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Quality by Design - Presentation by Naveen Pathak

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This document provides a summary of a presentation on Quality-by-Design (QbD) for biopharmaceuticals. It begins with an overview of QbD and its key principles of product and process understanding and control based on science and risk management. The presentation then discusses applying QbD concepts to coffee making as an example. Key aspects of coffee quality are identified and process parameters that impact quality are described. The presentation emphasizes using process understanding to develop a control strategy to ensure consistent quality. It also discusses integrating QbD with process validation approaches.

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Naveen Pathak Head, QbD Systems, Shire Quality-by-Design (QbD) for Biopharmaceuticals
The opinions expressed in this presentation are my own and do not represent those of my employer Shire Pharmaceuticals I am a shareholder of Shire Pharmaceuticals and other pharmaceutical companies through ownership of stocks and mutual funds  This presentation is intended for education, development and training purposes only Disclaimer
Naveen’s Bio • Current Role: Head QbD Systems, Process Development and Technical Services, (04/14– Present: Director), Shire, MA • Adjunct Professor (QbD), Keck Graduate Institute, Amgen Bioprocessing Center. • Associate Director, Manufacturing Science & Technology, Genzyme, MA • Principal Engineer, Process Development, Amgen, RI • Project Manager, Biological Manufacturing, H3Pharma Inc., Montreal • Senior Scientist (downstream), DSM Biologics, Montreal • Scientist, Core Technologies, Novartis Pharmaceuticals, NJ • Master of Science in Chemical Engineering, University of Oklahoma • Bachelor of Technology in Chemical Engineering, Indian Institute of Technology, Delhi • Project Management Professional, PMP, 2005-2010 • Drug Development, Temple University QA/RA program 3
What is Quality-by-Design? “Product and Process Understanding”….. [ICH Q8 (R2) Definition] “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.” INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE. This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA. QbD QRM Risk Assessment Tools DOE Statistics Control Strategy Process Understanding Documentation “An approach to rational design”… “Designing and developing a product and associated manufacturing processes that will be used during product development to ensure that the product consistently attains a predefined quality at the end of the manufacturing process.” Guidance for Industry, Quality Systems Approach to Pharmaceutical CGMP Regulations ; U.S. Department of Health and Human Services, Food and Drug Administration, September 2006 “Building in quality” …..
Making a Cup of Coffee (regular “non- QbD” approach) I want a cup of “good” coffee Monday: wow Awesome coffee! Tuesday: Yuck!! I should add a lot of coffee to get good taste…I will let it brew slow to get most out of it.. need Coffee grind…..whatever spoon I can get from DW..add a few, I am out of water bottles…oh I can just use tap water… did I use two filters yesterday…I guess
Coffee Making (QbD approach): Introducing QbD terms, CQA, CPP, and CRM • Buy good coffee beans • Grind your coffee just before brewing • Store your coffee properly • Use the right proportion of coffee to water • Focus on technique • The grind size of your coffee beans • The temperature of your water • The amount you agitate your coffee grounds during brewing • The ratio of water to coffee. When tasting coffee, professional coffee tasters, or “cuppers” as they are known, grade the coffees on a five basic taste characteristics. 1. Flavor 2. Acidity –Liveliness of the coffee 3. Body –The feel of the coffee in your mouth rather than the actual flavor. 4. Aroma – Coffee aroma is the fragrance of brewed coffee and is closely related to coffee flavor. 5. Finish – This is the sensation of brewed coffee vapors released after swallowing.
Coffee Making (QbD approach): Characterization
8 Coffee Making (QbD approach) NAVEEN PATHAK QbD course @ Bio manufacturing Education & Training Center (BETC), WPI
Zen and the Art of QbD •Understand your product and Quality you desire •Understand the process to make the product •Use Process Understanding to Control your Product Quality and consistency 9 NAVEEN PATHAK QbD course @ Bio manufacturing Education & Training Center (BETC), WPI
QbD  Value Proposition • Clear demonstration of control of risk to product quality • Visibility to process capability risk at commercialization • Efficient “first time right” PPQ approach • CPV program aligned with APQR and validation maintenance requirements • Continuous improvement of process capability by lifecycle approach to Qbd Challenge A pragmatic and systems based approach to QbD, which is right sized for both legacy and new products & Inclusive of internal & external manufacturing
Why Quality by Design? 11 1.) Regulatory agencies are increasingly expecting QbD-based business practices and methods to be employed throughout the product lifecycle even though full QbD or ‘Design Space’ filings are not required at this time. 2.) Potential product shortages as a result of manufacturing interruptions and process deviations, regulatory observations of our quality systems, and delays in regulatory filings • Market capture • Ability to meet product demand • Potential exclusivity • Earlier proof of concept • Lower-risk back-end expenditures • Smoother tech transfer • Well understood process with less upsets or deviations • More complete filing and better chance of approval
Warning letters from regulatory agencies that highlight lack of control strategy and process understanding
Mission: Rapid Commercialization and Sustainable Commercial Manufacturing Lifecycle Management PROCESS & ASSAY IMPLEMENTATION COMMERCIAL MANUFACTURING & LIFE CYCLE MANAGEMENT Stage 1 Process Validation: Process Design Stage 2 Process Validation: Process Performance Qualification Stage 3 Process Validation: Continued Process Verification Commercial Product PRODUCT DISCONTINUATION PROCESS & ANALYTICAL DEVELOPMENT PRODUCT DEVELOPMENT PVlifecycle TechnologyTransfer QbD/controlstrategy Continuousimprovement& CPV PDA Technical Report #60 Lifecycle approach to Process Validation…… Biopharmaceutical Product and Process Lifecycle
Timeline • Evolution of regional GMPs 1970s • Evolution of ISO 9000 approaches 1980s • FDA 21st Century initiative 2002 • ICH Quality Vision / Q8, Q9, Q10 2003 • FDA Quality Systems guide 2006 * • ICH Q10 Pharmaceutical Quality System 2008 • ICH Q8/9/10 IWG 2008 * FDA commitment to update or withdraw when Q10 issued A-Mab Case study 2.1  2009
• Publication and Sponsorship • CASSS http://www.casss.org • ISPE http://www.ispe.org • Maintain CMC Working Group interactions • Coordinate workshops • Develop training • Facilitate regulatory interactions Biopharmaceutical QbD Pilot: A-Mab Case Study A-Mab is a Public Document
QbD Related Expectations are Anchored in 21st Century cGMPs and Associated Guidelines Quality Risk Management Q9 Product and Process Understanding Q8 (R1) Q9, Q10 Q11 Pharmaceutical Quality System Q10 21st Century Quality Paradigm Lower Risk Operations Innovation and Continual Improvement Optimized Change Management Process Enhanced Regulatory Approaches Industry Status Emergence of these guidance documents fueled the case for the QbD Pilot
QbD Workflow
QbD and PV (Process Validation) Integrated Approach QTPP Construction CQA Assessment Parameter/Raw material Risk Assessment Process Development and Characterization Parameter /Raw material Classification Process Control Strategy Drug Discovery & Research PROCESS UNDERSTANDING PRODUCT UNDERSTANDING PAR CQA Ranges CPPs Analytical Control Strategy PVStage1:ProcessDesign (QTPP) Define desired quality characteristics of the product (CQA) Perform risk assessment to link quality attributes to clinical safety and efficacy Characterizati on & Criticality Study the impact of deliberate variations in process control parameters and raw material attributes (inputs) on proposed CQAs and determine parameter criticality Control Strategy Derived Based on understanding and control of sources of variability to ensure product quality and consistency Stage2 PPQ Process Qualification Based on Control Strategy Demonstrate that the process is capable of reproducible commercial manufacturing Stage3 CPV Process Monitoring Continued process verification (CPV) to ensure process remains in state of control; mechanism to identify and implement process improvements CONTROL STRATEGY Charac. Plan Risk to Patent Mitigated Lifecycle PV QbD stages Application of Quality Risk Management
Risk Assessment and Management QRM Total Risk is a function of: • Severity of the event if it were to occur (S) • Probability or Frequency of Occurrence (O) • Probability of Detection (D) Risk Priority Number (RPN) = S x O x D Quality Risk Management Sometimes an Uncertainty factor is also used to account for level of confidence in the information used for Risk Assessment
Quality Risk Management Methodologies
Control Strategy is based on a final Risk Assessment (Patient Risk) for each CQA Overall CQA Risk Assessment RPN CQA Criticality Assessment Severity Process Capability Occurrence Testing Strategy Detectability = X X Risk Assessment RPN = SxOxD Categorization of Process Parameters Design Space In-Process Controls Specifications Risk Assessment Severity of Impact x Certainty • Similar approach taken for Performance Parameters • The risk in this case is to Process Performance
NAVEEN PATHAK • The assessment process is via a risk based approach which includes • Determination of Severity score based on its potential impact on the following: - Safety/Immunogenecity - Potency/Efficacy - PK/PD • Determination of an “uncertainty” Score based on level of confidence in data used to score Severity Determination of Critical Quality Attributes (CQAs) Example Quality Attribute Criticality Assignment Matrix (CQAs shaded) Severity Uncertainty 10 7 5 3 10 7 5 3 1
NAVEEN PATHAK Parameter & Raw Material Impact Assessment From process flow diagrams, identify operating parameters and raw materials for each unit operation Identify impacted CQAs and performance parameters for each unit operation (Purpose of step) Score the potential impact of each parameter and raw material on each CQA and performance Potential impact is a risk estimation when parameter is varied over an “assessed range” INITIAL PARAMTER AND RAW MATERIAL IMPACT ASSESSMENT Unit Operation Purposeof the Unit Operation OperatingParamter/Raw material/component Unit of Measure Target AssessmentRange(LowerLimit) AssessmentRange(UpperLimit) Outputs(CQAs and non-CPAs) Notes/Comments/Justification PrimarySequence Aggregates Oxidizedspecies HostcellProteins HostCellDNA BSA DrugSubstance Concentration DrugProductConcentration Color Viraladventitiousagents Microbialcontaminants Endotoxin Mycoplasma Leachables Titer CellDensity Yield SetPoint NormalOperatingRange (LowerLimit) NormalOperatingRange (UpperLimit) Chromatography1: Cation Exchange Chromatography Early purificationstep which achieves significant reduction in process impurities. PrimaryBSA reduction step (in wash 2 and elution) resin Loading g/L 5.5 5.4 5.6 3 9 1 7 7 10 7 10 1 7 Multivariate (DOE) Temp OC 20 16 23 14 25 4 4 4 4 4 4 1 4 Other incorporatein other designs; temperaturemay still impact product stream stability so decision to study EQ/Load/W1 pH pH units 5.6 5.5 5.7 5.4 5.8 1 7 10 10 7 7 1 7 Multivariate (DOE) EQ/Load/W1 Cond. mS/cm 5.5 5 6 4 7 1 7 10 10 7 7 1 7 Multivariate (DOE) EQ/Load/W1 Flow rate cm/hr 150 140 160 125 175 1 4 4 4 4 4 1 4 None Wash 2 pH pH units 5.6 5.5 5.7 5.4 5.8 1 7 10 10 7 10 1 7 Multivariate (DOE) Wash 2 cond. mS/cm 13.5 13 14 11 15 1 7 10 10 7 10 1 7 Multivariate (DOE) Wash 1 volume CV 4 3.8 4.2 3.5 4.5 1 7 7 7 7 7 1 1 Univariate(OFAT) Wash 2 volume CV 6 5.8 6.2 5 10 1 7 7 7 7 10 1 7 Multivariate (DOE) Elution pH pH units 5.6 5.5 5.7 5.4 5.8 1 7 7 7 7 7 1 7 Multivariate (DOE) Elution volume CV 4 3.8 4.2 3.5 4.5 1 4 4 4 4 4 1 7 Univariate(OFAT) Elution cond. mS/cm 20 18 22 17 23 1 10 7 7 7 7 1 7 Multivariate (DOE) Avg harvest Age (from Bxr) Days 11 8 13 4 17 1 7 7 7 7 4 1 7 Univariate(OFAT) Pool Hold time Hrs <5 N/A 5 N/A 12 1 7 7 4 4 4 1 4 Univariate(OFAT) Column Bed height cm 18 17 19 16 20 1 4 4 7 7 7 1 4 Univariate(OFAT) Resin Ligand Density umol/ml 100 75 125 60 150 1 4 4 4 4 4 1 4 None Elution Pool bag Comp. 1 4 4 4 4 4 7 1 Other Extractablestudies Column Storage solution bag Comp. 1 1 1 1 1 1 7 1 Other Extractablestudies Skid valve diaphragm Comp. 1 1 1 1 1 1 4 1 None Characterization Plan
NAVEEN PATHAK Criticality Determination  Risk Quantitation of Impact Over Characterized Range Quantitative Qualitative Assess First/Next CQA Start Type of Criticality analysis Parameter judged to Practically Impact CQA For each parameter or material Parameter is Critical No Yes No Have all CQAs been assessed? Parameter is Non-Critical Yes No Parameter Interacts with other Parameters for impact Assess Multivariate Response Yes Risk/Impact Assessment Question Does the CQA vary significantly when the parameter is varied over the characterized range? Is the width of the NOR close to the PAR? Does the process lack robustness to variability within the NOR or PAR? Is the PAR close to the edge of failure?Final Impact Score can be 4. 7 or 10; score of 10  CPP
Control Strategy Risk Assessments (QRM1 & QRM2) Apply Process Controls QRM1 Apply Analytical Controls QRM2 Image adapted from Mab A case study
PACS: A source for key business and regulatory outputs Process & Analytical Control Strategy Technology Transfer Plan Process Validation Strategy & Plan Regulatory Dossier Manufacturing Batch Records Commercial Process Description Equipment validation Analytical Method validation plan
The Second Stage of Process Validation  PPQ  Center Piece of Tech Transfer Use Control Strategy to guide development of PPQ protocols Execute protocols at commercial scale to make DS and DP Document that Process and Analytical control could be demonstrated at commercial scale by successful execution of protocols Generally performed for n =3 but lower # can be used per justification Types of PPQ activities 1. Unit Operation PPQ 2. Ancillary PPQ/validation activities Process Validation (PPQ) Master Plan  Its all in here !
Continued Process Verification It is all about staying in control… Updated Control Strategy Additional Process Understanding Management Review Monitor Process Risk Review Assessment of validated state Risk Register Governance Processes (TOTAL) Extreme-6 High-5 Moderate B-4 Moderate A-3 Low B-2 Low A-1 <<<Impact>>> 1 2 1 4 3 Risk Profile Overview (# Risks by Impact and Likelihood): 0 0 0 17 0 2 0 4 4 0 0 1 78 2 0 0 0 00 1 <<< Likelihood >>> 0 1 1 1 2 1 6 Low-1 Moderate-2 4 High-3 0 0 5 Extreme-4 0 (TOTAL) 0
Quality by Design (Q-b-D) for Biopharmaceuticals • WHAT YOU WILL LEARN: • This course will take the students through the journey of using a combination of classroom presentations and case studies such that they will be “ready” to participate in Q-b-D related activities related to a Biotech product. • Introduction to Q-b-D principles- A science- and risk-based approach • Product understanding – Critical Quality Attributes (CQAs) – patient safety and needs • Process understanding • Development of Process and Analytical Control Strategy • Statistical Methods and data analysis • Quality Risk Management (QRM) • Design of Experiments (DOE) • Process Optimization & Response Surface Methodology– Ranges, Design Space, • Root causes analysis – FMEA, risk ranking and apply FMEA to Control Strategy selection • Technology Transfer to manufacturing and Continuous Process Verification Strategy • CASE Studies
Course Layout • 7 Modules over 3 days • Intro  CQA  Initial Impact DOE Classification  Control Strategy  Tech Transfer & CPV • An integrated case study • Start with a Fictitious Molecule and its Bioprocess • Complete a case study worksheet for all stages (CQA  Control Strategy) • Data provided for each stage to complete the worksheets for the case study
The Hands on Case Study is the Center Piece of the Course
Questions? Thank you for attending this webinar! Next Webinar: April 26, 2017 Reliability Engineering for Biomanufacturing

More Related Content

Quality by Design - Presentation by Naveen Pathak

  • 1. Naveen Pathak Head, QbD Systems, Shire Quality-by-Design (QbD) for Biopharmaceuticals
  • 2. The opinions expressed in this presentation are my own and do not represent those of my employer Shire Pharmaceuticals I am a shareholder of Shire Pharmaceuticals and other pharmaceutical companies through ownership of stocks and mutual funds  This presentation is intended for education, development and training purposes only Disclaimer
  • 3. Naveen’s Bio • Current Role: Head QbD Systems, Process Development and Technical Services, (04/14– Present: Director), Shire, MA • Adjunct Professor (QbD), Keck Graduate Institute, Amgen Bioprocessing Center. • Associate Director, Manufacturing Science & Technology, Genzyme, MA • Principal Engineer, Process Development, Amgen, RI • Project Manager, Biological Manufacturing, H3Pharma Inc., Montreal • Senior Scientist (downstream), DSM Biologics, Montreal • Scientist, Core Technologies, Novartis Pharmaceuticals, NJ • Master of Science in Chemical Engineering, University of Oklahoma • Bachelor of Technology in Chemical Engineering, Indian Institute of Technology, Delhi • Project Management Professional, PMP, 2005-2010 • Drug Development, Temple University QA/RA program 3
  • 4. What is Quality-by-Design? “Product and Process Understanding”….. [ICH Q8 (R2) Definition] “A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management.” INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE. This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA. QbD QRM Risk Assessment Tools DOE Statistics Control Strategy Process Understanding Documentation “An approach to rational design”… “Designing and developing a product and associated manufacturing processes that will be used during product development to ensure that the product consistently attains a predefined quality at the end of the manufacturing process.” Guidance for Industry, Quality Systems Approach to Pharmaceutical CGMP Regulations ; U.S. Department of Health and Human Services, Food and Drug Administration, September 2006 “Building in quality” …..
  • 5. Making a Cup of Coffee (regular “non- QbD” approach) I want a cup of “good” coffee Monday: wow Awesome coffee! Tuesday: Yuck!! I should add a lot of coffee to get good taste…I will let it brew slow to get most out of it.. need Coffee grind…..whatever spoon I can get from DW..add a few, I am out of water bottles…oh I can just use tap water… did I use two filters yesterday…I guess
  • 6. Coffee Making (QbD approach): Introducing QbD terms, CQA, CPP, and CRM • Buy good coffee beans • Grind your coffee just before brewing • Store your coffee properly • Use the right proportion of coffee to water • Focus on technique • The grind size of your coffee beans • The temperature of your water • The amount you agitate your coffee grounds during brewing • The ratio of water to coffee. When tasting coffee, professional coffee tasters, or “cuppers” as they are known, grade the coffees on a five basic taste characteristics. 1. Flavor 2. Acidity –Liveliness of the coffee 3. Body –The feel of the coffee in your mouth rather than the actual flavor. 4. Aroma – Coffee aroma is the fragrance of brewed coffee and is closely related to coffee flavor. 5. Finish – This is the sensation of brewed coffee vapors released after swallowing.
  • 7. Coffee Making (QbD approach): Characterization
  • 8. 8 Coffee Making (QbD approach) NAVEEN PATHAK QbD course @ Bio manufacturing Education & Training Center (BETC), WPI
  • 9. Zen and the Art of QbD •Understand your product and Quality you desire •Understand the process to make the product •Use Process Understanding to Control your Product Quality and consistency 9 NAVEEN PATHAK QbD course @ Bio manufacturing Education & Training Center (BETC), WPI
  • 10. QbD  Value Proposition • Clear demonstration of control of risk to product quality • Visibility to process capability risk at commercialization • Efficient “first time right” PPQ approach • CPV program aligned with APQR and validation maintenance requirements • Continuous improvement of process capability by lifecycle approach to Qbd Challenge A pragmatic and systems based approach to QbD, which is right sized for both legacy and new products & Inclusive of internal & external manufacturing
  • 11. Why Quality by Design? 11 1.) Regulatory agencies are increasingly expecting QbD-based business practices and methods to be employed throughout the product lifecycle even though full QbD or ‘Design Space’ filings are not required at this time. 2.) Potential product shortages as a result of manufacturing interruptions and process deviations, regulatory observations of our quality systems, and delays in regulatory filings • Market capture • Ability to meet product demand • Potential exclusivity • Earlier proof of concept • Lower-risk back-end expenditures • Smoother tech transfer • Well understood process with less upsets or deviations • More complete filing and better chance of approval
  • 12. Warning letters from regulatory agencies that highlight lack of control strategy and process understanding
  • 13. Mission: Rapid Commercialization and Sustainable Commercial Manufacturing Lifecycle Management PROCESS & ASSAY IMPLEMENTATION COMMERCIAL MANUFACTURING & LIFE CYCLE MANAGEMENT Stage 1 Process Validation: Process Design Stage 2 Process Validation: Process Performance Qualification Stage 3 Process Validation: Continued Process Verification Commercial Product PRODUCT DISCONTINUATION PROCESS & ANALYTICAL DEVELOPMENT PRODUCT DEVELOPMENT PVlifecycle TechnologyTransfer QbD/controlstrategy Continuousimprovement& CPV PDA Technical Report #60 Lifecycle approach to Process Validation…… Biopharmaceutical Product and Process Lifecycle
  • 14. Timeline • Evolution of regional GMPs 1970s • Evolution of ISO 9000 approaches 1980s • FDA 21st Century initiative 2002 • ICH Quality Vision / Q8, Q9, Q10 2003 • FDA Quality Systems guide 2006 * • ICH Q10 Pharmaceutical Quality System 2008 • ICH Q8/9/10 IWG 2008 * FDA commitment to update or withdraw when Q10 issued A-Mab Case study 2.1  2009
  • 15. • Publication and Sponsorship • CASSS http://www.casss.org • ISPE http://www.ispe.org • Maintain CMC Working Group interactions • Coordinate workshops • Develop training • Facilitate regulatory interactions Biopharmaceutical QbD Pilot: A-Mab Case Study A-Mab is a Public Document
  • 16. QbD Related Expectations are Anchored in 21st Century cGMPs and Associated Guidelines Quality Risk Management Q9 Product and Process Understanding Q8 (R1) Q9, Q10 Q11 Pharmaceutical Quality System Q10 21st Century Quality Paradigm Lower Risk Operations Innovation and Continual Improvement Optimized Change Management Process Enhanced Regulatory Approaches Industry Status Emergence of these guidance documents fueled the case for the QbD Pilot
  • 18. QbD and PV (Process Validation) Integrated Approach QTPP Construction CQA Assessment Parameter/Raw material Risk Assessment Process Development and Characterization Parameter /Raw material Classification Process Control Strategy Drug Discovery & Research PROCESS UNDERSTANDING PRODUCT UNDERSTANDING PAR CQA Ranges CPPs Analytical Control Strategy PVStage1:ProcessDesign (QTPP) Define desired quality characteristics of the product (CQA) Perform risk assessment to link quality attributes to clinical safety and efficacy Characterizati on & Criticality Study the impact of deliberate variations in process control parameters and raw material attributes (inputs) on proposed CQAs and determine parameter criticality Control Strategy Derived Based on understanding and control of sources of variability to ensure product quality and consistency Stage2 PPQ Process Qualification Based on Control Strategy Demonstrate that the process is capable of reproducible commercial manufacturing Stage3 CPV Process Monitoring Continued process verification (CPV) to ensure process remains in state of control; mechanism to identify and implement process improvements CONTROL STRATEGY Charac. Plan Risk to Patent Mitigated Lifecycle PV QbD stages Application of Quality Risk Management
  • 19. Risk Assessment and Management QRM Total Risk is a function of: • Severity of the event if it were to occur (S) • Probability or Frequency of Occurrence (O) • Probability of Detection (D) Risk Priority Number (RPN) = S x O x D Quality Risk Management Sometimes an Uncertainty factor is also used to account for level of confidence in the information used for Risk Assessment
  • 20. Quality Risk Management Methodologies
  • 21. Control Strategy is based on a final Risk Assessment (Patient Risk) for each CQA Overall CQA Risk Assessment RPN CQA Criticality Assessment Severity Process Capability Occurrence Testing Strategy Detectability = X X Risk Assessment RPN = SxOxD Categorization of Process Parameters Design Space In-Process Controls Specifications Risk Assessment Severity of Impact x Certainty • Similar approach taken for Performance Parameters • The risk in this case is to Process Performance
  • 22. NAVEEN PATHAK • The assessment process is via a risk based approach which includes • Determination of Severity score based on its potential impact on the following: - Safety/Immunogenecity - Potency/Efficacy - PK/PD • Determination of an “uncertainty” Score based on level of confidence in data used to score Severity Determination of Critical Quality Attributes (CQAs) Example Quality Attribute Criticality Assignment Matrix (CQAs shaded) Severity Uncertainty 10 7 5 3 10 7 5 3 1
  • 23. NAVEEN PATHAK Parameter & Raw Material Impact Assessment From process flow diagrams, identify operating parameters and raw materials for each unit operation Identify impacted CQAs and performance parameters for each unit operation (Purpose of step) Score the potential impact of each parameter and raw material on each CQA and performance Potential impact is a risk estimation when parameter is varied over an “assessed range” INITIAL PARAMTER AND RAW MATERIAL IMPACT ASSESSMENT Unit Operation Purposeof the Unit Operation OperatingParamter/Raw material/component Unit of Measure Target AssessmentRange(LowerLimit) AssessmentRange(UpperLimit) Outputs(CQAs and non-CPAs) Notes/Comments/Justification PrimarySequence Aggregates Oxidizedspecies HostcellProteins HostCellDNA BSA DrugSubstance Concentration DrugProductConcentration Color Viraladventitiousagents Microbialcontaminants Endotoxin Mycoplasma Leachables Titer CellDensity Yield SetPoint NormalOperatingRange (LowerLimit) NormalOperatingRange (UpperLimit) Chromatography1: Cation Exchange Chromatography Early purificationstep which achieves significant reduction in process impurities. PrimaryBSA reduction step (in wash 2 and elution) resin Loading g/L 5.5 5.4 5.6 3 9 1 7 7 10 7 10 1 7 Multivariate (DOE) Temp OC 20 16 23 14 25 4 4 4 4 4 4 1 4 Other incorporatein other designs; temperaturemay still impact product stream stability so decision to study EQ/Load/W1 pH pH units 5.6 5.5 5.7 5.4 5.8 1 7 10 10 7 7 1 7 Multivariate (DOE) EQ/Load/W1 Cond. mS/cm 5.5 5 6 4 7 1 7 10 10 7 7 1 7 Multivariate (DOE) EQ/Load/W1 Flow rate cm/hr 150 140 160 125 175 1 4 4 4 4 4 1 4 None Wash 2 pH pH units 5.6 5.5 5.7 5.4 5.8 1 7 10 10 7 10 1 7 Multivariate (DOE) Wash 2 cond. mS/cm 13.5 13 14 11 15 1 7 10 10 7 10 1 7 Multivariate (DOE) Wash 1 volume CV 4 3.8 4.2 3.5 4.5 1 7 7 7 7 7 1 1 Univariate(OFAT) Wash 2 volume CV 6 5.8 6.2 5 10 1 7 7 7 7 10 1 7 Multivariate (DOE) Elution pH pH units 5.6 5.5 5.7 5.4 5.8 1 7 7 7 7 7 1 7 Multivariate (DOE) Elution volume CV 4 3.8 4.2 3.5 4.5 1 4 4 4 4 4 1 7 Univariate(OFAT) Elution cond. mS/cm 20 18 22 17 23 1 10 7 7 7 7 1 7 Multivariate (DOE) Avg harvest Age (from Bxr) Days 11 8 13 4 17 1 7 7 7 7 4 1 7 Univariate(OFAT) Pool Hold time Hrs <5 N/A 5 N/A 12 1 7 7 4 4 4 1 4 Univariate(OFAT) Column Bed height cm 18 17 19 16 20 1 4 4 7 7 7 1 4 Univariate(OFAT) Resin Ligand Density umol/ml 100 75 125 60 150 1 4 4 4 4 4 1 4 None Elution Pool bag Comp. 1 4 4 4 4 4 7 1 Other Extractablestudies Column Storage solution bag Comp. 1 1 1 1 1 1 7 1 Other Extractablestudies Skid valve diaphragm Comp. 1 1 1 1 1 1 4 1 None Characterization Plan
  • 24. NAVEEN PATHAK Criticality Determination  Risk Quantitation of Impact Over Characterized Range Quantitative Qualitative Assess First/Next CQA Start Type of Criticality analysis Parameter judged to Practically Impact CQA For each parameter or material Parameter is Critical No Yes No Have all CQAs been assessed? Parameter is Non-Critical Yes No Parameter Interacts with other Parameters for impact Assess Multivariate Response Yes Risk/Impact Assessment Question Does the CQA vary significantly when the parameter is varied over the characterized range? Is the width of the NOR close to the PAR? Does the process lack robustness to variability within the NOR or PAR? Is the PAR close to the edge of failure?Final Impact Score can be 4. 7 or 10; score of 10  CPP
  • 25. Control Strategy Risk Assessments (QRM1 & QRM2) Apply Process Controls QRM1 Apply Analytical Controls QRM2 Image adapted from Mab A case study
  • 26. PACS: A source for key business and regulatory outputs Process & Analytical Control Strategy Technology Transfer Plan Process Validation Strategy & Plan Regulatory Dossier Manufacturing Batch Records Commercial Process Description Equipment validation Analytical Method validation plan
  • 27. The Second Stage of Process Validation  PPQ  Center Piece of Tech Transfer Use Control Strategy to guide development of PPQ protocols Execute protocols at commercial scale to make DS and DP Document that Process and Analytical control could be demonstrated at commercial scale by successful execution of protocols Generally performed for n =3 but lower # can be used per justification Types of PPQ activities 1. Unit Operation PPQ 2. Ancillary PPQ/validation activities Process Validation (PPQ) Master Plan  Its all in here !
  • 28. Continued Process Verification It is all about staying in control… Updated Control Strategy Additional Process Understanding Management Review Monitor Process Risk Review Assessment of validated state Risk Register Governance Processes (TOTAL) Extreme-6 High-5 Moderate B-4 Moderate A-3 Low B-2 Low A-1 <<<Impact>>> 1 2 1 4 3 Risk Profile Overview (# Risks by Impact and Likelihood): 0 0 0 17 0 2 0 4 4 0 0 1 78 2 0 0 0 00 1 <<< Likelihood >>> 0 1 1 1 2 1 6 Low-1 Moderate-2 4 High-3 0 0 5 Extreme-4 0 (TOTAL) 0
  • 29. Quality by Design (Q-b-D) for Biopharmaceuticals • WHAT YOU WILL LEARN: • This course will take the students through the journey of using a combination of classroom presentations and case studies such that they will be “ready” to participate in Q-b-D related activities related to a Biotech product. • Introduction to Q-b-D principles- A science- and risk-based approach • Product understanding – Critical Quality Attributes (CQAs) – patient safety and needs • Process understanding • Development of Process and Analytical Control Strategy • Statistical Methods and data analysis • Quality Risk Management (QRM) • Design of Experiments (DOE) • Process Optimization & Response Surface Methodology– Ranges, Design Space, • Root causes analysis – FMEA, risk ranking and apply FMEA to Control Strategy selection • Technology Transfer to manufacturing and Continuous Process Verification Strategy • CASE Studies
  • 30. Course Layout • 7 Modules over 3 days • Intro  CQA  Initial Impact DOE Classification  Control Strategy  Tech Transfer & CPV • An integrated case study • Start with a Fictitious Molecule and its Bioprocess • Complete a case study worksheet for all stages (CQA  Control Strategy) • Data provided for each stage to complete the worksheets for the case study
  • 31. The Hands on Case Study is the Center Piece of the Course
  • 32. Questions? Thank you for attending this webinar! Next Webinar: April 26, 2017 Reliability Engineering for Biomanufacturing

Editor's Notes

  1. Often confusion Broad and narrow definitions used Confused with DOE
  2. 14