Session Title Multiproduct p Processing g – A Large g Molecule p perspective p Janssen 22-May-2014 Patrick P t i k Sheehy Sh h Purification Business Unit Manager Janssen Biologics Ronan Hayes Pharmaceutical Development Manager Janssen Biologics Presentation Outline • Brief overview of Janssen Biologics Cork • Approach to New Product Introduction • How do we ensure Multiproduct p control • Future Opportunities • Future Challenges Overview of Janssen Biologics Cork ¾Large Molecule Drug Substance Manufacturing g ¾ Clinical and commercial mm monoclonal antibodies ¾Janssen Biologics Ireland, Cork Janssen Biologics, Ireland g , Warehouse Lab / Admin Central Utilities Production Adapting to changing Circumstances Initial Plan LM API Facility producing one main commercial product with the possibility that one LM API Facility producing one main commercial product with the possibility that one or two additional commercial products might also follow. Limited changeover / complexity Limited changeover / complexity Current State LM API facility producing multiple commercial, clinical and preclinical products yp g p , p p High lever of change over / Complexity Janssen Biologics Ireland – Process Capabilities Cell Culture • 2 x cell culture suites based on batch size • Cell culture Suite 1 (Perfusion Cell culture): Clinical and commercial capability at 1000L scale (all stainless steel). Utilise ATF technology • Cell culture suite 2 (Fedbatch Cell Culture ): Preclinical, Clinical and commercial capability at 1000L scale (Significant use of disposable’s). Purification • 2 x Purification Suites based on batch size • Purification Suite 1 (Batch size : 6‐22kg) : Clinical and Commercial capability linked to Cell Culture Suite 1 • Purification Suite 2 (Batch Size 1‐5Kg) : Preclinical, Clinical and Commercial capability linked to Cell Culture Suite 2. (Some use of disposable’s) Janssen Biologics Ireland – Key Products Name Disease Phase h p Simponi Stelara Sylvant RA Psoriasis Castlemans Disease Commercial Commercial Commercial Upstream (USP) or ( ) Downstream (DSP) at Cork USP & DSP DSP DSP Oh Other Products d 1 Product : PV complete 4 Products : Phase 3 complete 2 Products : Phase 2 complete 2 Products : Phase 2 complete 3 Products : Phase 1 complete 2 Products : Tox complete Immunology Infectious Disease Oncology M lti d t Sit K E bl Multiproduct Site Key Enablers • Controlled & Efficient product Changeover process p g p • Controlled & Efficient New Product Introduction process H How do we introduce new products ? d i d d ? Two Key Production Areas: Suite 1 Cell Culture & Purification • Cleaning Validation Complete Cleaning Validation Complete • Commercial & Late Stage Clinical Suite 2 Cell Culture & Purification • Cleaning validation not complete – cleaning verification • Two equipment Trains – q p Clinical/Commercial & Preclinical / • To date only used for the production of Clinical & Preclinical Products. New Product Introduction: Cleaning Validation / Verification Process Flow Suite 1 (Cell Culture& Purification) (Commercial & Clinical) New Product Introduction Suite 1 Prior to the introduction of each new product a detailed assessment is performed Prior to the introduction of each new product a detailed assessment is performed. – Process Data • Process Flow, Shared Equipment P Fl Sh d E i , Buffers B ff – Product Data – Class of molecule » i.e. monoclonal antibody – Product Concentration Product Concentration – Carbon Content – % Rinse Recovery Result » Ease of Recovery – % Swab Recovery Result » Ability to detect residue if any remain y y – Inactivation studies » Is the molecule active after exposure to cleaning conditions New Product Introduction Suite 2 Clinical /Commercial Equipment train: Prior to introducing the product Lab studies are complete – Product Data – % Rinse Recovery Result » Ease of Recovery Ease of Recovery – % Swab Recovery Result » Ability to detect residue if any remain – Inactivation studies » Is the molecule active after exposure to cleaning conditions Preclinical Equipment train: Dedicated equipment train for preclinical products, used where the above prerequisites studies are not complete prerequisites studies are not complete New Product Introduction • To date all products produced at the site have been very similar from a cleaning perspective i.e. – Same class of protein – all are mAb’s – Same carbon content 53 % carbon, – All readily recovered from product contact surfaces using swab & rinse. – All are fully inactivated by the cleaning agents Points to consider EMA Guideline on setting health based exposure limits for use in risk identification in the manufacture of different medicinal products in shared facilities BPOG / EFPIA submission – EMA Workshop Sep 2013 For biological and vaccine products, the determination of health based exposure limits, such as PDEs, assumes residual product after cleaning is active and the level of activity is comparable to product activity prior to residual product after cleaning is active and the level of activity is comparable to product activity prior to exposure to cleaning agents and conditions. Under typically used cleaning conditions, biological products such as monoclonal antibodies, therapeutic proteins and vaccines are known to degrade and denature rapidly, and are therefore likely to become pharmacologically inactive. If it can be demonstrated that the biological product becomes degraded after exposure to applicable cleaning conditions the determination of health product becomes degraded after exposure to applicable cleaning conditions, the determination of health based exposure limits should not be required. BPOG Submission – Annex 15 C t ll d & Effi i t Controlled & Efficient product Changeover process d t Ch • STEP 1: Multiproduct Risk Assessment • STEP 2: Multiproduct Processing SOP Focussed on 1) Segregation approach 2) Line Clearance Line Clearance 3) Material Flow 4) Personnel Flow 5)) Visual Management g Guidelines on equipment dedication during 1) Equipment Equipment dedication during campaigns 2) tagging of soiled equipment, 3) Equipment cleaning, 4) Equipment storage, 5) Equipment Utilisation, 6) Signage during campaigns, 7) Personnel flow Personnel flow 8) Materials movement “Get rid of the old” STEP 3 : Room Clearance f for each Processing suite hP i i Room Clearance SOP and suite specific Forms it ifi F • Each Processing Room clearance form has a unique identifier – referenced in Batch record • Completed to document Clearance of product Fixed equipment cleaning /verification Fixed equipment cleaning /verification Remove all product specific documentation Remove all waste Remove all waste. “In with the New” STEP 4: Product STEP 4: Product Changeover Procedures Product Changeover SOP and Forms • Ensure processing suite is ready for the next product campaign • Equipment and systems are as per product campaign are in place. • Document’s maintenance or automation ’ activities are completed e.g.., Method files loaded • Each processing room has an individual E h i h i di id l product changeover form Process Support Area : Equipment Cleaning – Soiled equipment is tagged and staged with the product name S il d i ti t d d t d ith th d t Cleaning Validation complete Cleaning Validation complete • All items are campaigned in the wash/COP area together. Cleaning Verification items A product cleaning campaign is run Room clearances performed between each campaign. campaign The equipment is not released for assembly or use until cleaning verification is complete. Multiproduct Processing procedure for Process Support area 21 Preclinical ‐ Product Approach • For Preclinical in Cell Culture 2 – Full use of disposables ‐ bypass of centrifuge – Dedicated Pre‐clinical columns ‐ removes need to Cleaning studies to be complete • For Preclinical in Purification Suite 2 – Dedicated Pre‐clinical equipment Train ‐ removes need to Cleaning studies to be complete – Dedicated Columns – di d l shared between products h db d Future Opportunities Future Opportunities Fully Disposable Processing Suites • Decreased Suite Turnaround time • I Increased Number of Product change‐overs/year : dN b fP d t h / • Cleaning verification requirements. – Disposable technology supports pre‐clinical/early phase production. • Fully Disposable suites now a possibility Stage 1: Completely disposable • Media Prep : Disposable SUM’s Stage 2: Completely disposable • Seed can also be a production Bioreactor • Optical pH and DO probes added to design on top of electrochemical • All Disposable assemblies Stage 3: Clarification • • • • Centrifuge is stainless Steel SUM’s for harvest collection B Break k bag b and d Filter Fil train i Disposable Pressure Sensor’s Disposable Stage 4 & 5: Direct Protein Capture and Viral inactivation /Fill • • • Chromatography Skids and Columns non disposable SUM’s SU s for o harvest a est collection co ect o 10L Bottles for Product storage Future Opportunities • Concurrent Production: – Risk assessment ongoing into possible multiproduct concurrent production in Cell Culture Suites d ll l • Expedited Equipment Turnaround. Expedited Equipment Turnaround – Online TOC supporting quicker release of equipment. Future Challenges Future Challenges Non Standard products: • New product class • Product Displaying Non standard characteristics Tighter Timelines: • Time to complete upfront cleaning studies Time to complete upfront cleaning studies Q Questions ? i ?