Application of enhanced process and product knowledge to facilitate the lifecycle management of a biopharmaceutical product Alan Gardner Biopharmaceutical CMC Regulatory Affairs GlaxoSmithKline Property of GlaxoSmithKline
Overview Objective Case study of an enhanced risk-based approach to change management to facilitate lifecycle management of a biopharmaceutical product Outline Background information Post-approval change management approach Risk based approach to technology transfer Lifecycle approach to process validation Comparability and stability studies Agency feedback Additional experience with a site transfer Conclusions Property of GlaxoSmithKline
Introduction PRODUCT: Monoclonal antibody IgG 1 Approved in US, EU, and numerous international countries Lyophilized drug product PRODUCT KNOWLEDGE IN ORIGINAL BLA/MAA File was traditional with some enhanced product knowledge elements embedded DS and DP process parameter classifications Critical, Key, Non-Key based on assessment of impact to product quality Non-Key Process Parameter - A process parameter that may be controlled to a defined range but has not been demonstrated to have a significant effect on process performance or product quality. Key K Process Parameter - A process parameter that t should be controlled to within a defined d range for optimal process performance. It is not deemed a critical process parameter because it does not affect critical product quality attributes or because of the minor extent to which it may affect overall process performance, or because it is readily controlled within a defined range. Critical Process Parameter - A process parameter that when not controlled within a defined range, may lead to a significant effect on a product quality attribute or process performance, such that the product may potentially fail to meet in-process control limits, release specifications r stability specifications. Property of GlaxoSmithKline
Post-Approval Change Management Subsequent to submission of the BLA/MAA, a critical post-approval change was identified that would benefit from an enhanced approach to facilitate its implementation and approval: An alternative Drug Product manufacturing site was needed to increase capacity and enhance security of supply New Drug Product site: existing company facility in EU Approved site for other products supplied to US, EU, and International markets 2X scaleup from current DP manufacturing site Several improvements to process and product components were also implemented Risk-based approach taken for technology transfer to new site Lifecycle approach taken to Process Validation To facilitate regulatory approval, a Comparability Protocol was submitted in US and a Post-Approval Change Management Protocol was submitted in EU CP/CMP was specific to site Filed during early stages of technology transfer activities
Risk-Based Approach to Technology Transfer FMEA conducted on changes in product components and process RPN = S x O x D RPN determined for all risks; categorized as High, Medium, Low, and insignificant Risk Mitigation plans identified for all Medium (6) and High (0) risks Stopper drying New disposable equipment (2 instances) Filter changes Filling pump differences Use of Pressure Rise Test instead of tc to monitor end of primary drying
Lifecycle Approach to Process Validation Stage 1 Process Development Studies to evaluate which changes, if any, are necessary to ensure that the control strategy is effective at the new site Implementation of risk mitigation from FMEA Stage 2 Process Qualification Science and risk based process validation studies to demonstrate control strategy Stage 3 Ongoing Process Verification Post-commercial activity intended to provide continuous assurance that the process remains in a state of control
Stage 1 Process Development Using the Risk Assessment conducted for technology transfer, studies were identified to understand impact of process differences, and identify any changes to operating parameters to ensure acceptable control strategy. Risk Stopper drying New disposable equipment (2 instances) Filter changes Filling pump differences Use of Pressure Rise Test instead of tc to monitor end of primary drying Study Stopper drying study Material compatibility Filter Vmax Pump compatibility Engineering run to correlate PRT and thermocouples
Stage 2 Process Qualification Conducted 3 full-scale batches of each vial strength Additional supporting studies conducted during Process Qualification batches, such as: Mixing Hold times 2 of 4 equivalent lyophilizers used during PQ phase Equivalency demonstrated on basis of identical design, equipment qualification studies, and confirmed through periodic monitoring
Stage 3 Ongoing Process Verification Focused on lyophilization step due to its potential to impact product quality relative to other steps Monitoring of process performance, including Release testing Process parameters In-process controls Yield f f 3 d th Extended sampling and testing for the first batches in the 3 rd and 4 th lyophilizers
Comparability and Stability Studies Comparability testing approach Release tests Characterization tests Stressed stability Stability studies Recommended and accelerated conditions Compare vs. historical stability data from original site
Agency Feedback on Protocol US FDA Comments/Requests Comparability study design aspects Acceptable to file new site as CBE-30 as long as acceptance criteria are met Lyos 3 & 4 data must be submitted as CBE-30 prior to distribution of product manufactured in those lyos, if not in original file EU EMA Comments/Requests Comparability study acceptance criteria GMP certificate for new site covering activities for the biological product Acceptable to file new site as Type IB with Stage 2 PV data
Additional EU Experience related to new site CMP Vaccine antigen (multivalent) manufacture transferred to a newly built facility outside EU New site; had not been inspected by an EU Competent Authority Scientific Advice meeting held prior to transfer to discuss approach PA CMP will be acceptable approach GMP certificate will be required prior to submission of data to register the new site PA CMP subsequently filed and approved After filing PA CMP, GSK requested inspection of new site Inspection was successfully completed prior to submission of data package
Limitations and Benefits of enhanced change management approach for introduction of new Drug Product site Potential limitations Approach required detailed knowledge of new site could be difficult to apply during original BLA/MAA So far it has not been tested outside of US/EU Benefits Focused technology transfer activities on most critical aspects to ensure successful transfer Enabled lifecycle process validation strategy to ensure effective control strategy leading up to and post-commercialization of the new site Enabled regulatory strategy utilizing i protocols to facilitate regulatory review/approval Ensures achievement of company objectives to increase capacity and enhance security of supply while ensuring product quality is not impacted.
Acknowledgements GSK technology transfer team including Massimo Rastelli Jim Colandene Christine Pannunzio Alicia Gilbert Mike James Richard Kettlewell ll Tom Smith Nancy Cauwenberghs