Six sigma

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Six sigma in pharmaceutical

industry
 Contents
• 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.)

3
 Why Pharmaceutical
Industry?
• Deals with vital
Products
• Life Saving
• Perfection is
essential
• Generics Market is
progressing
rapidly
• Variability is the main
problem with Generics
4
 Pharma Product Life
Cycle
Patent Exclusivity ( 20 yrs )
5 yrs 5 yrs 2 yrs 8-10 yrs

Lead Pre Reg. Launch &

Phase I Phase II Phase III
Selection Clinical Review Manufacture

Start Finish
Traditional Manufacturing
Earlier Later

• Start Earlier, Finish Later

•‘Receiver’ to ‘Co-Creator’
• Must Have Clear Competitive Advantage over Sister Sites

5
 Dimensions of the FDA’s Initiative
on
Pharmaceutical Quality for the 21st Century

Strong
Public Health
Protecti
on Time
Integrated quality International
systems orientation cooperation

Science-base
d Risk-based orientation
policies and standards

FDA Unveils New Initiative To Enhance Pharmaceutical Good Manufacturing Practices

6
 Dimensions of Pharmaceutical
Quality for the 21st
Century
• FDA initiatives
– cGMP
– Process Analytical Technology (PAT)
– ICH
• Quality tools
– TQM
– Six Sigma
– Fusion Management

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8
 Pharmaceutical cGMP’s for
the 21
Century
st

• 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
9
Pharmaceutical cGMP’s for the
21st Century
• Guiding Principles
– Risk-based orientation
– Science-based policies and standards
– Integrated quality systems orientation
– International cooperation
– Strong Public Health Protection

10
 Product and Process Quality
Knowledge: Science-Risk
Based cGMP’s
Quality by Design GMP/CMC FOCUS
1st
Process Design Principl Design qualification
es

MECHANISTIC
UNDERSTANDIN
Yes, Limited to the G Focused; Critical
Experimental Process Control
CAUSAL LINKS
Design Space PREDICT Points (PAT)
PERFORMANCE
DECISIONS BASED ON Extensive;
Maybe, UNIVARIATE APPROACH Every
Difficult to Step
Assesses DATA DERIVED (CURRENT)
TRIAL-N-ERROR
FROM EXPERIMENTATION 11
12
 What 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.

13
 What 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)

14
 PAT: Conceptual
Framework
Development/Optimization/Continuous Improvement
(DOE, Evolutionary optimization, Improved efficiency)
Incoming
LT Materials. Control of process critical
control points (PCCP). Multivariate
Specifications Systems
Process end point (PEPs’) range
Relevant to Approach
based on “performance” attributes.
“Process-ability”
PAC Risk
PAC PCCP PEP’s Classification
and
At-line Mitigation
In/On-Line Strategies
Process Analytical
Chemistry Tools CM Laboratory
PAC LT or other
IT
tests
Incoming material attributes
used to predict/adjust Chemometrics (CM)
optimal processing parameters and IT Tools Direct or inferential
within established bounds for “real time” assessment of quality
(more flexible bounds) control and decisions and performance
(at/on1-5line)
16
 International Conference on
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
Q8 “Design Space” Concept

• Multi-dimensional space defined by critical

vectors of product quality and
performance

– Examples of critical vectors

» Robust
deliverymanufacturing process
of product meeting its–specifications
consistent, reproducible
• Manufacturing options

» Stability (shelf-life) and

» Bioavailability
18
Knowledge based decisions:
Improved Ability to
Generalize
Pharmaceutical Development
Knowledge

raw material properties

process
conditions

environmental
Robust process
Stable and Bioavailable product

19
ICH cGMP
Q8 regulatory
oversight
C
o
m
p
a
n
y Risk
Process Post ’
Understanding approval s
change Q
u
a
l
CMC i
regulatory t
oversight y ICH
Q8&9
s
y
s 20
t
 ICH Q8 +
Process Propose
Understanding Q9
d
ICH Q Process
Process 10 Understanding
CMC Understanding
regulatory
CMC
oversight
regulatory
oversight CMC
regulatory
cGMP oversight

regulatory cGMP cGMP

oversight regulatory regulatory
oversight oversight

Company’s Company’s Company’s

Quality system Quality system Quality system

Post
approval Continuous
change PAC to Improvement
Continuous

Risk Improvement Risk

Risk
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Quality Programs Integration

22
 Evolution QC Six Sigma
Evolution

bles
a
en
Total Quality
T Control
PA Statistical
Inspection
Foreman
Operator
1900

1918

1937

1960

1980
"Real assurance of quality today requires far more than
good intentions, testing and inspection
A. V. Feigenbaum. activities,
Total Quality Control. 3rd Ed.,and a
McGraw-Hill,
23
1983
24
What is Six Sigma?
…
 Methodology for achieving goals and
objectives
 Quantitative technique for problem
solving
 Comprehensive improvement
process
Tools For Driving Sustainable Change

25
 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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 What Makes Six Sigma Different?
Adapted with permission from Hamadi Said, US Mint Philadelphia, PA

TQM Six Sigma

Real results that matter to
Solid tools but…. customers….

• Quality tool • Business tool

• Vague • Clear goals/deliverables
• goals • Clear, consistent metrics
• No • Rigorous timeline
• standard • Business-based
• metrics • Focus on customer
Open-ended, unstructured
Six Sigma builds on Lessons Learned from prior
Department-based approaches 22
77
 The Nature of Variation
Precise but not
Accurate

MMeeaannisisnnoot

tCCeennteterreedd
( (ititisisOOff fTTaargrg
eet)t;);
ththeeVVaariariatitoion

nisisSSmmaallll

Accurate
but not Precise
MMeeaannissiCCeen
. . . So how does this principle ((ittiissi OOnnTTaarrggeet
thht eneteretrrereeisesidLdLaarrggeeVV
translate into the real world? )t,),bbB (uB(ugigi St Sgi i2gmm
t
aarriaai titooi nn
 Six Sigma is… A
Quantitative
Methodology
Y= f(X1+X2+X3+…..Xn)
Today Customer


Target
Spec

3 6.6% Defects DPMO

1
2
2
3
308,537
3
Desired State
Target 66,807
4
6 No Defects! 6,210
1
 Sigma = Standard
5 Deviation
3
6
233
 Goal: Eliminate
6 Defects
3.4
29
“Move the Mean…Reduce Variability”
 Six
Sigma
 Many aspects of the
industry have adopted Six Sigma.
Both PAT and
6 are process oriented approaches
to achieving efficiencies, reduced cycle
time and improved quality

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 What “Six Sigma”
Means

-2 -3 -4 -5 -6 USL

+2 +3 +4 +5 +6 LSL

Cp = 0.67 Cp = 1.00 Cp = 1.33 Cp = 1.67 Cp = 2.00

As the process capability improves, defects become less and

less likely
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 Achieving Robustness

308,540 ppm
66807 ppm
6210 ppm
233 ppm 3 .4 ppm
USL

+2 +3 +4 +5 +6 LSL

Cp = 0.67 Cp = 1.00 Cp = 1.33 Cp = 1.67 Cp = 2.00

At 6, even process upsets do not produce defects

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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 wr ong medical
pr escr iptions each year
More than 3 0 0 0 newborns
accidentally
falling fr om the hands of
4 nur ses per hour
0 0 letters or would
doctors
never arriveeach
at their 33
destination year
 Why Six Sigma?
• Six Sigma embraces both continuous
improvement and breakthrough
performance. The process includes models
for manufacturing, design and
administrative services
Manufacturing & Administrative

Define Measure Analyze Improve Control

Design For Six Sigma (DFSS)

Define M easure Analyze Design Verify

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Covering the Space Defined by
the Directional Vectors
Pre-approval Inspection Compliance Program
Dispute Resolution Process
Risk
Pharmaceutical Inspectorate

Product Specialists on Inspection Process

Aseptic Procesing
Fusion
Integration Comparability Protocol
Process
Management
Perfection
ICH P2, Qb D, &
S I/ s

Risk
sy t n

PAT
ge

35
ar
 Fusion
ManagementTM
A tool for fusing PATand Six Sigma, TQM,
KAIZEN, Lean, Performance Excellence and
Management Systems to overcome
the existing constraints

36
The Quality Systems Opportunity
A Historical Note on Quality: Milestones in Quality Journey or
Lurching from Fad to Fad?

• Sampling Plans (‘50s)

• Zero-Defect Movement (‘60s) cGMPs
• ISO-9000 (‘80s)
• QS-9000 Pharmaceutical
• Malcolm Baldrige Award Quality
System
• European Quality Award for the 21st
• Total Quality Management Century

• Six Sigma
– The Ultimate Six Sigma -
“The Big Q”
K. R. Bhote and A. K. Bhote. World Class Quality (2000) ISBN 0-8144-0427 37
Generics Pharmaceuticals

• Problems Discussed with Generics

– Poor Activity
– Variability
– Poor Quality
– Adverse Reactions
– Instability

38
 Desired 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

39
 Desired 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

40
 Finally

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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 THANK YOU

PRESENTED BY
SUGALI RAVEENDRA NAIK

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