sept 17th 2003
DESCRIPTION
QUALITY BY DESIGN: The Means To Fundamental Manufacturing Science. G.K.Raju, Ph.D. Sept 17th 2003. OUTLINE. MOTIVATION “MANUFACTURING SCIENCE”: DIMENSIONS QUALITY BY DESIGN: THE LEVERAGES QUALITY BY DESIGN: THE COMPONENTS CONSIDERATIONS. QC 2. QC 3. QC 1. QC 4. BLEND. DRY MIX. - PowerPoint PPT PresentationTRANSCRIPT
© G.K.Raju, Ph.D. Manufacturing Science
Sept 17th 2003
QUALITY BY DESIGN:The Means To Fundamental Manufacturing Science
G.K.Raju, Ph.D.
© G.K.Raju, Ph.D. Manufacturing Science
OUTLINE
MOTIVATION “MANUFACTURING SCIENCE”: DIMENSIONS QUALITY BY DESIGN: THE LEVERAGES QUALITY BY DESIGN: THE COMPONENTS CONSIDERATIONS
© G.K.Raju, Ph.D. Manufacturing Science
“MANUFACTURING SYSTEM”
A “manufacturing system” is set of processes and systems (and people) bound by a common material and information flow.
Material Material
Information Information
WEIGH WETGRANULN
STEP FB DRY
STEP
BLEND
ENCAPSULATESIEVE
QC1QC3 QC4
DRY MIX
QC2
© G.K.Raju, Ph.D. Manufacturing Science
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
ACTIVE FORMULN FILL PACK
RESEARCH
DEVELOPMENT
MANUFACTURING
TIME
SPACE
PHARMACEUTICAL MANUFACTURING SYSTEM
COST
QUALITY
TIME
SAFETY
© G.K.Raju, Ph.D. Manufacturing Science
PROCESS A WITH QC TESTS
WEIGHING WETGRANULATION
STEP FB DRY
STEP
BLEND
ENCAPSULATESIEVE
• API• MICRO
• Particle Size• Description• ID• Assay• CU• Impurity• Dissolution• MICRO
QC1 QC3 QC4
DRY MIX
QC2
• LOD
© G.K.Raju, Ph.D. Manufacturing Science
QUALITY “TESTING” END OF LINECONSUMES SIGNIFICANT TIME
0
5
10
15
20
25
TIME (Days)
A B C D E F
Overall Cycle Time Components
Process TimesQC Testing Times
© G.K.Raju, Ph.D. Manufacturing Science
QUALITY “TESTING” END OF LINE MAKES IT DIFFICULT TO UNDERSTAND “EXCEPTIONS”
0 100 200 300 400 500 600 700 800
LOT NUMBER
OVE
RA
LL C
YCLE
TIM
ES
Lots without Exceptions
Lots with Exceptions
© G.K.Raju, Ph.D. Manufacturing Science
PHARMA MANUFACTURING CYCLE TIMES (DAYS):HALF A YEAR, LITTLE IMPROVEMENT….
COMPANY 2001 2000 1999 1998 1997 AVERAGEAbbott Laboratories 104.20 101.85 91.30 95.38 92.55 97.06American Home Products - Wyeth 189.07 171.06 271.06 287.33 214.67 226.64AstraZeneca 195.26 139.92 130.35 149.28 252.19 173.40Aventis 291.41 295.53 229.60 115.22 84.13 203.18Bristol-Myers Squibb 97.36 140.43 170.85 175.47 185.07 153.84Eli Lilly 179.12 156.76 156.58 181.14 169.00 168.52GlaxoSmithKline (Glaxo Wellcome-GSK) 172.20 243.65 330.00 272.63 211.86 246.07GlaxoSmithKline (SmithKline Beecham) 105.27 111.21 99.87 105.45Johnson & Johnson 114.52 119.03 132.93 139.11 128.40 126.80Merck 45.08 49.15 59.27 68.78 66.41 57.74Novartis 190.32 205.65 255.93 243.10 242.60 227.52Pfizer (Pfizer) 198.74 200.98 238.81 318.63 300.26 251.48Pfizer (Warner Lambert) 117.47 126.73 108.35 117.52Pharmacia Upjohn 208.43 192.11 193.53 173.10 155.82 184.60Roche 252.99 229.21 269.25 248.95 335.64 267.21Schering Plough 165.99 182.50 194.26 191.73 198.96 186.69INDUSTRY AVERAGE 171.76 173.42 184.15 181.11 177.86 177.66
* Derived from COGS numbers
© G.K.Raju, Ph.D. Manufacturing Science
OUTLINE
MOTIVATION “MANUFACTURING SCIENCE”: DIMENSIONS QUALITY BY DESIGN: THE LEVERAGES QUALITY BY DESIGN: THE COMPONENTS CONSIDERATIONS
© G.K.Raju, Ph.D. Manufacturing Science
“MANUFACTURING SCIENCE”:DIMENSIONS
Body of
Knowledge, Laws, Principles
Involved In The Transformation of
Materials and Information into Goods
for the Satisfaction of Human Needs
ExtentOf
Mfg.Science
© G.K.Raju, Ph.D. Manufacturing Science
“MANUFACTURING SCIENCE” : Levels of Knowledge
ExtentOf
Mfg.Science
OrQuality
By Design
LEVEL 1LEVEL 1
LEVEL 2LEVEL 2
LEVEL 4LEVEL 4
LEVEL 5LEVEL 5
LEVEL 3LEVEL 3
PROCESS KNOWLEDGEHow, Correlative ..
CAUSAL KNOWLEDGEWhy?
MECHANISTICKNOWLEDGE
FirstPrinciples
DESCRIPTIVE KNOWLEDGE: What, Etc, …
© G.K.Raju, Ph.D. Manufacturing Science
“MANUFACTURING SCIENCE”:The “Time” DimensionTHE DESIRED STATE
ExtentOf
Mfg.Science
Time
“Right First Time”
LEVEL 1LEVEL 1
LEVEL 2LEVEL 2
LEVEL 4LEVEL 4
LEVEL 5LEVEL 5
LEVEL 3LEVEL 3
FDA Minimum Requirement
Manufacturing Centric Approach to
Manufacturing Science(“learning by doing”)
Design/Development Centric Approach
Manufacturing Science(“learning before doing”)
© G.K.Raju, Ph.D. Manufacturing Science
“EXTENT OF MANUFACTURING SCIENCE”:COST, QUALITY AND TIME OPPORTUNITY
ExtentOf
Mfg.Science
Time
“Right First Time”
LEVEL LEVEL 11
LEVEL LEVEL 22
LEVELLEVEL 44
LEVEL LEVEL 55
LEVEL LEVEL 33
FDA Minimum Requirement
Manufacturing Centric Approach to
Manufacturing Science(“learning by doing”)
Design/Development Centric Approach
Manufacturing Science(“learning before doing”)
CostQualityTime
Opportunity
Desired
Actual
© G.K.Raju, Ph.D. Manufacturing Science
OUTLINE
MOTIVATION “MANUFACTURING SCIENCE”: DIMENSIONS QUALITY BY DESIGN: THE LEVERAGES QUALITY BY DESIGN: THE COMPONENTS CONSIDERATIONS
© G.K.Raju, Ph.D. Manufacturing Science
QUALITY BY DESIGN:THE LEVERAGES
ExtentOf
Mfg.Science
OrQuality
By Design
Time
“Right First Time”
LEVEL LEVEL 11
LEVEL LEVEL 22
LEVELLEVEL 44
LEVEL LEVEL 55
LEVEL LEVEL 33
FDA Minimum Requirement
Manufacturing Centric Approach to
Manufacturing Science(“learning by doing”)
Design/Development Centric Approach
Manufacturing Science(“learning before doing”)
StrategicLeverage Tactical
Leverage
© G.K.Raju, Ph.D. Manufacturing Science
QUALITY BY DESIGN:STRATEGIC 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)
© G.K.Raju, Ph.D. Manufacturing Science
QUALITY BY DESIGN:STRATEGIC 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
© G.K.Raju, Ph.D. Manufacturing ScienceWEIGHING
GRANULATION
FB DRY
MILLING
BLEND
FILMCOATINGCOMPRESS
BOTTLEPACKAGINGLEVEL 1:
INITIAL
WEIGHING
GRANULATION
FB DRY
MILLING
BLEND
FILMCOATINGCOMPRESS
BOTTLEPACKAGING
LEVEL 2:REPEATABLE
WEIGHING
GRANULATION
FB DRY
MILLING
BLEND
FILMCOATINGCOMPRESS
BOTTLEPACKAGING
LEVEL 4:MANAGED
LEVEL 5: OPTIMIZING
WEIGHINGBLEND
FILMCOATINGCOMPRESS
BOTTLEPACKAGING
WEIGHING
GRANULATION
FB DRY
MILLING
BLEND
FILMCOATINGCOMPRESS
BOTTLEPACKAGING
LEVEL 3:DEFINED
QUALITY BY DESIGN: A PROCESS ROADMAP
© G.K.Raju, Ph.D. Manufacturing Science
OUTLINE
MOTIVATION “MANUFACTURING SCIENCE”: DIMENSIONS QUALITY BY DESIGN: THE LEVERAGES QUALITY BY DESIGN: THE COMPONENTS CONSIDERATIONS
© G.K.Raju, Ph.D. Manufacturing Science
PROCESS & PRODUCT
Y = F(X) PerformanceMeasurement
A-prioriknowledge
InformationExchange
QUALITY BY DESIGN:COMPONENTS
Extent OfManufacturing ScienceOr Quality By Design
© G.K.Raju, Ph.D. Manufacturing Science
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
COMPONENTS OF “QUALITY BY DESIGN:A-PRIORI KNOWLEDGE
© G.K.Raju, Ph.D. Manufacturing Science
Current Approach Proposed Approach
x x xx
x
x
x
x
x
x
x
x
xxxxxx
x
xxxx
x
xxxxxxxxxxxxxxxxxx
x
xxxxxxxxxxxxx
xxxxxxxxxxxxxxxxxx
xx
x
Process Development
Commercial Production
1a
1b
2a
2b
COMPONENTS OF “QUALITY BY DESIGN:INFORMATION EXCHANGE: EXTENT AND TYPE
WHAT IS THE QUALITY AND QUANTITY OF DATA USED
© G.K.Raju, Ph.D. Manufacturing Science
ON-LINE TECHNOLOGY IMPACTSDOMINANT CYCLE TIMES
STEPS IN THE PROCESS/PLANT IN QC/QAProcess/Unit operationInterruption of the processSecuring of sample from processHolding of sample in plantDocumentation and verification of samplingTransferring of samples to QC labBatching of samples in QCPreparation of test samplesActual test - separationActual test - measurementTest data collection and processingDocumentation and verification of testingTransferring of results for reviewDecision regarding impact on process
Process/Process Step Primarily Manual OperationInventory Hold Actual test
On-line LIF, NIR, Pattern Recognition, etc.
© G.K.Raju, Ph.D. Manufacturing Science
CURRENT STATE
WEIGHING
GRANULATION
FB DRY
MILLING
BLEND
FILMCOATINGCOMPRESS
BOTTLEPACKAGINGLEVEL 1:
INITIAL
WEIGHING
GRANULATION
FB DRY
MILLING
BLEND
FILMCOATINGCOMPRESS
BOTTLEPACKAGING
LEVEL 2:REPEATABLE
WEIGHING
GRANULATION
FB DRY
MILLING
BLEND
FILMCOATINGCOMPRESS
BOTTLEPACKAGING
LEVEL 4:MANAGED
LEVEL 5: OPTIMIZING
WEIGHINGBLEND
FILMCOATINGCOMPRESS
BOTTLEPACKAGING
WEIGHING
GRANULATION
FB DRY
MILLING
BLEND
FILMCOATINGCOMPRESS
BOTTLEPACKAGING
LEVEL 3:DEFINED
MinimumRequirement
“MANUFACTURING SYSTEM” ROADMAP: CURRENT Relative To DESIRED State
© G.K.Raju, Ph.D. Manufacturing Science
Safety and Efficacy
Process Capability Associated With Critical-To-Quality (CTQ) Variables
Variability of Critical-To-Quality Variables
Predictive Ability Of Performance
COMPONENTS OF “QUALITY BY DESIGN:PERFORMANCE MEASUREMENT
© G.K.Raju, Ph.D. Manufacturing Science
“MANUFACTURING SCIENCE”: DESIRED RELATIVE TO CURRENT STATE
(Personal Opinion)
ExtentOf
Mfg.Science
Time
“Right First Time”
LEVEL LEVEL 11
LEVEL LEVEL 22
LEVELLEVEL 44
LEVEL LEVEL 55
LEVEL LEVEL 33
FDA Minimum Requirement
Manufacturing Centric Approach to
Manufacturing Science(“learning by doing”)
Design/Development Centric Approach
Manufacturing Science(“learning before doing”)
© G.K.Raju, Ph.D. Manufacturing Science
OUTLINE
MOTIVATION “MANUFACTURING SCIENCE”: DIMENSIONS QUALITY BY DESIGN: THE LEVERAGES QUALITY BY DESIGN: THE COMPONENTS CONSIDERATIONS
© G.K.Raju, Ph.D. Manufacturing Science
QUALITY BY DESIGN:IS THE EXTENT OF “RIGHT FIRST TIME”
Time (& cost)
AssociatedWith
Addressing Cause
ForNot
Being“Right”
Where “Right” is Measured
DEVELOPMENT
WARNING LETTER
FDA 483RECALLS
COMPLAINTS
FINAL QC TESTINGQA APPROVAL
IN-PROCESS TESTING
REJECTS
CONSENT DECREE
Prevention
Appraisal
Internal Failure
External FailureCommon Focus
© G.K.Raju, Ph.D. Manufacturing Science
“MANUFACTURING SCIENCE” :IMPLICATIONS
ExtentOf
Mfg.Science
OrQuality
By Design
LEVEL LEVEL 11
LEVEL LEVEL 22
LEVEL LEVEL 44
LEVEL 5LEVEL 5
LEVEL LEVEL 33
PROCESS KNOWLEDGEHow, Correlative ..
CAUSAL KNOWLEDGEWhy?
MECHANISTICKNOWLEDGE
FirstPrinciples
DESCRIPTIVE KNOWLEDGE: What, Etc, …
LEVEL LEVEL 55 •Lower Risk
•Higher Process Understanding•Lower Variability•Lower Costs
© G.K.Raju, Ph.D. Manufacturing Science
“MANUFACTURING SCIENCE” : IMPLICATIONS
ExtentOf
Mfg.Science
OrQuality
By Design
LEVEL LEVEL 11
LEVEL LEVEL 22
LEVEL LEVEL 44
LEVEL LEVEL 33
PROCESS KNOWLEDGEHow, Correlative ..
CAUSAL KNOWLEDGEWhy?
MECHANISTICKNOWLEDGE
FirstPrinciples
DESCRIPTIVE KNOWLEDGE: What, Etc, …
LEVEL LEVEL 55
FDA