continuous processing progress in manufacturing · bayer group structure slide 3 continuous...

Dr. Berthold Boedeker, Bayer AG, Biological Development

Cell World Conference, San Francisco, May 25-26 2017

Continuous Processing Progress in Manufacturing


Agenda

• Biologics at Bayer

• Regulatory support / drivers aof continuous processing

• Bayer’s approach to continuous processing

• Most common perfusion systems

• Set-up, characteristics, cell retention system

• Integration of downstream processing

• Options and limits of continuous processing

• Technical feasibility, economics, plant design, validation

• Concept study: plant design standard fed batch vs. disposable continuous processing facility

• Conclusions and Outlook

Bayer Group Structure

Continuous Processing Progress in Manufacturing Slide 3

Board of Management

Pharmaceuticals Consumer Health Crop Science

Animal Health

Corporate Functions & Business Services

Covestro (around 64%) Currenta (60%)

One of the leading innovative companies in the healthcare industry


Pharmaceuticals Division

• Largest division of Bayer in terms of sales

• One of the fastest growing pharma companies worldwide

• Sales of 16.42 billion Euro in 2016

• Global headquarter in Berlin, Germany

• 40,100 employees worldwide in 2016

• Largest German pharma company

• Focus on prescription products, especially for cardiology, oncology, hematology,

women’s healthcare, and ophthalmology

• Radiology franchise with contrast-enhanced diagnostic imaging equipment and

contrast agents

Biologics @ Bayer Pharmaceuticals

Product

Betaferon® /Betaseron® Kogenate® Eylea®

Indication Multiple sclerosis Hemophilia A Wet Age-related

Macular Degeneration

Market Worldwide Worldwide Ex-US

Product

presentation Lyo-vial in kit Lyo-vial in kit Liquid-vial

Volume High

(double digit million vials)

Medium

(one digit million vials) Growing

Manufacture External In-house External


FDA encourages manufacturers to use continuous processing because of the perceived advantages:

Improvement of product quality because of steady state operations (limiting processing variables)

Improved patient access because of lower costs

Indeed also industry expects pronounced advantages:

Improved product quality

Reduced CoGs

Modular manufacturing in standardized plants using standard processes

Less facility investment

Easy site to site transfer


Regulatory support / drivers of continuous processing

Preconditions to enable continuous processing

Continuous

Processing

Advancement of disposable technologies

On-line or in-line analytics

Perfusion culture experience

PAT Technologies

Advancements in closed processing Processing automation


• Mainly within Bayer Engineering & Technology department

• Participation in German state funded consortium program

• Established a 10 L model processing unit for completely continuous processing from production fermenter to

virus filtration (classical mAb process)

• Disposable settlers or ATFs used for cell retention

• Multi-column chromatography systems

• Dual set-up for UF/DF/membrane operations

no true continuous processing but continuous product flow in discontinuous individual systems

• --- unit is running and can be visited in Leverkusen


Bayer’s approach to continuous processing

Conclusion; doable, but very difficult to run and control

• 30 + years of production of rec Factor VIII in perfusion

• Batch/fed-batch not suited because of fragility of the protein in culture

• short residence time of the product

• “open” cell retention system removing dead cells and debris (inclined plate settler)

• 10-15 fermenter volumes/day yield in high volumetric production

• Extensive process validation efforts compared to batch

• BLA: 2-3 run of full length preparing several qualifying lots, duration 6-12 months,

show seed to seed as well as early/mid/late fermentation consistency


Bayer‘s experience with perfusion


Long term continuous fermentation of rec FVIII

Time t [d]

Cell

co

ncen

trati

on

[10

6 v

c/m

L]

Via

bil

ity [

%]

10

100

1

10

100

0 20 40 60 80 100 120 140

1

Cell concentration

Viability

production of unstable

protein q/V = 10 /d

Dr. Konstantinov, Bayer Corp.,

Dechema 2002, Frankfurt

External filtration unit

favorite ATF (alternate tangential filtration)

Continuous centrifugation

now also available as disposable unit


Commonly used perfusion systems

All systems have a limited use time, therefore for continuous processing always 2

systems are set up in parallel: 1 in use, 1 to switch to

(presented at the Biomanufacturing Summit, San Diego, 2013

Commercial Perfusion System: ATF Perfusion System from Refine Technol.


• Limited scalability

• Easy to operate, but

• moving parts

• Clogging possible (2 systems in parallel)

• Low perfusion rates of max 2 fermenter volumes per day

• Accumulation of dead cells/debris may impact product quality over time

• Cell bleed adds another level of operational complexity

• No real steady state conditions possible


Features of ATFs


Integration of perfusion fermentation into continuous downstream operation

• Parallelized small disposable multi-columns operated batchwise in sequence without interrupting product

flow

Well established, several systems available

Chromatographies

• 2-systems-approach 1 in use, 1 to switch to Filtration /

adsorption

• Either continious via low pH elution or

• Batch-wise with 2 units

Collect product upt to a certain volume, decouple, inactivate, continue with continuous operation

pH inactivation

Virus filtration • See filtration


Technologies of the future to support continuous processing

Disposable

Closed processing

In-line dilution for large liquid volumes

Ball-room facilities

Flexible facilities

Alternatives to chromatographies:

membrane absorbers, precipitation

Higher binding gels

On-line monitoring

PAT tools

Represents innovative concept to enable parallel processing of different products in the same low

classification containment without upstream and downstream seggregation

Concept addressed in the following paper:

Simon Chalk et.al., „Challenging the Cleanroom Paradigm for Biopharmaceutical Manufacturing of Bulk Drug

Substances“, BioPharm International, Aug. 1, 2011.

Based on the key assumptions that technological advances including single use sytems have continuously

reduced the risk of environmental impact on processing.

Most steps can be securely performed closed or functionally closed.

The few remaining open processing steps have to be addressed independently (i.e. portable laminar flow hood,

isolator technology)


Ball-room plant design concept (1)

Basic thinking is that in a closed or functionally closed system, the process stream is isolated from the

environment

Remaining open operations (cell expansion, column packing, powder additions) have to be addressed

separately, i.e. in small areas with classical containment set up, or closed solutions

Potential breach of the closed system is the major risk, which has to be addressed:

- prove no contamination or cross-contamination

- intense microbial monitoring

Maintaining the closed system status has to be addressed by a risk based approach with appropriate risk

mitigation strategies considering each process step or operation


Ball-room plant design concept (2)

Most facilities nowadays are of hybrid design combining elements of classical hard-

piped with single use elements.

In order to evaluate differences of a closed systems, disposables and continuous

processing based ballroom facility to such a fed-batch hybrid set-up, a concept

study was performed by Bayer:

Joergen Magnus, Bayer Technology Services

at 12th Annual Biolog. Production Forum, Düsseldorf (2013)


Facility of the future: Comparison of standard fed-batch to disposable based continous processing facility


Comparison to facility with traditional design and similar production capacity

Purpose

• Produce material for phase 3 clinical trials

Design

• Stainless steel equipment

• Functionally closed processing

• Fed-batch fermentation

• Operations are separated in different rooms

Building concept

• 5 levels

• ~ 5000 m² total area

• ~ 1400 m² cleanroom (class D+C)

Purpose

• Production for market

Design

• 100 % single use process equipment

• Closed processing

• Continuous processing

• Ball-room production

Building concept

• 2 levels

• ~ 1200 m² total area

• ~ 360 m² cleanroom (class D+C)

Cell culture pilot plant (Wuppertal) Biofacility of the future


Design principle: 100 % single use technology

Media bag Buffer bag Buffer bag

Fermenter Filter – UF/DF Chromatography Product bag

Single use Bioreactor

+ single use tubings,

bags, sensors, etc

Single use

filter cartridges

Pre-packed columns

No need for CIP or SIP


Design Principle: Continuous Processing

• Continuous fermentation with cell retention

• Continuous depth

• Continuous chromatography using

simulated moving bed technology

• Continuous UF / DF

• Continuous virus inactivation

Upstream Downstream

• Cell specific productivity

• Cell density

• Perfusion rate

Bioreactor performance depending on


Closed processing in single-use systems

Γ-sterilized

Γ-sterilized

Γ-sterilized

Sterile tubing

fuser or aseptic

connector


Design Principle: Ball-room Production

Ball-room includes:

All process units

All media and buffer containers

All media and buffer preparation tanks

But does not include

Seed lab

Bulk filling room (post viral area)

Design Principles

• 100 % S.U. process equipment

• Continuous processing

• Closed processing

• “Ball Room” production in class D (except seed lab and final filling)

Benefits

• Shorter engineering, construction, commissioning, qualification and validation times

• Decoupling of equipment from building

• Smaller building footprint

• Energy and water saving

• Reduced investment and production cost


Benefits of continuous processing in a biofacility of the future concept

Reduced complexity


Pro‘s and Con‘s of continuous processing

• lower plant footprint

• lab-like infrastructure

• easier to build and validate

• easy to operate, if fully

automated

• easy site to site transfer

• lower CoGs

• individual unit operations difficult to get

continuous

• risk of product quality issues because of

perfusion operation

• glycosylation depends on specific

perfusion rate

• glycosylation different to fed-batch

(transition issues)

• no real steady state possible

• same quality over complete run length

needed

• titer dilution (harvest)

• batch definition

• increased process validation effort

• immature technologies yet (especially in DSP)

• scalability problematic

• process characterization problematic

• scale down models upstream

• extended validation effort

• development/operations/facilities in-house

infrastructure for fed-batch

• cell lines/culture media optimized for long fed-

batch process with cells in stationary phase


Bottlenecks of continuous processing

• lack of automation

• on-line monitoring and control

• complex biological systems

• regulatory acceptance and experience

• maintaining microbial control

• Integrate disposables use, closed systems operation and parts of continuous

processing to obtain a flexible, easy to validate and operate facility using lowered

containment classification than current standard

• Fermentation preferred fed-batch, in few cases perfusion (molecule dependent)

• DSP could be done partly continuous, if technologies advance correspondingly

- chromatographies via multi-column units

- membrane adsorbers instead of chromatographies

- filtration in parallel mode


Currently preferred processing strategy

This website/release/presentation may contain forward-looking statements based on current assumptions and

forecasts made by Bayer management.

Various known and unknown risks, uncertainties and other factors could lead to material differences between

the actual future results, financial situation, development or performance of the company and the estimates

given here. These factors include those discussed in Bayer’s public reports which are available on the Bayer

website at http://www.bayer.com/.

The company assumes no liability whatsoever to update these forward-looking statements or to conform them

to future events or developments.


Forward-Looking Statements

continuous processing progress in manufacturing · bayer group structure slide 3 continuous...

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