Single Use Bioreactor Scale up: Introduction of a 2000L ... · Single Use Bioreactor Scale up:...

Single Use Bioreactor Scale up: Introduction of a 2000L SUB

Equipment Train in 12 months

Finesse CellWorld San Fransisco April 2017

Claire Walsh BSc, MSc

BioProcess Skills and Technology,

Operations, Janssen Sciences Ireland

ONE TEAM Making the Difference for Patients WORLDWIDE0Finesse CellWorld San Francisco

Presentation overview:• My Story

• Janssen Sciences Ireland

• Janssen Process overview

• Brief overview of the original 1000L SUB project

–Project drivers and scope–Timeline

• Outline of the 2000L SUB Project

–Project Drivers and scope–Timelines–Engineering Run data, including Raman probe

data• Benefits and Limitations

• Q & A1April 2017Finesse CellWorld San Francisco

My Story

• Completed a BSc in Biochemistry and an MSc in Biotechnology in University College Cork

• Completed a Student Placement in PDMS in Janssen

• Travelled and worked in Australia before returning to Janssen to work in multiple roles including New Process Development Projects, Global Standardisation Projects, New Product Introductions/Tech transfers, Daily Process Support and Engineering Projects

2April 2017Finesse CellWorld San Francisco


CorkJanssen Pharmaceutical SciencesJanssen Sciences IrelandDePuyJanssen R&D

LimerickVistakon

DublinJ&J ConsumerJ&J Medical Janssen Alzheimer ImmunotherapyJanssen (Marketing)


CorkJanssen Pharmaceutical SciencesJanssen Sciences IrelandDePuyJanssen R&D

LimerickVistakon

DublinJ&J ConsumerJ&J Medical Janssen Alzheimer ImmunotherapyJanssen (Marketing)

Janssen Sciences Ireland


Key Products include: Simponi, Stelara, Darazalex, Prezista, Invega Sustenna and Risperidal

Focus for the future

April 2017Finesse CellWorld San Francisco 6

Focus for the future


Janssen Process overview


• Clinical Suite (SUBs)

–Single Use Technology

–Fed batch process

• Commercial Suite – Stainless Steel Bioreactors– Perfusion process









Clinical Suite (SUBs)

Single Use TechnologyFed batch process







• Commercial Suite Stainless Steel BioreactorsPerfusion process

Disposable Cell Culture Process Train: Project Drivers


Decision to move JNJ Platform from Perfusion to Fed Batch─ Historically Janssen Cell Culture Processes were

perfusion based

Outsource of Upstream Fed Batch Processing to CMOs─ Limited in house experience in Fed Batch

Decision made to provide back-up internal supply chain capacity for Fed Batch material

1000L SUB Project Scope


• Capability for pre-clinical, clinical and commercial production

• Project must deliver−2 x 1,000 Single Use Bioreactors −The capability to have 2 Single Use Bioreactors in

operation with 9 months notice

• Project cannot interfere with the current clinical / commercial manufacturing schedule or approved Operational areas

• Project must cost less than $21m including all works

• The new suite must be integrated into existing Automated Systems

• Multi product capability on a campaign basis

• Maximize use of disposable technologies

Why choose to go disposable?


• Batch Turnaround time

• Product change over capabilities

• Cleaning validation requirements–Disposable technology supports pre-clinical/early

phase production

• Installation and Qualification–Reduction in overall IOQ activities

• In-house historical disposables experience

What was the equipment selection criteria?


• The following criteria was applied to the equipment and disposables selection process:– Bag film defined as CX514 material – An Integrator with GMP experience– Availability of novel disposables– The control system needed to integrate into the existing site

systems– Customizable Assemblies

What did the Project Deliver?


Fully Disposable PreCulture Train

Single Use Bioreactors (SUBs)1 x 250L Seed SUB2 x 1000L Production SUB

Single Use Mixers (SUMs)Harvest Collection SUMDPC (Chromatography) StepsMedia Prep

Disposable Bio-containers for sampling and media/buffer storage

Extensive array of disposable assemblies

Project timelines


October 2010 to July

2011

• Engineering Design, Procurement and Construction (10 months)

July 2011 to November

2011

• Commissioning and Qualification and Engineering Runs (16 weeks)

December 2011 to Feb

2012

• First Phase 1 Clinical Campaign (12 weeks)

Original Suite Layout


Cell Culture Suite 2 Layout


What happened next?


• Huge amount of experience gained using disposables

• On-going Process Improvements building in extra reliability and decreasing both set-up and turnaround times

• Increasing demand in the clinical suite

………Requirement to increase capacity

2000L SUB Project Scope


• Additional fed batch capacity required

• Install and Qualify a 2000L SUB and associated equipment train

• Detailed design required in order to maximize capacity with footprint available

• Relocate an existing processing suite to remodel for 2000L SUB

• Suite handover within 12 months

• Project must cost less than €5.1m including all works

Cell Culture Suite 2 pre-2000L SUB


Cell Culture Suite 2 incl. 2000L SUB


Cell Culture Suite 2












Project timelines


Oct 2015 to Mar 2016

•CAR approval, Engineering Design, Procurement and Construction part 1

Mar 2016 to Aug 2016

•Construction part 2•Equipment FAT•Commissioning and Qualification

Aug 2016 to Sep 2016 (12 weeks)

•Engineering Runs

•First GMP batch thawed in PreCulture 16 Nov 2016

Complete Disposable Cell Culture Train


PreCulture Fully Disposable

250L, 500L, 1000L and 2000L SUB Capacity

2000L and 3000L SUM Capacity

DPC and VIN SUM capacity

Process Flow (up to Viral inactivation)


MediMea

250L/500L Seed SUB to 1000L/2000L Production SUB

2000L/3000L SUM

PreCulture Process Flow


• Historical experience with disposables technology here (common process to the Commercial suite)

• Flask Stages from 125mL to 500mL capacity

• Wavebag stages from 2L to 50L capacity

Seed and Production SUBs


• Seed SUB250L and 500L CapacityDeltaV Recipe Driven ControlOption to use as both a seed and a production SUBProcess duration ≤ 4 days (Product dependent)Process parameters: pH, DO, Temp, Agitation

• Production SUB1000L and 2000L capacityDeltaV Recipe Driven ControlProcess duration ≤ 21 days (Product dependent)Process parameters: pH, DO, Temp, AgitationMedia and Antifoam addition

Harvest Train


• Centrifuge Use (not all products) Non-disposable

• Depth Filters (POD filters)– Fully disposable assembly train– Pressure sensors pre and post filter set-up

• Polishing filter post Depth Filters

• Harvest Collection SUM (2000L and 3000L capacity)– Agitation– Temperature control– Sampling points

3000L SUM: New Technology


3000L SUM: New Technology


Process Monitoring in the SUBs


• pH – Controlling probes:

Electrochemical probe– Optical pH probes in the

process of being proved out

• DO– Controlling probes:

Electrochemical probe– Optical pH probes in the

process of being proved out

• Temperature– Thermowell built into the

disposable SUB bag

• Agitation – Built in sheath in the

disposable SUB bag– Shaft inserted into the

sheath prior to each batch

– This is then connected to the motor to drive the impeller

• Pressure– Built in Pressure Sensor

in the disposable SUB bag

39Finesse CellWorld San Francisco April 2017

2000L SUB, 1000L SUB and Small Scale Satellite RunRaman Data

Engineering Run Cell Culture Data Comparison

Cell Growth Comparisons


Cell Performance Comparisons


Metabolite Data


Raman Background


Correlated the spectra to the off-line dataModel developed for each key process parameter (eg: Glucose, Lactate) you’re interested in measuring. Model development is time intensivePossible future applications include:─ Potential for use as an inline monitor, therefore

reducing the reliance on off-line instruments─ Feed cycle optimisation

* Research funded by the Irish Research Council

Raman Data: Glucose


2000L SUB

5L Scale

Black Dots: Daily Off-line measurements

Red Line: Raman Data

Raman Data: Ammonia


2000L SUB

5L Scale



Raman Data: Lactate


2000L SUB

5L Scale



Benefits


System Set up time and turnaround time

Increased Flexibility for Operations

Cross contamination risk reduction

C & Q: time savings

Reduced Capital Investment and Rapid install time

No Cleaning Validation requirements

Ease of Product Change over

Footprint saving

Design Flexibility (Bag re-design, quick and easy)

Incorporation of new technology (quicker)

Great relationship and customer experience with Finesse

Limitations


x Scale up limitations

x Lack of a sight glass in the bag design

x Lead times on bags

x Leachables and Extractables studies

x No confirmation of integrity pre-use

x No pressure transfer

x Minimum mixing volume (other options becoming available)

Acknowledgments

• Liz Dooley

• Nicola Sheehan

• Seán Coomey

• Anne O’Leary

• Dan Olden

• 2K SUB Core Project Team

• Carl Rafferty (funded by the Irish Research Council)


• Engineering Team in Cork

• C & Q Team in Cork

• Operations team in Cork

• Automation

• Finesse and their Support Team


Summary


Implemented Fully Disposable Cell Culture

Equipment Train

Installed on time and within budget

Minimal disruption to existing Operations

Integration with existing site systems

Replication of design including scale up

Data to prove successful scale up

In line with the Credo to customer and patients

Back-up Slides


Details sent to Cell World

• Business case for 2000L SUB train – clinical capacity constraint etc.

• Background on the Design of the 2000L SUB Suite

• Engineering run and scale up data (including Ramen data)

• Comparison between Stainless Steel Manufacturing and Single Use Technology

Abstract (max 200 words):

1. CREATIVE DESIGN | Overview of the design process for the delivery of the new Cell Culture manufacturing suite. Sharing of lessons learned.

2. MEASURING SUCCESS | To demonstrate our success, we will openly share our process data comparisons of engineering runs vs lab scale for the 2000L SUB train.

3. BREAKING TRADITION | Janssen experience of breaking away from Stainless Steel manufacturing and giving Single Use a well-deserved seat at the table.


Disposable Cell Culture Process Train


Pre Culture 30ml – 50LSeed – SUB 250LProduction -SUB 1000L

Harvest -2000LMedia -500LProcess Vessels –200-500L

Media Preparation

• 500L Single Use Mixer (WV >100L)

• Recirculation Line

• Powdertainer addition port

• Liquid addition Lines

• Media Transfer Train

–0.45/0.22 10” Durapore filter–2 x 0.1um 4” Opticap Filters (sterile boundary)–200L Media Storage Bags


Prove out of probes

• Advantages– Proven Technology– Process Range

• Disadvantages– Autoclaved– Polarisation Time -DO(~6Hrs)– Contamination Risk

• Advantages– Ease of Use– Integral to the Bag– Good correlation with e chem

• Disadvantages– Technology in early

development– Limited GMP instances

Electrochemical Optical

Finesse CellWorld San Francisco 56April 2017

DO Probe Trends – Batch 1


0102030405060708090

0 2 4 6 8 10 12 14 16 18

% D

isso

lved

Oxy

gen

Culture Days

Batch 1 Reusable DO Batch 1 Single Use DO



0102030405060708090

100

0 2 4 6 8 10 12 14 16 18

% D

isso

lved

Oxy

gen

Culture Days




0102030405060708090

0 2 4 6 8 10 12 14 16 18

% D

isso

lved

Oxy

gen

Culture Days


pH Probe Trends – Batch 1


6.5

6.6

6.7

6.8

6.9

7

7.1

7.2

7.3

7.4

7.5

0 2 4 6 8 10 12 14 16 18

pH

Val

ues

Culture DaysBatch 1 Reusable pH Batch 1 Single Use pH

Single Use pH Evaluation


6.5

6.6

6.7

6.8

6.9

7

7.1

7.2

7.3

7.4

7.5

0 2 4 6 8 10 12 14 16 18

pH

Val

ues

Culture DaysBatch 2 Reusable pH Batch 2 Single Use pH

+ Procurement

+ Engineering Design

+ Construction

+ Commissioning

+ Qualification

Phase 1 Clinical Campaign+ Clinical Campaign

+ Engineering Run

14Dec11

Cell Culture Suite 2 - Project Milestone Map

Finesse CellWorld San Francisco 62April 2017


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