Quality by Design for Legacy Products A Contradiction?

Transcription

1 Quality by Design for Legacy Products A Contradiction? Qualification and Verification of Manufacturing Process throughout the Product Life Cycle Dr. Joerg Gampfer WCBP CASSS Conference Washington DC Jan

2 QbD as basis for Process Validation FDA Process Validation guideline 2011 Applies to: Entire product lifecycle: Stage I Process Design Stage II 2.1 Equipment Qualification 2.2 Process Performance Qualification Stage III Continued Process Verification 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 Development Commercialization PV guideline does not mention QbD but instead references science & risk-based principles described in ICH Q8,9,10,11 2

3 QbD applies to Legacy and Development 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) Legacy Products: Development Products: Stepwise towards pro-active Design 3

4 QbD: Risk Management Principles Establish Knowledge which impact process variation has on our product and the impact product variation has on the patient. Input Variation CPPs CQAs C C C Process Parameter Variation Quality Attribute Variation Potential Patient Harm Time LSL USL Upper Spec PP Potency Lower Spec ph LSL USL Waste / Loss of Profits LSL USL Temperature C Control Strategy 4

5 Relating Product and Process Customer, Business and Market Driven Definition of Product TPP QTPP Quality and Business attributes Risk Evaluation CQAs, CBAs (*) Product Description (*) Critical Business Attributes (CBA): Attributes influencing business needs and manufacturability (Quality) Target product profile is used to establish product attributes. Criticality can be assessed for business or quality aspects ( CQAs / CBAs) Build Process Knowledege Correlating Process Parameters to Product Attributes CQAs CBAs Process Steps & Parameters Process Risk Evaluation PP, CPPs Process Knowledge: PP, CPPs, RPN 5

6 Linking QbD and Process Validation Process Validation following QbD principles ensures efficient Lifecycle Management TPP QTPP CQA CBA CPP Process Flow Control Strategy PPQ EQ CPV M&C PV Stage I: Establish Control Strategy PV Stage II: Confirm Control Strategy PV Stage III: Update Control Strategy Continuous Improvement Establishing feedback loops between Process Design, Qualification and Verification ensures pre-defined product quality and optimal business results 6

7 Control Strategy 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. 7

8 Opportunities for Legacy Products From Development Data from Routine Manufacturing Platform Knowledge Continously update Control Strategy for maintaining or improving: Process Performance Continous collection of process data increases process knowledge: Opportunities for identification of criticality Opportunities for identification more efficient controls Product Quality Use for improvement of process performance and product Quality 8

9 Capturing Product and Process Knowledge Quality Target Product Profile Process Design Identify Critical Quality Attributes Identify Critical Process Parameters Identification of CQA/CPP relationship Establish Process Controls Process Qualification Continued Process Verification 9

10 Defining CQAs for Legacy Products Methodology used to define CQA: 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 Assessment performed with participants from all related facilities. Representatives of the Pre-Clinical and Clinical Affairs group participated. 10

11 Defining CPPs Identifying Process impact on Product Quality Divisional methodology Manufacturing experience, Platform data Validation data Development reports List of CPPs & Report issued 11

12 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. Occurrence LSL USL ph Process Spread LSL USL Process Spread Detection Priority Actions Acceptable, no further action required Acceptable, but investigate reduction Not acceptable, reduction required 2G. POTENTIAL CAUSES / INPUT CONTROLS 2H. TEST CONTROLS Potential Causes of Failure Incorrect amounts of components Input Controls O Test Controls D PN Actions / Rationale (Status) Specifications for buffer components 2I. RISK EVALUATION / ACTIONS S O D PN 1 In-line ph sensor 1 5 Not required Sources of Data SPC Charts / Capability Analysis Product Control Records 12

13 Deployment of Control Strategy Evaluating current Control Strategy and identifying opportunity for improvements The process includes the following steps: 1- Selecting Process Elements, Stage three deployment: objective 2- Selecting Monitoring Points & Limits, 3- Collecting Process Data, 4- Consolidating & Trending Data, and finally, 5- Reacting to Significant Events. 13

14 Improving the Control Strategy along Life Cycle What is driving changes to Control Strategy? 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 14

15 Systematically decrease Process Risks Use of PFMEA to identify Opportunities for better Controls Scatterplot of Avg Total Risk vs Avg Detection Risk Avg Total Risk 17,5 15,0 12,5 10,0 Chemostat Harv esting, filtration and dilution Buildup- 40 L; 320 L ; 2500L bioreactors Inoculum Roller bottles Inoculum Roux F lasks A22 Max single risk ,5 Media Hold Tank Nanofiltration skid 5, Avg Detection Risk Improve the Detection in the overall risk (S*O*D) If required improve input controls to reduced Occurence 15

16 Better Process Control by Process Understanding Prediction of Protease Activation Time using upstream process conditions Example 1 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. 16

17 Better Process Control by Process Understanding Control of MAb Elutionsprofile Example 2 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 Scatterplot of Delta CIT vs UV-Start CIT Blue Visual class = Reference Atypical Green = typical elution profile Evolution Red Typical = aging column Typical-ref Black = critical state Delta CIT Regression fit (E3) Delta CIT = (UV RT-Start CIT) Typical elution profile with the parameters used at 280 nm peak UV-Start CIT

18 Approach to Continous Improvement Continued Process Verification governs process improvements PPQ Initial CPV Late CPV Initial CPV Plan late CPV Plan CPV report Update risk evaluation Periodic CPV report Annual Product Review Continous Improvement Plan Update Controls Strategy Process Changes Continued Process Verification can be used to support efficient continous improvement activities along the product life cycle CONFIDENTIAL WCBP/ CASS Washington DC January

19 Thank you for your attention 19