Professor Charles Cooney of MIT An Integrating Framework for Continuous Bioprocessing

AN INTEGRATING FRAMEWORK FOR CONTINUOUS BIOPROCESSING Prof. Charles L. Cooney Department of Chemical Engineering MIT Cambridge, MA USA 3rd International Symposium of Continuous Manufacturing 3-4 October 2018 London 1

Opening Question in the soliloquy To be continuous or not to be? – that is the question

Followed by :

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Seeking a Framework for Advanced Manufacturing of Biologicals An Exercise in Sense Making

WHY WHAT HOW

• WHY do we want to change what we do now?

• WHAT is happening in the lab, process development and manufacturing and WHAT do we want to achieve?

• What is the vision for advanced manufacturing 4.0 and the Factory of the Future to meet industry needs?

• HOW will we implement change?

• Technology lens • Regulatory lens • Business lens

• Is there resistance to change?

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From Both Sides Now Joni Mitchell, 1967

I've looked at clouds from both sides now From up and down and still somehow It's cloud's illusions I recall I really don't know clouds at all

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Is there clarity in your GOAL vs.

A ASPIRATIONS? MATTER OF

IT IS PERSPECTIVE

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WHAT IS THE GOAL IN PHARMACEUTICAL/BIOTECH MANUFACTURING?

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A journey into uncertainty is embracing risk We begin with an ASPIRATION

Ama Dablam, 7,000 m, 7 Khumbu Region, Nepal

Clarity in your GOAL as you embrace & manage risk along each step of the journey

Approaching Ama Dablam Summit at 7,000 m 8

The GOAL of pharmaceutical manufacturing is the sustained delivery of a quality (safe and efficacious) product to the patient

Delivery to the Patient

Sustain the Business

Value Cycle a Framework for Innovation and Operation Corporate R&D Funding

Clinical Trials & Regulatory Approval

Invention

Scale & Manufacturing

Preclinical Development

Basic Research

Proof of Mechanism

IDEA Unmet Medical Need

Supply Chain

Patient Use Profit

Reinvest in Research & Return to Investors

Patient Population

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State of the Industry Health Care Pricing Pressures

Patent Expiration

BIOTECHNOLOGY & PHARMACEUTICAL INDUSTRY

Low R&D Productivity

Rx Dynamics & Precision Medicine 11

Extending a Platform

Delivery of Differentiated Products to the Patient

Fusion Proteins MAB

BsMAB ADC Biosimilars

We know how to do this but we can do it better

Biobetters 12

Disruptive Technologies The New Modalities

• Gene Therapy

– Replace protein replacement therapy – Repair thru gene knockdown and regulation

• • • • •

Immune regulation Gene editing RNA therapeutics (siRNA, mRNA) Microbiome Cell Therapy

Do we know how to do this?

– Replacement or repair – Regenerative medicine

We must consider the future of New Therapeutic Modalities 13

Core Principles in a Vision for Advanced Manufacturing • Manufacturing lies on the critical path between science and the patient • Markets will be larger or smaller volume but with uncertain demand • One must assure adequate supply by indication and market geography • Regulatory guidelines provide the grammar and analytics the vocabulary for communication across the value chain • Safety and Efficacy, aka Quality, are sacrosanct • Profit from product sales must support business continuity and future product development 14

WHY Change?

What is the problem and thus, value proposition?

• Competitive dynamics are changing with generic (biosimilar) and therapeutic substitution – Therapeutic Commoditization • Accelerated regulatory protocols require speed in process development • Pricing pressure creates COGS pressure • Many new products are aimed at specialty, aka smaller, markets and one needs agility across scale • Product portfolios require flexibility to meet market needs • Emerging markets are maturing - China is No. 2 and RoW is growing at >15% 15

Historical Perspective to Meet Product Demand – Industrial Evolution • Industrial Intensification – – – –

Steel Chemicals Food Pharmaceuticals

Batch

• Driven by business need – – – –

Need to reduce cost Desire to decentralize manufacturing Robust quality Flexibility to meet product demand

Continuous or Integrated 16

Lesson 1

It is about the Business Case Change is driven by the value proposition and the business case – Speed – time to clinic, tech transfer, process productivity, RTR, scale-up – Quality – reduction in CQA variance, robust process performance – Cost – CapX, OpX, RoI, Cost of Quality, Inventory – Flexibility – multiple products in pipeline, Speed uncertain demand to support clinical and Cost commercial, agility in supply

Quality Flexibility 17

WHAT do we want to achieve?

• The primary driver for change is the Business Case – Increased capacity from installed or new facility – Faster time to clinic and market – Reduced COGS – Flexibility in meeting demand – Managing tech transfer (expansion, CMO, partner) – Decentralized manufacturing to address new markets 18

There are Constraints to Change • Installed & depreciated capacity – Need for new CapX

• Aging workforce

– Technical and operational competency

• Management mindset – prior experience, organizational structure and cognitive bias • Regulatory affairs vs. Regulatory agencies

– Does regulation reinforce status quo or reward innovation?

– Managing historic and modern manufacturing – Is the interface fit-for-purpose?

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Lesson 2

It is not about continuous manufacturing

3 I

Innovation is NOT Continuous Bioprocessing BUT Intensification, Integration and Interrogation to meet delivery of drug product to the patient The HOW is implementing Intensification, Integration and Interrogation to address the business need 20

WHY Intensification & Integration • Enhanced kinetics à faster synthesis, slower degradation and fewer by-products • Increased productivity à Smaller size • Integration across the process à Simplicity • Single-Use Technology à Faster set-up • Connected & Closed à Aseptic operation • Sensors & Automation à Robust quality 21

Attributes of Process Intensification

Speed Cost Quality Flexibility

• Increasing the Capacity across each unit process with reduced foot print, CapX and OpX • Process productivity and capacity • Shorter time to clinic and launch • Reduction of residence time to reduce CQA variance • Implementing QbD to facilitate change

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Attributes of Process Integration

Speed Cost Quality Flexibility

• Simplify to process design & operation • Cell retention to enable extended fed-batch and perfusion to increase productivity • Interface perfusion to continuous capture • Take advantage of flow thru purification and formulation • Implement PAT and global process control • Operate with smaller footprint, lower CapX & OpX and modular design • Reduced QC labor & cost

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Transition from traditional to CB Media

Bioreactor

Reduce Reduce

Harvest Hold

Clarification

X

X

Clarified Harvest

Protein A Capture

X

Intermediate Purification

Reduce

Polish

X

Reduce

Reduce

Current technology: fed-batch or perfusion • Efficiency • Simplicity • Flexibility • Quality • Cost • Facility • Mobility • Standardization

Viral Inact

X

Unform DS

Reduce

New platform Purified Product

Media Continuous

Small footprint Source: Konstantin Konstantinov

Small, flexible, portable multi-product facility International Symposium on Continuous Manufacturing of Pharmaceuticals MIT, May 20-21, 2014

Attributes of Process Interrogation • A product is defined by its CQAs

Speed Cost Quality Flexibility

– Do we known them, can we control them?

– How does variance impact the patient experience?

• Sampling, sensing, interpreting and learning to improve • Building first principle process models to facilitate process change • Implementing Machine Learning • Implementing PAT for monitoring and control to assure process and product (CQAs, CPPs) and compliance • Enable RTR from the process 25

Lesson 3

The regulatory process provides a path to the patient Analytics are the Vocabulary and Guidelines are the Grammar

CMC Application: Data Design QMS Answers

Based on scientific data

OR

Regulatory: Framework Guidelines Experience Capability Questions

Based on patient needs Four regulatory agencies cover the major markets: FDA, EMA, PMDA & CFDA

Enabling the HOW The Technology Enablers - Upstream • High performance cell lines: product quantity & purity • Molecular design of product for quality & manufacturability • Cell retention (>150m cells/ml) to enhance productivity • Enhance production with N-1 technology • Concentrated, defined media to support high cell density performance • HTST media sterilization to address adventitious agents • Single-Use Bioreactors • In-line single use sensors 27

Enabling the HOW

The Technology Enablers - Downstream • Multi-column chromatography with column cycling • Improved resins: specificity, DBC, cleaning • Flow through chromatography and membrane adsorption • SPTFF • On/in-line sensors for process control and compliance • At-line multi-attribute method (MAM) • Viral inactivation and removal technology • Continuous lyophilization, spray drying, electrospray for DP • Novel unit processes, e.g. precipitation, crystallization, extraction 28

Enabling the HOW The Technology Enablers - Process • Single-Use technology • Ball Room facilities design and operation • Connected and closed systems with aseptic connections, low shear pumps, flow control and in-line flow measure and mixing • Modular facility design enabling scale out • PAT and QbD • Process control with in/on-line sensors and models • MAM in process development and at-line • Emerging application of AI and ML • Electronic batch records (EBR) 29

How are we doing?

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Building the Business Case Intensification and Integration

• Business need: Select from Menu below – Pipeline portfolio on accelerated pathways • • • •

Speed Cost Quality Flexibility

Potential for high demand but uncertain forecast Specialty product with low demand but growth potential Unstable and stable proteins, some with narrow CQAs Multiple modalities (Gene or cell therapy, vaccines, exosomes, microbiome)

– Market pressure • • • •

Pricing driving COGS reduction to support margin Growing market requires early expansion Competition as biosimilar or therapeutic substitution Tech transfer flexibility to new facility, CMO or partner

– Technology presence

• Build a test facility to explore and de-risk capability 31

Alternative Process Configurations for Intensification and Integration

32 Source: Konstantinov and Cooney, JPS 2014

Hybrid Case 1

Intensification of USP

Speed Cost Quality Flexibility

• Seek greater capacity from USP or need to make an unstable product • DSP is working fine and has adequate capacity for enhanced productivity upstream • Use N-1 Technology to start with enhanced inoculum • Implement cell retention and perfusion with concentrated media to support >100m cells/ml • Process intensification permits use of SU Bioreactors in ballroom facility 33

Hybrid Case 2

Intensification of DSP

Speed Cost Quality flexibility

• Current USP is working very well • Need DSP to handle higher & variable load • Management challenge: increase capacity without major CapX and be prepared to handle more products sooner in pipeline • Build out intensified & Integrated DSP with MCC for capture, flow through chromatography, viral filtration & SPTFF to drug substance • Maintain current batch DP finish • Implement PAT for control and compliance

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Hybrid Case 3

Integrating USP with continuous capture

Speed Cost Quality flexibility

• Perfusion USP provides continuous flow of product at modest concentration (e.g. 2 g/L) • Use MCC to capture and concentrate product from clarified bioreactor effluent prior to batch DSP • Management challenge: use high productivity of perfusion process to permit use of small volume reactors for preparation of clinical lots • Implement single-use bioreactors with cell retention and connect outlet to small MCC capture and accumulate product at >95% purity for subsequent batch DSP • Process is built out in a ballroom facility with flexibility to handle multiple products and adjust demand through operating time.

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What questions remain?

Here is a sampling?

• Validation and verification strategy for intensified and integrated processes assuring CQAs and viral clearance • Confidence in Real Time Release • Aseptic sampling and potency assays • Innovation around drug product • First principle models supported by in/on-line sensors • Establishing comparability following change • Validating start-up, change and perturbations in integrated processes • Need scale down capability to explore design space • Ability to get global regulatory approval • Do I have an organizational structure – Process Development, Regulatory Affairs, Tech Ops – Fit-forPurpose?

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How are we doing?

• Excited by what is being accomplished • Fearful that it will take too long • Saddened that it has taken so long 37

Advanced Biologics Manufacturing Are we ready?

• Operating in a new technology ecosystem

– Dependencies on material suppliers and collaborators – Need for closer relationship with multiple regulators

• Flexibility to address uncertainty in markets, products, technology – are the physical and human assets in place?

• Is your QMS appropriate and enabled?

• Do you have a culture receptive to innovation and change with an appetite for risk?

• Efficient utilization of legacy assets and modern modular platforms?

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Call to Action!

Prepare for the future • Clarity in the Value Proposition is essential • Intensification and Integration to address speed, quality, cost and flexibility • Interrogation facilitates control, learning and compliance • Analytics link the science to the patient • Modular platforms provide optionality to meet demand across multiple modalities • Collaboration amongst all stakeholders is necessary to sustain innovation • Mind the Gap: traditional interfaces - physical, organizational, & disciplinary need to be bridged 39

When you reach the summit you are 25% towards your goal

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