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

1. Technology Transfers & QualityKenan KösoğluNovartis ÜrünleriEskişehir, 25th May., 2012

2. Technology Transfer & Quality 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

3. 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

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

5. 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

6. 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

7. 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

8. 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

9. 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

10. Technology Transfer & Quality Planning Phase (Transfer Master Plan-1) Why planning phase is most cruical ? • 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. 10 | Tech Transfer & Quality / Novartis / May.2012

11. Technology Transfer & Quality Planning Phase (Transfer Master Plan-2) Importance of Stability studies ? • 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 Dissolution profile test studies ? 11 | Tech Transfer & Quality / Novartis / May.2012

12. 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

13. 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

14. 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

15. 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

16. 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

17. Thank You ! Questions & Answers