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Quality by Design for Legacy Products - A Contradiction ?

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Anthony Grenier

This document discusses applying Quality by Design (QbD) principles to both new product development and legacy products throughout the product lifecycle. It describes the three stages of process validation according to FDA guidelines and how QbD can be the basis for process validation. While new products must go through all three stages, legacy products focus on Stage III continued process verification. The document provides examples of how to define critical quality attributes and critical process parameters for legacy products using risk assessments and process knowledge. It also discusses using continued process verification to continuously improve process understanding, control strategies, and product quality over time.

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Qualification and Verification of Manufacturing Process throughout the Product Life Cycle 1 Quality by Design for Legacy Products A Contradiction ? Dr. Joerg Gampfer WCBP 2015- CASSS Conference Washington DC Jan 27-29 WCBP/ CASSS Washington DC January 2015
2 FDA Process Validation guideline 2011 Stage I Process Design Stage II 2.1 Equipment Qualification 2.2 Process Performance Qualification Stage III Continued Process Verification Applies to: • Entire product lifecycle: Development Commercialization PV guideline does not mention “QbD” but instead references science & risk-based principles described in ICH Q8,9,10,11 Defines commercial process based on knowledge gained through development and scale-up Confirms process design is capable of reproducible commercial manufacturing Assures continuous state of control during production QbD as basis for Process Validation WCBP/ CASSS Washington DC January 2015
3 Legacy Products: Development Products: Stepwise towards pro-active Design QbD principals can be applied to both legacy products and new development FDA Process validation guideline requires: o New Developments: Stage I, Stage II, Stage III (“Process Design” is an integral part of process validation) o Legacy Products: Stage III (Continued Process Verification) QbD applies to Legacy and Development WCBP/ CASSS Washington DC January 2015
4 Potential Patient Harm Quality Attribute Variation Process Parameter Variation Input Variation Time pH Temperature Time pH Temperature PotencyPotency Upper SpecUpper Spec Lower SpecLower Spec LSLLSL USLUSL USLUSLLSLLSL LSLLSL USLUSL PPPP Waste / Loss of Profits C C C C Control StrategyControl Strategy CPPsCPPs CQAsCQAs Potential Patient Harm Quality Attribute Variation Process Parameter Variation Input Variation Time pH Temperature Potency Upper Spec Lower Spec LSL USL USLLSL LSL USL PP Waste / Loss of Profits CC CC CC CC Control Strategy CPPs CQAs Establish Knowledge which impact process variation has on our product and the impact product variation has on the patient. QbD: Risk Management Principles WCBP/ CASSS Washington DC January 2015
5 TPP QTPP Quality and Business attributes Risk Evaluation CQAs, CBAs (*) Product Description Process Risk Evaluation CQAs CBAs Process Steps & Parameters PP, CPPs Process Knowledge: PP, CPPs, RPN Customer, Business and Market Driven Definition of Product Build Process Knowledege Correlating Process Parameters to Product Attributes (Quality) Target product profile is used to establish product attributes. Criticality can be assessed for business or quality aspects ( CQAs / CBAs) (*) Critical Business Attributes (CBA): Attributes influencing business needs and manufacturability Relating Product and Process WCBP/ CASSS Washington DC January 2015
Linking QbD and Process Validation 6 TPP QTPP CQA CPP Process Flow Control Strategy PPQ EQ CPV PV Stage II: Confirm Control Strategy M&C Continuous Improvement CBA PV Stage I: Establish Control Strategy PV Stage III: Update Control Strategy Process Validation following QbD principles ensures efficient Lifecycle Management Establishing feedback loops between Process Design, Qualification and Verification ensures pre-defined product quality and optimal business results WCBP/ CASSS Washington DC January 2015
7 A control strategy is the development and implementation of adequate controls to ensure the continued repeatability of process performance and the ongoing assurance of finished product quality. Control Strategy WCBP/ CASSS Washington DC January 2015
8 From Development Opportunities for Legacy Products Data from Routine Manufacturing Platform Knowledge Continously update Control Strategy for maintaining or improving: • Process Performance • Product Quality Continous collection of process data increases process knowledge: • Opportunities for identification of criticality • Opportunities for identification more efficient controls Use for improvement of process performance and product Quality WCBP/ CASSS Washington DC January 2015
9 Identification of CQA/CPP relationship Process Qualification Process Design Quality Target Product Profile Identify Critical Quality Attributes Identify Critical Process Parameters Establish Process Controls Continued Process Verification Capturing Product and Process Knowledge WCBP/ CASSS Washington DC January 2015
1010 Defining CQAs for Legacy Products Definition of a list of QA • Product Specification • Characterization studies • Manufacturing Experience workshop • Organized with all critical functions Identificatio n of CQA • CQA Assessment report • Inclusion of CQAs in the Manufacturing Process Control Plan (MPCP) • Issuance of the RACT (Risk Assessment and Control Table) for legacy product Methodology used to define CQA: Assessment performed with participants from all related facilities. Representatives of the Pre-Clinical and Clinical Affairs group participated. WCBP/ CASSS Washington DC January 2015
1111 Defining CPPs List of CPPs & Report issued Validation data Development reports Divisional methodology Manufacturing experience, Platform data Identifying Process impact on Product Quality WCBP/ CASSS Washington DC January 2015
2G. POTENTIAL CAUSES / INPUT CONTROLS 2H. TEST CONTROLS Potential Causes of Failure Input Controls O Test Controls D PN Actions / Rationale (Status) S O D PN Incorrect amounts of components Specifications for buffer components 1 In-line pH sensor 1 5 Not required 5 1 1 5 2I. RISK EVALUATION / ACTIONS Identify Controls for CPPs Complete Process FMEA • Process input variation and errors which could cause the failures are identified. • The probability of occurrence and detection is estimated, given the implemented controls. A Priority Number is calculated to evaluate risk and drive action, if needed. pH | Process Spread | LSL USL LSL USL | Process Spread | Acceptable, no further action required Not acceptable, reduction required 1-12 ActionsPriority 13-52 52-125 Acceptable, but investigate reduction Sources of Data SPC Charts / Capability Analysis Product Control Records Occurrence Detection 12WCBP/ CASSS Washington DC January 2015
1313 Stage three deployment: objective Deployment of Control Strategy The process includes the following steps: 1- Selecting Process Elements, 2- Selecting Monitoring Points & Limits, 3- Collecting Process Data, 4- Consolidating & Trending Data, and finally, 5- Reacting to Significant Events. Evaluating current Control Strategy and identifying opportunity for improvements WCBP/ CASSS Washington DC January 2015
14 Improving the Control Strategy along Life Cycle • Taking long range variation into account • Capture influence of additional factors ( e.g. change in raw materials) • Apply new technologies • React to new requirements ( e.g. metal impurities) • Further shift from end-product testing to controlling unit operations What is driving changes to Control Strategy ? WCBP/ CASSS Washington DC January 2015
5550454035302520 17,5 15,0 12,5 10,0 7,5 5,0 Avg Detection Risk AvgTotalRisk 12 16 30 36 40 45 risk single Max A 22 Nanofiltration skid Media Hold Tank Harv esting, filtration and dilution C hemostat Buildup- 40 L; 320 L ; 2500L bioreactors Inoculum Roller bottles Inoculum Roux F lasks Scatterplot of Avg Total Risk vs Avg Detection Risk 15 • Improve the „Detection“ in the overall risk (S*O*D) • If required improve „input controls“ to reduced „Occurence“ Use of PFMEA to identify Opportunities for better Controls Systematically decrease Process Risks WCBP/ CASSS Washington DC January 2015
Better Process Control by Process Understanding 16 Prediction of Protease Activation Time using upstream process conditions Plasma factor concentrates are a complex mix of a multitude of coagulation factors with multiple interactions and feed back reactions. Low yields were attributed to the inability to reliably predict the generation time to achieve a desired activation profile. This time variation is a major issue for manufacturing, i.e. the lack of resource planning. Using MVDA a set of 8 parameter in various upstream processes have been identified, which allow to predict the generation time with an accuracy of some hours. The prediction was often better than the parallel IPC testing in two labs. Example 1 WCBP/ CASSS Washington DC January 2015
0.400.350.300.250.200.150.10 0.45 0.40 0.35 0.30 0.25 0.20 0.15 UV-Start CIT DeltaCIT Atypical Evolution Typical Typical-ref Visual class Scatterplot of Delta CIT vs UV-Start CIT Delta C IT =0.9473 (UV RT-Start C IT)+0.03560 Regression fit (E3) Control of MAb Elutionsprofile Affinity chromatography is used for purification manufacturing. Chromatograhpic columns tend to compound with frequent use resulting in reduced purification and yield. Small changes in the shape of the elution profile have been identified (Multivariate Analysis) , which are associated with this trend. Based on this, the operator dependent decision could by replaced by an operator independent model. Typical elution profile with the parameters used at 280 nm peak. Blue = Reference Green = typical elution profile Red = aging column Black = critical state Better Process Control by Process Understanding Example 2 WCBP/ CASSS Washington DC January 2015
CONFIDENTIAL 18 Approach to Continous Improvement PPQ Initial CPV Late CPV Initial CPV Plan Update risk evaluation CPV report Continous Improvement Plan • Periodic CPV report • Annual Product Review late CPV Plan Update Controls Strategy Process Changes Continued Process Verification can be used to support efficient continous improvement activities along the product life cycle Continued Process Verification governs process improvements WCBP/ CASS Washington DC January 2015
19 Thank you for your attention WCBP/ CASSS Washington DC January 2015

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Quality by Design for Legacy Products - A Contradiction ?

  • 1. Qualification and Verification of Manufacturing Process throughout the Product Life Cycle 1 Quality by Design for Legacy Products A Contradiction ? Dr. Joerg Gampfer WCBP 2015- CASSS Conference Washington DC Jan 27-29 WCBP/ CASSS Washington DC January 2015
  • 2. 2 FDA Process Validation guideline 2011 Stage I Process Design Stage II 2.1 Equipment Qualification 2.2 Process Performance Qualification Stage III Continued Process Verification Applies to: • Entire product lifecycle: Development Commercialization PV guideline does not mention “QbD” but instead references science & risk-based principles described in ICH Q8,9,10,11 Defines commercial process based on knowledge gained through development and scale-up Confirms process design is capable of reproducible commercial manufacturing Assures continuous state of control during production QbD as basis for Process Validation WCBP/ CASSS Washington DC January 2015
  • 3. 3 Legacy Products: Development Products: Stepwise towards pro-active Design QbD principals can be applied to both legacy products and new development FDA Process validation guideline requires: o New Developments: Stage I, Stage II, Stage III (“Process Design” is an integral part of process validation) o Legacy Products: Stage III (Continued Process Verification) QbD applies to Legacy and Development WCBP/ CASSS Washington DC January 2015
  • 4. 4 Potential Patient Harm Quality Attribute Variation Process Parameter Variation Input Variation Time pH Temperature Time pH Temperature PotencyPotency Upper SpecUpper Spec Lower SpecLower Spec LSLLSL USLUSL USLUSLLSLLSL LSLLSL USLUSL PPPP Waste / Loss of Profits C C C C Control StrategyControl Strategy CPPsCPPs CQAsCQAs Potential Patient Harm Quality Attribute Variation Process Parameter Variation Input Variation Time pH Temperature Potency Upper Spec Lower Spec LSL USL USLLSL LSL USL PP Waste / Loss of Profits CC CC CC CC Control Strategy CPPs CQAs Establish Knowledge which impact process variation has on our product and the impact product variation has on the patient. QbD: Risk Management Principles WCBP/ CASSS Washington DC January 2015
  • 5. 5 TPP QTPP Quality and Business attributes Risk Evaluation CQAs, CBAs (*) Product Description Process Risk Evaluation CQAs CBAs Process Steps & Parameters PP, CPPs Process Knowledge: PP, CPPs, RPN Customer, Business and Market Driven Definition of Product Build Process Knowledege Correlating Process Parameters to Product Attributes (Quality) Target product profile is used to establish product attributes. Criticality can be assessed for business or quality aspects ( CQAs / CBAs) (*) Critical Business Attributes (CBA): Attributes influencing business needs and manufacturability Relating Product and Process WCBP/ CASSS Washington DC January 2015
  • 6. Linking QbD and Process Validation 6 TPP QTPP CQA CPP Process Flow Control Strategy PPQ EQ CPV PV Stage II: Confirm Control Strategy M&C Continuous Improvement CBA PV Stage I: Establish Control Strategy PV Stage III: Update Control Strategy Process Validation following QbD principles ensures efficient Lifecycle Management Establishing feedback loops between Process Design, Qualification and Verification ensures pre-defined product quality and optimal business results WCBP/ CASSS Washington DC January 2015
  • 7. 7 A control strategy is the development and implementation of adequate controls to ensure the continued repeatability of process performance and the ongoing assurance of finished product quality. Control Strategy WCBP/ CASSS Washington DC January 2015
  • 8. 8 From Development Opportunities for Legacy Products Data from Routine Manufacturing Platform Knowledge Continously update Control Strategy for maintaining or improving: • Process Performance • Product Quality Continous collection of process data increases process knowledge: • Opportunities for identification of criticality • Opportunities for identification more efficient controls Use for improvement of process performance and product Quality WCBP/ CASSS Washington DC January 2015
  • 9. 9 Identification of CQA/CPP relationship Process Qualification Process Design Quality Target Product Profile Identify Critical Quality Attributes Identify Critical Process Parameters Establish Process Controls Continued Process Verification Capturing Product and Process Knowledge WCBP/ CASSS Washington DC January 2015
  • 10. 1010 Defining CQAs for Legacy Products Definition of a list of QA • Product Specification • Characterization studies • Manufacturing Experience workshop • Organized with all critical functions Identificatio n of CQA • CQA Assessment report • Inclusion of CQAs in the Manufacturing Process Control Plan (MPCP) • Issuance of the RACT (Risk Assessment and Control Table) for legacy product Methodology used to define CQA: Assessment performed with participants from all related facilities. Representatives of the Pre-Clinical and Clinical Affairs group participated. WCBP/ CASSS Washington DC January 2015
  • 11. 1111 Defining CPPs List of CPPs & Report issued Validation data Development reports Divisional methodology Manufacturing experience, Platform data Identifying Process impact on Product Quality WCBP/ CASSS Washington DC January 2015
  • 12. 2G. POTENTIAL CAUSES / INPUT CONTROLS 2H. TEST CONTROLS Potential Causes of Failure Input Controls O Test Controls D PN Actions / Rationale (Status) S O D PN Incorrect amounts of components Specifications for buffer components 1 In-line pH sensor 1 5 Not required 5 1 1 5 2I. RISK EVALUATION / ACTIONS Identify Controls for CPPs Complete Process FMEA • Process input variation and errors which could cause the failures are identified. • The probability of occurrence and detection is estimated, given the implemented controls. A Priority Number is calculated to evaluate risk and drive action, if needed. pH | Process Spread | LSL USL LSL USL | Process Spread | Acceptable, no further action required Not acceptable, reduction required 1-12 ActionsPriority 13-52 52-125 Acceptable, but investigate reduction Sources of Data SPC Charts / Capability Analysis Product Control Records Occurrence Detection 12WCBP/ CASSS Washington DC January 2015
  • 13. 1313 Stage three deployment: objective Deployment of Control Strategy The process includes the following steps: 1- Selecting Process Elements, 2- Selecting Monitoring Points & Limits, 3- Collecting Process Data, 4- Consolidating & Trending Data, and finally, 5- Reacting to Significant Events. Evaluating current Control Strategy and identifying opportunity for improvements WCBP/ CASSS Washington DC January 2015
  • 14. 14 Improving the Control Strategy along Life Cycle • Taking long range variation into account • Capture influence of additional factors ( e.g. change in raw materials) • Apply new technologies • React to new requirements ( e.g. metal impurities) • Further shift from end-product testing to controlling unit operations What is driving changes to Control Strategy ? WCBP/ CASSS Washington DC January 2015
  • 15. 5550454035302520 17,5 15,0 12,5 10,0 7,5 5,0 Avg Detection Risk AvgTotalRisk 12 16 30 36 40 45 risk single Max A 22 Nanofiltration skid Media Hold Tank Harv esting, filtration and dilution C hemostat Buildup- 40 L; 320 L ; 2500L bioreactors Inoculum Roller bottles Inoculum Roux F lasks Scatterplot of Avg Total Risk vs Avg Detection Risk 15 • Improve the „Detection“ in the overall risk (S*O*D) • If required improve „input controls“ to reduced „Occurence“ Use of PFMEA to identify Opportunities for better Controls Systematically decrease Process Risks WCBP/ CASSS Washington DC January 2015
  • 16. Better Process Control by Process Understanding 16 Prediction of Protease Activation Time using upstream process conditions Plasma factor concentrates are a complex mix of a multitude of coagulation factors with multiple interactions and feed back reactions. Low yields were attributed to the inability to reliably predict the generation time to achieve a desired activation profile. This time variation is a major issue for manufacturing, i.e. the lack of resource planning. Using MVDA a set of 8 parameter in various upstream processes have been identified, which allow to predict the generation time with an accuracy of some hours. The prediction was often better than the parallel IPC testing in two labs. Example 1 WCBP/ CASSS Washington DC January 2015
  • 17. 0.400.350.300.250.200.150.10 0.45 0.40 0.35 0.30 0.25 0.20 0.15 UV-Start CIT DeltaCIT Atypical Evolution Typical Typical-ref Visual class Scatterplot of Delta CIT vs UV-Start CIT Delta C IT =0.9473 (UV RT-Start C IT)+0.03560 Regression fit (E3) Control of MAb Elutionsprofile Affinity chromatography is used for purification manufacturing. Chromatograhpic columns tend to compound with frequent use resulting in reduced purification and yield. Small changes in the shape of the elution profile have been identified (Multivariate Analysis) , which are associated with this trend. Based on this, the operator dependent decision could by replaced by an operator independent model. Typical elution profile with the parameters used at 280 nm peak. Blue = Reference Green = typical elution profile Red = aging column Black = critical state Better Process Control by Process Understanding Example 2 WCBP/ CASSS Washington DC January 2015
  • 18. CONFIDENTIAL 18 Approach to Continous Improvement PPQ Initial CPV Late CPV Initial CPV Plan Update risk evaluation CPV report Continous Improvement Plan • Periodic CPV report • Annual Product Review late CPV Plan Update Controls Strategy Process Changes Continued Process Verification can be used to support efficient continous improvement activities along the product life cycle Continued Process Verification governs process improvements WCBP/ CASS Washington DC January 2015
  • 19. 19 Thank you for your attention WCBP/ CASSS Washington DC January 2015