Designing Of Pat Based Quality System

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Designing Of Pat Based Quality System

  1. 1. Welcome toRisk-Based Drug Quality SystemFDA & ICH JOINT PROPOSAL FOR DESIRED STATE Revisit Presentation By Satendra K Vishwakarma PhDMay 27, 2011 1
  2. 2. Announcement The contents, views and graphics, in thispresentation, are collected from various sources.Presenter of this presentation believes that all thereported materials are Up-to-Date and is ONLY for INFORMATION, NOT for IMPLEMENTATION. For more Information, visit FDA & ICH web sites. Thank You May 27, 2011 2
  3. 3. Current State of Affairs in Pharma Industry.Introduction – Summary of ICH Quality Topics.Desired Guiding Principles & Fulfillments.  Why best available science-based policies and standards.  Identification of desired state of quality manufacturing by design space.  Manufacturing process science and understanding of critical controls (PAT).  Risk- based quality review and management.Summary, Thoughts & Questions. May 27, 2011 3
  4. 4. UNDERSTANDING THE BASICSRigorous Manufacturing Standards Same Drug Purity Check Solid Dosages Generic Formulations Quality standards comparable to Reference Listed Drug (RLD) May 27, 2011 4
  5. 5. Introduction Current State of Affairs Thesis of Critical Path : There has been a Failure of Predictability INDUSTRY FACTORS■ Reluctance to innovate / invest in manufacturing sector compared to R&D.■ Most processes are fixed with variable materials, resulting in variable quality of product.■ Emphasis on getting product out discourages early work on process and changes after marketing. PRODUCT FACTORS■ Increasing trend towards manufacturing-related problems.■ Low manufacturing process efficiency-cost implications.■ Excessive amounts of product non-conformances/OOS.■ Slow innovation, modernization & technologies adoption.■ Rising trend of recalls 176/1998–354/2002 & Supplements. May 27, 2011 5
  6. 6. Introduction Current State of Affairs Thesis of Critical Path : There has been a Failure of Predictability REGULATORY FACTORS■FDA’s emphasis was on institution of basic procedures and recordkeeping--evolved to cGMP.■Empirical quality methodologies are approaching their theoretical effectiveness.■High burden on FDA resources. OVERALL CONCLUSION “The present state is focused on documentation, following SOPs validating the process, changing SOPs meeting specifications, and not changing the process leading to high risk of drug efficacy and public health.” May 27, 2011 6
  7. 7. Current Affairs Findings & Recommendations Inadequate QA  Drug not made at site Functions 2% 8% Inadequate SOP 2%  Contamination 13% Facility withdrawn  Pending Regulatory 3% Action 18% Previous Deviations  Firm Not Ready 25% persists 7%  Inadequate Lab Others 15% controls 7%FDA’s Risk-Based “cGMPs for the 21st Century”“PAT Initiative” and “Generic Drug Equivalence” issues are on the agenda. May 27, 2011 7 Thomas J Arista, FDA’s Data Sep 2003 – April 2004
  8. 8. Vision Desired State of 21st Century FUTURE CHALLENGES AND OPPORTUNITY■ Currently FDA attempting to drive innovation and investment in manufacturing sector via compliance / enforcement actions.■ New level of scientific understanding & new technologies can provide Science & Engineering-Based Approach over Rule-Based Approach. Product quality achieved and assured by design of processes. Product specifications based on mechanistic understanding of how formulation and process factors impact product performance.■ Accelerate GGP, setup and adopt ICH Q6A + PAT-based efficient approach (as a platform) to achieve ICH Q10. May 27, 2011 8
  9. 9. Vision Desired State of 21st Century SCIENCE & RISK – BASED REGULATORY APPROACH■ Regulatory support and flexibility during development & implementation.■ 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. May 27, 2011 9
  10. 10. Vision Desired State of 21st Century OVERALL CONCLUSION■ “The desired state, by contrast, would focus on data analysis, understanding critical to quality attributes, measuring process capability, performing continuous quality verification, and undertaking continuous improvement to maintain consistent product quality.”■ Minimize risks of poor process quality and reduce (regulatory) concerns. May 27, 2011 10
  11. 11. GuidelinesGMPSPECIFICATIONDESIGN ICH Q1 Stability ICH Q2 Analytical Procedures ICH Q3 Impurities ICH Q4 Pharmacopoeia ICH Q5 Biotechnological / Biological Products ICH Q6 Specifications ICH Q7 current GMPs / current GGPs ICH Q8 Pharmaceutical Development ICH Q9 Quality Risk Management ICH Q10 Quality Management M4 Q Common Technical DocumentVisit ICH Web Page for Guideline details on definition, development, May 27, 2011 extensions, revision or maintenance. 11
  12. 12. Guidelines Highlights of ICH Q6A SpecificationsTest Procedures and Acceptance Criteria for NewDrug Substances and New Drug Products. Definition of SpecificationA list of tests, references to analytical procedure,and appropriate acceptance criteria which arenumerical limits, ranges, or other criteria for thetests described. Characterization  Consistency Potency  Purity Degradation / Impurity  Identity May 27, 2011 12
  13. 13. ICH Pharmaceutical DevelopmentCURRENT STATE : TESTING TO DOCUMENT QUALITY ICH Q6A :Terminology Decision Characteristics Specifications In Process Controls Development Design Process Validation GMP Controls May 27, 2011 13
  14. 14. PAT The Goal and Characteristics of Pharmaceutical Quality Decision System Goal ICH Q6A Characteristics “The quality of drug substances and drug  products is determined by their design, development, in-process controls, GMP controls, process validation, and by specifications applied to them throughout development and manufacture.” Life-cycle May 27, 2011 14 Ajaz S. Hussain CDER FDA Ball State University Muncie, IN, 2005
  15. 15. ICH Therapeutic Equivalence Matter Pharmaceutical Product Development Information Current Paradigm 21st Century ParadigmSame Drug, Strength, Same Drug, Strength,Dosage form, Safety, Quality Dosage form, Safety, Quality+Pharmaceutical +Quality by DesignEquivalence (Designed to be equivalent )+Bioequivalence +Verified by in-vivo Testing (Demonstrate bioequivalence)= Therapeutic Equivalence = Therapeutic Equivalence Pharmaceutical Product Development Information (PPDI) (ICH CTD, ICH Q8) in ANDA may help OGD be more efficient. PPDI is an opportunity and the only existing mechanism to justify rational specifications & emphasize quality by design. May 27, 2011 15 Modified from Robert Lionberger, Office of Generic Drugs, FDA
  16. 16. ICHWhat is the ICH Q8 Opportunity? DESIRED STATE : DESIGNING TO BUILD QUALITY Specifications In Process Controls Development Absent or variable in US CMC Design Sections Process Validation ICH Q8  GMP Controls “…where the provision of greater understanding of pharmaceutical andmanufacturing sciences can create a basis for flexible regulatory approaches.” May 27, 2011 16
  17. 17. PAT Desired State and RegulationScience based mechanistic process understanding & development & improvement.Process integrated quality manufacturing and process control system.Predictability quality by design & design space.Consistency quality system guidelines assuring the processes, performing continuous quality verification, undertaking evaluation and continuous improvement.Regulatory science knowledge in control, simulation, process, preformulation, bioceutics.Risk based approach for quality attributes, comprehensive CMC & ANDA review. May 27, 2011 17
  18. 18. ICH ICH Q8 Journey CMC: The Desired StateProduct specifications based on mechanistic understanding of how formulation and process factors impact product performance.Product quality and performance achieved and assured by design of effective & efficient (robust) manufacturing processes (QbD).An ability to effect continuous improvement & continuous "real time release" assurance of quality."real time release“ means Quality Control Reduction of End Product May 27, 2011 Release Testing 18
  19. 19. PAT FDA Journey FDA Review: The Desired StateScience & Risk based Specifications.Greater product and process knowledge allows regulatory decisions based on actual risks (Mantra : Increase Analytical & Statistical tools to reduce Source of Process Variabilities and relate to Clinical Relevance).Define design space and manage the changes within design space (Mantra : Manage your own SUPAC Concept & Real Time Release). Design Space is the established range of scientific parameters that has been demonstrated to provide assurance of quality. May 27, 2011 19
  20. 20. PATProduct & Process Quality Knowledge Science-Risk Based CMC & cGMPsQuality by Design cGMP/CMC FOCUSProcess Design First Design qualification Principle MECHANISTICYes, Limited to UNDERSTANDING Focused; CriticalExperimental Process ControlDesign Space CAUSAL LINKS Points (PAT) PREDICT PERFORMANCE DECISIONS BASED ON Extensive;Maybe, UNIVARIATE APPROACH Every StepDifficult to (Current)Assesses DATA DERIVED FROM TRIAL-N-ERROR EXPERIMENTATION May 27, 2011 20 Concept initiated by Ajaz S. Hussain, CDER, FDA, PQRI 2005
  21. 21. VariabilityVariability Process Capability Stability May 27, 2011 21 Modified from Original Concept Ajaz S. Hussain, CDER, US FDA
  22. 22. Variability Measuring Process Variability Total variability σ2Total ■ The overall understanding of variation contributed by measurement systems and product components is critical for statistical analysis. Assuming independent variable – ■ σ2Product + σ2Measurement = σ2Total ■ + = True Product Variation Measurement Variation Experimental Variation ■ σ2Measurement = σ2Repeatability + σ2Reproducibility Common Cause Vs. Special Cause Variability Process capability = Customer Needs / Process Ability May 27, 2011 22 Modified from Lucinda Buhse, Division of Pharmaceutical Analysis, FDA
  23. 23. VariabilityAnalytical Variability ControlChemical Imaging Technologies…Next? High Speed Molecular Microscopy Chemical Information Content and Data Processing Raman Mid-IR SEM/EDS NIR Luminescence UV-Visible Absorbance SEM Increasing Molecular Size or Molecular ComplexicityMay 27, 2011 23 Finger Printing Molecular State and Complexicity in Process
  24. 24. PAT FDA’s PAT Journey from “Testing Quality in…” to “Building Quality in…” Pharmaceutical Process Analytical TechnologyProcess Analytical Technology (PAT) is a system for designing, analyzing, and controlling manufacturing processes based on timely measurements (i.e., during processing) of critical quality parameters and performance attributes of raw and in- process materials and processes to assure acceptable end product quality at the completion of the process. May 27, 2011 24
  25. 25. PAT FDA’s PAT Journey from “Testing Quality in…” to “Building Quality in…” Pharmaceutical Process Analytical TechnologyProcess Analytical Technology involves optimal applications of process analytical chemistry tools, feedback process control strategies, information management tools, and /or product /process optimization strategies to the manufacture of pharmaceuticals.Note The term Analytical in PAT is viewed broadly to include chemical, physical, microbiological, mathematical, and risk analysis conducted in an integrated manner. May 27, 2011 25
  26. 26. FDA’s End of PAT Journey PAT from “Testing Quality in…” to “Building Quality in…” You Said for Process Analytical Technology The goal of PAT is to understand and control the manufacturing process science – Ajaz S. Hussain<<The quality can not be tested into products; it should be built-in or should be by design>> Change is inevitable – except from vending machine – Robert C. Gallager It is not mandatory to change. Survival is not mandatory – W. Edward DemingQuality by May 27, 2011 PAT = ∫∫∫ SbK + QbD + QbR ? 26
  27. 27. PATKNOWLEDGE–BASED QUALITY Moving Towards cGMP End Point Six  Sigma Quality System “The cGMP”     “The Big Q or GMP +”May 27, 2011 27 Modified from Ajaz S. Hussain, CDER, FDA, PQRI 2005
  28. 28. Beginning of End Good Guidance Practices A Control How can we assure the process stays fixed? M Quality and Improve Customer How can we fix the process? G Regulatory Strategy Analyze What are the root cause of problem? Manufacturing Design I and Quality Solution Measure Quality Formulation Development How frequent is it occurring? and Technology Transfer S Understand and DefineMaterials, Reverse-engineering, Analytical What is the scope of problem? Supports and Information Technology 6 FDA’S CMCs & cGMPsMay 27, 2011 28
  29. 29. QbR Risk–Based Review Question–Based Review for CMC and ANDAsRisk or question–based CMC Review concentrateon Scientific Relationship between CMC and theProduct Characteristic and its ultimate impact onTherapeutics Performance as promised in thelabel to the customer.The objectives of QbR System are to transformCMC REVIEW into science- and risk- basedpharmaceutical quality assessment thatincorporates the CONCEPT & PRINCIPLES ofPharmaceutical cGMPs for the 21st Century : ARisk-Based Approach and Process AnalyticalTechnology initiatives. QbR acts as an interface.FDA Regulation in FLEXIBILE STATE on DESIRED STATE May 27, 2011 29
  30. 30. QbR Risk–Based Review The Major Critical Review Areas Science is understanding variability and reproducibility in nature. Chemometrics / Statistics is making decisions about nature in the presence of variability. Experimental Design is reducing and controlling variability in ways which make statistical theory applicable to decisions about nature. Justification of design trials and statistical aspects should be set out in the protocol. Confirmatory Trials are necessary to provide firm evidence of efficacy and safety. Evaluation of Evidence and decision on approvability.“Quality can not be assessed, tested or inspected into the product. It has to be built into it.” May 27, 2011 30
  31. 31. QbR Risk–Based Review The Major Critical Review Chapters ICH Q8 – Drug Product Development Report. M4Q eCTD - Drug Product Guidance. cGMP Initiative – Quality by Design, mechanistic understanding (Formulation, Polymorphism, and Product Performance). Process Development Report. Risk Assessment – SUPAC, In-vitro Performance Test vs In-vivo QC Dissolution and Product’s Identity, Stability, Strength, Purity and Quality, etc….etc….etc…. 1. Assure product quality through the design and performance-based specifications. Reduce OOS. 2. Maintain continuous improvement & reduce CMC Supplements/Amendments through risk assessment. 3. Enhance review quality through review questions. May 27, 2011 31
  32. 32. QbR Risk–Based Review Current One size fits all including BE criteria. Question-based Review Three-tiered assessment of manufacturing Tier 1 applies to all dosage forms. Tier 2 applies to dosage forms that are not solutions (Equivalent to current practice). Tier 3 applies to dosage forms that are not solutions, IR tablets, or IR capsules. Process development report – CTD, ICH Q8 Strongly recommended for dosage forms that are not solutions, IR tablets, or IR capsules. May 27, 2011 32
  33. 33. QbR Formulation Science & Design Elements of QbD : Bioavailability MANUFACTURING PROCESS SCIENCE  DRUG (s) EXCIPIENTSPHYSICAL-CHEMICAL PHYSICAL-CHEMICALPROPERTIES FORMULATION PROPERTIESIN-VITRO PHYSICALCHEMICAL ATTRIBUTES  IN-VIVO PHYSICAL CHEMICAL ATTRIBUTES Gastrointestinal Track PHARMACOKINETIC  PROPERTIESPHYSIOLOGICAL Whole BodyVARIABLES CLINICAL  PROPERTIES May 27, 2011 Bioavailability 33
  34. 34. QbRFormulation Science & DesignSignificance of Connectivity and Longevity in Product Development through PAT Early and Analytical Testing Preformulation Procedures Stability Specifications Evaluation In vitro Vendor Core Formulation Release Testing Qualification Functional Method Activities Validation Reverse Transfer Engineering Reference Method Standard Development Characterization OptimizationMay 27, 2011 34
  35. 35. QbRFormulation Science & DesignSignificance of Connectivity and Longevity in Product Development through PAT Disintegration of Formulation Drug Drug Characteristics Dissolution PC and Stability Bioequivalence ____________________________________ Bioavailability Drug Drug Absorption Excretion Drug Drug Metabolism DistributionMay 27, 2011 35
  36. 36. QbR Formulation Science & Design Why Design Process Critical to FDA?Quality by Design paradigm.Product Development Information Report is where you demonstrate the drug is highly variable.  Source of Variability (Mechanistic Understanding). Drug Substance (common between Generic & RLD), Formulation (Generic Biostudies could be higher/ lower)  Justify use of Bioequivalence Study design other than 80-125% confidence interval.Product development report is where you justify equivalence of design. May 27, 2011 36 Lawrence Yu, Office of Generic Drugs, FDA, 2004
  37. 37. QbRFormulation Science & Design Why Design Process Critical to FDA? Variability in API and inactive ingredient group (IIG). Formulation design: rapid release.  Demonstrate by dissolution comparison under physiologically relevant conditions.  Waive if BCS class I. Confirm with in vivo study. Variability in the formulation of RLD.  Design for equivalence begins with characterization of RLD.  Generic product should recognize variability is an issue and target the mean performance.  Current system: no reward for generic that is less variable. May 27, 2011 37 Lawrence Yu, Office of Generic Drugs, FDA, 2004
  38. 38. QbR Formulation Science & Design Current Practice Reasons for design decisions not fully explained. Example of Deficiency  QbD The drug substance has a primary amine group. Spray dried lactose is used as a diluent in the formulation. Please discuss potential drug -excipient interaction. Question - based Review (QbR)  PAT Q: What is the formulation intended to do? (IR,MR, CR) Q: What mechanism does it use to accomplish this? Q: Were any other formulation alternatives investigated and how did these perform? Q: Is the formulation design consistent with the dosage form classification in the label?  SbK May 27, 2011 38 Modified from Gary Buehler & Lawrence Yu, OGD, FDA, 2005
  39. 39. QbR Formulation Science & Design Product Design for an ANDA of a Highly Variable Drug Understand what the RLD is supposed to do and Origin of Variability. Design for Equivalence. Directly evaluate Equivalent Product Performance – verify the design. Use Bioequivalence Study Design for highly variable drugs. Review Pharmaceutical Development (Quality by Design) Report.  Understand what the problem is, as well as the real fundamentals i.e. physical and chemical parameters.”  Make coherent, science based decisions.” May 27, 2011 39 Lawrence Yu, Office of Generic Drugs, FDA, 2004
  40. 40. QbRManufacturing Process Science Current Practice Limited information submitted Example of Deficiency  QbD + PAT Please explain how you will provide assurance that the product batches are mixed adequately” Question-based Review  PAT + SbK Q: How were the critical steps in the process identified?  PAT + SbK Q: What are the critical process parameters for each critical step and how were they identified, monitored, and/or controlled? May 27, 2011 40 Modified from Gary Buehler Director, Office of Generic Drugs, FDA, 2005
  41. 41. Beginning of EndMeasuring and Development Data Control of Variability through Intelligent Automation Protocols are roadmap for required Data Quality. Identification of all critical steps and variables. Science-based specification and controls allow focus on high risk areas to reduce supplements. Lack of adequate development data suggests – ■ Possibility of unidentified critical steps. ■ Higher risk in post-approval changes. When “Best Practices” are employed ■ Risk of poor product quality is minimized. ■ Lower risk in post-approval changes will allow down regulation of reporting category. May 27, 2011 41
  42. 42. Summary Take Home PointsEstablish formulatory material search and match data base library within organization.A fundamental scientific premise is that quality cannot be tested into a product. Rather, quality must be built into the product throughout the manufacturing process; one cannot assure quality by testing for it at the end of the manufacturing process or at a later point.Design, evaluate and document preformulation & formulation development study protocols.Optimized formulation variables at early stage of development. (pay now or pay later). May 27, 2011 42
  43. 43. Summary Take Home PointsBetter utilization of modern scientific, technical, and chemometrics tools for pharmaceutical product design space at the ground level.Implement proper physiocharacterization techniques, In Silico tools, Linear accelerated temperature range effects on degradation.Established qualified links between materials, process, product and application (MPPA).ICH Q6A – A suitable starting place for the generic industry and regulators to move from current state to ICH Q8, Q9, Q10 – desired state. May 27, 2011 43
  44. 44. Summary Take Home PointsPharmaceutical Development is a learning process that describe both success and failures as a part of the story which demonstrates Quality by Design (QbD) and Design Space.Early awareness on science - based review / question - based review after submission – development cycles, formulation time, formulation manufacturing parameters (critical process parameters), cycle deviation, etc.Depend more on scientific justification and on in-process testing, not on end product testing, when making regulatory decisions. May 27, 2011 44
  45. 45. ThoughtsTechnology Replaces Technology “eCTD Drug Submission is a 1-Step Synthesis. QbD demands to change from Current Solution State to Solid StateTechnology to minimize Process and Drug Quality Risk.” “Majority of current off-line chemical analytical methodology is equivalent to narrow range pH test strips.”A Fundamental Analytical Variability May 27, 2011 45
  46. 46. AcknowledgementsAjaz S. Hussain &FDA’s Visionary PAT Team May 27, 2011 46 Out of Control (OOC)?...... Just like OOS and OOT?
  47. 47. Thank YouAre you ready to move on to PAT from PAC? May 27, 2011 47
  48. 48. “If we can’t describe scientifically and technologically whatwe are doing as a process, we don’t know what we’re doing.” May 27, 2011 48

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