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MCSGP Process Development andScale-up with Contichrom fi
Contichrom fi : Benefits using MCSGP
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ENABLES the large volume purification
of chemicals and biologics
the generation of lifecycle extensions for marketedbiologics
SAVES 30% CAPEX & 50% OPEX
Purity increase by 50%
Yield increase by 50%
Throughput increase 10x
Buffer reduction by 75%
ACCELERATES
Discovery of leads
Development retaining
product profile at upscaling
Contichrom fi & MCSGP explained
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Contichrom fi : All-in -one proces capabilities
Contichromfi Preparative HPLC/FPLC
MCSGP
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Capture-SMB / SMB
Sequentialchromato-
graphy
Batch Batch
MCSGP process principle: recycle until its pure
Conventional batchchromatography
ChromaCons novelinternal recycling chromatography
(MCSGP)Reprocess impure
productimpureproduct to waste
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time
more and purer product
time
pure product
to waste
Cut narrow = obtain purer product
Contichrom : all-in -one process solutions
Process challenge
Ternary separation Binary separation
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Very difficultseparation
i.e. product-relatedimpurities
MCSGP
Difficult separationi.e. Biologics
MCSGP
Baseline separated
Batch
Difficult separation
SMB
Baseline separated
Batch
Batch to MCSGP process switch
Record design batch chromatogram
Fraction analysis
Separation? no
Resin / buffer / loading conditions
Batch
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MCSGP run
Yield/ Purity OK MCSGP fine-tuning
End
yes
no
yes
MCSGP Design (Wizard)
MCSGP
MCSGP process development
productquality
Required Thresholdquality
Threshold quality = scalable process+ purity+ controlled impurities+ economic yield
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Time of processdevelopment
In order to achieve a required threshold quality wi th an optimized batch process, extensive process developme nt has to be performed. Switching to MCSGP from a simple, non-optimized batch process yields a superior product qu ality in a shorter time
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Contichrom Software
Contichrom fi software
Wizards with graphical user interface for easy method programming Automated conversion from batch to MCSGP process Extensive library of pre-defined methods for all standa rd operations
Fast and secure process developmentFast and secure process development
Intuitive software for operation of batch and MCSGP Active flow path highlighted in flowsheet
Easy to operateEasy to operate
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Active flow path highlighted in flowsheet Pause/continue functionality, even for continuous chromatographic operations
Detailed evaluation capabilities with standardized PDF reports Data export functions
Integrated evaluation and reportingIntegrated evaluation and reporting
Full audit trail and change control User management hierarchy provides high operationa l and data security FDA 21 CFR Part 11 compliant
Full data security and traceabilityFull data security and traceability
Step 1:retrieve chosenchromatogram ofbatch run fromdatabase
Automated conversion of batch to MCSGP method
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Step 2: interactive definitionof product range (red) andrecycling fractions (blue): pull bars to defineboundaries (dotted lines)
Step 3:push button to convert batch toMCSGP process
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Contichrom Equipment Segmentation and Partners
Contichrom fi segmentation
API Output
1 g/day 10 g/day 100 g/day 1 kg/day 10 kg/day
Contichromfi lab (10/100)Launched03/2012
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Contichromfi pilot 500
Contichromfi process (180 L/hr)
LaunchQ1/2013
Launch12/2012
Contichromfi pilot customizedLaunch12/2012
Contichrom fi Supply Chain
Equipment Manufacturing
For Lab & small molecule pilot scale
For Pilot Scale GMP(Biologics)
Distribution & after sales service
Lab-scale & small molecule pilotscale: KNAUER and partnersworldwide, BJCXTH in BRIC countries
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For Pilot Scale GMP(Biologics)
For Process Scale
For pilot scale GMP: Pilot 500 (off-theshelf standardized design) orcustomized pilot-scale design: worldwide through partners
For process scale: customizeddesign with qualified engineeringpartners: worldwide through partners
Contichrom fi Supply Chain
Lab-10: 8-10 weeks (130k$) Pilot-500 GMP (500 ml/min):
(off-the-shelf version is under development, currently only an custom engineered solution is available, delivery time from order ca. 9 month),
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available, delivery time from order ca. 9 month), estimated 300k$
Process: is always a custom engineered solution, delivery time currently ca. 12 month), price depends on output and extras, an offer can be compiled by M+W Process Industries and/or NNE who have detailed insight in the equipment
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Contichrom fi compliance overview
Guideline Distribution for Biotech Manufacturing
Original Vector Gene Sequence
Host Cell Expression Vector
Expression clone
GeneticDevelopment
Q5AQ5BQ5EQ5D
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Master Cell Bank MCB
Fermentation
Working Cell Bank WCB
Purification
Drug Substance
Sterile Filtration Aseptic Filling
Drug Product
Cell banks
Drug SubstanceProduction
Drug ProductProduction
Q5D
Q5AQ5CQ5EQ6BQ11
Q5EQ6BQ8R2
M4Q9Q10
M4Q9Q7
Applicable ICH Guidelines
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ICH Q11 Development and Manufacture of Drug Substance
ASTM, GMP and Guidelines Interrelations
Japan GMPs
ICH Q9
EU GMPsUS GMPs
Quality RiskManagement can beused to determine
Elements shall besuitable..correct
materials calibrated
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used to determineextent of qualification
materials calibrated These regulations are
the basis forqualification
ASTM Standard
ISPE C&Q Baseline GuideWhat are the keyelements and principles
to accomplish risk-basedverification/qualification
How to peform the keyelements and
principles from ASTM standard
GMP Contichrom fi equipment - Standards
Customized equipment designed and produced by partnerengineering companies (e.g. M+W, NNE Pharmaplan)
Compliant with all applicable standards for biopharmaceuticalprocess equipment such as ASME, ASTM
Compliant with ASTM E 2500-07: standard guide for specification, design and verification of pharmaceutical and biopharmaceutical
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design and verification of pharmaceutical and biopharmaceuticalmanufacturing systems and equipment,
Compliant with 21 CFR Part 11: Code of Federal Regulations: electronic records and electronic signatures
Compliant with EU GMP Annex 11 and Chapter 4: Regulations forcomputerized systems
ASTM E 2500-07 Standard
A standard approach for validating equipment, facilities, processes Streamlined process Risk based (ICH Q9 Quality Risk Mgm) QbD develop then employ best practices
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QbD develop then employ best practices More consistent qualification Supports current regulatory guidance (FDA, ICH)
- Knowledge (expert) based- Risk based
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Process development andValidation Issues
Quality by Design (QbD )
A central concept in quality is that quality can not be tested for. Quality must be designed and built into the production process (QbD)
For the equipment this means that the equipment design and the associated process is crucial. Thus
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design and the associated process is crucial. Thus the MCSGP process in conjunction with the equipment must be designed
Relevant Guidelines: ICH Q7-11 and the new FDA Process validation guideline (Jan 2011)
In addition, for some intrinsic equipment features, applicable standards such as ASME, ASTM E 2500 are applied
QbD
SafetyEfficacy
(SE)
Manufact.Process
(P)
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QualityAttributes
(A)
Qualityby
SE
A
P
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byDesign
Ref: Moheb Nasr
SE
A
P
QbD
QbD approaches most relevant for downstream: Through risk assessment, identify parameters that
could impact product quality and process performance. Use this information to design uni- and multi-variateprocess characterization studies
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Use of scale-down models for process characterizationstudies to define design space
Development of a linkage model for all chromatographic DSP steps to define overall design space
SE
A
PSE
A
P Translating CQA to a Manufacturing Design Space
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CMC Regulatory Aspects
Batch definition: defined by the process strategy, starting material (fermentation batch),
formulation quantity
A specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits, and is produced according to a single manufacturing order during the same cycle of manufacture
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manufacture
It appears, therefore, that regulatory definitions are already in place to support the concept of a period of time,
