Implementation of 2000L SUB and

Disposable Clarification System in

Existing cGMP Facility

Dave Wolton

CMC Biologics

2011-10-25

Overview

• CMC Biologics

• Why is the 2000L a game changer?

• Integration into Existing Facility

• Defining the Bioreactor Process

• Facility Design Challenges

• Disposable Harvest System

• Lessons Learnt

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CMC Biologics

Contract Manufacturer of Biological Therapeutics utilizing

MAMMALIAN & MICROBIAL CELL CULTURE TECHNOLOGIES

• Cell-line Development – CHEF1™ technology • Upstream/Downstream – process development and manufacture • Analysis, Characterization, Formulation, Quality and Regulatory

Target

& Lead

ID

Pre-

tox Tox Phase I Phase II Phase III

Commercial

Production

CMC Biologics

Background to why I believe the

2000L is a game changer

• 13 years at contract manufacturer in Slough 2000L

scale

• 6 years producing Enbrel in a 6 x 12,000L plant

• 1 year designing 12 x 1000L SUB plant

• Approximately 1 million Euros spent on basis of design

• Moved to CMC 2 years ago

CONFIDENTIAL 4

– Plant runs for 300 days per year

– Protein A Cycles per batch approx. 4

– Harvest two reactors every 2 days

– Assumed product campaigns are the norm

– Cell culture only work days

= 2 x 12,000L stainless plant

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Blockbuster ‘in market supply’

potential of the 2000L SUB factory

Output from model

Plants of the future

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6 x 12,000L stainless

12 x 2,000L Disposable Conventional design

12 x 2,000L Disposable Lean design

Plants of the future

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Reactor hall 15M x 15M

Copenhagen 2000L SUB

Implementation and proof of

concept

2000L SUB

• 2000L capacity retrofitted to a 100L stainless

steel suite

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Aim of the project

• Increase US/DS capacity to match launch/commercial

production (MAB): 2000L

• Integrate into existing facility without affecting current

clinical manufacturing

• Minimize limited company recourses

• Project used 1 Engineer and two validation resources

• Meet cGMP requirements – EMEA, FDA

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2000L SUB in 100L SS facility

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Microbial 2x 1500L

CCI 2x 750L

CCII 100L

CCIII 300L

Stainless Steel

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SIP

CIP

HPW

Automatic valves

DCS

70 elastomers

Disposable Bioreactor

• Minimize limited

company recourses

• Low level of

atomization

• Off the shelf

• High flexibility

• Waste – Supported by

existing infra-structure

at CMC Biologics

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SIP

CIP

HPW

DCS

Waste

Defining the Bioreactor Process

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Project Plan

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7 months from start to finish

Right. On time.

Vendor:

• Security of supply

• Market leader in number of units sold

• Back up in both USA and Europe

• We already use their single use mixers,

100L, and 500L SUBs

• Willingness to negotiate a bag supply

agreement

• Track record in supplying disposables

• Conventional design

• Compact storage

• Wide choice of control systems

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Vendor: EZ controller

• Wheel in wheel out seed reactor concept

• Simple

• Robust

• Large number of units sold

• Fast to set up, train on and validate

• Compact (can be mounted on the SUB)

• Cost effective to have multiple units on

multiple SUB’s

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Factory Acceptance Testing

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Installation

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Installation

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Reception as

it was

Installation

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Installation

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Reception as

it looks now….

Engineering Run - Inoculation

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XG2Cb

2000L SUB data

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• The light blue

datapoints

represent the

2000L SUB

• The other data is

from 500L SUB

runs of the same

product

Disposable Harvst System

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Integrated 2000L depth filter system

Lessons Learnt

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• Decide on controller early – This will impact timelines

and complexity

• Agree who mounts the control system and where it will

be mounted

• Do a cost benefit analysis on the seed strategy

• Take into account fabrication and shipping costs/time

• Be careful in regards vessel orientation and hose

location

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Summary

• Slide from Johannes R. Roebers, PhD

Thanks to…

• Andreas Mark Arnung, CMC Biologics

• Christian Skjødt, CMC Biologics

• Esben Eggertsen, CMC Biologics

• Gustavo Mahler, CMC Biologics

• Henrik Knudsen, CMC Biologics

• Jakob Ravnsborg, CMC Biologics

• Johannes R. Roebers PhD, Elan

• Mads Laustsen, CMC Biologics

• Martin Oscar Miret Hattel , CMC Biologics

• Martin Kelly, Thermo Scientific

• Ronni Glenn Refstrup Hansen , CMC Biologics

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CONFIDENTIAL 30

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