Principal approach to CPV :

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1 Principal approach to CPV : Integration with Quality Systems & Operating Mechanisms J. Gampfer, Baxalta, Vienna Austria Baxalta Principal Approach to CPV J. Gampfer Page 1

2 Baxalta Principal Approach to CPV J. Gampfer Page 2 It is all about:

3 Systematic approach according to ICH & FDA guidance s Upper Spec Lower Spec The applicant should base the inputs and outputs studied on their potential criticality and justify their selection. For those which are not studied further it may be needed to explain how it is ascertained that these are kept within the range that has been shown to be non-critical. Input Variation Process Parameter Variation Quality Attribute Variation C C C Potential Patient Harm PP/CPPs CQAs / CBAs LSL USL Waste / Loss of Profits PP ph HCP C Control Strategy Inputs: Process Risk Assessment Outputs: Product Risk Assessment Baxalta Principal Approach to CPV J. Gampfer Page 3

4 Steps during Development Identify market need & molecule Analyse market and patient need identify and describe molecule and application Establish QTPP: Understand the molecule and functionalities Identify Critical Quality Attributes Understand function of CQAs and CBAs: Understanding the relationship between CQA and the clinical safety & efficacy profile. Identify Critical Business Attributes and performance indicators Establish Process Flow The product is the process Design commercially viable process Process Characterization Identify critical impact on product quality and process consistency Establish Control Strategy Continuous Improvement (Update Control Strategy ) What is critical? How is it controled? Define mechanisms that ensures consistent manufacturing Analyse process capability and identify opportunities to improve product quality and process consistency Baxalta Principal Approach to CPV J. Gampfer Page 4 4

5 QbD + Process Validation: Connecting the pieces Product Development Creating Knowledge Using Knowledge Desired Outcomes A end to end activity with a common objective On-going: QbD is a structured method for product development ensuring consistent manufacturing of high quality product Combination of knowledge management and systematic risk evaluation is used to establish efficient control mechanisms Continued response from the process enables adequate adjustment of controls Pending: and triggering of efficient continues process improvement activities Baxalta Principal Approach to CPV J. Gampfer Page 5

6 QbD + Process Validation: Connecting the pieces Product Development Creating Knowledge Using Knowledge Desired Outcomes A end to end activity with a common objective Stage 1: Process Development Stage 2: EQ & PPQ Stage 3: CPV (inital) CPV (late) On-going: QbD is a structured method for product development ensuring consistent manufacturing of high quality product Combination of knowledge management and systematic risk evaluation is used to establish efficient control mechanisms Continued response from the process enables adequate adjustment of controls Pending: and triggering of efficient continues process improvement activities Baxalta Principal Approach to CPV J. Gampfer Page 6

7 A Lifecycle Approach Process Development following QbD principles TPP QTPP Quality CQA Consistency CBA CPP Process Flow Control Strategy PPQ EQ M&C CPV Process Development - Stage 1: Establish Control Strategy Qualification- Stage 2: Confirm Control Strategy Cont. Verification - Stage 3: Update Control Strategy Continuous Improvement Systematic Development is a basis for efficient controls & robust manufacturing processes TPP: Target Product Profile CQA: Critical Quality Attribute PPQ / EQ: Process / Equip.Perf. Qual. QTPP: Quality Target Product Profile CCA: Critical Compar. Attribute CPP: Critical Process Parameters M&C: Monitoring & Control CPV: Cont. Process Verif. Baxalta Principal Approach to CPV J. Gampfer Page 7 7

8 Control Strategy along the product lifecycle Elements of Control: Stage I: Establish Control Strategy Stage II: Verify Control Strategy Element 8 Facility and Equipment Controls (cgmp and Procedural) Element 1 Direct in-process monitoring or control of Product Quality Attributes Element 2 Monitoring or Control of Process Parameters or Material Attributes that are functionally linked to Product Quality Attributes Stage III: Update Control Strategy Element 7 Control of Raw Materials (including cell banks) Control Strategy for Product Quality and Process Performance Attributes Element 3 Direct in-process Monitoring or Control of Process Performance Attributes Continous Improvement Element 6 Drug Substance and Drug Product Stability Monitoring Element 5 Drug Substance and Drug Product Specifications (including routine release, periodic monitoring, validated process removal and comparability) Element 4 Monitoring or Control of Process Parameters or Material Attributes functionally linked to Process Performance Attributes Baxalta Principal Approach to CPV J. Gampfer Page 8

9 A general roadmap for CPV was established with the BPOG framework Special thanks to: Mark DiMartino (Amgen Ranjit Deshmukh (AstraZeneca) BPOG membership is a strong representation of the world s biologics medicine manufacturers CPV Topic: Member Representation AbbVie Amgen AstraZeneca Biologics Baxter Bayer Biogen BMS Janssen Lonza Merck Patheon Pfizer Regeneron Roche / Genentech Genzyme GSK Sanofi Shire Baxalta Principal Approach to CPV J. Gampfer Page 9

10 INDUSTRY CASE STUDY: CONTINUED PROCESS VERIFICATION (CPV) FOR A BIOTECH PRODUCT BPOG s Continued Process Verification (CPV) encompasses a written plan for monitoring a licensed biopharmaceutical manufacturing process, then documenting and reporting the results. CPV reporting provides a basis from which to improve process understanding, and hence risk assessment, control strategy, and ultimately process improvement. This case study describes one of the first crosscompany efforts to be compiled on CPV in response to the FDA s 2011 process validation guidance. Free of charge access to full case study We describe general approaches to implementing CPV and offer some specific recommendations on the content of a CPV Protocol, along with associated rationale. These recommendations are based on a typical cell culture production process for making a fictitious monoclonal antibody product described in the A-Mab Case Study. Consequently, these recommendations may not apply directly to specific products or processes, but the principles and concepts described can be considered where applicable. Baxalta Principal Approach to CPV J. Gampfer Page 10 Biophorum Operations Group Ltd

11 1 2 Stage 1: Process Dev. Stage 2: EQ & PPQ Stage 3: CPV (inital) CPV (late) Baxalta Principal Approach to CPV J. Gampfer Page 11

12 Baxalta Principal Approach to CPV J. Gampfer Page 12

13 CPV Strategy: Scope of Data Collection and Analysis Plans Typically starts with the PPQ batches Informed by clinical or scale up batch data Two phases: Initial, Short-term: Stage 3a Prior to Statistical Process Control (SPC) Accumulate ~30 batches to set limits based on statistical significance Review parameters and update risks Late, Long-Term: Stage 3b Introduce SPC with rules for alerts Continue ongoing process verification Understand variation and trends Identify opportunities to continuously improve process Baxalta Principal Approach to CPV J. Gampfer Page 13

14 How to use information from CPV? Development work / PPQ CPV Plan CPV Execution Periodic CPV Report Propose changes to CPV Input To: APR / PQR Continuous Improvement Identify opportunities for improvement Approach to re-validation activities CPV is an ongoing activity continuously verifying the manufacturing process, reacting to changes and identifying opportunities for improvement Baxalta Principal Approach to CPV J. Gampfer Page 14

15 Interaction with other other operational mechanisms: Implementation & Inspection Link to Annual Product Review / Product Quality Review and other Quality systems Input to Post Approval Changes and Continuous Improvement Life cycle changes to CPV Approach to Process Revalidation Covered in this presentation Change Control Any other Baxalta Principal Approach to CPV J. Gampfer Page 15

16 BPOG Perspective Implementation and Inspection: 1 CPV Plan will be product specific, and generally facility specific In the case where the same product is manufactured at multiple facilities, a cross site review is warranted. The CPV plan itself may take the form of a pre-approved protocol or have procedural requirements, this will vary by company. The CPV plan is a lifecycle document that will be updated overtime. Signals identified from the plan are evaluated and documented at a minimum in a CPV report. The initial minimum requirements for a CPV plan are a prioritized subset of critical process outputs such as CQAs. Generally the approach is not to include CPV plans into submission, but provide CPV plan/report upon inspection(nodding on FDA side) Questions: Is there a difference between legacy and development products? Biophorum Operations Group Ltd Baxalta Principal Approach to CPV J. Gampfer Page 16

17 BPOG Perspective: CPV Relationship to APR and other Quality Systems 2 CPV Alerts are typically statistically based, and are reliant on many assumptions and historical knowledge. Risk based decisions should be used to determine the level of investigation required for an alert. Alerts and actions generated by CPV require a pragmatic relationship with the formal quality system. Alerts should not automatically be part of the non-conformance system, rather an escalation procedure should be used to determine when the alert passes into the non-conformance system. Alerts should not hold up lot release as they are not OOS. A escalation process to link to deviations systems should exists. These alerts and actions are summarized and reviewed in CPV reports, and are subject to management review as part of the APR. The ultimate outcome of these evaluations is an assessment on the effectiveness of the product s control strategy and if an update is warranted. Biophorum Operations Group Ltd General objective: Focus investigation time on important issues. Baxalta Principal Approach to CPV J. Gampfer Page 17

18 BPOG Perspective Post Approval Changes: 3 CPV continues to feed into the product and process knowledge that was started during Stage 1 Development. This should lead to process changes that will ultimately improve process and product robustness. Changes initiated out of CPV are data rich and should simplify the regulatory pathway. Improving process performance may lead to increased white space between specifications, indicating good process capability. Good process capability should not be a driver to tighten specifications. Questions: Biophorum Operations Group Ltd Should this be linked to ICH Q12 discussions? Baxalta Principal Approach to CPV J. Gampfer Page 18

19 BPOG Perspective Lifecycle Changes: 4 CPV plans are expected to be lifecycle documents, as are a product s control strategy. Over time, new variation may be identified, necessitating the addition of new parameters. Alternatively parameters may be identified as redundant, highly capable, predictive by another measure or well controlled. The ability to add and remove parameters from a CPV plan in an expedient manner is critical to promoting continued gains in process understanding. Changes to the monitoring strategy in the CPV plan may or may not impact the control strategy of a product. The quality system should be utilized to determine when the control strategy should be updated. Biophorum Operations Group Ltd Baxalta Principal Approach to CPV J. Gampfer Page 19

20 Decision Path for Life Time changes to CPV How to react to (e.g.): Unexpected incident reported CPV data out of trend, signal detected Change notification communicated A business process should be introduced to govern life time changes to CPV Outcome: Evaluate impact Update CPV Plan from: Biophorum Operations Group Ltd Baxalta Principal Approach to CPV J. Gampfer Page 20

21 Approach to Process Revalidation How can CPV support justify approach to re-validation? Decision blocks in the flow chart could be used to determine the risk due to the changes and data could be proportional to the decision block. Scientifically justified relationship between CQAs, CPPs, Control Strategy, CPV plan and data from CPV could support any post approval changes. The degree of effort for re-validation could be risked based General question: Is the process in a state of control? Baxalta Principal Approach to CPV J. Gampfer Page 21

22 Key Learning Points Differences in regulatory histories of biotech companies lead to different perspectives on response(s) to regulatory guidelines Continued Process Verification is a logical consequence of as product development following QbD principals With a common purpose, differences can be recognised and accounted for, quickly establishing a consistent position (or else clear reasons for divergence!) Establishing a CPV plan is complex, requiring a cross-functional team with a range of knowledge working together to be comprehensive and deliver real results Establishing a CPV program can open opportunities for increasing efficiency of continuous improvement activities Simple and cost-effective IT solutions are needed to support CPV implementation Baxalta Principal Approach to CPV J. Gampfer Page 22

23 Thank you for your Attention! I hope there is time for a lot of good discussions during the panel sessions Baxalta Principal Approach to CPV J. Gampfer Page 23