Unveiling the Soundscape Music for Psychedelic Experiences
Six sigma and pharmaceutical industry4
1. 11
Quality Horizons First Annual Forum
Quality in Healthcare
Under the patronage of His Excellency
Eng. Saeed Darwazah
Minister of Health – Hashemite Kingdom of Jordan
Amman - April 2006
Quality Horizons
Towards Excellence in Health ServicesTowards Excellence in Health Services
3. 33
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.)
4. 44
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
5. 55
Launch &
Manufacture
Lead
Selection
Pre
Clinical
Phase I Phase III
Reg.
Review
Phase 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 Manufacturing
Start
Earlier
Finish
Later
6. 66
Dimensions of the FDA’s Initiative onDimensions of the FDA’s Initiative on
Pharmaceutical Quality for the 21Pharmaceutical Quality for the 21stst
CenturyCentury
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
7. 77
Dimensions of Pharmaceutical QualityDimensions of Pharmaceutical Quality
for the 21for the 21stst
CenturyCentury
• FDA initiatives
– cGMP
– Process Analytical Technology (PAT)
– ICH
• Quality tools
– TQM
– Six Sigma
– Fusion Management
9. 99
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
10. 1010
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
11. 1111
Product and Process QualityProduct and Process Quality KnowledgeKnowledge::
Science-Risk Based cGMP’sScience-Risk Based cGMP’s
Quality by Design
Process Design
Yes, Limited to the
Experimental
Design Space
Maybe,
Difficult to
Assesses
GMP/CMC FOCUS
Design qualification
Focused; Critical
Process Control
Points (PAT)
Extensive;
Every
Step
(CURRENT)DATA DERIVED FROM
TRIAL-N-ERROR EXPERIMENTATION
DECISIONS BASED ON
UNIVARIATE APPROACH
CAUSAL LINKS
PREDICT PERFORMANCE
MECHANISTIC
UNDERSTANDING
1st
Principles
13. 1313
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.
14. 1414
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)
15. 1515
PAT: Conceptual FrameworkPAT: Conceptual Framework
Incoming
Materials.
Specifications
Relevant to
“Process-ability”
Incoming material attributes
used to predict/adjust
optimal processing parameters
within established bounds
(more flexible bounds)
PACPAC
PACPAC
PACPAC
PCCPPCCP
LTLT
CMCM
ITIT
Direct or inferential
assessment of quality
and performance (at/on-line)
Control of process critical
control points (PCCP).
Process end point (PEPs’) range
based on “performance” attributes.
PEP’s
Chemometrics (CM)
and IT Tools
for “real time”
control and decisions
At-line
In/On-Line
Process Analytical
Chemistry Tools Laboratory
or other
tests
LTLT
Development/Optimization/Continuous Improvement
(DOE, Evolutionary optimization, Improved efficiency)
Multivariate
Systems
Approach
Risk
Classification
and
Mitigation
Strategies
17. 1717
International Conference onInternational 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.
18. 1818
Continuous Improvement – Emerging ICHContinuous 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
19. 1919
Knowledge based decisions: ImprovedKnowledge based decisions: Improved
Ability to GeneralizeAbility to Generalize
Pharmaceutical Development
Knowledge
environmental
raw material properties
process
conditions
Robust process
Stable and Bioavailable product
23. 2323
1900 1918 1937 1960 1980
Operator
Foreman
Inspection
Statistical
Total Quality
Control
Evolution
Six 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
25. 2525
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
26. 2626
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.
27. 2727
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 toReal 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
28. 2828
The Nature of VariationThe Nature of Variation
. . . So how does this principle
translate 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
29. 2929
Six Sigma is… ASix Sigma is… A QuantitativeQuantitative
MethodologyMethodology
Sigma = Standard Deviation
Goal: Eliminate Defects
“Move the Mean…Reduce Variability”
1σ
2σ
3σ
Target
Customer
Spec
3σ 6.6% Defects
Today
1σ
3σ
6σ
Target
No Defects!
Desired State
6σ
2 308,537
3 66,807
4 6,210
5 233
6 3.4
σ DPMO
Y= f(X1+X2+X3+…..Xn)
30. 3030
Six SigmaSix Sigma
Many aspects of the industry have
adopted Six Sigma. Both PAT and
6σ are process oriented approaches to
achieving efficiencies, reduced cycle
time and improved quality
31. 3131
What “Six Sigma” MeansWhat “Six Sigma” Means
As the process capability improves, defects become less and
less likely
-3σ
+3σ
Cp = 1.00
-4σ
+4σ
Cp = 1.33
-5σ
+5σ
Cp = 1.67
-6σ
+6σ
Cp = 2.00Cp = 0.67
-2σ
+2σ
µ
USL
LSL
32. 3232
Achieving RobustnessAchieving Robustness
At 6σ, even process upsets do not produce defects
308,540 ppm
66807 ppm
6210 ppm
233 ppm 3.4 ppm
+2σ
Cp = 0.67
+3σ
Cp = 1.00
+4σ
Cp = 1.33
+5σ
Cp = 1.67
+6σ
Cp = 2.00
µ
USL
LSL
33. 3333
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
year
More than 3000 newborns accidentally
falling from the hands of nurses or
doctors each year
Two long or short landings at Chicago
airport each day
400 letters per hour would never arrive at their
destination
34. 3434
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
35. 3535
Covering the Space Defined by theCovering 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
Systems/Integr
ICH P2, QbD, & RiskICH P2, QbD, & Risk
IntegrationFusion
Management
36. 3636
Fusion ManagementFusion ManagementTMTM
A tool for fusing PAT and Six Sigma, TQM,
KAIZEN, Lean, Performance Excellence and
Management Systems to overcome the
existing constraints
37. 3737
The Quality Systems OpportunityThe Quality Systems Opportunity
A Historical Note on Quality: Milestones in Quality Journey orA 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
Pharmaceutical
Quality
System
for the 21st
Century
39. 3939
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
40. 4040
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
41. 4141
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.
42. 4242
HowHow Machiavellian …Machiavellian …
"Whoever"Whoever
desiresdesires
constantconstant
success mustsuccess must
change hischange his
conduct withconduct with
the times."the times."
43. 4343
HowHow Machiavellian …Machiavellian …
"There is nothing more"There is nothing more
difficult to take in hand, moredifficult to take in hand, more
perilous to conduct, or moreperilous to conduct, or more
uncertain in its success, thanuncertain in its success, than
to take the lead in theto take the lead in the
introduction of a new order ofintroduction of a new order of
things. Because the innovatorthings. Because the innovator
has for enemies all those whohas for enemies all those who
have done well under the oldhave done well under the old
conditions, and lukewarmconditions, and lukewarm
(indifferent, uninterested)(indifferent, uninterested)
defenders in those who maydefenders in those who may
do well under the new. "do well under the new. "
CIO
What is Six Sigma? In a nutshell, Six Sigma is, most uniquely, a STATISTICAL quality methodology. This is the “heart and soul” of Six Sigma and I’ll describe this in more detail in a moment. But, Six Sigma is not JUST statistics. It is also quality improvement process and tools , which ensure the implementation and control activities that deliver real change and improvements in the company. And, probably most importantly, Six Sigma is a pervasive, single-minded, company-wide culture…and nothing short of it. Jack Welch has called 6 Sigma the most important initiative GE has ever undertaken…And, that is a significant statement when you take into consideration the revolutionary changes that Jack has led at GE over the past 20 years. Let me explain some of these points a little more clearly.
Product Vectors - GE’s term for their “Programs of Excellence” GE Medical - technology, IT, CAP/WorkOut/Six Sigma/LEAN GE Power GE Capital GE Construction/Engineering Innovation - GE is committed to aggressive new product development and to being a market leader in health care. Ability and interest to think outside the box Leadership development - long track record of systematic cultivation of leaders and systems and structures for identifying, mentoring and rewarding/retaining outstanding leaders Focus on results - A business-results mind set that is in their DNA
Both processes are flawed and will produce dissatisfied customers. Knowing if the problem is with the accuracy (the Mean) or the scatter (expressed as Sigma) helps us choose improvements that are more likely to succeed. We can also track exactly how much out process has improved!
First, Six Sigma is a statistical Quality Methodology. Of course, “Sigma” is just another word for standard deviation…And this begins to give you a feel for what is at the heart of Six Sigma. These implies that we UNDERSTAND variation…and our quality performance in these terms. The focus of Six Sigma is on Statistical process control…of EVERY process, including processes beyond manufacturing…like Services, Sourcing, Order to Remittance, Delivery & Installation, Customer Service, and even Sales an d Marketing. The essence of Six Sigma statistical analysis centers squarely on reducing and eliminating ERRORS. I can’t think of a more direct, and objective approach to Quality improvement than that. And, in the FINAL analysis…Six Sigma is essentially about “moving the mean…and reducing the standard deviation”. That is the lens through which we fundamentally view Quality improvement, from a Six Sigma perspective. In summary, Six Sigma is FIRST a rigorous, MEASUREMENT-based approach to Quality.
This slide shows the effect of reducing total defects per unit as we increase process capability and lead to six-sigma control. We don’t widen the specs to Six Sigma; we reduce sigma! Why isn’t five sigma good enough? Or four? Why not three? There’s very little out of spec when the specs are at ±3 sigma…..
This slide will show how a six-sigma process will tolerate more variance within the process and prevent defects from occurring. The reason is that ±3 is not robust. A process upset of 1.5 will result in a large DPU count. Even ±4 limits are not especially robust. Maybe ±5 is acceptable as an initial goal, but only at ±6 do we have confidence that initially undetected process upsets will not result in unacceptable performance. This will be discussed in detail later. For now: JUST TELL THEM without getting into details. This is an INTRODUCTION chapter. Why 1.5 sigma shift? We’ll deal with that tomorrow. Naturally, a catastrophic process upset will produce large numbers of defects for a short period -- until the problem is fixed -- but using problem-solving and process control, these disturbances will be “few and far between” and the overall performance will approach the ideal.
Generally accepted model (most literature) also: plan, do, check, act .