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MCSGP Process Development andScale-up with Contichrom ®
Contichrom ® : Benefits using MCSGP
2© ChromaCon - 2012
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 ® & MCSGP explained
3© ChromaCon - 2012
Contichrom ®: All-in -one proces capabilities
Contichrom® Preparative HPLC/FPLC
MCSGP
4© ChromaCon - 2012
Capture-SMB/ SMB
Sequentialchromato-
graphy
Batch Batch
MCSGP process principle: recycle until it‘s pure
Conventional batchchromatography
ChromaCon‘s 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
8© ChromaCon - 2012
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 ® 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 standard 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
10© ChromaCon - 2012
• 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 operational 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
11© ChromaCon - 2012
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 ® segmentation
API Output
1 g/day 10 g/day 100 g/day 1 kg/day 10 kg/day
Contichrom® lab (10/100)Launched03/2012
13© ChromaCon - 2012
Contichrom® pilot 500
Contichrom® process (180 L/hr)
LaunchQ1/2013
Launch12/2012
Contichrom® pilot customizedLaunch12/2012
Contichrom ® 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 ® 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 ® compliance overview
Guideline Distribution for Biotech Manufacturing
Original Vector Gene Sequence
Host Cell Expression Vector
Expression clone
GeneticDevelopment
Q5AQ5BQ5EQ5D
17© ChromaCon - 2012
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
18© ChromaCon - 2012
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 …
19© ChromaCon - 2012
used to determineextent of qualification
materials calibrated …These regulations are
the basis forqualification
ASTM Standard
ISPE C&Q Baseline GuideWhat are the key
elements and principlesto accomplish risk-basedverification/qualification
How to peform the keyelements and
principles from ASTM standard
GMP Contichrom ® 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
22
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)
24
QualityAttributes
(A)
Qualityby
SE
A
P
25© ChromaCon - 2012
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
26
� 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
27© ChromaCon - 2012
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, being a "batch" for the sake of tracking and quality assurance. This interpretation, if accepted, would assist in moving to continuous processing which is by definition a single cycle of manufacture.
� the overall DSP remains batch although instead of one column it is constituted of twin columns (the standard MCSGP configuration)
CMC Regulatory Aspects
Blending Batches of Intermediates or APIs ICH Q7A ( 8.4)� For the purpose of this document, blending is defined as the
process of combining materials within the same specification to produce a homogeneous intermediate or API. In-process mixing of fractions from single batches (e.g., collecting several centrifuge loads from a single crystallization batch) or combining fractions from several batches for further processing is considered to be part
29
from several batches for further processing is considered to be part of the production process and is not considered to be blending.
� Acceptable blending operations include, but are not limited to:� Blending of small batches to increase batch size
� Blending of tailings (i.e., relatively small quantities of isolated material) from batches of the same intermediate or API to form a single batch
CMC Regulatory Aspects - ICH Q11
Development and Manufacture - Critical Quality Attri butes� Product-related impurities can be isolated and characterized more easily
with Contichrom® during development (see Contichrom® in Discovery and Development applications) and the product profile can be tailored and defined based on the pharmacological activity/potency and safety characteristics
� The product profile can then be defined and “frozen” during development
30
� The product profile can then be defined and “frozen” during development and scale-up
� The quality profile of a continuous or a «steady-state» process is much more homogenous than with a batch process due to� No need for API sub-batches
� Stationary phase usage is more homogeneous
� Improved performance
� Scalable process
� Online control: critical quality attributes can be controlled online or at line, compliant with QbD and PAT.
CMC Regulatory Aspects
Possible validation issues for MCSGP� Equipment validation and documentation through FAT/SAT (ex-factory)
and DQ, IQ with supplier and OQ, PQ at customer’s premises
� Process validation � see subsequent slides
� Characterization of the batch process (breakthrough curves with purified molecule and the load)
31
� Process simulation
� Lab tests to verify predicted process
� Resin life study
� Test of robustness, definition of PAR of the process � Design Space
� Implementation at the industrial scale including PQ of equipment
� Process validation at scale
� Virus validation using Labscale Contichrom® equipment or conventional batch column chromatography in a scaled down model, similar to batch chromatography (defined residence time in relation to virus inactivation)
Regulatory Requirements: Guidance for Industry Process V alidation Jan. 2011
1. Process Design: The commercial process is defined during this stage based on knowledge gained through process development and scale up activities. (Perform also former qualification activities: DQ, IQ)
� Verify equipment and utilities “build and installation”
� Verify process operation in all operating ranges, DoE
� Challenge in routine production: loads, interventions and stoppages
� Define critical attributes
� Establish a process control strategy w/out PAT
2. Process Qualification: During this stage, the process design is confirmed as being capable of
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2. Process Qualification: During this stage, the process design is confirmed as being capable of reproducible commercial manufacturing. Including qualification of the facility, utilities and equipment. Definition of Design Space. (Perform also former qualification activities: OQ, PQ)
� Combines qualified equipment and trained personnel with commercial manufacturing process, control procedures and components to produce commercial batches
� Ref. to ASTM E2500 standard on equipment and facility verification
� Process Performance Qualification (PPQ)
3. Continued Process Verification: Maintenance, continuous verification, and process improvement. On-going assurance that routine production process remains in a state of control. Assessed by collecting and monitoring information during commercialisation.
� Continually assure that the process remains in a state of control.
� Continued monitoring at the level established during PQ until significant data is available to generate significant variability estimates.
PV Guideline Structure
33© ChromaCon - 2012
FDA Process Validation Guideline 2011
Stage 1
Process DesignStage 2
Process Qualification
Stage 3
Continuous Verification
Stage 2a
Design of Facility,
Qualification of Utilities,
Stage 2b
Performance
Qualification
ICH Q8
ICH Q9
ICH Q10
34© ChromaCon - 2012
Qualification of Utilities,
Equipment
Qualification
Approach
ASTM
E-2500
ISPE ASTM E-2500 Implementation Guide
Stage 1
Slide Concept – Thanks to Dr. Christopher Smalley, M erck Co. , BioSterile Validation ss Design
ISPE Good Practice Guide-Applied QRM in C&Q
ICH Q11
Validation References
� Guidance for Industry- Process Validation: General Principles and Practices - January 2011 Current Good Manufacturing Practices (CGMP) Revision 1 www.fda.gov/downloads/.../UCM070336.pdf
� Final Version of Annex 15 Title: Qualification and validation to the EU Guide to Good Manufacturing Practice http://ec.europa.eu/health/files/eudralex/vol-4/pdfs-en/v4an15_en.pdf
� ICH Q7a Section 12 on validation
35
� ICH Q7a Section 12 on validation http://www.fda.gov/cder/meeting/ICH_Q7A/index.htm
� ICH Q11 (step 4) http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf
� PDA Technical Report No. 14 (2008) Validation of Column-based Chromatography Processes for the Purification of Proteins
36
Use of the Contichrom® Platform in GMP mfg ensuring compliance, quality
and reduced CAPEX, OPEX
GMP manufacturing
Mammalian MAb Production – Batch Downstream Processin g
IntermediateStorage
IntermediateStorage
ViralFiltration
20m2
Cation ExchangeDia: 1.6mCV: 600LBed: 30cm
Anion ExchangeDia: 1.6mCV: 600L
37© ChromaCon - 2012
BulkFiltration
(BDS)3m2
UF/DF Step80m2
IntermediateStorage
Bed: 30cm Bed:30cm
Hydrophobic InteractionDia: 1.6mCV: 600LBed: 30cm
I.B.ICryoPreservation
System
Mammalian MAb Production – MCSGP Downstream Processin g
IntermediateStorage
ViralFiltration
2m2
Cation ExchangeDia: 16cmCV: 60LBed: 30cm
Anion Exchange or Mixed-modeDia: 16cmCV: 60L
38© ChromaCon - 2012
BulkFiltration
(BDS)0.3m2
UF/DF Step8m2
IntermediateStorage
Bed: 30cm CV: 60LBed:30cm
I.B.ICryoPreservation
System
39
Process Development Issues: product residence time in MCSGP
Transit times for step
� MCSGP can be designed to have same (or shorter) transit time compared to batch
Harvest Capture Polish 1 Polish 2
40
batchchromatography
- Protein A -
batchchromatography
– AIEX -
batchchromatography
– HIC -
Conventionalscheme:
batchchromatography
- Protein A -
MCSGPchromatography
– AIEX -
MCSGPchromatography
- HIC
Optimizedscheme:
Transit time: 72 hrs 48 hrs 48 hrs(example)
Product residence time distribution : batch
� Batch chromatography
product residence
probability
41
� Typical values of product residence time at probability maximum: 0.5hrs-2hrs
product residencetime in unit1hr
Residence time distribution : MCSGP� MCSGP chromatography
product residence
probability
batch
MCSGP
1hr
42
� Typical values of residence time at probability maximum: same as batch
� Residence time distribution is broader than in batch
� Residence time distribution in MCSGP can be designed
� The more compound is recycled, the broader the residence time distribution
� Maximum residence time in MCSGP ca. 2-4x batch residence time
product residencetime in unit
1hr
43
Process Development Issues: MCSGP Process Robustness
Example 1: varying mAb profilesFeed Product
Avastin®(Bevacizumab)
(variable isoform content) (Contichrom-purified)
44
Erbitux®(Cetuximab)
Herceptin®(Trastuzumab)
Ref: T. Müller-Späth, M. Krättli, L. Aumann, G. Ströhlein, M. Morbidelli: Increasing the Activityof Monoclonal AntibodyTherapeutics by ContinuousChromatography (MCSGP), Biotechnology andBioengineering, Volume 107, Issue 4, pages 652-662, 1 November 2010
Example 2: varying mAb profiles
� Robustness of process against feed quality variations� Feed spiked with mAb isoforms
Blue: Regula Feed
Blue:
Feed Product
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Regular FeedRed: High W feed
FeedBlue: Regular FeedRed: Spiked feed
Blue: Regular FeedRed: Spiked feed
MCSGP product purity: Not affected by change of fee d.
Purified with same MCSGP process conditions
Biotechnology and Bioengineering 107(4):652–662