Six sigma and pharmaceutical industry4

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Quality Horizons First Annual ForumQuality in Healthcare

Under the patronage of His Excellency

Eng. Saeed DarwazahMinister of Health – Hashemite Kingdom of Jordan

Amman - April 2006

Quality Horizons

Towards Excellence in Health ServicesTowards Excellence in Health Services

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ContinuousAvailability

OperationalSimplicity

FinancialAdvantage

Abdulaziz Saddique Pharm.D., CPHQ, CSSBB

Certified Six Sigma Master Black Belt

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ContentsContents

• Why Pharmaceutical Industry

• Pharmaceutical Product life cycle• Dimensions of the FDA’s Initiative on Pharmaceutical

Quality for the 21st Century

• Quality Tools (TQM, Six Sigma etc.)

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Why Pharmaceutical Industry?Why Pharmaceutical Industry?• Deals with vital

Products• Life Saving• Perfection is essential• Generics Market is

progressing rapidly• Variability is the main

problem with Generics

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Launch & Manufacture

Lead Selection

Pre Clinical

Phase I Phase IIIReg.

ReviewPhase II

8-10 yrs

Patent Exclusivity ( 20 yrs )

Pharma Product Life CyclePharma Product Life Cycle

2 yrs

• Start Earlier, Finish Later•‘Receiver’ to ‘Co-Creator’• Must Have Clear Competitive Advantage over Sister Sites

5 yrs 5 yrs

Traditional ManufacturingStart Earlier

Finish Later

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Dimensions of the FDA’s Initiative on Dimensions of the FDA’s Initiative on Pharmaceutical Quality for the 21Pharmaceutical Quality for the 21stst Century Century

FDA Unveils New Initiative To Enhance Pharmaceutical Good Manufacturing Practices

Strong Public Health

Protection

Integrated quality systems orientation

Science-based policies and standards

Risk-based orientation

International cooperation

Time

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Dimensions of Pharmaceutical Quality Dimensions of Pharmaceutical Quality for the 21for the 21stst Century Century

• FDA initiatives – cGMP – Process Analytical Technology (PAT)– ICH

• Quality tools– TQM– Six Sigma– Fusion Management

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Pharmaceutical cGMP’s for the 21Pharmaceutical cGMP’s for the 21stst CenturyCentury

• A science and risk-based approach to product quality regulation incorporating an integrated quality approach– incorporate most up-to-date concepts of risk

management and scientific advances

– encourage innovation and continuous improvement

– ensure that submission review and cGMP inspection are coordinated and synergistic

– consistency and systems effective utilization of resources

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Pharmaceutical cGMP’s for the 21Pharmaceutical cGMP’s for the 21stst CenturyCentury

• Guiding Principles– Risk-based orientation

– Science-based policies and standards

– Integrated quality systems orientation

– International cooperation

– Strong Public Health Protection

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Product and Process Quality Product and Process Quality KnowledgeKnowledge: : Science-Risk Based cGMP’sScience-Risk Based cGMP’s

Quality by DesignProcess Design

Yes, Limited to theExperimentalDesign Space

Maybe, Difficult toAssesses

GMP/CMC FOCUS Design qualification

Focused; Critical Process Control Points (PAT)

Extensive; EveryStep (CURRENT)

DATA DERIVED FROM

TRIAL-N-ERROR EXPERIMENTATION

DECISIONS BASED ONUNIVARIATE APPROACH

CAUSAL LINKSPREDICT PERFORMANCE

MECHANISTICUNDERSTANDING

1st Principles

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What is PATWhat is PAT

PAT is the Food and Drug Administration - Center for Drug Evaluation and Research's model for

developing a regulatory framework to facilitate introduction of new manufacturing technologies

that enhance process efficiencies.

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What is PATWhat is PAT

Scientific principles and tools supporting innovation

• PAT Principles– Process Understanding – Risk-Based Approach– Regulatory Strategy to accommodate innovation– Real Time Release

• PAT Tools– Multivariate Tools for Design, Data Acquisition and Analysis (Six Sigma)– Process Analyzers (Six Sigma)– Process Control Tools (Six Sigma)– Continuous Improvement and Knowledge Management Tools (KAIZEN,

TQM, Lean Processing)

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PAT: Conceptual FrameworkPAT: Conceptual Framework

IncomingMaterials.

SpecificationsRelevant to

“Process-ability”

Incoming material attributesused to predict/adjust

optimal processing parameterswithin established bounds

(more flexible bounds)

PACPACPACPAC

PACPAC

PCCPPCCP

LTLTCMCMITIT

Direct or inferentialassessment of quality

and performance (at/on-line)

Control of process criticalcontrol points (PCCP).

Process end point (PEPs’) rangebased on “performance” attributes.

PEP’s

Chemometrics (CM)and IT Tools

for “real time”control and decisions

At-lineIn/On-Line

Process AnalyticalChemistry Tools Laboratory

or othertests

LTLT

Development/Optimization/Continuous Improvement (DOE, Evolutionary optimization, Improved efficiency)

MultivariateSystems Approach

RiskClassificationand MitigationStrategies

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International Conference on International Conference on Harmonization (ICH)Harmonization (ICH)

• The International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) is a unique project that brings together the regulatory authorities of Europe, Japan and the United States and experts from the pharmaceutical industry in the three regions to discuss scientific and technical aspects of product registration.

• The purpose is to make recommendations on ways to achieve greater harmonization in the interpretation and application of technical guidelines and requirements for product registration in order to reduce or obviate the need to duplicate the testing carried out during the research and development of new medicines.

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Continuous Improvement – Emerging ICH Continuous Improvement – Emerging ICH Q8 “Design Space” ConceptQ8 “Design Space” Concept

• Multi-dimensional space defined by critical vectors of product quality and performance

– Examples of critical vectors

» Robust manufacturing process – consistent, reproducible delivery of product meeting its specifications

• Manufacturing options

» Stability (shelf-life) and

» Bioavailability

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Knowledge based decisions: Improved Knowledge based decisions: Improved Ability to Generalize Ability to Generalize

Pharmaceutical Development Knowledge

environmental

raw material properties

process conditions

Robust process

Stable and Bioavailable product

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Process Understanding

Post approval change

Risk

CMC regulatory oversight

Company’sQuality system

cGMP regulatory oversight

ICH Q8

ICH Q8&9ICH Q8&9

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Risk




Post approval change

ContinuousImprovement


Risk




PAC to Continuous

Improvement


Risk




ICH Q8 + Q9 ProposedICH Q 10

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Quality Programs IntegrationQuality Programs Integration

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1900 1918 1937 1960 1980

Operator

Foreman

Inspection

Statistical

Total Quality Control

EvolutionSix Sigma

"Real assurance of quality today requires far more than good intentions, testing and inspection activities, and a traditional quality-control department. It takes the same business, managerial, and technical depth to assure the quality and quality cost of a product as it does to design, make, sell, and service the product itself - depth that starts well before production begins and ends only with a satisfied customer."

A. V. Feigenbaum. Total Quality Control. 3rd Ed., McGraw-Hill, 1983

PAT enables

QC Evolution

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What is Six Sigma?… What is Six Sigma?… Methodology for achieving goals and

objectives

Quantitative technique for problem solving

Comprehensive improvement process

Tools For Driving Sustainable Change

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What is six sigma?What is six sigma?

You’ll be able to: • Identify what % of revenue (approximate) is lost to poor quality at

3,4,5 & 6 sigma levels? • Explain the Success/Change Formula. • Identify the yield and DPMO at 4 sigma. • Explain the differences between Six Sigma and TQM? • Explain Customer Critical Criteria. • Explain three different meanings used for Six Sigma? • Explain the elements of the Scientific Method. • Define SIPOC

– Explain each component • Define DMAIC?

– Explain each component • List and discuss the seven core competencies for Six Sigma Plus.

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Solid tools but….Solid tools but….

• Quality tool

• Vague goals

• No standard metrics

• Open-ended, unstructured

• Department-based

• Focus on product quality

Real results that matter to Real results that matter to customers….customers….

• Business tool

• Clear goals/deliverables

• Clear, consistent metrics

• Rigorous timeline

• Business-based

• Focus on customer

Six Sigma builds on Lessons Learned from prior approaches

TQM Six Sigma

What Makes Six Sigma Different?Adapted with permission from Hamadi Said, US Mint Philadelphia, PA

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The Nature of VariationThe Nature of Variation

. . . So how does this principletranslate into the real world?

Mean is Centered ( it is On Target), but

there is Large Variation (Big Sigma!)

Mean is Centered ( it is On Target), but

there is Large Variation (Big Sigma!)

Accurate but not Precise

Mean is not Centered ( it is Off Target);

the Variation is Small

Mean is not Centered ( it is Off Target);

the Variation is Small

Precise but not Accurate

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Six Sigma is… A Six Sigma is… A QuantitativeQuantitative MethodologyMethodology

Sigma = Standard Deviation

Goal: Eliminate Defects

“Move the Mean…Reduce Variability”

1

2

3

TargetCustomer

Spec

36.6% Defects

Today

1

36

Target

No Defects!

Desired State

6

2 308,537

3 66,807

4 6,210

5 233

6 3.4

DPMO

Y= f(X1+X2+X3+…..Xn)

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Six SigmaSix Sigma Many aspects of the industry have

adopted Six Sigma. Both PAT and 6are process oriented approaches to achieving efficiencies, reduced cycle time and improved quality

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What “Six Sigma” MeansWhat “Six Sigma” Means

As the process capability improves, defects become less and less likely

-3

+3

Cp = 1.00

-4

+4

Cp = 1.33

-5

+5

Cp = 1.67

-6

+6

Cp = 2.00Cp = 0.67

-2

+2

USL

LSL

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Achieving RobustnessAchieving Robustness

At 6, even process upsets do not produce defects

308,540 ppm66807 ppm

6210 ppm233 ppm 3.4 ppm

+2

Cp = 0.67

+3

Cp = 1.00

+4

Cp = 1.33

+5

Cp = 1.67

+6

Cp = 2.00

USL

LSL

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Six Sigma: Ambitious Objective?

Near Perfection 99.99966 % = 6.0 σ, less than 3.4 defects per million opportunities, sounds excessive!!!

Why isn’t 99.9% already GOOD ENOUGH in our everyday lives (or 1000 ppm or 4.6σ)?

It would mean:

4000 wrong medical prescriptions each yearMore than 3000 newborns accidentally falling from the hands of nurses or doctors each yearTwo long or short landings at Chicago airport each day

400 letters per hour would never arrive at their destination

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Why Six Sigma?Why Six Sigma?

Define Measure Analyze Design Verify

Define Measure Analyze Improve Control

• Six Sigma embraces both continuous improvement and breakthrough performance. The process includes models for manufacturing, design and administrative services

Design For Six Sigma (DFSS)

Manufacturing & Administrative

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Covering the Space Defined by the Covering the Space Defined by the Directional VectorsDirectional Vectors

Risk

Science

Pre-approval Inspection Compliance Program

Dispute Resolution Process

Process Perfection

PATPAT

Pharmaceutical Inspectorate

Product Specialists on Inspection Process

Comparability Protocol

Aseptic Procesing

Syste

ms/In

tegra

tion

ICH P2, QbD, & RiskICH P2, QbD, & Risk

IntegrationFusion

Management

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Fusion ManagementFusion ManagementTMTM

A tool for fusing PAT and Six Sigma, TQM, KAIZEN, Lean, Performance Excellence and

Management Systems to overcome the existing constraints

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The Quality Systems Opportunity The Quality Systems Opportunity A Historical Note on Quality: Milestones in Quality Journey or A Historical Note on Quality: Milestones in Quality Journey or

Lurching from Fad to Fad?Lurching from Fad to Fad?

• Sampling Plans (‘50s)

• Zero-Defect Movement (‘60s)

• ISO-9000 (‘80s)

• QS-9000

• Malcolm Baldrige Award

• European Quality Award

• Total Quality Management

• Six Sigma– The Ultimate Six Sigma - “The Big Q”

cGMPs

K. R. Bhote and A. K. Bhote. World Class Quality (2000) ISBN 0-8144-0427

PharmaceuticalQualitySystem

for the 21st

Century

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Generics PharmaceuticalsGenerics Pharmaceuticals

• Problems Discussed with Generics– Poor Activity– Variability– Poor Quality– Adverse Reactions– Instability

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Desired StateDesired State

Product quality and performance achieved and assured by design of effective and efficient manufacturing processes

Product specifications based on mechanistic understanding of how formulation and process factors impact product performance

Continuous "real time" assurance of quality

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Desired StateDesired State

Regulatory policies tailored to recognize the level of scientific knowledge supporting product applications, process validation, and process capability

Risk based regulatory scrutiny relate to the: level of scientific understanding of how formulation

and manufacturing process factors affect product quality and performance, and

the capability of process control strategies to prevent or mitigate risk of producing a poor quality product

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FinallyFinally

Integrated Six Sigma (Fusion Management) is the answer to Process Perfection, overall

quality assurance, the most efficient system for Cost Saving, Waste elimination and continual improvement of your products

and services.

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How How Machiavellian … Machiavellian …

"Whoever "Whoever desires desires constant constant success must success must change his change his conduct with conduct with the times."the times."

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How How Machiavellian … Machiavellian … "There is nothing more "There is nothing more difficult to take in hand, more difficult to take in hand, more perilous to conduct, or more perilous to conduct, or more uncertain in its success, than uncertain in its success, than to take the lead in the to take the lead in the introduction of a new order of introduction of a new order of things. Because the innovator things. Because the innovator has for enemies all those who has for enemies all those who have done well under the old have done well under the old conditions, and lukewarm conditions, and lukewarm (indifferent, uninterested) (indifferent, uninterested) defenders in those who may defenders in those who may do well under the new. "do well under the new. "

CIO

Six sigma and pharmaceutical industry4

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