Pharma&Biotech

Elise-marie Seng / , Basel / 10. Mai 2012

A CMO’s View on Platform Technologies

A3P BioProduction 2013 BioPurification, Lyon, France

Pharma&Biotech

Louise Ingram/ Lonza Biologics / 18 Jun 13

2Mai-13

Disclaimer

Certain matters discussed in this presentation may constituteforward-looking statements. These statements are based oncurrent expectations and estimates of Lonza Group Ltd, althoughLonza Group Ltd can give no assurance that these expectationsand estimates will be achieved. The actual results may differmaterially in the future from the forward-looking statementsincluded in this presentation due to various factors. Furthermore,Lonza Group Ltd has no obligation to update the statementscontained in this presentation.

3Mai-13

Lonza Overview

■ Life sciences driven company

■ Headquartered in Basel (Switzerland)

■ Sales of CHF 2.692 billion in 2011

■ Global operations:■ 45 major production and R&D facilities■ Employs over 11,000 people

■ Global leader in microbial control and custom manufacturing:■ Hygiene ■ Water treatment ■ Active pharmaceutical ingredients both chemical and biological■ Cell therapy

■ Leading positions in product market niches:■ Endotoxin detection■ Cell-based research products■ Nutrition ingredients■ Performance intermediates

4Mai-13

Our State-of-the-art Slough (UK) Site Is for Pre- and Early Clinical Supply

Location■ 11 miles from

Heathrow airport

Footprint■ 105,000 sq. ft. (cGMP)■ 55,000 sq. ft. (PD)

Track record■ cGMP since 1983

Capacities■ 2 x 200L (Airlift)■ 1 x 500L (Stirred)■ 1 x 800L (Stirred) ■ 1 x 1,000L (Single-use) ■ 2 x 2,000L (Airlift)■ Associated purification suites

Notes■ Designed for multi-product concurrent

manufacturing

5Mai-13

We Have Mammalian Production and Development Sites on 3 Continents

Riverside

Kou řim, CZ

Braine, BE

Nansha

Portsmouth

Singapore

Slough, UK

Porriño, SPWalkersville

Verviers, BE

Visp, CH

Hopkinton

Tuas (Singapore)Mammalian cell culture200L to 20,000L cGMPProcess R&D Services

Portsmouth, NH (USA)Mammalian cell culture1,500L to 20,000L cGMP

Porriño (Spain)Mammalian cell culture4 x 10,000L cGMP

Slough (UK)Mammalian cell culture200L to 2,000L cGMPProcess R&D Services

6Mai-13

Presentation Overview

1. PlatformProcesses

2. Platform Technologies; enable platform processes

10yr evolution3. Efficiency in Execution

1 2 3 4 50

5,00010,00015,00020,00025,00030,00035,00040,00045,00050,000

Buf

fer

Con

sum

ptio

n (L

)

Fermentation Titre (g/L)

7Mai-13

What Is a Platform Process?

1. Pre-defined sequence of unit operations

2. Requires minimal process development of critical parameters

3. Minimum variation of raw materials and steps into operations

Optimization of cost of goods.

Stability studies on process intermediates.

Full evaluation of polishing steps.

Process specific virus validation study is required.

8Mai-13

DSP Platform Evolution, Round 1

Primary goal■ Eliminate gel filtration

Process & technology■ Cation exchange

9Mai-13

Evolutionary Pressures on DSP Processes

■ Titres of 3-6g/L now routine at clinical phase GMP manufacturing

■ 4x20kL bioreactors in both Portsmouth & Singapore

■ 22H11 – GS-CHO from CHOK1 host■ LB01 - GS-CHO from CHOK1SV host■ CY01 – clone of LB01

2005

0

1000

2000

3000

4000

5000

6000

22H11orig

22H11 v1 22H11 v2 LB01 v2 LB01 v3 LB01 v4 LB01 v5 CY01 v5

Ant

ibod

y C

once

ntra

tion

(mg/

L)

2001

10Mai-13

Mid 2000’s, the DSP Bottleneck

Consider a 5 fold increase in fermentation titre from 1 to 5g/Lwith no change in Downstream Technology

1. Significant increase in time required for purification■ Reduced number of batches per annum, inflated COG/g

2. Significant increase in raw materials■ e.g. Four fold increase in buffer consumption

1

2

3

4

5

Time In Purification

Fer

men

tatio

n T

itre

(g/L

)

Target Batch Length

1 2 3 4 50

5,00010,00015,00020,00025,00030,00035,00040,00045,00050,000

Buf

fer

Con

sum

ptio

n (L

)

Fermentation Titre (g/L)

11Mai-13

Limitations of Compressible Media. Reduced processing speed.

12Mai-13

Increasing Titres at low binding capacities,Massive Demand for Buffer

13Mai-13

Impact on Global Manufacturing Base

14Mai-13

DSP Platform Evolution, Round 2

Primary goals■ Alleviate DSP bottleneck

■ Processing time■ Buffer demand

■ Increase process safety

Process & technology■ Less compressible matrices

■ Higher binding capacities■ Faster flowrates

■ Small pore virus filtration

15Mai-13

Chromatography Platform Change (Protein A)

10

20

30

40

rmp.ProA Hyper D FPOROS 50A

ProSep 700AMabSelect

2.0 g/L 0.5 g/L

2.0 g/L 0.5 g/L

2.0 g/L 0.5 g/L

(D)

(B)

(C)

(A)

Dyn

amic

Bin

ding

Cap

acity

(g/L

)(C

/Co=

0.01

%)

ProSep 1000A

2.0 g/L 0.5 g/L

2 4 6 8 10 12

10

20

30

40

Residence Time (min)

2 4 6 8 10 12

Immunoglobulin binding domains

Gly29Ala mutation

Z domain■ MabSelect■ MabSelect SuRe

E D A B C XMSs

16Mai-13

Impact of Rigid Matrices & VRF changes on DSP Time

Rigid matrices across 3 steps■ rmp Protein A to MabSelect & SuRe■ Q Sepharose to CaptoQ/HyperD■ SP Sepharose to CEX/HIC/CHT

17Mai-13

Impact of Rigid Matrices, Higher DBCs on Buffer Demand

2x Reduction

18Mai-13

Traditional Buffer Preparation-GMP Production

19Mai-13

Single Use Buffer Prep Pilot Plant, Non -GMP

■ Existing laboratory space, retrofitted with 4*600kg balances and overhead lightning mixers

0 15 30 45 60 75 90 105 1200

50

100

150

200

5

6

7

8

0

2

4

6

8

10

12

Time (min)

Vol

ume

(L)

pH

(-)

Con

duct

ivity

mS

/cm

20Mai-13

Traditional vs. Single Use Buffer Prep

Stainless Buffer Prep 98 m2

128 L/m2.day-maximum

Pros■ Near closed system■ Rapid pressure filling of bags

Cons■ Ageing CIP system■ Inflexible■ Tank schedule conflicts■ 1000L tank most heavily utilized■ Room dedicated to buffer prep

Disposable Buffer Prep 41m2

195 L/m2.day-expandable

Pros■ Highly flexible 50-500L make-up■ No single balance over-utilized■ No CIP, no complicated instructions■ Rapid tank turnaround

Cons■ Slow bag filling (<20L/min)■ Open system!■ Retrofitted room, WFI take-off locations

and heights not optimum for prep tanks■ Not bottom draining

21Mai-13

Disposables… Bags

Impact of rising titres and process complexity on buffer demand in downstream processing

Buffer demand for 12h Protein A recovery operations(2000L batch, 3g/L titre)■ 1 x 500L 0.1M NaOH■ 2 x 500L Equil + PLW1 + PLW3■ 1 x 500L Strip (PEW)■ 1 x 500L PLW2■ 2 x 500L Load■ 1 x 500L Elution buffer■ 2 x 500L Flowthrough■ 1 x 500L Elution waste■ 1 x 500L Levtech Eluate■ 8 different solutions, 6000L/12h!

Impact of rising titres and process complexity on buffer demand in downstream processing

22Mai-13

Intermediate Product Storage in Bags

23Mai-13

Batch Length Always Exceeds Purification Time! – Discuss…

25/0

9/20

06

27/0

9/20

06

29/0

9/20

06

01/1

0/20

06

03/1

0/20

06

05/1

0/20

06

07/1

0/20

06

09/1

0/20

06

11/1

0/20

06

13/1

0/20

06

Val

ue A

dded

Value addedPurification time (h)

Non value addedSetup/Tear downHold/Wait/Delay

3kg 3 step process

One example■ 19 days to complete 59h purification■ 13% value added purification work

Types of Waste■ Defects■ Over Production■ Transportation■ Movement■ Waiting■ Inventory■ Over Processing

24Mai-13

Single Use Chromatography Column and Flowpaths (AKTA Ready)

■ Reduced validation■ No cleaning chemicals■ No utilities - water

■ Reduced turnaround time (75% per step)

■ Reduced cross contamination risk

25Mai-13

Integrated systems, reducing setup/tear down time

■ Offshelf systems replacing bespoke, one off setups.■ Increased reliability, standardisation

26Mai-13

DSP Platform Evolution, Round 3

Primary goals

■ Alleviate DSP bottleneck

■ Focus; v.high titre■ Processing time

■ Hours and days

■ Buffer demand

Process & technology

■ Membrane filtration

■ Focused step optimization■ Binding capacities

27Mai-13

Membrane Chromatography

Functional groups are on inner walls of cross-linked cellulose network

Open pores and accessible ligands mean that there is negligible diffusion required for binding; convection is the rate limiting factor

No need to pack and test a chromatography membrane – “plug and play”

Disposable - no post-use cleaning validation of large chrom columns

Ideal for flow through polishing of impurities

Reduced buffer consumption

Higher flow rates are possible due to larger pores allows much faster processing than packed beds

Con

vect

ion

Diffusion

a

b

28Mai-13

For some IgG >3,000 mg/ml capacities are possible

Loading Capacity for Q Membranes

500 1000 1500 2000 2500 30000

200

400

600

800

1000H

ost C

ell P

rote

in (

ng/m

g)

Loading Capacity (mg/ml)

Load HCP = 952 ng/mg

29Mai-13

Membrane ChromatographyHigh Capacity, Small Size!

Bed volume 3 ml = 6 g/cycle for 2,000 g/L capacity

Bed depth 8 mm15 ml/min (5BV/min)

Bed volume 0.08ml

Bed depth 4mm

0.4ml/min (5 BV/min)

Two 2 units in series � 8 mm bed height, 0.16 ml

= 320 mg/cycle for 2,000 g/L capacity

30Mai-13

Impact of Membrane Chromatography onDSP Time

31Mai-13

Impact of Membrane Chromatography on Buffer Demand

2x Reduction

2x Reduction

32Mai-13

Platform Processes and Technologies Must Be

■ Fast to develop ■ Capable at scale

33Mai-13

Near Future-refining the platform

■ Next Gen■ Protein A?

■ Next Gen■ Virus Filtration

34Mai-13

Conclusions

■ Platform Processes established■ Well established, maturing■ Behaves predictably…with outliers!

■ Platform Technology adoption is increasing■ Disposables, bags, filters, columns, membranes■ Integrated systems; mixing, filtration, UF

■ Execution, competitive advantage■ Rapid development■ GMP Production.

35Mai-13

Acknowledgments

■ Lee Allen

■ Jim Davies

■ Abdel Zemmar

■ Samit Patel

■ Mardon McFarlane

■ Lyndsey Morse

■ Lonza Purification Development