1. Validation is Always Part of the Picture Ongoing Validation (DOE, IQ, OQ, PQ, PV)* Pre-INDPhase IPhase IIPhase III Commercial Manufacturing * DOE = Design of Experiment IQ = Installation Qualification OQ = Operational Qualification PQ = Performance Qualification PV = Process Validation Specification Development Final process validation Re-validation The extent of IQ, OQ, PQ, validation, etc. depends on complexity of product 6 sigma target

2. GMPValidation of new premises VALIDATION Clean area Premises Manufacturing Processes Equipment Manufacturing Support Syst. Utility Systems Analytical Methods Personnel Training Aseptic Processing In-Process Control - HVAC System - LAF Units - Cold Storage - Env. Monitoring - Facility Cleaning - Transfer hatches - Verifi. of classific. - Water systems - Plant Steam - Pure/Clean Steam - Process Gases - Sterilizers - Depyrogenators - SIP Systems - CIP Systems - Washing - Waste Systems - Fermentors - Scales - Incubators - Filtration Units - Filling Equipment - Computerised systems - Fermentation - Separation - Purification - Filtration - Filling Packaging & Labeling - Media Fills- Packaging - Labeling - Process Measurem. - Visual Inspection - Label Control - Sampling - GMP - Gpwning valid.. - SOPs - Equipment - Processes - Chemical - Cleaning valid - Physical - Sterility tests - Biological - Stability

15. Assignment of Drug Review

16. 1.0Regional Administrative Information 1.1ToC of Module 1 or overall ToC, including Module 1 2.1ToC of the CTD (Mod 2,3,4,5) 2.2Introduction 2.3Quality Overall Summary 2.4Nonclinical Overview 2.5Clinical Overview 2.7Clinical Summary 2.6Nonclinical Written and Tabulated Summaries Module 1 Module 3Module 4 Module 5 2.1 2.2 2.3 2.42.5 2.62.7 1.0 Quality Nonclinical Study Reports Clinical Study Reports Module 2

17. Paper CRF Process Gather Data Record on Source Transcribe to CRF File Copy of CRF Monitor CRF Updates to DM Copy to DM Data Processing Issue Queries to Sites Compare to Source Answer Query To DM Is Response OK? YES NO

18. eCRF Gather Data Record on Source Transcribe to e-CRF Monitor e-CRF with Source Generate electronic Query Answer on-line Queries Approve e-CRF e-CRF Printed for Site Retention Data Manager, Project Manager and Clinical Monitor Data (offline edit checks, manual review)

19. Protocol Development Protocol Concept Stage Review/Approval Investigator/IND Holder Cooperative Group Protocol Development Department Review Institutional Scientific Review IND Holder Institutional Review Board Food and Drug Administration Protocol Approval Clinical Trial Monitoring Investigator Institutional Review Board Data Safety and Monitoring Board IND Holder Food and Drug Administration 1-6 Months Time Line 2-3 Months 2-3 months 2-6 years

20. THE R&D PROCESS Development Discovery Development Approximately 10–15 years from idea to marketable drug Preclinical studiesClinical studies CHEMISTRY/ PHARMA- COLOGY IND*PHASE IPHASE IIPHASE IIINDA**PHASE IV Search for active substances Toxicology, efficacy studies on various types of animals Regulatory review Efficacy studies on healthy volunteers Clinical studies on a limited scale Comparative studies on a large number of patients Regulatory review Continued comparative studies *Investigational New Drug Application for permission to administer a new drug to humans 50–150 persons 100–200 patients 500–5,000 patients Registration, market introduction **New Drug Application Application for permission to market a new drug KNOWLEDGE LEVEL 2–4 yrs. 2–6 months3–6 yrs.1–3 yrs. TIME SPAN Early Clinical 20/09/2015 72

21. Drug Phases

22. Principl e Testing Key Activities: Submission Single Ascending Dose study Multi Ascending Dose study Proof of Principle studies Manufacture route identification Dev. formulation for concept testing & onwards Dev. Patient Risk Management Plans Achieved Objectives: Safety Effectiveness Business Plan Dose 1-3 years Early Clinical Drug Development PRINCIPLE TESTING Prod. Maint. Launch and PLC Dev. for Launch Concept testing Principle Testing Preclin. Dev. Pre- nom. Lead Opt. Lead Id. Hit Id. Target Id. TG MS 123455.5689 FTIM 11.522.5345 7 74

23. Phase I dose escalation scheme

24. CTMS: Flow

25. Ad Hoc Querying Ad Hoc Querying Portal Reporting Desktop Source Systems Web Server Data Mining OLAP/Cubes SDD Platform Metadata Management Version Control Analysis and Reporting Regulatory Submission and Document Management Biomedical Trial Data Warehouse Web Hosting 21 CFR Part 11 Compliance Data Quality, Cleansing, Validation, Aggregation, Enrichment ETL Q (Defined Business Rules) ETL Q (Defined Business Rules) Access Engines Meta Data Clintrial Connector Opentext Electronic Submissions Clintrial eTrial eClinical Other Oracle CROs OpenText EDC Drug Development

26. Sources of Error in a Study Omission, mis-communication Transcription Programming, summary tables Statistical interpretation Clinical interpretation Data entry errors