mcsgp process development - uvison · establish a process control strategy w/out pat 2. process...

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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


Contichrom ®: All-in -one proces capabilities

Contichrom® Preparative HPLC/FPLC

MCSGP


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


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


• 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


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


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


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


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 …


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

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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


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


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)


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

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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

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� 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.


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)

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� 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


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


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

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� 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

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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


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


BulkFiltration

(BDS)0.3m2

UF/DF Step8m2

IntermediateStorage

Bed: 30cm CV: 60LBed:30cm

I.B.ICryoPreservation

System

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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

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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

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� 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

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� 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

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Process Development Issues: MCSGP Process Robustness

Example 1: varying mAb profilesFeed Product

Avastin®(Bevacizumab)

(variable isoform content) (Contichrom-purified)

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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

mcsgp process development - uvison · establish a process control strategy w/out pat 2. process...

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