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Modeling and Process Control Strategies for Efficient

Manufacturing

IBC Asia BioProcess & Technology Summit 2015 28-29 October, Singapore

Mayank GargShantha Biotechnics Private Limited (A Sanofi Company)

Presentation snapshot

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● Statistical Process Control (SPC) within Quality by Design (QbD) framework

● Driver for SPC

● SPC and beyond

● Univariate and Multivariate SPC

● Process Characterization post commercialization

● Cost-benefit analysis of Real-time SPC/PAT

SPC within QbD framework

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization● Cost-benefit analysis of Real-time SPC/PAT

Product Design

Process Design

Continuous Improveme

ntProcess

Monitoring/ Control strategy

CQA

CpK

Design Space(V1)

Design Space(V2)

Critical Process Parameters

Critical Raw MaterialsRaw Materials

Process Parameters

Driver for SPC

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization

x

y

z

Key Performance Indicator

Input Output

Current ObjectiveSPC

CQA

CpK <1 CpK >1

Significant effect of input on CQA

Strong relationship of output parameters on CQA

● Cost-benefit analysis of Real-time SPC/PAT

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization

W A ShewhartUnivariate Control charts1920s

Multivariate Control chartsH. Hotelling

Principal Component Analysis (PCA)H. Hotelling

CUSUM & EWMA chartsE.S. Page and Roberts

Partial Least Square (PLS)H. Wold

2004 Process Analytical Technology (PAT)

1930s

1940s

1950s

1970s

FDA

• DOE• Process Analyzer• Data Analysis• Process Monitoring• Process Controllers• Knowledge/Risk Management• Continuous Improvement

SPC and beyondMajor Milestones

● Cost-benefit analysis of Real-time SPC/PAT

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization

Univariate to MultivariateOut of Control

Univariate

● Cost-benefit analysis of Real-time SPC/PAT

1σ

1σ

2σ

2σ

3σ

3σ

CUSUM plot

CUSUM plot

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization

Univariate

Univariate to MultivariateOut of Control

● Cost-benefit analysis of Real-time SPC/PAT

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization

Bivariate

Multivariate

Univariate<<<<

Score plot

Univariate to MultivariateOut of Control

● Cost-benefit analysis of Real-time SPC/PAT

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization

Variables

Age

Batche

s

Process Data

Univariate to MultivariateOut of Control

Univariate Data Online Data Profile Data Analytical Data

● Cost-benefit analysis of Real-time SPC/PAT

Process CharacterizationPost Commercial Launch

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization

Process Data Acquisition Data Modeling

Process control

Improvement

Trials/DOELiterature

Deviation/FailureInvestigations

Com

mer

cial

Sca

le

Lab/Pilot Scale

Multi-stage approach

● Cost-benefit analysis of Real-time SPC/PAT

Relationship of Input parameters with CQAs

Relationship of Output parameters with CQAs

Relationship of KPIs with Input parameters

Stage 1

Stage 2Stage 3

Process CharacterizationPost Commercial Launch

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization

Identification of CPPs

Severity(Statistical Modeling)

y

n

Occurrence(Screening analysis)

Univariate CpK (against spec)

Multivariate One-time (against golden batch/control limits)

Multivariate Time-series (against golden batch/control limits)

Multivariate regression models (relationship of Selected PPs with CQAs)

Con

trol S

trate

gy

Design Space

! It is preferred to study Multiple steps at once

Stage 1

Experience(DOE + Literature)

Input variables

● Cost-benefit analysis of Real-time SPC/PAT

DOE CPPs

Relationship of PPs with CQAs

Process CharacterizationPost Commercial Launch

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization

Severity(Statistical Modeling)

y

n

Occurrence(Screening analysis)

Univariate CpK/OOT (against spec/control limits)Multivariate One-time

(against golden batch/control limits)Multivariate Time-series

(against golden batch/control limits)

Multivariate regression models (relationship of Selected PIs with CQAs)

Stage 2

● Cost-benefit analysis of Real-time SPC/PAT

Identification of KPIs

! It is preferred to study Multiple steps at once

Relationship of Output with CQAs

Process CharacterizationPost Commercial Launch

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization

y

n

Stage 3

Severity(Mechanistic + MV Statistical modeling)

Mechanistic and MV predictive models (relationship of Selected PPs with KPIs)

● Cost-benefit analysis of Real-time SPC/PAT

Identification of CPPs

! It is preferred to study Individual steps

Design Space

DOE

CPPs

Relationship of KPIs with PPs

Process CharacterizationPost Commercial Launch

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate to Multivariate SPC● Process Characterization post commercialization

y

n

Feed back to the controller

Real-time Analyzers for KPIs(Direct or surrogate analytical

methods)

Feedback loop with Actuator

● Cost-benefit analysis of Real-time SPC/PAT

Identification of CPPs

Severity(Mechanistic + MV Statistical modeling)

Mechanistic and MV predictive models (relationship of Selected PPs with KPIs)

Design Space

DOE

CPPs

Stage 3 Relationship of KPIs with PPs

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate and Multivariate SPC● Process Characterization post commercialization● Cost benefit analysis of Real-time SPC/PAT

Cost benefit analysisCapital Investment

Process AnalyzersNIR,IR, FTIR, NMR, MS, LCMS, GC etc

Data Acquisition/AggregationSCADA, PI System, LIMS, Middleware, Historian Server, etc

Data Analysis/VisualizationSIMCA, JMP, ProcessPad, PI Procesbook, etc

Process Controller/AutomationFeedback control loops, Control valve actuators, etc

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● SPC within Quality by Design (QbD) framework● Driver for SPC● SPC and beyond● Univariate and Multivariate SPC● Process Characterization post commercialization● Cost benefit analysis of Real-time SPC/PAT

Cost benefit analysisAdvantages

• Lower failure rate• Higher productivity• Improved robustness• Lower FTEs• Cycle time reduction• Higher plant efficiency• Improved Product Quality• Quicker investigations• Lower QC testing• Higher Regulatory acceptability

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Thank you