Learnings from EBE Cross-Industry informational sharing session on development and licensing of biologics/device combination products

Transcription

1 Learnings from EBE Cross-Industry informational sharing session on development and licensing of biologics/device combination products Serge Mathonet, Sanofi R&D May 9, EU CMC Strategy Forum, Paris

2 Scope Focus was on prefilled autoinjector/pen e.g. single-use, disposable, handheld mechanical injection device integrating a prefilled syringe, that administers, over a defined period, a fixed dose of high concentration monoclonal antibodies solution into SC tissue. mab concentration would typically range from 50 to 150 mg/ml with self-delivery time for 1ml up to 20 seconds EBE set a topic group early 2015 to address/share CMC challenges associated with bringing these products to the market through organizing a cross industry information sharing session At the time of the cross-industry information sharing session (April 2015), only Simponi (RA) and Cosentyx sensoready prefilled pen (Psoriasis) has been approved for commercialisation. To date two addtional mab products in prefilled pen presentations have been approved (Praluent and Repatha - hypercholesterolemia). 2 EU CMC STRATEGY FORUM MAY 9,2016 EBE SATELLITE SESSIION

3 EBE cross-industry information sharing session in Novartis Basel, Switzerland April 30, 2015 Full day cross-industry informal sharing session on prefilled pens/prefilled pen injectors focusing on technical/regulatory challenges to be overcome to ensure first pass BLA/MAA approval Agenda items: Workshop on commercial control strategy from components to the combined product, setting acceptance criteria and shelf life establishment (Meg Leahey, Leahey Global Regulatory CMC Biologics and Device CMC group for combination products, Pfizer Device Development Cosentyx Sensoready Pen - Wolfgang Papst, Senior Expert Packaging and Device How to achieve 21 CFR Part 4 compliance for a legacy prefilled syringe product - Mike Wallenstein, Senior Compliance professional, Novartis Agency advice on location of device information and content in Module 3 -Serge Mathonet, Global RA-CMC Biological Product, Sanofi R&D Simponi Smartjet AutoInjector BLA/MAA and Post-approval Filing Overview, Jason Lipman, Global RA CMC Medical Devices and Combination Products, Amgen 3 EU CMC STRATEGY FORUM MAY 9,2016 EBE SATELLITE SESSIION

4 Focus on learnings from the Workshop on commercial control strategy from components to the combined product 4 EU CMC STRATEGY FORUM MAY 9,2016 EBE SATELLITE SESSIION

5 Key Learnings/Questions (CQA/Control Strategy) Risk-based approach for control strategy is based on data from - Hazard Identification and Human Factors studies as foundation for risk management plan that is basis for control strategy Device Risk Management (ISO [3] and IEC 62366) versus Quality Risk Management for drug constituent (ICH Q9) Learnings from clinical trials to be included in development of control strategy and acceptance criteria - e.g. injection time; BLGF might be based on literature Functional specifications and Acceptable Quality Limits (AQL s managed through site quality system) set based on usability, clinical performance and safety but also taking into consideration components specifications / AQL and aging effect Understanding of assembly process /product characterisation drive any drug product attributes on final release 5 EU CMC STRATEGY FORUM MAY 9,2016 EBE SATELLITE SESSIION

6 Key Learnings/Questions (CQA/Control Strategy) There is an overlap in functional release testing with drug product attributes potential opportunity to streamline but to date experience has been 5+ functional tests on release - Lean approach to eliminating sources of component variability, introducing best in class components, device design change shall allow optimising system integration, minimize product complaint rate to best standard and reducing the amount of functional release testing Use same principles and tools as for CQAs but might look at using different terminology to differentiate and need to clearly define Good practice is to establish these with risk management plan with key consideration to usability and safety 6 EU CMC STRATEGY FORUM MAY 9,2016 EBE SATELLITE SESSIION

7 Key Learning/Questions (Functional Testing) Strive to keep additional functionality/ product testing to a minimum for routine batch release - For those functionality aspects of the device that would not be influenced by the presence of product, is there an opportunity for these to be validated and not part of the routine batch to batch testing (in-process or release)? Possible inputs into control strategy: - Device constituent supplier testing, in-coming and in-process testing as it relates to either on-line or stage testing - Is there an opportunity to demonstrate acceptable functionality for device based on data sets obtained earlier than final release testing and thus not retested on release? 7 EU CMC STRATEGY FORUM MAY 9,2016 EBE SATELLITE SESSIION

8 Functional performance control strategy Matrix Critical Quality Attributes Device Developmen t Product Validation Supplier testing Control Strategy Incoming and Inprocess testing Release Stability Effective Functional ity Safety Efficacy (both device and product related attributes) Design Control Process and Risk Assessments Characterisati on Studies (demonstrate no adverse impact to quality from process handling) Human Factor and Usability Evaluations Design Verification Dose accuracy ISO Additional functionality testing per device design Container Closure Integrity (if applic.) AI Subassemblies testing (e.g performance testing on AI to be used in commercial manufacturing, assembled with reference PFS) In-coming testing on subassemb lies as critical raw material component In-process testing during manufactu re Functiona l testing Functional testing Overall expiry of combination product Expiry of device/ functional components (Aging effect) Validation Studies (PQ versus PV) 8 EU CMC STRATEGY FORUM MAY 9,2016 EBE SATELLITE SESSIION

9 Setting PFP specifications and control strategy Test Impact Acceptance criteria rationale E /Bioactivity PK/ PD S- Drug/ Device Immuno genicity Usabili ty Injection Time X X X x HFS/Clinical experience Dose Accuracy X X X X Delivered volume shall be no less than labeled volume Injection Depth X X X X Based on prior knowledge on sc tissue depth Container closure integrity (dye ingress) AQL Comme nsurate to criticalit y and device supplier capabilit y Control Strategy (Supplier, Incoming, CIPC, Release, Stability) -Syringe incoming testing (silicon, BLGF) -Bulk PFS BLGF release/stability testing -IJT testing PFP Release/Stab -CIPC filling weight consistency bulk PFS process -Expellable volume bulk PFS release -Dose accuracy PFP release/stability testing -Device supplier testing (Inj. Depth Assembled AI) X X -CCP: e.g. insertion force/assembly force -CCIP: PFP Visual Controls -CCIT PFS release/stability testing -PFP stability testing 9

10 Setting PFP specifications and control strategy Test Impact Acceptance criteria E /Bioactivity PK/PD S- Drug/ Imm Usability rationale Device uno geni city AQL Control Strategy (Supplier, Incoming, CIPC, Release, Stability) Needle cover activation force (NCAF) Actuator Button Activation force (ABAF) X AI not usable if higher force needed x AI not usable if higher force needed EN 894-3*:, 35 N. MIL-STD-1472F* maximum force for pushing of buttons with 23 N, minimum force for unintended activation with 5 N Commens urate to criticality and device supplier capability -Device supplier testing (NCAF Assembled AI) - PFP release/stability testing case by case - Device supplier testing (ABAF Assembled AI) - PFP release/stability testing case by case Visual appearance and defects - Visible particles X X USP<1>, <790>/EP ) Essentially/Practically Free from visible particle 0.65 % major defect) - Visual inspection of PFS at end of manufacturing and on PFS stability testing 10 Applicable standards MIL-STD-1472F, Department of Defense Design Criteria Standard: Human Engineering (5) EN 894-3: Safety of machinery Ergonomics requirements for the design of displays and control actuators Part 3: Control actuators CEN/TR 614-3: Safety of machinery Part 3: Ergonomic principles for the design of mobile machinery IEC 62366: Medical Devices Application of usability engineering to medical devices (IEC 62366:2007)

11 Criticality scoring (severity x likelihood) Device related attributes - Criticality scoring e.g. Severity levels Life-threatening (death could occur) Results in permanent impairment of body function or permanent damage to a body structure. Necessitates medical or surgical intervention. Temporary or reversible (without medical intervention). Limited (transient, minor impairment or complaints). No adverse health consequences Hazard cannot be assessed with the data currently available. Likelihood CQA like attributes e.g. Through tracking of Device adverse event and technical complaints in clinical trials or commercial setting - E.g. Injection time Same approach to criticality scoring as for drug CQA 11 ADC kick-off meeting Ursula Busse ADC challenges Business Use Only

12 2016 priorities for the Topic Group Develop - Case study on risk based approach to Prefilled pen control strategy - Position Paper on Module 3 Dossier organization /requirement for Device and CMC information - Case study on post-approval change assessment Introducing New site - Pre-filled pen assembly, labeling, packaging Introducing Device changes e.g. Auto Injector design change, syringe changes, component changes 12 EU CMC STRATEGY FORUM MAY 9,2016 EBE SATELLITE SESSIION

13 Thank You to the Topic Group members Serge Mathonet (Sanofi, Global Regulatory Affairs CMC Biologics) Maged Darwish (Roche, Technical Regulatory, Biologics) Mike Wallenstein (Novartis Pharma, Senior Compliance professional) David.M.Ottolangui (GSK, Device Technology GSK) Heather GUERIN (Janssen, CMC Regulatory Affairs Device expert) Meg Leahey(Pfizer, Global Regulatory CMC Biologics and Device CMC group for combination products (Pfizer, Ireland at the time, now with BMS) Amanda Matthews (Pfizer, Regulatory CMC) Feuerstein, Ulrike (Abbvie, Primary Packaging Development for parenterals ex CMC Submission groups for prefilled pens) Rajiv Gupta (Medimmune, Device Development) 13 EU CMC STRATEGY FORUM MAY 9,2016 EBE SATELLITE SESSIION