final product Migrants in process leachables Extractables potential leachables (exaggerated dissolution conditions) Raw materials and component suppliers

31 Compliance Concerns in Industry Understanding FDA / RHA expectations Design / validation of the disposable - what are the procedures for broken bags, refiltrations, etc, and have those been extensively tested? (EHS/Employee safety) Microbial control element, how are bags sterilized, containment assured, and sampling conducted Vendor and User site? Impact of extractables and leachables and to that point - What amount of stability testing and or product quality impact testing does a specific molecule have with the proposed disposable. Global registration considerations: change in the US, must also be approved by countries throughout the world. This can take considerable time so: Supply chain needs to be brought into the picture early so that bridging stocks can be created and maintained Differing levels of acceptance novel technologies or process changes globally. Time lines need to managed when proposing a change. Overall message - each product team needs the appropriate time to evaluate changes on a global level and to plan for its implementation

32 MOC Qualification - High-level Overview Milestones & Costs Est. Timelines: Months 3-6 Months 2 Months High-Level Process Steps: (SOP 1190) Acceptability of Film for General Use (Stage 1) Compatibility with Intended Process Use (Stage 2) CoA Verification (Stage 3) Material Suitability Microbial Integrity Extractable Study Toxicological Evaluation Chemical Compatibility Leachable Study Toxicological Evaluation Verification that the bioprocess bag received matches what is specified in the specification Estimated Costs: ~$150K USD ~$90K USD ~$5K USD Key Takeaways: The process to introduce new films can take up to 26 months and cost up to $400,000 USD due to: Extractable & Leachable studies (if the vendor has not qualified per our procedure)4 Toxicological Evaluation Ownership by sponsor at Roche (technical SME to Shepard process). SOP updates, Validations for MOC, Regulatory filings / SUT evaluations Courtesy of Jon Miller, Procurement

33 Critical Aspects / Challenges Standardized Extractables Testing Roche is a member of the BPOG group BPOG member companies have collaborated to define a standardized extractables testing protocol Provides common understanding of BPOG consensus position on the application of the standardized extractables protocol in practice The output resources and information is specially tailored for Single Use Suppliers (SUS) Contract Research Organizations (CROs) Regulators

34 WHAT IS NEXT FOR SUT FLEXIBLE FACILITIES?

35 Background Single-use bioprocessing technology is a rapidly evolving technology that focuses on the application of disposable bioprocessing equipment and accessories for biopharmaceutical manufacturing The central idea behind the usage of single-use bioprocessing technology is to decrease the cost associated with complicated steps such as cleaning, sterilization, and maintenance of steel-based bioreactor systems This technology is used in a broad range of biopharmaceutical applications such as filtration, mixing, purification, upstream expression, storage, and separations The use of disposables in flexible modular facilities will impact where biopharmaceuticals can be made geographically, enabling production wherever assets can be best utilized and production costs minimized SOURCE: Global Single-Use Bioprocessing System Market

36 High-Level Vision of Manufacturing at Roche SOURCE: How to Manufacture Small Volume Products, Slide Courtesy of Jim Miller, PTB Admin, 2012

37 Overview of Biopharma SUT Market Trends The trend towards adoption of single-use equipment continues, with rapid changes in this market projected Single-use equipment, particularly for upstream manufacture (e.g., bioreactors), now thoroughly dominates pre- commercial, i.e., small- to mid-scale R&D and trials supply manufacture, while fixed stainless steel equipment continues to dominate commercialscale manufacturing There will be incredible growth in the single-use systems revenue as these systems start to be used for commercial manufacture The potential of disposable systems to reduce expensive infrastructure and operational costs can help move toward creating flexible facilities in Emergent Global Markets

38 Facility of the Future As the drive towards more targeted therapies with smaller niche populations continues, biopharmaceutical manufacturers will need to produce a larger number of products in the same facilities with more changeovers Disposables allow a significantly reduced capital outlay, lowering the risk associated with building these facilities The use of disposables in flexible modular facilities will impact where biopharmaceuticals can be made geographically, enabling production wherever assets can be best utilized and production costs minimized SOURCE: BioPlan, Report and Survey of Biopharmaceutical Manufacturing Capacity and Production, 2015

39 Introduction to the Modular Approach Incremental innovations Current state Disposables Modular flexible plants 50% the start-up time 30% less invest GE s KUBio G-Con s FlexMoSys

40 Modular Approach May Improve Response to Changes in Network Demand Background Modular pharmaceutical manufacturing involves setting up small, modular manufacturing units closer to customers/ demand Such systems are currently in development - including GE Kubio (Xcellerex) modular plant Estimates on efficiencies delivered in such processing suites include: 30-40% footprint reduction 50% less energy usage 40% less total CAPEX project cost On paper more applicable for supply networks for fragmented product portfolio and volatile demand The advantage is that a site is engineered by replicable self-stending cells that can be replicated rapidly to scale to demand Potential impact Provides opportunity to bring additional flexibility and capacity into the supply chain to meet pockets of emerging demand

41 Three Main Technologies Influencing Facility Design Rightsizing capacity Margin pressure Technologies Modularity Low relevance Disposables Medium relevance Continuous production High relevance Trends Increasing quality oversight Proximity to end markets of supply sources Greater flexibility Smaller batch sizes Takeaways Modularity, by definition, is relevant across each trend Disposables can be highly beneficial in low volume settings to alleviate margin pressure and allow proximity to end markets or supply sources while controlling for quality Continuous production is geared at achieving improved margins

42 CASE STUDY #1: [2x1000L New Facility] Textbook Example of SU vs. MU Investment Costs Pictured below: Comparison of investment costs for Single-Use (SU) and Multiple-Use (MU) facilities. Multiple-Use Option Capital $ 42 M Single-Use Option Capital $ 31M Choosing the SU option saves 11M (27%) in investment costs SOURCE: Single-Use Technology in Biopharmaceutical Manufacture. Eibl et al, 2011

43 CASE STUDY #2: [2x1000L New Facility] Textbook Example of SU vs. MU Running Costs Pictured below: Comparison of running costs per year for Single-Use (SU) and Multiple-Use (MU) facilities. Multiple-Use Option Running Cost 8M Single-Use Option Running Cost 9M It costs 1M more per year to run SU facility, due to consumables SOURCE: Single-Use Technology in Biopharmaceutical Manufacture. Eibl et al, 2011

44 CASE STUDY #3: [1x1000L Retrofit] Disposables at the Genentech Clinical Plant The implementation of disposables (bulk freeze containers and buffer hold bags) at the Oceanside Clinical Plant (OCP) generated the following annual savings: $60,000 in direct labor time in set-up and cleaning of stainless steel tanks $250,000 in WFI generation costs $7,259 in savings of >900 L of CIP 100 and >400 L of CIP million liters of WFI saved by lowered rounds of CIPs > 20 metric tons of CO2 carbon footprint reduction SOURCE: Disposables Manufacturing Strategies - Impact on Design, Operations, and the Environment, Adam Goldstein, 2009

45 CASE STUDY #4: [3x2000L New Facility] BioSolve Software Evaluation of MU vs. SU Multiple-Use Option Capital $ 60.6 M CoG $/g Single-Use Option Capital $ 43.3M CoG $/g Choosing SU Option saves $17M in capital investment, and saves 30 $/g in CoG SOURCE: Techniques for Evaluating SUT Cost Analysis, Biopharm Services Slides, 2010

46 CASE STUDY #5: [6x2000L New Facility] Merck Evaluation of 6x 2KL facility Pictured above: Merck evaluation of 6x2000L finds that SU Facility can be cost favorable. SOURCE: Economics of Continuous Processing vs. Traditional Batch, Merck Slides, 2015

47 Merck Presentation on Modular Design SOURCE: Economics of Continuous Processing vs. Traditional Batch, Merck Slides, 2015

48 Merck Presentation on Modular Design SOURCE: Economics of Continuous Processing vs. Traditional Batch, Merck Slides, 2015

49 DESIGN CONCEPTS

50 The Ballroom Concept Definition: The ballroom concept refers to a large manufacturing area that has no fixed equipment and minimal segregation due to the use of functionally closed systems Pictured Left: 3D Model of a Ballroom Type Facility Although the minimal segregation seen in the ballroom concept is beneficial in some ways, it is not recommended due to present regulatory concerns. SOURCE: Pharmaceutical Engineering Magazine, Lessons Learned in the Ballroom, David Wolton, 2014

51 The Dance Floor Concept Definition: The dance floor concept is similar to the ballroom concept, but is a smaller and more defined space that is to be considered as an alternative to the ballroom concept As of September 2015, the following three (3) biopharmaceutical companies are working with David Wolton to build facilities implementing the Dance Floor Concept: Two (2) multinational biopharma companies based out of the EU One (1) biosimilars manufacturer in India Pictured Left: View of the dance floor (a) 3 x 2,000 L bioreactor suite (b) Buffer/media preparation areas The dance floor concept features the following: -Leaner: minimal movement of totes, just in time production of media and buffer -Smaller: only space provided for ergonomic access, close proximity of all associated equipment, vertical height utilized -Standardized: use of standardized disposables minimizing errors and simplifying training -Reliable: defined tubing routes, static equipment SOURCE: Pharmaceutical Engineering Magazine, Lessons Learned in the Ballroom, David Wolton, 2014

52 Box in Box Concept

53 Example of a Roche Disposables CMO SOURCE: Avid as Disposable Biologics Manufacturing Partner, Slides, 2015

54 Example of a Roche Disposables CMO SOURCE: Avid as Disposable Biologics Manufacturing Partner, Slides, 2015

55 Example of a Roche Disposables CMO SOURCE: Avid as Disposable Biologics Manufacturing Partner, Slides, 2015

56 Acknowledgements Global MSAT Sumaiya Lee Oliver Molina Michelle Wong Sherina Malkani Andy Brewer Eric Ng Process Development Ekta Mahajan Quality Audra Mathews Trishna Ray Chaudhuri Corporate Engineering Carl Johnson Procurement Tara Ponce Marion Glenn Bulk Freeze team Justin Bourret Eric Ng Mark Nolden Ferdinand Alte Nina Xiao

57 Questions Adam Goldstein Global Mfg Sciences Genentech Inc, A Member of the Roche Group Goldstein.Adam@gene.com

58 Doing now what patients need next

59 ASTM Shipping / Transportation over view Page 59

60 Testing at Full Scale - ASTM Movies of Testing