Validation is Always Part of the Picture

1. Validation is Always Part of the Picture Commercial Manufacturing Pre-IND Phase I Phase II Phase III Final process validation Specification Development Re-validation Ongoing Validation (DOE, IQ, OQ, PQ, PV)* * DOE = Design of Experiment IQ = Installation Qualification OQ = Operational Qualification PQ = Performance Qualification PV = Process 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 Utility Systems Manufacturing SupportSyst. Equipment Manufacturing Processes • 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 Aseptic Processing Packaging & Labeling In-Process Control Personnel Training Analytical Methods • Process Measurem. • Visual Inspection • Label Control • Sampling • GMP • Gpwning valid.. • SOPs • Equipment • Processes • Media Fills • Packaging • Labeling • Chemical - Cleaning valid • Physical - Sterility tests • Biological - Stability

4. Risk Management in Clinical Trials

6. Study Approval Process

7. Auditing & Inspection Auditing & Inspection

8. Auditing & Inspection

9. Auditing & Inspection

13. Prtocol Approval

14. Protocol Approval Process

15. Assignment of Drug Review

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

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 YES Is Response OK? To DM Issue Queries to Sites NO Answer Query Compare to Source

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

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

20. THE R&D PROCESS Development Preclinical studies Clinical studies 18/09/2014 Discovery Early Clinical Development CHEMISTRY/ PHARMA-COLOGY IND* PHASE I PHASE II PHASE III NDA** PHASE IV 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 Search for active substances Toxicology, efficacy studies on various types of animals *InvestigationalNew Drug Application for permission to administer a new drug to humans KNOWLEDGELEVEL 50–150persons 100–200patients Registration, market introduction 500–5,000patients KNOWLEDGELEVEL **New Drug Application Application for permission to marketa new drug TIME SPAN 2–6 months 3–6 yrs. 1–3 yrs. 2–4 yrs. Approximately 10–15 years from idea to marketable drug 72

21. Drug Phases

22. Early Clinical Drug Development PRINCIPLE TESTING FTIM MS 1 2 3 4 5 5.5 6 7 8 9 Target Id. Hit Id. Lead Id. Lead Opt. Pre- nom. Preclin. Dev. Principle Testing Concept testing Dev. for Launch Launch and PLC Prod. Maint. TG 1 1.5 2 2.5 3 4 5 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 Principle Testing 1-3 years 74

23. Phase I dose escalation scheme

24. CTMS: Flow

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

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

27. SAE Reporting

28. SAE Reporting in EEA

29. Regulatory Inspection

30. Structure of NDA