Penwest MCC E5B8L80X Brooklyn

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QUALITY BY DESIGN The Means To Fundamental
Manufacturing Science
G.K.Raju, Ph.D.
Sept 17th 2003
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OUTLINE

• MOTIVATION
• MANUFACTURING SCIENCE DIMENSIONS
• QUALITY BY DESIGN THE LEVERAGES
• QUALITY BY DESIGN THE COMPONENTS
• CONSIDERATIONS

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MANUFACTURING SYSTEM

• A manufacturing system is set of processes and
  systems (and people) bound by a common material
  and information flow.

Information
Information
Material
Material
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PHARMACEUTICAL MANUFACTURING SYSTEM
SPACE
RESEARCH
QUALITY
ACTIVE
FORMULN
FILL
PACK
DEVELOPMENT
TIME
ACTIVE
FORMULN
FILL
PACK
COST
MANUFACTURING
ACTIVE
FORMULN
FILL
PACK
SAFETY
TIME
5
PROCESS A WITH QC TESTS
BLEND
STEP
FB DRY
DRY MIX
WEIGHING
WET GRANULATION
STEP
ENCAPSULATE
SIEVE
QC1
QC3
QC4
QC2

• Particle Size

• LOD

• API
• MICRO

• Description
• ID
• Assay
• CU
• Impurity
• Dissolution
• MICRO

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QUALITY TESTING END OF LINECONSUMES
SIGNIFICANT TIME
Overall Cycle Time Components
25
20
15
TIME
(Days)
Process Times
10
QC Testing Times
5
0
A
B
C
D
E
F
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QUALITY TESTING END OF LINE MAKES IT DIFFICULT
TO UNDERSTAND EXCEPTIONS
Lots with Exceptions
Lots without Exceptions
OVERALL CYCLE TIMES
0
100
200
300
400
500
600
700
800
LOT NUMBER
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PHARMA MANUFACTURING CYCLE TIMES (DAYS)HALF A
YEAR, LITTLE IMPROVEMENT.
Derived from COGS numbers
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OUTLINE

• MOTIVATION
• MANUFACTURING SCIENCE DIMENSIONS
• QUALITY BY DESIGN THE LEVERAGES
• QUALITY BY DESIGN THE COMPONENTS
• CONSIDERATIONS

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MANUFACTURING SCIENCEDIMENSIONS

• Body of
• Knowledge, Laws, Principles
• Involved In The Transformation of
• Materials and Information into Goods
• for the Satisfaction of Human Needs

Extent Of Mfg. Science
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MANUFACTURING SCIENCE Levels of Knowledge
LEVEL 5
First Principles
Extent Of Mfg. Science Or Quality By Design
MECHANISTIC KNOWLEDGE
LEVEL 4
LEVEL 3
CAUSAL KNOWLEDGE Why?
PROCESS KNOWLEDGE How, Correlative ..
LEVEL 2
DESCRIPTIVE KNOWLEDGE What, Etc,
LEVEL 1
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MANUFACTURING SCIENCEThe Time DimensionTHE
DESIRED STATE
Right First Time
LEVEL 5
Manufacturing Centric Approach to Manufacturing
Science (learning by doing)
Design/Development Centric Approach Manufacturing
Science (learning before doing)
LEVEL 4
Extent Of Mfg. Science
LEVEL 3
LEVEL 2
FDA Minimum Requirement
LEVEL 1
Time
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EXTENT OF MANUFACTURING SCIENCECOST, QUALITY
AND TIME OPPORTUNITY
Right First Time
Desired
LEVEL 5
Cost Quality Time Opportunity
Design/Development Centric Approach Manufacturing
Science (learning before doing)
LEVEL 4
Manufacturing Centric Approach to Manufacturing
Science (learning by doing)
Extent Of Mfg. Science
LEVEL 3
Actual
LEVEL 2
FDA Minimum Requirement
LEVEL 1
Time
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OUTLINE

• MOTIVATION
• MANUFACTURING SCIENCE DIMENSIONS
• QUALITY BY DESIGN THE LEVERAGES
• QUALITY BY DESIGN THE COMPONENTS
• CONSIDERATIONS

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QUALITY BY DESIGNTHE LEVERAGES
Right First Time
LEVEL 5
Extent Of Mfg. Science Or Quality By Design
Manufacturing Centric Approach to Manufacturing
Science (learning by doing)
LEVEL 4
Strategic Leverage
Tactical Leverage
LEVEL 3
Design/Development Centric Approach Manufacturing
Science (learning before doing)
LEVEL 2
FDA Minimum Requirement
LEVEL 1
Time
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QUALITY BY DESIGNSTRATEGIC LEVERAGE Learning
Before Doing

• Significantly Enhanced Level of Product Process
  Understanding BEFORE Commercial Manufacturing
• Enables Mechanistic Basis for Setting Product and
  Process Quality Specifications
• Impact Over Whole Lifecycle
• Easier to Make Fundamental Process Design Changes
  (Fewer Regulatory Barriers)

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QUALITY BY DESIGNSTRATEGIC LEVERAGE Learning
By Doing

• Enhanced Level of Product Process
  Understanding DURING Commercial Manufacturing
• Potential To Leverage Large Amounts of Production
  Data
• Investigation/Exceptions Provide Opportunity To
  Learn
• Difficult to Make Significant Product Process
  Changes
• Rarely an environment to develop mechanistic
  understanding

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QUALITY BY DESIGN A PROCESS ROADMAP
LEVEL 5 OPTIMIZING
FILM COATING
BOTTLE PACKAGING
COMPRESS
WEIGHING
BLEND
LEVEL 4 MANAGED
LEVEL 3 DEFINED
FILM COATING
BOTTLE PACKAGING
GRANULATION
MILLING
COMPRESS
WEIGHING
FB DRY
BLEND
LEVEL 2 REPEATABLE
LEVEL 1 INITIAL
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OUTLINE

• MOTIVATION
• MANUFACTURING SCIENCE DIMENSIONS
• QUALITY BY DESIGN THE LEVERAGES
• QUALITY BY DESIGN THE COMPONENTS
• CONSIDERATIONS

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QUALITY BY DESIGNCOMPONENTS
Extent Of Manufacturing Science Or Quality By
Design
PROCESS PRODUCT
Y F(X)
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COMPONENTS OF QUALITY BY DESIGNA-PRIORI
KNOWLEDGE

• How Much Was Known About This Product Process
  Before?
• API
• Excipients
• Etc.
• What Kind of A-Priori Knowledge Exists?
• First Principle Knowledge
• Mechanistic Knowledge
• Causal Knowledge
• Correlative Knowledge
• Descriptive Knowledge

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COMPONENTS OF QUALITY BY DESIGNINFORMATION
EXCHANGE EXTENT AND TYPE
WHAT IS THE QUALITY AND QUANTITY OF DATA USED
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ON-LINE TECHNOLOGY IMPACTSDOMINANT CYCLE TIMES
On-line LIF, NIR, Pattern Recognition, etc.
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MANUFACTURING SYSTEM ROADMAP CURRENT Relative
To DESIRED State
LEVEL 5 OPTIMIZING
FILM COATING
BOTTLE PACKAGING
COMPRESS
WEIGHING
BLEND
LEVEL 4 MANAGED
LEVEL 3 DEFINED
FILM COATING
BOTTLE PACKAGING
GRANULATION
MILLING
COMPRESS
WEIGHING
FB DRY
BLEND
CURRENT STATE
LEVEL 2 REPEATABLE
Minimum Requirement
LEVEL 1 INITIAL
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COMPONENTS OF QUALITY BY DESIGNPERFORMANCE
MEASUREMENT

• Safety and Efficacy
• Process Capability Associated With
  Critical-To-Quality (CTQ) Variables
• Variability of Critical-To-Quality Variables
• Predictive Ability Of Performance

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MANUFACTURING SCIENCE DESIRED RELATIVE TO
CURRENT STATE(Personal Opinion)
Right First Time
LEVEL 5
Design/Development Centric Approach Manufacturing
Science (learning before doing)
Manufacturing Centric Approach to Manufacturing
Science (learning by doing)
LEVEL 4
Extent Of Mfg. Science
LEVEL 3
LEVEL 2
FDA Minimum Requirement
LEVEL 1
Time
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OUTLINE

• MOTIVATION
• MANUFACTURING SCIENCE DIMENSIONS
• QUALITY BY DESIGN THE LEVERAGES
• QUALITY BY DESIGN THE COMPONENTS
• CONSIDERATIONS

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QUALITY BY DESIGNIS THE EXTENT OF RIGHT FIRST
TIME
CONSENT DECREE
WARNING LETTER
Time ( cost) Associated With Addressing
Cause For Not Being Right
External Failure
Common Focus
FDA 483
RECALLS
COMPLAINTS
Internal Failure
REJECTS
QA APPROVAL
Appraisal
FINAL QC TESTING
IN-PROCESS TESTING
DEVELOPMENT
Prevention
Where Right is Measured
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MANUFACTURING SCIENCE IMPLICATIONS
LEVEL 5
LEVEL 5
First Principles

• Lower Risk
• Higher
• Process
• Understanding
• Lower
• Variability
• Lower
• Costs

Extent Of Mfg. Science Or Quality By Design
LEVEL 4
MECHANISTIC KNOWLEDGE
LEVEL 3
CAUSAL KNOWLEDGE Why?
PROCESS KNOWLEDGE How, Correlative ..
LEVEL 2
DESCRIPTIVE KNOWLEDGE What, Etc,
LEVEL 1
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MANUFACTURING SCIENCE IMPLICATIONS
LEVEL 5
First Principles
LEVEL 4
Extent Of Mfg. Science Or Quality By Design
MECHANISTIC KNOWLEDGE
LEVEL 3
CAUSAL KNOWLEDGE Why?
FDA
PROCESS KNOWLEDGE How, Correlative ..
LEVEL 2
DESCRIPTIVE KNOWLEDGE What, Etc,
LEVEL 1