Technology Transfers & Quality Kenan Kösoğlu Novartis Ürünleri Eskişehir, 25th May., 2012

Technology Transfer & Quality Quality not only concerned with the drug product What is QC ? Quality also needs to be considered & comprehend all activities around the production / tech transfers What is QA ? Documentation Communication Project management Change management Rules & Regulations (GMP, corporate, Health Authorities, legal requirements, etc...) Production process Quality control process, standard operation procedures, manuals All other activities related production process We need to assure fast “time to market “ and continuous supply with Quality at competitive cost while leading tech transfers with minimized one time cost. 2 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Objectives & Reasons of Technology Transfers Technology Transfer from R&D to regular (large-scale) production from site to site (regular productions) why tech transfers needed? Objectives / Reasons : Strategy of production site / corporation Capacity optimization & harmonization Technology of Granulation, Tabletting, Coating Site area changes Productivity & financial effectiveness of the site/company Life cycle of the products & site product portfolio management Dosage forms (TAB, FCT, SCT, Capsules, EFT, LOZ, ...) Pharmaceutical Sector Legal requirements of products, production process & regulations Product base changes & competition 3 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Life Cycle of products When to start for Tech Transfer Projects ? 4 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Project Management Tool in Technology Transfers Scope Complexity of the project Local vs. multi market , # of SKU, # of countries, dosages, etc Cost : Project budget, cash flow, investment management Time management : Launch the products within planned time Resource Management : Human, Technical Know-how, Machine & Equipment Stakeholder management Project sponsor, manager & team with roles & responsibilities Who will be in project team ? 5 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Environment We are living in global environment which effect directly decisions and plans on tech transfers. Requirements need to be followed and applied properly during tech transfer projects : Patients Doctors, universities, ... Diseases Health Authorities (all countries) , government & legal requirements Corporate requirements Pharmaceutical Sector & GMP Rules World technology trends Samples of environment effects on tech transfers? 6 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Functions in Organization during the Transfer Quality do not focus only the production . It is must that all activities within the organization (cross-functional) needs to be managed considering Quality. Project management Health, Safety & Environment Supply chain management / logistics Regulatory & Medical Marketing Engineering Quality Assurance & Quality Control IT Systems Legal requirements Finance Personal Why Quality needed for those activities too ? 7 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Phases in Tech Transfer Evaluation & Approval Phase Financial & Technical Ffeasibility of the tech transfer, capability & resource mang. Planning Phase : Tech Transfer Project plan : Who, What, When, How,.. Technical Phase : Validation productions as per Planning Phase Regulatory & Registration Phase : Regulatory documentation & submissions to Health Authorities Logistics & Execution Phase : To ensure the first supplies properly as per planned at the previous phases How much time needed for each phase ? 8 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Evaluation & Approval Phase Corporate & Site strategy Current & long term site capacity Investment need, tooling , equipment (technical feasibility) Incremental human resources need Available technology, infrastructure, layout , know-how New countries, audit requests Product basis requirements Project volume figures Brand life cycle status & long term forecasts Competition & generics Regulatory requirements by Health Authorities Financial figures & costs (financial feasibility) Cost per pack Cost per worker Which risks available & how to eliminate them? 9 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Planning Phase (Transfer Master Plan-1) Validation Strategy Process Validation Protocol Packaging Validation Protocol Cleaning Validation studies On-site technical visit & good communication practice between GS vs. RS Qualification, calibration & comparison of equipments, infrastructure Product annual review data , previous trends (stability, OOS, etc..) Update, review current process before the tech transfer, check lessons learned from previous tech transfers, review GS documentation & knowledge Site production area conditions (temperature, humidity, light, ..) Evaluate all IPC (test methods & specifications) & plan all parameters Planning of manufacturing lines, equipment & infrastructure : Decide which lines will be used for the related tech transfer Check microorganism requirements Prepare master batch records/production documents before the validation production. Why planning phase is most cruical ? 10 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Planning Phase (Transfer Master Plan-2) Registration Strategy Stability Protocol, conditions, shelf life decision Method Transfer (lab to lab) : Lab capacity & capability TM Testing Monograph update if needed (raw mat., drug product,..) Dissolution profile requirements (medias, conditions, time points, ..) Raw Material & Drug substance specs, comparison & supplies Pack material specs, comparison & supplies Change management (trace & document all changes) Document transfer , know-how & information from R&D & giving sites Plan GMP audits / inspections in case needed Country approvals ( 1-24 months) Submission strategy & groupings EU Countries with 3 months stability data RoW Rest of the World countries with 6 month stability data Evaluate Health Authority requirements during planning phase and take into consideration properly not to face conflict at registration phase Importance of Stability studies ? Importance of Dissolution profile test studies ? 11 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Planning Phase (Transfer Master Plan-3) Logistics Strategy HSE requirements of the transferred product Transport conditions, storage conditions Product status (hazardous, flammable, ..) Technical requirements of pack materials and availability Data management, system definitions Transfer check list Site Storage & warehouse conditions (temperature, humidity, light, ..) Train all staff concern with the transferred product & process Get ready in terms of purchasing, supply chain, logistics If needed perform investment plans Bridging inventory calculations Plan the budget & resource management Plan communication management tools Regular informative & decision meetings Committee meetings, status reports Importance of planning logistics strategy at planning phase ? 12 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Technical Phase Perform the validations as per Transfer Master Plan and Documents & information decided at Planning Phase Validation Report Stability tests & studies Stability report Perform dissolution profile comparison tests within both sites Dissolution profile comparison report Executed Batch Records / production QC release & test results All changes & deviations needs to be classified & documented (planned protocols vs. actual reports) Which difficulties could be in technical phase ? 13 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Regulatory & Registration Phase Collection of the documentation created from technical phase CMC document writing Communication with all stakeholders to perform the documentation properly considering Quality. Submissions to Health Authorities (HA) “right at first time” not to cause variations Reply questions from HAs Document the changes properly as planned at registration strategy Follow approvals & reply HA questions Requests from HAs ; Samples, Reference materials Certificates (GMP, CPP, ...) Previous Audit reports Why “right at first time” is important ? 14 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Logistics & Execution Phase Logistics activities : Define production lead-time, minimum order quantities, system Definition of the products, raw materials, BOM, Routing, etc... Complete the artwork studies as per registered designs Start communication & activities with suppliers & customers Complete financial activities such as costing & pricing Check short, mid & long term plans, capacity Last supplies to giving site First supplies from receiving sites Handover from Transfer Project team to regular functions : Correct & on-time handover Full handover might be within 1-3 years Alignment of regular productions according to registered process during the tech transfer How to handover ? 15 | Tech Transfer & Quality / Novartis / May.2012

Technology Transfer & Quality Best Practices & lessons learned Good project planning at Technology Transfers are crucial and this ensures the volumes at the site as estimated and cause positive effect on corporate strategy & competitiveness at long term. Weak project plans & wrong bridging inventory quantities could cause ; Stock-out Write-off cost One time cost Less income Risk to loose the brand Less reliability of brand / corporation Project Planing - Quality Eliminate all risks with good team working ..... 16 | Tech Transfer & Quality / Novartis / May.2012

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