Six sigma and pharmaceutical industry4
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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
- 2. 22 Continuous Availability Operational Simplicity Financial Advantage Abdulaziz Saddique Pharm.D., CPHQ, CSSBB Certified Six Sigma Master Black Belt
- 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
- 8. 88
- 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
- 12. 1212
- 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
- 16. 1616
- 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
- 21. 2121 Process Understanding Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight Post approval change Continuous Improvement Process Understanding Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight PAC to Continuous Improvement Process Understanding Risk CMC regulatory oversight Company’s Quality system cGMP regulatory oversight ICH Q8 + Q9 Proposed ICH Q 10
- 22. 2222 Quality Programs IntegrationQuality Programs Integration
- 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
- 24. 2424
- 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
- 38. 3838 Generics PharmaceuticalsGenerics Pharmaceuticals • Problems Discussed with Generics – Poor Activity – Variability – Poor Quality – Adverse Reactions – Instability
- 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
- 44. 4444
Editor's Notes
- 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 .