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Upstream Processing Considerations In An Emerging Biosimilars Business

Dr. Matthew Cheeks

Head of Upstream ProcessingPOLPHARMA BIOLOGICS

4th March 2015Biosimilar Drug Development World

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

2Matthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars

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Content Overview

• Background• Meeting the challenges of USP in a competitive

business environment• Covering the fundamentals• Accelerating development• Sustaining progress

• Summary• Acknowledgements


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BackgroundBackgroundMatthew Cheeks / Polpharma Biologics Upstream Processing Considerations In An Emerging Biosimilars

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BackgroundPolpharma Biologics

• Established in 2012

• Privately owned

• 2500 m2 laboratory space located in Poland

• Comprehensive range of development and manufacturing services

• Focused on biosimilars

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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

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


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Background Barriers in the biosimilars business


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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)

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


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Agenda


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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


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Covering the fundamentalsBegin with the end in mind

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• 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


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• 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 fundamentalsBalancing USP costs and time


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• Predefined templates and decision algorithms optimize:• Selection of the right CMO partner• Evaluation and ranking of cell line potential • Seamless process transfer

Covering the fundamentalsBalancing USP costs and time


Case study 1• Product Type: • IgG4 antibody

• Mechanism of Action: • Binds target and prevents subsequent

immunological activity• Originator’s cell line:• Hybridoma


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Case study 1

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• Systematic assessment of potential solutions offered by CMO partners

Step 1 Step 2 Step 3

6CMOs

Engaged

3CMOs

Progressed

1CMO

Advanced


• Cell line potential systematically evaluated throughout development via decision points

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Decision Point 1 – Pool material proximity to CQA’sProduct concentration

Decision Point 2 – Clone Material characterization. Monoclonality.

Decision Point 3 – Clone stability study

Decision Point 4 –material characterization Manufacturability

Case study 1


Case study 1• Changes in ranking along the development lineage

of a lead clone

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Quality AttributeEarly

Development(pools)

Mid Development

(Clones & Flasks)

LateDevelopment

(Reactors & Processes)

Potency

Glycosylation

Isoform Distribution

Objective and Quantitative Decision Making

(Cell, Process and Product Understanding)


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


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Overview


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Accelerating developmentManaging the risk to quality

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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?

Case study 2

• Product Type: • IgG1 antibody

• Mechanism of Action: • Binds target and prevents subsequent

immunological activity• Originator’s cell line:• Hybridoma


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Forward Processing Criteria

Pass / Fail

MoA and CQA’s

Product Concentration

Platform Process

Cell line

Analytical Methods

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Case study 2

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Case study 2


Lessons LearnedManaging 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


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Overview


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Sustaining ProgressScalable manufacturing then process robustness

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Section 3

• Process control

• Process performance

Demonstrable comparability between the lab scale and manufacturing scale bioreactors first


Sustaining ProgressAdvanced 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


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Sustaining ProgressAutomation 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


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• Fast and reliable experiment design, execution, analysis and evaluation

• Powerful tool for exploring and navigating experimental space


Sustaining ProgressDoE methods improving understanding and optimization of manufacturing processes

Agenda


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• 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

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SummaryFinding the Right Upstream Processing Solutions In An Emerging Biosimilars Business?


Acknowledgements

• Piotr Zien

• Rafal Derlacz

• Klaus Martin

• PB’s Analytical Technical Development Team

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(PBU)* Pharma Business Unit(FCBU)** Fine Chemicals Business Unit

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Time allowed for questions

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bddw mar15

Documents

polpharma biologics

forwardlooking statements

clinical effects

safetydefinitive data

equalchemical stability

current expectations

world class resources

pkpd data correlates