Flexible Production of Biopharmaceuticals A CMO Perspective · 2018-10-22 · S. Schmidt June 1,...

Flexible Production of

Biopharmaceuticals –

A CMO Perspective

Dr. Stefan R. Schmidt MBA

VP Process Science and Production

June 1, 2016 S. Schmidt 2

Agenda

1 Introduction

Development phases 2

Molecules 3

Process 4

Facility/Equipment 5

Conclusions 6


Drug Discovery and Development

Source: Medicines in Development, Heart Disease and Stroke, PhRMA Report 2013

10-15 years and $ 1.2 billion including costs of failure from experimental drug

to FDA approved product!

Currently ~ 30 % of new drugs are biologicals


FDA Approvals

Morrison, Nature Biotech, 2016


Small Molecule vs. Large Molecule Manufacturing

Jacoby, Deloitte, 2015

Cell factory steps

1. Transcription

2. Translation

3. Secretion


Protein Expression in Eukaryotic Cells

secretion

1

2

3


Typical Biopharmaceutical Production Process (mAb)

Levine, BioProcessing Int, 2013


Factors Impacting Manufacturing Flexibility

Molecules

● PTM host cell

● Biosimilars

Development stage

● Entry point

● Clinical development

Facility/equipment

● Scale

● Steel vs. disposable

● Batches, volume

Process

● Titer

● Platform

● Batch vs. continuous


Agenda

1 Introduction


Molecules 3

Process 4


Conclusions 6

Typical entry points for a CMO

● Cell line generation

● Process development

● Process transfer

● Scale up


Different Entry Points for CMO Services

Cell line

development

Process

development Upstream

processing Downstream

processing

Fill &

Finish

Preclinical

development

Clinical

Phase 1

Clinical

Phase 2

Clinical

Phase 3 Market

Typical reasons for using CMOs:

● Special services no available in-house

● Offer capacity without investment

● Expertise in difficult proteins


Decision Tree to Assess Flexibility

PTM

Low titerSensitiveor toxic

Low dose,few patients

MoleculeProkaryotic

host

Eukaryotic host

Batchprocess

Continuousprocess

Yes

No

Yes Yes

No No

Yes

No

Disposableequipment

Stainless steelequipment

● Molecule

● Process

● Equipment


Agenda

1 Introduction


Molecules 3

Process 4


Conclusions 6


Recombinant Molecules

1. Generation mABs 2. Generation Fut. Therapies

Examples Insulin, EPO,

IFN, HGH

Humira®,

Avastin®

Enbrel® (Fusion)

Kadcyla® (ADC)

Glybera® (VBB)

Provenge® (CT)

Molecule

Types

Low level of

complexity

SS-bridges,

glycosylation

Human design,

complex

Human design,

natural origin

Manufacturing Pro- or eu-

karyotic host

Eukaryotic

host

Complex/simple

manufacturing

Mammalian cells,

low level of DSP

Therapy Replacement Antagonistic,

agonistic

New MoA,

combination

“somatic”,

systemic

Dosing Highly active,

low dose

High dose Lower doses,

less frequent

Singular dose (?)

Manufactured by Rentschler

Biosimilars

Reverse engineering for biosimilar candidates


Biosimilars limit Flexibility

McCamish et al. Clin Pharmacol Ther. 2012 Mar; 91(3): 405-417


Agenda

1 Introduction


Molecules 3

Process 4


Conclusions 6


Batch vs. Continuous Manufacturing

Jacoby, Deloitte, 2015

● Advantages


Continuous Bioprocessing

http://www.continuous-bioprocessing.com/

Cost (-) Productivity (+)

• Smaller equipment

• Smaller footprint

• Lower investment

• Higher cell densities

• Higher product concentration

• Higher yield

Quality (+) Flexibility (+)

• Natural process

• Constant nutrient level

• Removal of metabolites

• Less stress

• Efficient facility (resin) utilization

• Less product change overs (CIP/SIP)

• Easier backup through smaller facilities

• Single use for market production?

• No scale up issues (extending perfusion)






Continuous Processes (USP)

18

DSP

Feed

Cell removal

Simplified description

● Feed is continuously added

● Metabolites and product is continuously removed

● Bleeding of cells possible to adjust optimal cell concentration

Disadvantages

● Long cultivation times (sterility)

● Scalability of cell separation device

● Storage of harvest

Different schools of thought:


Continuous Processes (DSP)

19

No columns:

Continuous Countercurrent Tangential

Chromatography™ (CCTC)

Multiple columns:

Simulated moving bed (SMB)


Platform Process – Pro/Con

Pro

Con

CMO perspective:

Not necessarily beneficial due to huge variability in proteins

But: utilize a modular approach with detail know how

● Highly standardized

● Lower costs (e.g.

materials, documents…)

● Accumulated experience

● Process understanding

● Rapid procedure

● Predictability of results

● Sequence of steps with

minimal conditioning

● Ability to react on variations

(titer, pI, aggregation)

● Low interest to implement

improvements

● Favouring of compatible

molecules

(manufacturability vs.

efficacy)

● Pipeline with similar

molecules needed

Productivity has doubled every 1.5 years


High Titer Processes

Issues

● Higher cell density

● Longer process time

● Higher solids content

● More particle diversity (size and physical

properties)

● Higher proportion of fine particles

● Use of flocculants (CaCl2, K2HPO4) to

remove cells, debris, HCPs and DNA

● Precipitation and removal by centrifugation

or filtration

P. Ball, W. Noe, P. Seymour (bptc) 2011-14


Evolution of Mammalian Biomanufacturing

Odum, ISPE, 2013

1980 1985 1990 1995 2000 2005 2010 2015

0.01 g/L

$ 10.000/g

0.5 g/L

$ 1000/g

5 g/L

$ 300/g 10 g/L

$ 100/g

Fixed single product

facilities

FDA Guidance

Multi-Prod MFG Fixed Multi-Product Facilities

Emerging Contract Manufacturers

Flexible

manufacturing

Next generation

bioprocessing

Intro 15K 6-pack plants Intro disposable tech


Agenda

1 Introduction


Molecules 3

Process 4


Conclusions 6


Utilization of Disposables

0% Hybrid 100% [DSP]

[USP]100%

Hybrid

0%

Disposable

Technology

Stainless

Steel

R&D, clinical

production

Small scale

Production

<2000L

Large scale

production,

Dedicated facility

Is this really true?

Shire 4x 2000L

single-use

bioreactor facility for

Gaucher’s disease

drug VIPRV

Disposables offer many advantages but are not always optimal


SWOT Analysis of Disposables in Biomanufacturing

Strength

• Low investment (fast amortization)

• Small footprint (no piping)

• Simple & quick expansion (flexibility)

• Short implementation time

• Reduced qualification & maintenance

• Elimination of cleaning (QA/QC)

• Fast product change over (capacity)

• No cross-contamination risk (safety)

Weakness

• Scalability (reactors, columns, TFF)

• Transport sensitivity (columns)

• Increased waste

• Repetitive consumable costs

• Long supply lead times

• Storage requirements

• Limited standardization

Threat

• Supplier dependency

• Extractables & leachables effect

Opportunity

• Continuous processing

• Orphan drug manufacturing

• Scale suitable for clinical supply


CMO Perspective on Disposables

Cost

Time Quality

● Suite savings

● Flexibility

● Customer ownership

● Investment/Inventory

● Shipping

● Storage space

● Monopoly of suppliers

● Delivery times

● Supply chain

● Labor savings

● Changeover

● Supplier qualification

● Certificates

● L&E data

● Customizable

● Transportation

● Performance


Disposables at Rentschler

● Very fast establishment, locations close to market

● Preferred use of disposables

● Easy to scale out and multiply

● Ballroom concepts

● Optimal process flow


Modular Facilities

Advantages: construction

● HVAC cost saving: containing the equipment, surrounding area can be

reclassified

● Rapid reconfiguration of the facility, easy cleaning and fast construction.

Disadvantage: Container movement

● Moving heavy weights can often be challenging and require special safety

precautions

● A “non-value add” operation (wasted effort).

● Increased possibility of mix-up

Disadvantage: Inventory

● Increases risk of stock-out

● Larger volumes of inventory

● Higher cost


Ballroom Concept

● Closed processing protects the product from the room environment

● Allows the facility requirements to be dramatically reduced in terms of product

protection—in other words, the facility is a non-impact system (as defined in

ISPE’s Baseline Guide)

● As the facility is no longer protecting the product, it can be simplified:

o reduced risk of product contamination

o reduced project cost and schedule

o improved operations

o reduced operational costs

● Best utilization of mobile equipment

● Reconfiguring to match any process

● Low CAPEX ideal for early phases


Design Requirements: Impact of Closed Systems


Agenda

1 Introduction


Molecules 3

Process 4


Conclusions 6

Development stage

● The later in the process the less flexibility is possible

● CMOs can accept projects at any development stage

Molecules

● Mammalian cells are capable to express a wider range of molecules than

microbes

● Flexibility is reduced in the case of biosimilars that need to match certain quality

attributes

Process

● Platform processes limit flexibility

● Continuous process can cover same capacity at smaller footprint

● High titer processes put pressure on DSP

Facility/Equipment

● The introduction of disposable equipment improves flexibility

● Mobile equipment can be reconfigured to match any process (scale limit!)

● Modular facilities allow faster adaptation to new processes


Conclusions

4th Laupheim Biotech Days

June 13 to 14, 2016

Schloss Großlaupheim, Laupheim, Germany


Announcement

Topic

Fusion Proteins –

delivering novel

therapeutic options

Flexible Production of Biopharmaceuticals A CMO Perspective · 2018-10-22 · S. Schmidt June 1,...

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