Quality by-Design (QbD) by Mr. Nitin Kadam.

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Quality by-Design (QbD) by Mr. Nitin Kadam.

  1. 1. QUALITY – by – DESIGN (QbD)QUALITY – by – DESIGN (QbD)Implementation in Formulation DevelopmentImplementation in Formulation DevelopmentFor (ANDAs)For (ANDAs)ByMr. Nitin M. KadamMr. Nitin M. Kadam M. Pharm.M. Pharm.QbD Team (Formulation Development Compliance)Global Scientific & Regulatory AffairsWockhardt Research Center, Aurangabad.
  2. 2. What is QbD ???What is QbD ???QbD Definition as per ICH in ICH-Q8RQbD Definition as per ICH in ICH-Q8R““ A systematic approach to pharmaceutical development thatA systematic approach to pharmaceutical development thatbegins with predefined objectives and emphasizes product andbegins with predefined objectives and emphasizes product andprocess understanding based on sound science and quality riskprocess understanding based on sound science and quality riskmanagement.”management.”It means designing and developing formulations andmanufacturing processes to ensure predefined product qualityobjectives.
  3. 3. What is QbD ???What is QbD ???A more systematic approach to development can include, for example,A more systematic approach to development can include, for example,incorporation of prior knowledge, result of studies using design of experiments,incorporation of prior knowledge, result of studies using design of experiments,use of quality risk management and use of knowledge management throughuse of quality risk management and use of knowledge management throughout life cycle of the product.out life cycle of the product.Product quality life cycle is all about the practical means for the implementationProduct quality life cycle is all about the practical means for the implementationof ICH guidance’s on ICH Q8 (Pharmaceutical Development), Q9 (Quality Riskof ICH guidance’s on ICH Q8 (Pharmaceutical Development), Q9 (Quality Riskmanagement) and Q10 (Pharmaceutical Quality System), based on soundmanagement) and Q10 (Pharmaceutical Quality System), based on soundscientific, engineering and business principles.scientific, engineering and business principles.
  4. 4. What QbD dose in product development ???What QbD dose in product development ???QbD identifies characteristics that are critical to quality from the perspective ofQbD identifies characteristics that are critical to quality from the perspective ofpatients, translates them into the attributes that the drug product shouldpatients, translates them into the attributes that the drug product shouldpossess, and establishes how the critical process parameters can be variedpossess, and establishes how the critical process parameters can be variedto consistently produce a drug product with the desired characteristics.to consistently produce a drug product with the desired characteristics.For this the relationships between formulation & manufacturing processFor this the relationships between formulation & manufacturing processvariables (i.e. CMAs of API and excipient and CPPs) and productvariables (i.e. CMAs of API and excipient and CPPs) and productcharacteristics (QTPP) are established and sources of variability identifiedcharacteristics (QTPP) are established and sources of variability identified(CQAs).(CQAs).This knowledge is then used to implement a flexible and robust manufacturingThis knowledge is then used to implement a flexible and robust manufacturingprocess that can adapt and produce a consistent product over time.process that can adapt and produce a consistent product over time.
  5. 5.  QbD principles increase product understanding and process knowledge.QbD principles increase product understanding and process knowledge. The increased process knowledge and product understanding resultingThe increased process knowledge and product understanding resultingfrom QbD can increase the efficiency of manufacturing processes; reducefrom QbD can increase the efficiency of manufacturing processes; reduceproduct recalls and compliance actions, resulting in cost savings forproduct recalls and compliance actions, resulting in cost savings forpharmaceutical companies.pharmaceutical companies. By reducing uncertainty and risk, QbD can allow industry and regulators toBy reducing uncertainty and risk, QbD can allow industry and regulators tofocus their resources in the most critical areas. Because much morefocus their resources in the most critical areas. Because much moreprocess understanding has been demonstrated and expressed in theprocess understanding has been demonstrated and expressed in thedossier.dossier.What QbD dose in product development ???What QbD dose in product development ???
  6. 6.  QbD filings also can help facilitate GMP inspections by theQbD filings also can help facilitate GMP inspections by theregulators and decrease the number of post-approval regulatoryregulators and decrease the number of post-approval regulatorysubmissions required to make process changes.submissions required to make process changes.What QbD dose in product development ???What QbD dose in product development ???
  7. 7.  The QbD-based pharmaceutical manufacturing process will beThe QbD-based pharmaceutical manufacturing process will beadjustable within aadjustable within a design spacedesign space, providing a robust process that is, providing a robust process that ismanaged with amanaged with a control strategycontrol strategy developed using modern statisticaldeveloped using modern statisticalprocess control methodsprocess control methods (DOE)(DOE) and enabling a lifecycle approach toand enabling a lifecycle approach tovalidation/continuous process verificationvalidation/continuous process verification.. Product specifications will be based on desired productProduct specifications will be based on desired productperformance characteristics and will be part of a risk-based qualityperformance characteristics and will be part of a risk-based qualitycontrol strategy.control strategy.What QbD dose in product development ???What QbD dose in product development ???
  8. 8. Pharmaceutical QbD is a systematic, scientific, risk-based,Pharmaceutical QbD is a systematic, scientific, risk-based,holistic and proactive approach to pharmaceuticalholistic and proactive approach to pharmaceuticaldevelopment that begins with predefined objectives anddevelopment that begins with predefined objectives andemphases product and processes understanding andemphases product and processes understanding andprocess control.process control.In my words ….In my words ….A systematic and knowledge based scientific approach of maintainingA systematic and knowledge based scientific approach of maintainingCQAsCQAs by well definedby well defined control strategycontrol strategy andand design spacedesign space by establishingby establishingcombination and interaction ofcombination and interaction of CMAsCMAs andand CPPsCPPs to provide predefinedto provide predefinedQTPP.QTPP.What is QbD in brief ???What is QbD in brief ???
  9. 9. What is Design Space ???What is Design Space ???It is a multidimensional combination and interaction of inputIt is a multidimensional combination and interaction of inputvariables (variables (CMAsCMAs––ccriticalritical mmaterialaterial aattributes) and processttributes) and processparameters (parameters (CPPsCPPs––ccriticalritical pprocessrocess pparameters ) that havearameters ) that havebeen demonstrated to provide assurance of quality.been demonstrated to provide assurance of quality.Most Important….Most Important….Out of Design Space Initiation of Post Approval ChangesOut of Design Space Initiation of Post Approval Changes
  10. 10. 1.1.2.2.A QbD based ANDA should include…….A QbD based ANDA should include…….
  11. 11. A demonstration of processA demonstration of processunderstanding through theunderstanding through theidentification of critical processidentification of critical processparameters (CPPs)parameters (CPPs)Development of a Control StrategyDevelopment of a Control Strategythat ensures the product reliablythat ensures the product reliablymeets the predefined objectivesmeets the predefined objectives4.4.3.3.A QbD based ANDA should include…….A QbD based ANDA should include…….
  12. 12. • Defining Quality Target Product Profile (QTPP)• Identification of Critical Quality Attributes (CQAs) : Critical/Non Critical• Identification of Critical Material Attributes (CMAs)• Initial Risk Assessment for Drug Substance Attributes• Justification for Initial Risk Assessment for Drug Substance Attributes• Selection of Excipients (Provide Rationale / Justification)• Excipients Compatibility Studies• Development of Q&Q formula for initial Formulation Development• Initial Risk Assessment for Formulation ComponentsImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  13. 13. • Designing Development Strategies• DOE for Optimization of Formulation• Defining Design Space for CQAs, CMAs or Formulation Components• Pilot Bioequivalence Studies• Update of Initial Risk Assessment for Drug Substance Attributes• Update of Initial Risk Assessment for Formulation Components• Justify the Levels of Risks changed• Well Defined Control StrategyImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  14. 14. ImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…• Development of Manufacturing Process• Initial Risk Assessment for Manufacturing Process• DOE for Optimization of Manufacturing Process• Defining Design Space for identified CQAs or CPPs• Pilot Bioequivalence Study• Justify the Levels of Risks changed• Well Defined Control Strategy
  15. 15. • Scale-up from Lab to Pilot Scale & then Commercial Scale• Pre-exhibit / Exhibit Batch• Update of Initial Risk Assessment for Manufacturing Process• Pivotal Bioequivalence• Control Strategy for Drug Product• Container Closure System• Development Studies to be supported with Stability StudiesImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  16. 16. Defining Quality Target Product Profile (QTPP)Defining Quality Target Product Profile (QTPP)It contains prospective summary of the desired product features withrespect to quality, safety, efficacy.QTPP Element Target JustificationDosage form,Route of Administration,Strength,Pharmacokinetics,Stability,Drug product quality attribute,Container Closure system, etc.ProductSpecificPharmaceutical equivalentrequirement or specific.
  17. 17. Identification of Critical Quality Attributes (CQAs) and definingIdentification of Critical Quality Attributes (CQAs) and definingits criticalityits criticalitySummarize the CQAs on the basis of quality attributes identified as atarget along with the justification for being CQAQA of DP Target Is it CQA? JustificationIt should includeproduct andprocess specificquality attributesDesiredqualityBased on impactof attribute onQTPPStatement shouldclearly justify theCQA criticality levelscientifically as wellas technically.Drug Product CQAs:Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution,Degradation Products, etc.
  18. 18. Identification of Critical Material Attributes (CMAs)Identification of Critical Material Attributes (CMAs) Physical characterization of Drug SubstancePhysical characterization of Drug SubstancePhysical, PSD, pH-solubility, Hygroscopisity, MP, Flow, Solid State Form, Polymorphism, etc. Chemical Characterization of Drug SubstanceChemical Characterization of Drug SubstancepH, pKa, FDS, Stability, etc. Biological Characterization of Drug SubstanceBiological Characterization of Drug SubstancePartition coefficient, BCS, etc.……….to identify the CMAs
  19. 19. Initial Risk Assessment for Drug Substance AttributesInitial Risk Assessment for Drug Substance AttributesIt involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based onIt involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based onsafety and efficacy linked to scientific knowledge ultimatelysafety and efficacy linked to scientific knowledge ultimatelyDrugProductCQAsDrug Substance AttributesA B C DX LowY MediumZ HighDrug Substance Attributes:SSF, PSD, Moisture, Hygroscopisity, RS, Solubility, Flow, Chemical Stability, etc.Drug Product CQAs:Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, DegradationProducts, etc.
  20. 20. Justification for Initial Risk Assessment for Drug Substance AttributesJustification for Initial Risk Assessment for Drug Substance AttributesTable should provide the impact of drug substance attributes on CQAsand scientific as well as technical justification for the level of riskidentifiedDrug SubstanceAttributesDrug ProductCQAsJustificationA,B,C,D, etc. X,Y,Z,etc justification for the levelof risk identified
  21. 21.  Selection of Excipients (Provide Rationale / Justification) Excipients Compatibility Studies Development of Q&Q formula for initial Formulation DevelopmentImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  22. 22. Initial Risk Assessment for Formulation ComponentsInitial Risk Assessment for Formulation ComponentsDrugProductCQAsFormulation ComponentsE F G HX LowY MediumZ HighIt involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based onIt involves quality risk evaluation in three levels, LOW, MEDIUM, HIGH based onsafety and efficacy linked to scientific knowledge ultimatelysafety and efficacy linked to scientific knowledge ultimatelyFormulation Components:Drug substance PSD, Diluent ratio, Diluent PSD, Disintegration level, Lubricant Level, etc.Drug Product CQAs:Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution, DegradationProducts, etc.
  23. 23. Justification for Initial Risk Assessment for Formulation ComponentsJustification for Initial Risk Assessment for Formulation ComponentsTable should provide the impact of Formulation components on CQAsand scientific as well as technical justification for the level of riskidentifiedFormulation Components Drug ProductCQAsJustificationE,F,G,H, etc. X,Y,Z,etc justification for the levelof risk identified
  24. 24.  Designing Development Strategies Design of Experiments (DoE) for Formulation Development(This information includes DOE implementation in Product Development by usingcommercially available DOE software e.g. Minitab, Design Expert, Stat Graphics, etc.)DOE should be carried out at, two main stages of Product development,1.To optimize formulation2.To optimize manufacturing processFormulation Development…Formulation Development…
  25. 25. Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation DevelopmentWhy DoE?Why DoE?To find answers of following common questions,1.What is an optimum formulation?2.How does the optimum change if changes are made to formulation or process?3.Which variables is sensitive to the machine or process?4.For performance consistency , what are the limits for these variables?5.How one design can effectively troubleshoot the problem?To save Time, To Reduce Cost, To get Reliable Quality.The factors to be studied in a DoE could come from the risk assessmentThe factors to be studied in a DoE could come from the risk assessmentexercise or prior knowledge.exercise or prior knowledge.
  26. 26. DOE Flow…DOE Flow…
  27. 27. Key Elements of Experiments…Key Elements of Experiments…
  28. 28. Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation DevelopmentDoE to be apply and discuss in brief with respect to Design Steps as follows,1.Screening DoE: Selection of only vital factors from the factors identified in initial riskassessment.2. Characterization DoE: Choice of experimental design which gives potential interactions inselected vital factors.3.Performance of experiments.4.Statistical analysis of data.5.Conclusion along with recommendations if any.DoE in terms of factors, levels, response variables, design applied, significance andnon significance (p-value)
  29. 29. Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation DevelopmentThree basic principles of statistical experimental designs,Three basic principles of statistical experimental designs,1.1.RandomizationRandomizationBy properly randomizing the experiments, the effects of uncontrollable factors that may bepresent can be “averaged out”.2.2.BlockingBlockingIt is the blocking arrangement of experimental units into groups (blocks) that are similar toone another. Blocking reduces known but irrelevant sources of variation between groups andthus allows greater precision in the estimation of the source of variation under study.3.3.ReplicationReplicationIt allows the estimation of the pure experimental error for determining whether observeddifferences in the data are really statistically different.
  30. 30.  Factorial Designs – Identify the vital factors that affect yourprocess or product. Then you can make breakthroughimprovements. Response Surface Methods (RSM) – Find the idealprocess settings. Achieve optimal performance. Mixture design techniques – Discover the optimalformulation. Combined designs - Combine process variables, mixturecomponents and categoric factors in one design!Design of Experiments (DoE) for Formulation DevelopmentDesign of Experiments (DoE) for Formulation Development
  31. 31.  Defining Design Space for CQAs, CMAs or Formulation Components Pilot Bioequivalence Studies Update of Initial Risk Assessment for Drug Substance Attributes Update of Initial Risk Assessment for Formulation Components Justify the Levels of Risks changed Well Defined Control StrategyImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  32. 32.  Manufacturing Process DevelopmentManufacturing Process Development It involves identification of all possible known material attributes andcritical process parameters that could impact the performance of theprocess. Initial Risk Assessment for Manufacturing ProcessInitial Risk Assessment for Manufacturing Process Risk assessment can be done for each unit operation ofmanufacturing process steps separately depends up on the criticalconsiderations for process optimization. Based on the selected process and CMAs, Initial risk assessmentcan be done.(Stage of risk assessment is not fixed. Risk assessment is depends on thecriticality of manufacturing process steps.)
  33. 33. DrugProductCQAsManufacturing Process Steps(Each unit operation process step should becover)I J K LX LowY MediumZ HighManufacturing Steps:Mixing, Granulation, Lubrication, Compression, Coating, etc.Drug Product CQAs:Physical Attribute, Assay, Content Uniformity, Drug Release/ Dissolution,Degradation Products, etc.Initial Risk Assessment for Manufacturing ProcessInitial Risk Assessment for Manufacturing Process
  34. 34. Justification for Initial Risk Assessment of Manufacturing ProcessJustification for Initial Risk Assessment of Manufacturing ProcessTable should provide the impact of Formulation components on CQAsand scientific as well as technical justification for the level of riskidentifiedFormulation Components Drug ProductCQAsJustificationE,F,G,H, etc. X,Y,Z,etc justification for the levelof risk identified
  35. 35. • DOE for Optimization of Manufacturing Process (Each unit step)• Defining Design Space for identified CQAs or CPPs• Pilot Bioequivalence Study• Justify the Levels of Risks changed• Well Defined Control StrategyImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  36. 36. • Scale-up from Lab to Pilot Scale & then Commercial Scale• Pre-exhibit / Exhibit Batch• Update of Initial Risk Assessment for Manufacturing Process• Pivotal Bioequivalence• Control Strategy for Drug Product• Container Closure System• Development Studies to be supported with Stability StudiesImportantImportant QbDQbD Aspects & Development Flow…Aspects & Development Flow…
  37. 37. Formulation Development Report Flow As PerFormulation Development Report Flow As Per QbDQbD1.1. Executive Summary1.2. Analysis of Reference Listed Drug1.2.1. Clinical1.2.2. Pharmacokinetics1.2.3. Drug Release1.2.4. Physicochemical Characterization1.2.5. Composition1.3. Quality Target Product Profile1.4. Dissolution Method Development & Bioequivalence Studies.1.4.1. Development Dissolution Method1.4.2. Pivotal / Pilot Bioequivalence Study2.1. Components of Drug Product2.1.1. Drug Substance2.1.1.1. Physical Properties2.1.1.2. Chemical Properties2.1.1.3. Biological Properties2.1.1.4. Initial Risk Assessment of Drug Substance Attributes
  38. 38. 2.1.2. Excipients2.1.2.1. Excipients Compatibility2.2. Drug Substance2.2.1. Formulation Development2.2.1.1. Initial Risk Assessment of the Formulation Components2.2.1.2. Drug substance Particle Size Selection For Drug Product2.2.1.3. Process Selection2.2.1.4. Formulation Development Studies (#1, #2, #3, etc.)2.2.1.5. Prototype Formulation2.2.1.6. Formulation Development Conclusion2.2.1.7. Updated Risk Assessment for Drug Substance2.2.1.8. Updated Risk Assessment of the Formulation Components2.2.2. Overages2.3. Manufacturing Process Development2.3.1. Initial Risk Assessment of the Drug Product Manufacturing Process2.3.2. Each Unit Operation Development (Granulation, Compression, Coating)Formulation Development Report Flow As PerFormulation Development Report Flow As Per QbDQbD
  39. 39. 2.3.3. Scale-up From Lab Scale to Pilot Scale and Commercial Scale2.3.3.1. Scale-up of Each Process Step (Granulation, Compression, Coating)2.3.4. Pre-exhibit Batch2.3.5. Exhibit Batch2.3.6. Updated Risk Assessment of The Drug Product Mfg. Process2.4. Container Closure System2.5. Microbiological Attributes2.6. Compatibility2.7. Control Strategy2.8. Development Conclusion***~ ~***~ ~ THE ENDTHE END ~ ~ ***~ ~ ***Formulation Development Report Flow As PerFormulation Development Report Flow As Per QbDQbD
  40. 40. Product Development & Life CycleProduct Development & Life Cycle
  41. 41. Intelligent PeoplesIntelligent Peoplesdoesnt makedoesnt makeMISTAKES…MISTAKES…But…..But…..mistakesmistakesmake peoplesmake peoples
  42. 42. Thank You…Thank You…Mr. Nitin M. KadamMr. Nitin M. Kadamnitkadam@gmail.comnmkadam@wockhardt.comhttp://nitinkadam.webs.comQuestions are welcome….

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