BDDW Mar15
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Dr. Matthew Cheeks of Polpharma Biologics discusses upstream processing considerations for an emerging biosimilars business. He covers balancing development costs and timelines, accelerating development through managing quality risks, and sustaining progress with scalable manufacturing and process robustness. Two case studies demonstrate how Polpharma evaluates cell lines and makes objective, data-driven decisions to develop biosimilar products in a competitive business environment.
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BDDW Mar15
- 1. Upstream Processing Considerations In An Emerging Biosimilars Business Dr. Matthew Cheeks Head of Upstream Processing POLPHARMA BIOLOGICS 4th March 2015 Biosimilar Drug Development World
- 2. Disclaimer • All statements in this presentation are based on the current expectations of the Polpharma Biologics group • Where forward-looking statements are made no assurance should be taken that expectations will be achieved • All slides in this presentation are incomplete without verbal comments • Polpharma Biologics has no obligation to update the statements contained in this presentation 2 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 3. Content Overview • Background • Meeting the challenges of USP in a competitive business environment • Covering the fundamentals • Accelerating development • Sustaining progress • Summary • Acknowledgements 3 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 4. BackgroundBackground Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business 4
- 5. Background Polpharma Biologics • Established in 2012 • Privately owned • 2500 m2 laboratory space located in Poland • Comprehensive range of development and manufacturing services • Focused on biosimilars 5 Integrated Labs on the Ground Floor R&D Meth. Dev. R&D Gen. Lab Analytical Lab. Supp. Rooms Pilot Plant GMP Admin. Common Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 6. Background Not all proteins were created equal… • Chemical stability and post-translational modifications drive protein heterogeneity • Associated clinical effects are very complex • Highly similar analytical and PK/PD data correlates with lower risk of clinical differences Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business 6
- 7. Background Barriers in the biosimilars business Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business 7 Understanding: product and process, potency, identity, purity and safety Definitive data for efficacy and safety Final Stability In depth product characterization Structural and functional product characterization (Orthogonal, quantitative and sensitive)
- 8. Background Philosophy on being competitive • Manufacturing must be founded on sound science and engineering principles • Embracing innovation allows substantive progress • Scalability, responsiveness and speed • Navigate uncertainty by applying corporate values and vision • World class performance expected from world class resources 8 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 9. Agenda 9 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 10. Overview • Covering the fundamentals • Begin with the end in mind • Balancing USP costs and time • Case study 1 • Accelerating development • Managing the risk to quality • Case study 2 • Sustaining progress • Process robustness and scalable manufacturing 10 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 11. Covering the fundamentals Begin with the end in mind 11 • The innovators mechanism of action (MoA) is fundamental • Hard limits to ‘biosimilarity’ • Sourcing location, expiry dates and number of lots determine flexibility • Analytical method integrity & capability, overall panel of methods selected as well as the results obtained determine reliability Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 12. 12 • Expect substantive shifts in product characteristics predominantly through cell line selection • Limits to altering media/feed composition or setpoints • What cannot be changed? • Cell lines and processes together determine manufacturing success • Assess range of cells lines • Assess range of platform processes Covering the fundamentals Balancing USP costs and time Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 13. 13 • Predefined templates and decision algorithms optimize: • Selection of the right CMO partner • Evaluation and ranking of cell line potential • Seamless process transfer Covering the fundamentals Balancing USP costs and time Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 14. Case study 1 • Product Type: • IgG4 antibody • Mechanism of Action: • Binds target and prevents subsequent immunological activity • Originator’s cell line: • Hybridoma 14 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 15. Case study 1 15 • Systematic assessment of potential solutions offered by CMO partners Step 1 Step 2 Step 3 6 CMOs Engaged 3 CMOs Progressed 1 CMO Advanced Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 16. • Cell line potential systematically evaluated throughout development via decision points 16 Decision Point 1 – Pool material proximity to CQA’s Product concentration Decision Point 2 – Clone Material characterization. Monoclonality. Decision Point 3 – Clone stability study Decision Point 4 – material characterization Manufacturability Case study 1 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 17. Case study 1 • Changes in ranking along the development lineage of a lead clone 17 Quality Attribute Early Development (pools) Mid Development (Clones & Flasks) Late Development (Reactors & Processes) Potency Glycosylation Isoform Distribution Objective and Quantitative Decision Making (Cell, Process and Product Understanding) Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 18. Lessons Learned: Covering the fundamentals? • Seek deep understanding of product MoA • Reliability and flexibility in USP development • Reference material • Candidate cell lines • Manufacturing platform processes • Robust, templated, methods permit objective and effective decision making 18 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 19. Overview 19 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 20. Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business Accelerating development Managing the risk to quality 20 Section 2 • Product specific data from the clinic limited during early phases of process development • Careful consideration of analytical data • How do combinations of quality attributes exert a clinical effect? • Which assays ought to be used for measuring critical quality attributes? • Comprehensive assessment of risk • What to include at the clone selection stage?
- 21. Case study 2 • Product Type: • IgG1 antibody • Mechanism of Action: • Binds target and prevents subsequent immunological activity • Originator’s cell line: • Hybridoma 21 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 22. Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business Forward Processing Criteria Pass / Fail MoA and CQA’s Product Concentration Platform Process Cell line Analytical Methods 22 Case study 2
- 23. 23 Case study 2 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 24. Lessons Learned Managing the risk to quality • Mechanistic understanding of possible immuno- pharmacological effects in clinic must feed into development decisions • Go / No Go decisions based on scientific evidence • Robust, templated, methods permit objective and effective decision making 24 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 25. Overview 25 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 26. Sustaining Progress Scalable manufacturing then process robustness 26 Section 3 • Process control • Process performance Demonstrable comparability between the lab scale and manufacturing scale bioreactors first Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 27. Sustaining Progress Advanced quantitative methods • Prerequisite for mapping the design space for scale down activities • USP focus on the macro and micro-environment of the cell culture • Requires understanding effects from: • Hydrodynamics • Mass Transfer • Geometric design • Materials of construction • Heterogeneity from the cell culture 27 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 28. Sustaining Progress Automation with disposables in R&D • Faster high resolution mapping of the process design space via robotics • Cell line development • Earlier more consistent readouts of PQ from candidate cell lines • Enhanced media and feed formulations • Enhanced process characterization • Earlier identification of multifactor interactions in cell culture processes 28 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 29. 29 • Fast and reliable experiment design, execution, analysis and evaluation • Powerful tool for exploring and navigating experimental space Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business Sustaining Progress DoE methods improving understanding and optimization of manufacturing processes
- 30. Agenda 30 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 31. • Clear corporate values and vision • Application of state of the art technology, expertise and global quality standards • Sound science underpins the reliability and flexibility of USP work • Optimised, evidence based, quantitative decision making approaches allow sustained improvements, reducing the risk for failure 31 Summary Finding the Right Upstream Processing Solutions In An Emerging Biosimilars Business? Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 32. Acknowledgements • Piotr Zien • Rafal Derlacz • Klaus Martin • PB’s Analytical Technical Development Team 1 2 3 5 7 8 9 10 4 (PBU)* Pharma Business Unit (FCBU)** Fine Chemicals Business Unit 6 32 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
- 33. Time allowed for questions <<<Dziękuję and Koniec >>> 33 Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars Business
Editor's Notes
- Thank you for the kind introduction. And I want to thank the organisers for opportunity to speak today. This is my first BDDW conference and I am delighted to be with you.
- But before we begin I must provide you with this disclaimer. Which essentially states that Polpharma will not be held to account should you decide to engage in any financial activiites based upon the information you hear today.
- Okay, So I selected the title – upstream processing considerations in an emerging biosimilars business really because I wanted - to tell you a story about some tremendous progress which is being made at Polpharma - You see I moved from the highly efficient and structured world of the CMO industry into a small startup environment and ever since I have been actively building out capabilities and I want to share some of the insights I have gained from those activities with you. - To begin the presentation I will provide some brief background to Polpharma. - Then I will then detail some of the fundamentals which have enabled the progress I mentioned earlier, then move into a few examples of how we have been accelerating development and then wrap up with some information on how we plan to sustain progress - With that information in hand we will then progress on to the presentation summary then wrap up with some acknowledgements to those who have contributed, without whom this presentation would not hae been possible.
- Okay Background
- Where we begin. Why do I describe it as emerging?
- - The challenge of the biosimilars business means demonstrating no clinically meaningful differences, in terms of safety and efficacy, between the reference and your proposed product. - However as we all know not all proteins were created equal, chemical stability together with Post translational modifications drive the enormous potential for heterogeneity, seen in industrially produced recombinant proteins . - Apriori Understanding the clinical effects imparted from this heterogeneity is very complex and exteremly expensive. But that challenge is not impossible, because the pursuit of highly similar analytical and PK/PD data is a known route to success
- - This slide provides a diagramittic illustration of the challenges along that route. Where at the early stages one must be acutely focused on Analytical work. In aprticular structural and functional characterization. Followed by … But behind all that from the USP perspective lie a number of key challenges. And these challenges must be answered.
- So from the standpoint of entry into the biosimilars industry – there is quite a daunting challenge. But we beliee that we can be competitive and the key to that lies in the philosophy we are taking to work each day. That is to say – Manufacturing must be founded on sound science… - Additionally Big strides forward as only beign possible by embracing innovation. In particular technologies which are possible to scale, which are flexible and those which are fast (capable of shortening timelines) But moving beyond this we recognize that their will be times of uncertainty, and to prevail under such conditions we believe a strong corporate vision and values are required. - AT Polpharma what we say is …
- Okay with the background in hand I want to now take you to the body of the presentation.
- Here we can see what I will be presenting in detail. Firstly, in the USP fundamentals section I want to really highlight some of the basic foundational information required for USP work. In this section I will also present key part of the USP strategy which has enabled us to balance our costs whilst not sacrificing productivity. I will highlight some key lessons in a case study also. The Next section will focus on how the USP team has been accelerating its efforts at development With specific reference to how we have been managing the risk to quality I will also present a case study here to demonstrate key lessons The final section, sustaining progress in an emerging biosimilars business will focus on what it takes to achieve process robustness and scaleable manufacturing.
- When we launch our USP program we have basic tenets which we try to adhere to: I wil lshare these with you. The end point for USP is being as close to biosimilairty as possible and it is critically important to understand where that goal is. Typically one assumes that the goal comes from CQA analysis, which is partly true but a precursor of this is obtaining deep understanding of the innovators MoA. I really cannot stress how important this is. Another very important realisation for us is that there are Hard limits to the goal and these are found through actual analytical experimentation on reference product So then… Flexibility in USP is a function of … Reliability of USP development work is …
- Another fundamental tenet of our USP work is that we expect cell line selection to be the major opportunity for influencing program feasibility. There is quite a lot of talk about what process setpoints alterantions, or atlternatively modifications of the media/feed comptisions can do, but its important to know how much can be changed. Perhaps even more so, what cannot be changed. Lastly once a suitable cell substrate has been identified the focus for us becomes integrating the cell line into a valueable manufacturing process. The take home message from all of this has got to be then. Assess a range of cell lines Assess a range of platform process to maximize chances of manufacturing success.
- To help navigate the uncertainties of cost and time associated with USP, Polpharma uses structured decision making tools. We use the tools to screen the potential utility from a large numbers of cell lines and process offered by CMO’s. Other key areas where these tools have proven exteremly value is in the area of cell line selection together with process transfer.
- To emphasize some of the key points Ive just mentioned I put together a Case study for illustration. What we are talking about here is a project focussed on …
- As mentioned we systematically screen potential solutions. This is a simple algorithm which quantitatively ranks and assesses CMO partners on the basis of a broad panel of criteria The tool provides us with a recommendation to engage a particular CMO service provider based on our predefined requirments .
- In this particular study we progressed all the way to the end of the cell line construction. I want to highlight that we assured active involvement in the development process by insisting on the incorporation of decision points into the program at key stages.
- And at the end of the program here is the tale of the tape. Ive produced a table here to illustrate the extent of change which was experienced along the development lineage for the lead clone. As it happened the ancestor pools did not produce product which was within the hard limits referred to earlier. But as it progressed through flasks and eventually into the bioreactor its true colours shone through and we What I really want to point out here is that we could have lost this clone. It was the application of objective and quantitative decision decision making tools which really made the difference.
- Summary key points from this section. Basic ground work in USP means seeking Together its the variety of the reference material, candidate cell lines and manufacturing processes which determine the reliability and flexibility of USP development And perhaps most importantly the adoption and application of optimized decision making methods is essential for efficiency.
- High uncertainty requires careful identification of surrogate analytical data, together with a sound assessment of risk. So the question then becomes which attributes to assay during development. Comprehensive assessment of risk supporting development decisions Here is a tool which we have used to help us navigate through clone selection.
- Advanced quantitative methods used for characterising Process Design Space and Scaling Models Precise Replication of the macro and micro-environment of the cell culture required during scaling.
- Automated miniaturized bioreactor systems allow more comprehensive exploration of the design space through experimental methods based on advanced statistics Enhanced assessments (faster, broader and more precise) of the desirability among more candidate cell lines
- Plan is to Tell you the story of how we arrived at these simple principles