PDA Virtual Training Optimizing Processes 03 2006

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Optimizing Biopharmaceutical Processing

by Value - Added Services

Optimization – Two Prong Approach

2. of an existing process step & chain

Upstream Fermentation | Cell culture tech.

Purification Form | Fill

Media-Filtration-Media bags

Bioreactors Cell harvestingContaminantremoval

Concentration Target purification

Virus removal Sterile filtration

Buffer prep | Filtration

Discovery Pre Clinical Phase I Phase II Phase III Commerical

1. during development & process scaling

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1. Optimization Potential in the Development & Scaling Phase


SequenceSelection

mg

RouteDevelopment

g

ProcessDevelopment

1-10 kg

ProcessScaleup10-50 kg

PilotBatches

100-300 kgCommerical

IND BLA/NDA

Prerequisites:Up & down scalability

Identical design & configuration of either equipment or process

Defined & repeatable & documented test methodologies/results

Constant material composition in all scales

Proper time frame definition & hand-over to next phase

Scale- Up/Down Opportunities

Equipment:

Pumps

Fermentation

Centrifugation

Purification

Filtration

Valves

Concentration

Examples of adequate scalability:

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Why is Scalability Needed ?

Smooth scale-up from development phase, down from process scale

Ease of validation, due to the utilization of existing development phase results

Optimization of processes and improved equipment choice

Performance evaluation of comparable process equipment

Reduction of product losses during testing

Scale-Up/Down – Important Factors

Equipment requires linear scaling (performance predictions)

Equipment design criteria requires to be similar or equal (reproducible results)

Material and components within equipment should not change with scaling (validation & extractable issues)

Process parameters need to be kept (minimum variability)

Process design should stay constant (reproducibility & comparability)

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Involvement of Value – Added Services - Examples


Equipment design & testing

Validation servicesFiling support

Training

New innovativetechnologies

Quality system design

Process design supportProcess step integration

Example Filtration – Equipment design & testing

Filtration area (cm2)

Flow per filter cm²Flow per filter element

Important Factor:Flow per cm² hasto be constant

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Development Phase Optimization – Potential Savings

Biopharmaceutical equipment development focus on small scales:

$ Reduction of multiple validation steps/studies – cost reduction, faster time-to-market

$ Opportunity for process optimization - yield enhancement

$ Reduction of product losses during development – cost reduction, enhanced test numbers

$ Excelleration of regulatory compliance/filing – faster time-to-market

2. Optimization Potential of an Existing Process Step or Chain

Prerequisites:Open minded approach to new technologies and improvements

Up & down scalability

Appropriate test procedures which reflect large scale results

Possibilities of process equipment integration

Validation support & services








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Examples of Technology Changes

Time Frame – a Drug Development Cycle

3 x higher flow2-3 x higher throughput

much less leachablesreliably integrity testablehigher thermal strength

higher flow rateswider retention rating

higher thermal strengtheasy, faster cleaning

full automation

higher sensitivityno user interferencehigh user friendliness

full automationreliable data logging

Examples – Savings by Process Optimization of Sterilizing Filter

Adsorptivity(difference between 85 % down to 25 %per 10“ filter cartridge; depending on the drug product:losses of $ 30 to > $ 65.000per filtration run)

0

10

20

30

40

50

60

70

80

90

IgF

Rec

over

y (%

)

CA PVDF PES1 PES2 PES3 PES4

IgF Adsorption Different Membrane Materials

Sizing/Dead-Volumes(flow rate/throughput enhancementsreduce the required equipment size,i.e. flush volumes, dead-volumes etc.annual potential savings and/or revenue enhancement of $ mil)

0

2040

60

80

100120

140

0.5 1 1.5 2 2.5

Differential Pressure (bar)

Flow

Rat

e (l/

min

)

1. Generation 2. Generation 3. Generation

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Examples – Savings by Process Optimization of Tanks/Mixing

Disposable Mixing(lower capital investment and storage needs due to the elimination of multiple sets of tanks (one for use, one incleaning), no cleaning , i.e. no down-time, higher capacity utilization, multi-product use posibilities, less man hours, less cleaning solution costs – one more batch per week due to higher capacity utilization adds tens of millions of revenue)

Disposable Bags(low or no capital investment, low storage space needs,no cleaning, i.e. no down-time, higher capacity utilization,multi-product use posibilities, less man hours, less cleaningsolution costs - one tank cleaning can take up to 6 hoursand costs up to $ 10,000 per tank total)

Validation Support – Example – Extractable Testing

Blank 24h 50°C 48h 50°C 120h 50°C0

2

4

6

8

10

12

14

16

18

20

22

0

2

4

6

8

10

12

14

16

18

20

22

Gamma-Bag Extraction with DI-Water at 50°C

pH

/ A

cetic

Aci

d [m

g/ l]

Acetic Acid

TOC

pH

Conductivity

TO

C [m

g/l]

/ Con

duct

ivity

[µS

/cm

]

Extraction Time and Temperature

Any polymeric system requires leachable/extractable testing

with the actual product or a model solvent under process

conditions

Value-Added Service

CONFIDENCE®

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Downstream Systems Integration

From Fermentation to Clarification to Concentration to Purification

Source: Sartorius

Source: Sartorius

Source: Kendro/Carr

Source: Sartorius

Source: Sartorius

Examples - Downstream Integration

From Fermentation to Clarification to Concentration to Purification

Source: Bayer AG

Source: Sartorius

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Involvement of Value – Added Services - Examples

Validation services

Optimization services

Filing support

Process integration

Training

Conclusion

Optimization is a two prong approach starting in the developmentphases and continuing in existing processes

Optimization requires appropriate equipment scalability to perform multiple trials at low product losses and requirements

Optimization trials require to be defined to be able to determine the realistic needs; e.g. a 47 mm disc trial can only be used as an indicator trial and has to be verified and assured

Optimization properly performed can create not only savings, butespecially additional revenue; real world example – 1 batch more per week means $ 1.2 bio/year

Optimization tasks & projects can and should be supported by thevalue-added service of the vendor

PDA Virtual Training Optimizing Processes 03 2006

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