sept 17th 2003

© G.K.Raju, Ph.D. Manufacturing Science

Sept 17th 2003

QUALITY BY DESIGN:The Means To Fundamental Manufacturing Science

G.K.Raju, Ph.D.


OUTLINE

MOTIVATION “MANUFACTURING SCIENCE”: DIMENSIONS QUALITY BY DESIGN: THE LEVERAGES QUALITY BY DESIGN: THE COMPONENTS CONSIDERATIONS


“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


ACTIVE FORMULN FILL PACK



RESEARCH

DEVELOPMENT

MANUFACTURING

TIME

SPACE

PHARMACEUTICAL MANUFACTURING SYSTEM

COST

QUALITY

TIME

SAFETY


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


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


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


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


OUTLINE



“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


“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, …


“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”)


“EXTENT OF MANUFACTURING SCIENCE”:COST, QUALITY AND TIME OPPORTUNITY

ExtentOf

Mfg.Science

Time


LEVEL LEVEL 11

LEVEL LEVEL 22

LEVELLEVEL 44

LEVEL LEVEL 55

LEVEL LEVEL 33






CostQualityTime

Opportunity

Desired

Actual


OUTLINE



QUALITY BY DESIGN:THE LEVERAGES

ExtentOf

Mfg.Science

OrQuality

By Design

Time


LEVEL LEVEL 11

LEVEL LEVEL 22

LEVELLEVEL 44

LEVEL LEVEL 55

LEVEL LEVEL 33






StrategicLeverage Tactical

Leverage


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)


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


OUTLINE



PROCESS & PRODUCT

Y = F(X) PerformanceMeasurement

A-prioriknowledge

InformationExchange

QUALITY BY DESIGN:COMPONENTS

Extent OfManufacturing ScienceOr Quality By Design


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


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


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.


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


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


“MANUFACTURING SCIENCE”: DESIRED RELATIVE TO CURRENT STATE

(Personal Opinion)

ExtentOf

Mfg.Science

Time


LEVEL LEVEL 11

LEVEL LEVEL 22

LEVELLEVEL 44

LEVEL LEVEL 55

LEVEL LEVEL 33







OUTLINE



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


“MANUFACTURING SCIENCE” :IMPLICATIONS

ExtentOf

Mfg.Science

OrQuality

By Design

LEVEL LEVEL 11

LEVEL LEVEL 22

LEVEL LEVEL 44

LEVEL 5LEVEL 5

LEVEL LEVEL 33




FirstPrinciples


LEVEL LEVEL 55 •Lower Risk

•Higher Process Understanding•Lower Variability•Lower Costs


“MANUFACTURING SCIENCE” : IMPLICATIONS

ExtentOf

Mfg.Science

OrQuality

By Design

LEVEL LEVEL 11

LEVEL LEVEL 22

LEVEL LEVEL 44

LEVEL LEVEL 33




FirstPrinciples


LEVEL LEVEL 55

FDA

sept 17th 2003

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