boedeker bayer bils 2016

Berthold Boedeker Bayer Pharma AG; Biologics - Biotech Development

Bio-manufacturing and Facility of the Future: benefits and challenges of recent innovations

9th Bioinnovation Leaders Summit Berlin, Feb. 2016

Agenda   New Bayer

  Status Quo of biologics manufacturing

  Disposables – benefits and limitations

  Facility of the Future / modern plant design

  Continuous processing

  Comparison of a standard fed-batch steel versus a continuous processing based disposable facility

  Conclusion and outlook

Bayer provides solutions based on innovations

In all areas of our business, we invent, develop and market new molecules which influence the biochemical processes in living organisms.

Our Life Science businesses hold leadership positions

Life Sciences

!  Strong in research and development

!  Leadership positions in core therapeutic areas, e.g. in cardiology, ophthalmology, women‘s health & certain segments of oncology

!  Successful market launches, e.g. Xarelto, Eylea, Xofigo

!  Crop Protection: no. 2 with a highly diversified R&D portfolio

!  Seeds: no. 7 but with leading positions in canola, cotton, vegetables and rice

!  Animal Health: no. 3 in the companion animal market (CAP)2

Crop Science1 Pharmaceuticals Consumer Health

!  No. 2 with leadership positions in key categories (dermatology, gastrointestinal disease) and strong brand recognition

!  Strong geographic footprint

!  Focused on consumer-centric innovation

≈26,800 ≈38,000 ≈11,700

Unique and diversified portfolio mitigates risks

1 Incl. Animal Health (will report as a business unit directly to Liam Condon) 2 Companion animal products 3 Expected headcount on January 1, 2016

FTE3

Best-Selling Pharmaceutical Products

[ € million ] %

First Nine Months 2015

First Nine Months 2014

Change Fx adj.

%

3rd Quarter 2015

Xarelto™ 1,163 1,602 +37.7 +37.1 Eylea™ 540 874 +61.9 +57.1 Kogenate™ 808 869 +7.5 +0.7

Mirena™ product family 594 742 +24.9 +9.8 Nexavar™ 571 661 +15.8 +6.1 Betaferon™ / Betaseron™ 629 634 +0.8 -9.2

YAZ™ / Yasmin™ / Yasminelle™ 570 538 -5.6 -5.0 Adalat™ 435 481 +10.6 +0.8

Aspirin™ Cardio 356 393 +10.4 +2.3 Glucobay™ 310 381 +22.9 +4.1

Avalox™ / Avelox™ 285 294 +3.2 -3.5 Stivarga™ 161 236 +46.6 +29.3 Xofigo™ 128 188 +46.9 +27.5 Total 6,861 8,189 +19.4 +12.0 Proportion of Pharmaceuticals sales 78% 80% Fx & p adj. = currency- and portfolio-adjusted

Drug Discovery - Biologics

Biologics Research Biologics Development

Elberfeld, Wuppertal

! Monoclonal antibody process development and clinical manufacture

! Batch-fed fermentation! Microbial fermentation! Antibody drug conjugate

production

Berkeley, California

! Process development and clinical manufacture of hemophilia pipeline

! Perfusion-based fermentation

! Production cell line and MCB generation

Biologics Landscape •  Access to medicine •  Health Care costs / reimbursement •  Personalized medicine -  From blockbuster to specifically patient designed biologics

•  Regional production set-up •  Biosimilars -  Opportunities

-  Regulation

-  Pricing

" Consequences for industry " CoGs pressure " Fast product turnover in flexible multi-product plants

Technology drivers for cell culture industry

•  High titer cell line

•  Chemically defined media

•  Fast and efficient PD

•  Robust production processes

•  Disposable technology

•  Closed systems operation

•  Modular plant

•  Ball-room plant

•  Continuous processing

New products after replacement proteins and mAbs

Complex and specifically designed molecules -  Bispecific / multispecific

-  Sort half life molecules

-  ADCs / RIA

-  Cancer immunotherapies

-  Active site molecules

will need new / modified production technologies

Cell therapies

Renaissance of gene therapy?

Status Quo in Commercial Manufacturing of Biologics from Mammalian Cell Culture

•  85 – 90 % of all products are produces in fed-batch culture, most in large facilities (“steel temples”) in a complex GMP infrastructure with high degree of segregation and automation

•  10 – 15 % are produced in perfusion culture at high cell density by cell retention using a similar GMP and segregation environment, which represent a continuous upstream operation followed by classical batch purification

New Trends in Mammalian Production

•  Smaller fermenter volumes needed because of personalized medicine and high production titers

•  Use of disposables instead of hard-piped equipment

•  Development of upstream and downstream completely or functionally closed systems based mainly on disposables, which should reduce environmental segregation and simplify facility design and operation (ballroom plant concept)

•  Desire to produces several products in parallel (several products at a time) in addition to the current campaign mode (one product at a time per suite)

•  Regional production set-up needs facilities which are faster and inexpensive to built

Impact of Disposables on Protein Production from Mammalian Cells •  Complete production processing for biologics can be done in disposables, except:

-  Centrifugation

-  Chromatography skids

-  Large UF / DF

•  The following unit operations are available:

-  Mixing / holding / distribution of media and buffers

-  Seed expansion and production fermentation

-  Cell removal by depth filters

-  Chromatography columns

-  UF / DF/ virus filtration

However, different vendors with different hook-up and connection systems often result in custom made (expensive) solutions

Benefits of disposables •  Simplification of processing by replacing highly controlled, hard-piped

equipment and utilities by single-use based, stand-alone equipment connected through flexible tubings

Main advantages of single use:

-  plant design and construction: easier, faster, less expensive, less complex

-  construction in a „lab-like“ infrastructure possible

-  plant qualification/valiation: faster, less effort

-  plant operation: overall cost-efficient, main savings in utilities, water, steam, CIP, SIP, etc., less depriciation

-  faster product change

-  lower COGs

-  fast and low risk transfer to different sites (emerging markets)

General Limitations in Disposable Use •  Different units from different vendors -  Interchangeable connections missing

-  Lack of “standardization” among supplier

•  2nd supplier concept

•  Validation packages -  Extractables, leachables

•  Quality oversight of disposable vendors

•  Regulatory support files

•  Routine production measures (avoid human errors)

Risk Mitigation Strategies Using Disposables •  Work with vendors on improving quality standards -  pressure testing of bags -  in depth inspection for particles , etc. -  in depth quality control audits -  visualization of complete manufacturing process for dsiposables

•  Initiative by industry for joint vendors standardization

•  Implement 2nd supplier concept -  easy for hold bags, filters, catridges, etc -  difficult and time consuming for single use bioreactors

Example of a Current Disposable-based Fed-Batch Process

200 L BIOSTAT® STR ~ 4 days 1000 L BIOSTAT® STR

14 - 18 days

Cell Sep: Dead-End Filtration

Clarified Harvest

Cell Culture: ~ 35 days

Seed-Train Expansion 1 mL cryo-vial/Shaker Flasks ~ 14 days

New Trends in Mammalian Production Plants

Upstream and downstream completely or functionally closed systems based mainly on disposables

Produce several products in parallel (several products at a time) in addition to the current campaign mode (one product at a time per suite)

Reduction in HVAC/seggregation requirements (ballroom concept)

Reduction/avoidance in hard-piping (SIP/CIP)

Faster and inexpensive to build

Based on ballroom design ?

Single Use versus Steel based Plant Design using the current Containment Concepts (1)

Same seggregation/airlocks/room classification/gowning/dedicated equipment and personell concept as currently state of the art

Simplification of processing by replacing highly controlled, hard-piped equipment and utilities by single-use based, stand-alone equipment connected through felxible tubings

Main advantages of single use:

- plant design and construction: easier, faster, less expensive, less complex

- construction in a „lab-like“ infrastructure possible

- plant qualification/valiation: faster, less effort-

- plant operation: overall cost-efficient, main savings in utilities, water, steam, CIP, SIP, etc., less depriciation

- faster product change

- lower COGs

Single Use versus Steel based Plant Design using the current Containment Concepts (2)

Main disadvantages of single use:

- limited in size of operation units (bags)

- labor intensive

- manual operations

- potential for operator failures

- dependency on bag vendor quality

- more waste - inactivation followed by incineration

Current new plants are often constructed as mixed mode plant combining disposable and hard-piped processing steps

Ballroom Plant Design Concept (1)

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)


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 separetely, i.e. in small areas with classical containment set up

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 addresse by a risk based approach with appropiate risk mitigation strategies considering each process step or operation


The following risks were addressed and mitigation strategies provided using detailed failure mode and effects analysis tools:

- temporary breakable connections

- open manipulation in process stream

- charging raw materials during media or solution prep

- equipment prep

- cleaning or maintenance

- in-process sampling

- unexpected breach of a closed system element

There are indeed first facilities, which were designed, built and qualified according to the concept of using risk-mitigated closed systems, which have much lower containment /room classification requirements and are used for at least clinical production

Scheme for Continuous Perfusion Culture with External Retention Device

Production of recombinant Factor VIII

Structure 2332 Amino Acids 23 Cysteins

Product / year 150 g (1 Billion units) Assays / batch 400+

Employees Manufacturing: 700 Quality Control: 300

WFI / year 20 Million Liters

Sales 2008 848 Million Euro

B

Heavy Chain 90 - 210kD

B-region 19 glycosylation sites

80kD Light Chain

90kD portion Heavy Chain

A1

C2 C1 A3 B

A2 6 glycos. sites

Long Term Continuous Fermentation of rec FVIII

Time t [d]

Cel

l con

cent

ratio

n [1

06 v

c/m

L]

Viab

ility

[%] 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

Perfusion Culture Features •  High volumetric throughput (perfusion 1 – 15 fermenter volumes /

day) •  Low residence time of product in the fermenter – low impact of “-ase”

activities, degradation •  Physiological steady state conditions -  Adjusted by specific perfusion rate

•  Small scale fermenters for commercial production

" Product types -  Low titer -  Productivity correlated to cell growth -  Fragile, fast degrading proteins -  toxic

Continuous Bio-Manufacturing

•  Currently hot topic in the industry

•  Advocated by regulatory authorities in the context of lean, low costs and well controlled production

•  Well established for chemical compounds

•  Goal is to define a continuous process using perfusion technology combined with continuous filtration and chromatography operations

Differences between perfusion and continuous processing

Perfusion •  Batch-wise harvest collection

•  One or several harvest batches are then combined to one DSP batch

•  Each product batch represents a certain time interval of perfusion fermentation

Continuous Processing •  Completely continuous operation

without harvest collection

•  Cell removal is either done -  by the cell retention system or -  by continuous depth filtration

using 2 filters per line (1 in use, the other ready for use)

Mostly used cwell retention system: ATF Perfusion System from Refine Technol. (presented at the Biomanufacturing Summit, San Diego, 2013

Features of the ATF System

•  Scalable •  Operation in dual mode -  One unit in use, the other prepared to be used

•  Perfusion rates of 1 – 3 fermenter volumes per day

•  Complete cell retention avoiding cell clarification step

•  Accumulation of dead cells and debris – cell bleed needed

Options for Continuous Downstream Processing

•  Continuous chromatography using a battery of small scale columns operated sequentially

•  Continuous operation of membrane absorbers in bind / elute mode as alternative to column chromatography

•  Continuous operation of membrane absorbers in flow-through mode

Status: •  Currently established for continuous operaton up to capture step

Protein A for mAbs •  Several units commercially available

Options and Limits of Continuous Processing

Pros

•  Small investment in equipment

and facility

•  Large scale GMP production in a

lab-like environment

•  Easy scale-up by adding same

size units

•  Easy transfer to other sites

(decentralized production)

Cons

•  Complex operation

•  Technical feasibility not

established yet

•  Batch definition ?

•  Potential product quality issues

by long term fermentation

•  Increased validation effort






  Comparison of a standard fed-batch versus a continuous processing based disposable facility


Cell culture pilot plant in Wuppertal

Purpose •  Produce material for phase 3 clinical trials Design •  Stainless steel equipment •  Functionally closed processing •  Fed-batch fermentation •  Operations are separated in different rooms

Comparison of a fed-batch facility with a disposable facility using continuous processing

Biofacility of the future

Purpose •  Production for market Design •  100 % S.U. process equipment •  Closed processing •  Continuous processing •  Ballroom production

Building Concept •  5 levels •  ~ 5000 m2 total area •  ~ 1400 m2 cleanroom (class D and C)

Building Concept •  2 levels •  ~ 1200 m2 total area •  ~ 360 m2 cleanroom (class D and C)

Design Principle: “Ball Room” Production

page23

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)

Pag 40

Flows

Personnel

Material

Product

Waste

Layout 1st floor – Production Level

Cleanroom classification

Black

Class E

Class D

Class C

Summary and Conclusions

Single-use technologies are maturing allowing to produce most cell culture process steps in disposables instead of hard-piped systems

•  Simpler operation in a lab-like environment

•  Issues: 2nd supplier, standardization and regulatory support files

Disposable based flexible facilities with functionally closed operation units are developing into an alternative or supplement to the standard hard-piped based steel plants:

•  For lower volume products

•  Faster to build, smaller foot print, less complex in Engineering, simpler to qualify and validate, lower in costs, easier to operate, lower COGs

•  Similar containment and seggregation concept compared to classical plants

Single –use technologies and continuous processing further reduce the footprint of flexible ballroom plants with less or no seggregation and containment (facility-of-the-future):

•  Different products at a time, no seggregation upstream/downstream

•  Issue: How to handle steps, which still need (functionally) closed systems?

•  Regulatory acceptance/complexity of continuous operations

Thank you!

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boedeker bayer bils 2016

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