31/01/14 MSAT Strategies for Manufacturing Excellence
in Pharma & BioPharma: QbD 2.0
Jose C. Menezes, PhD
Technical University of Lisbon, Portugal
Founder of 4Tune Engineering Ltd
Joao E. Machado, MSc | Pedro Felizardo, PhD
4Tune Engineering Ltd
be#er processes, be#er products © QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
Outline
! Introduction
Bio/Pharma QbD 1.0
! Current QbD/PAT Practice
Sample, Process-Step, Production Line, Life-Cycle
! MSAT Strategies: QbD 2.0
Manufacturing Excellence over Life-Cycle
! Conclusions
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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1 31/01/14 Generally Accepted QbD Workflow
ISPE PQLI Guide, 2011 -­‐ update from Pharm. Eng. (2010),30(2),1-­‐6
FDA, EMA & ICH
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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Foundations of QbD
as Manufacturing Science
Joseph M. Juran (1904-2008)
The “father of quality”
Quality Planning, Quality Control, Quality Improvement
William E. Deming (1900-1993)
The “father of modern quality control”
Plan-Do-Check-Act
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2 31/01/14 Juran’s Quality Planning Matrix
Juran JM (1992), Juran on Quality By Design, Bass J Ed.
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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Juran’s QC Matrix vs. QbD
Patients
TPPs
TPPs
CQAs
CQAs
CPPs
CPPs
Design
Space
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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3 31/01/14 Current Thinking on QbD
1987 Validation Guidance Revised
The lifecycle concept links product and process development, qualifica7on of the commercial manufacturing process, and maintenance of the process in a state of c o n t r o l d u r i n g r o u 7 n e c o m m e r c i a l produc7on. Related Guidelines: ICH Q8, Q9, Q10 and Q11 Related Concepts: Design Space (DS), DOE & QbD, Process Analy7cal Technology (PAT) QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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QbD’s Tools & Implementation Stages
•  QbD Tools
①  Risk-Assessment on Prior Knowledge
②  Design of Experiments (DoE) and PAT Tools
③  Multivariate Process Data Analysis (MVA), Modeling &
Control
④  Continuous Improvement over Life-Cycle (LCM)
•  QbD Implementation Stages
① 
② 
③ 
④ 
Product Realization
Process Development
Process Industrialization
Product Routine Manufacturing
1
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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4 31/01/14 The First Decade of PAT & QbD in Pharma
Data, InformaAon, Knowledge, Intelligence Letters, Words, Phrases, Texts
Spelling, Vocabulary, Grammar, Meaning
Can you read this ?
if yuo cna raed tihs, yuo hvae a sgtrane mnid too !
Cna yuo raed tihs? Olny 55 plepoe out of 100 can.
i cdnuolt blveiee taht I cluod aulaclty uesdnatnrd waht I was rdanieg. The
phaonmneal pweor of the hmuan mnid, aoccdrnig to a rscheearch at
Cmabrigde Uinervtisy, it dseno't mtaetr in waht oerdr the ltteres in a wrod
are, the olny iproamtnt tihng is taht the frsit and lsat ltteer be in the rghit
pclae. The rset can be a taotl mses and you can sitll raed it whotuit a
pboerlm. Tihs is bcuseae the huamn mnid deos
not raed ervey lteter by istlef, but the wrod as a wlohe.
Azanmig huh? yaeh and I awlyas tghuhot slpeling
was ipmorantt !
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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Is QbD more expensive ?
Price per Product Unit Design for Six-Sigma (DfSS)
slide adapted from “Design for Six-Sigma”, SKF (Sweden)
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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5 31/01/14 Outline
! Introduction
Bio/Pharma QbD 1.0
! Current QbD/PAT Practice
Sample, Process-Step, Production Line, Life-Cycle
! MSAT Strategies: QbD 2.0
Manufacturing Excellence over Life-Cycle
! Conclusions
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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Process Development & Manufacturing
Sample, Process-Step, Production Line, Life-Cycle
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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6 31/01/14 Systems Engineering
Process & Information Flows
...
SYSTEM*
INPUTS
CPPs operating variables
•  Ability to understand parts •  See interconnecAons ...
OUTPUTS
CQAs quality specs
•  Ask “what-­‐if” quesAons •  Be capable of system redesign ________________________________________________
* production-line, process-step, analytical-instrument
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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PAT is at the center of QbD !
ISPE PQLI Guide (2011)
Pharm. Eng. (2010),30(2),1-6
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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7 31/01/14 Lessons we have learned ?
! PAT Monitoring
Measure whole samples to assess process, not sample
parameters
! Batch Processing
1st sample is not just one more sample
! Consecutive Batch Steps
End-to-End Analysis
! PAT Solutions
Support QbD over the life-cycle not just processunderstanding
! QbD Solutions
Consistency across different implementations within same
technology (process/product) platform
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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Consistency of QbD Implementations
requires knowledge-­‐management approaches !   over batch history !   during development and during manufacturing !   analysis of several runs of same unit-­‐opera7on !   across process flow-­‐sheet !   during manufacturing !   same lot throughout several unit-­‐ops !   over process history !   integra7ng development and manufacturing !   end-­‐to-­‐end process analysis throughout life-­‐cycle QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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8 31/01/14 Outline
! Introduction
Bio/Pharma QbD 1.0
! Current QbD/PAT Practice
Sample, Process-Step, Production Line, Life-Cycle
! MSAT Strategies: QbD 2.0
Manufacturing Excellence over Life-Cycle
! Conclusions
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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Manufacturing Excellence
§  Operational Excellence
§  There is no clear-cut definition of OPEX either in
theory or in practice.
§  The overuse of OPEX to name almost every
improvement activity launched at an
organization, obscured rather clarified its
meaning.
Friedli et al. (2010)
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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9 31/01/14 What sets Excellent Manufacturing Sites
apart from weaker performing ones
Supply
Chain
Unit Op
#1
Unit Op
#2
CPP1
CPP2
CPP…
CPP1
CPP2
CPP…
CQA1
CQA2
CQA…
…
CQA1
CQA2
CQA…
Unit Op
#...
CPP1
CPP2
CPP…
Unit Op
#n
CQA1
CQA2
CQA…
CPP1
CPP2
CPP…
TPP
CQA1
CQA2
CQA…
KPI’s
KPI’s
KPI’s
Excellent Manufacturing Sites have higher performance on a holistic level !
In almost all cases this is not achieved by having all KPIs at their best values.
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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Thinking in Systems: : End-to-End
Implies the holistic (end-to-end) consideration of the system
Drug Substance
Manufacturing
Supply
Chain
Unit Op
#1
Unit Op
#2
…
Unit Op
#...
Unit Op
#n
TPP
Drug Product
Manufacturing
Supply
Chain
Unit Op
#1
Unit Op
#2
…
Unit Op
#...
Unit Op
#n
TPP
Biologics
Manufacturing
Supply
Chain
Unit Op
#1
Unit Op
#2
…
Unit Op
#...
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
Unit Op
#n
TPP
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10 31/01/14 Thinking in Systems: over Life-Cycle
Implies the holistic (end-to-end) consideration of the system
Process Version #1
Supply
Chain
Unit Op
#1
Unit Op
#2
…
Unit Op
#...
Unit Op
#n
TPP
Unit Op
#n
TPP
Unit Op
#n
TPP
Process Version #2
Supply
Chain
Unit Op
#1
…
Unit Op
#...
Process Version #m
Supply
Chain
Unit Op
#1
Unit Op
#2
…
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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A Subtle Change (2011 -)
a move towards a Systems view
Pharm. Eng. (2010),30(2),1-­‐6 ISPE PQLI Guide, 2011 !   Incremental improvements: minor changes over batch-history
!   “Disruptive” improvements: major changes over life-cycle
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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11 31/01/14 Lean-Six Sigma vs PAT-QbD
for already existing processes/products
• 
• 
• 
• 
Lean
Manufacturing Eliminates Waste Standardizes work Con7nuous Flow Pull strategy Six Sigma
• 
• 
• 
• 
Minimizes process varia7on Stable and predictable process results. Improves process understanding Iden7fy & control causes of defects Focus on Accuracy
Focus on ProducAvity Lean Six Sigma (LSS)
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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A Systems-Engineering Approach
DIKI* Solutions
Intelligence
for your data
to PAT/QbD
Implementations
Data
Information
Knowledge
Intelligence
Added value increase
Unit
operations
Process
Products
Overall
system
Monitor
Control
Quality
Continuous
improvement
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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12 31/01/14 World-Class (Class A) Performance
Manufacturing-­‐Sciences (QbD based) + Manufacturing-­‐Technologies (OE based) applied on an holisAc (end-­‐to-­‐end) sense over the life-­‐cycle MSAT
adapted from Friedli et al. (2010)
The Pathway to Operational
Excellence in the Pharma Industry.
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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The 1st Decade of PAT & QbD in Pharma
Several Guidelines & Guidances: e.g., ICH Q8 through Q11
ICH Q11 (May, 2012) “QbD/PAT Inside”
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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13 31/01/14 QbD 2.0: MSAT Approaches
•  for existing Processes & Products: QbD 1.0
–  PAT Tools
≈
–  QbD Implementations ≈
LEAN
(better processes)
SIX SIGMA (better products)
QbD 1.0: design is based on KPIs of individual steps
•  for new Processes & Products: QbD 2.0
–  DFSS
–  OE
–  KM
End-to-End systems-thinking
Performance is defined on a holistic level
Part of Life-Cycle of QbD Fillings & Implementations
QbD 2.0: Manufacturing Excellence through MSAT approaches
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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Outline
! Introduction
Bio/Pharma QbD 1.0
! Current QbD/PAT Practice
Sample, Process-Step, Production Line, Life-Cycle
! MSAT Strategies: QbD 2.0
Manufacturing Excellence over Life-Cycle
! Conclusions
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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14 31/01/14 MSAT: QbD 2.0
Manufacturing-Sciences & Technologies
•  QbD & PAT align with L6S
for implementations to existing processes & products
•  Systems-Thinking a Must !
designing for Six-Sigma Performance over Life-Cycle
•  For any process & product (new or existing)
Manufacturing-Sciences (QbD) and ManufacturingTechnologies (OE) must be applied holistic (end-to-end)
over life-cycle.
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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The Future of Manufacturing
www.plattform-i40.de
• 
• 
• 
• 
Horizontal integration through value network
End-to-end integration of engineering across the entire value chain
Vertical integration and networked manufacturing systems
Holistic systems engineering spanning the different technical disciplines.
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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15 31/01/14 better processes, better products ©
Thank you !
[email protected]
tune (verb) adapt, adjust, conform, fix, integrate, modulate, regulate, Gghten, bring into harmony QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
booth # 203 QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
16 31/01/14 Q&A Discussion Points
• 
Manufacturing-Sciences & Technologies (MSAT) align different
disciplines to support technical operations.
• 
Quality as a manufacturing-science established in other processing
industries +25 years ago made recently its way into pharma and
biopharma manufacturing.
• 
As the first decade of PAT and QbD ends, these new disciplines are
being adopted and are reshaping the bio/pharma industries.
• 
Even if the paradigm of process monitoring intensification combined
with science-based process engineering has been transforming the
way process industrialization and higher product quality consistency is
performed, there are still several road-blocks to be overcome.
QbD 2.0: MSAT for Manufacturing Excellence | IFPAC 2014, Washington DC (US)| Jan. 22-24st, 2014 | © 4Tune Engineering 2014
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