| Slide 1 of 59 April 2008 Pharmaceutical Development with Focus on Paediatric formulations WHO/FIP Training Workshop Hyatt Regency Hotel Sahar Airport Road Andheri East, Mumbai, India 28 April 2008 – 2 May 2008

| Slide 2 of 59 April 2008 Pharmaceutical Development with Focus on Paediatric formulations Presented by: Dr A J van Zyl Technical Officer Head of Inspections HSS/PSM/QSM

| Slide 3 of 59 April 2008 Inspections (PQ) In this presentation: WHO pre-qualification programme and inspections Norms and standards Inspection activities –APIs –FPPs –BE studies –QC labs Inspection findings Summary and conclusion

| Slide 4 of 59 April

| Slide 5 of 59 April 2008 Inspections Compliance Corrective actions Compliance Manufacaturers: APIs Excipients; Finished Products Clinical /Contract Research Organizations Inspections Prequalification QC Laboratories Corrective actions Compliance

| Slide 6 of 59 April routine Follow- up concise special Complaints Monitoring compliance Monitoring compliance Monitoring compliance Monitoring compliance Monitoring compliance Batch verification Batch verification Batch verification Batch verification Batch verification Pharmaceutical Development with Focus on Paediatric formulations

| Slide 7 of 59 April 2008 Complex situation Inspection planningteamsconductreports corrective actions culturecomplaintsverification Norms and standards Pharmaceutical Development with Focus on Paediatric formulations

| Slide 8 of 59 April 2008 Quality concerns Several developing countries – some serious quality concerns in some cases Also in developed countries Weak implementation and enforcement of GMP and GCP "Double standards" e.g. products for export Pharmaceutical Development with Focus on Paediatric formulations

| Slide 9 of 59 April 2008 Team of inspectors for each inspection –WHO PQ inspector plus PIC/S member country plus local country inspector (observer) –Some cases – capacity building (recipient country) APIs, Finished products, BE studies –GMP, GCP, GLP, GSP, GDP... Preparation: –SMF –Product information –Inspection reports, complaints etc Assessment procedure - inspections

| Slide 10 of 59 April 2008 Manufacturers: Normally over 3 days Covers all aspects of GMP –Quality management, Quality assurance, Premises, Equipment, Documentation, Validation, Materials, Personnel, Utilities (e.g. HVAC, water)... Also data verification (dossier) including stability data, validation (process), development batches and bio batches Quality control laboratory – specifications, reference standards, methods of analysis, validation and qualification Clinical sites: Normally over 2 days Covers all aspects of GCP and GLP –Ethical considerations, Protocol, Volunteers etc Data verification Clinical part –Clinic, Pharmacy and related areas, data verification Bio-analytical part –Laboratory and data verification Statistical analysis Assessment procedure - inspections

| Slide 11 of 59 April 2008

| Slide 12 of 59 April 2008 Inspections Compliance Corrective actions Compliance Manufacaturers: APIs Excipients; Finished Products Clinical /Contract Research Organizations Inspections Prequalification QC Laboratories Corrective actions Compliance

| Slide 13 of 59 April 2008 Inspections Compliance Corrective actions Compliance Manufacaturers: APIs Excipients; Finished Products Clinical /Contract Research Organizations Prequalification QC Laboratories Corrective actions Compliance GPNCL GLP GCP GMP GPCRO GMP GPNCL Pharmaceutical Development with Focus on Paediatric formulations

| Slide 14 of 59 April 2008 Standards International consultation process The WHO Expert Committee – review and adopts Executive Board World Health Assembly Printed in respective TRS and WHO web site

| Slide 15 of 59 April 2008 USP BP Ph. Eur. Ph. Int. Prequalification Programme: Priority Essential Medicines

| Slide 16 of 59 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 17 of 59 April 2008

| Slide 18 of 59 April 2008

| Slide 19 of 59 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 20 of 59 April 2008 New York Times 2007

| Slide 21 of 59 April 2008 In this presentation: WHO pre-qualification programme and inspections Norms and standards Inspection activities –Active Pharmaceutical Ingredients –Finished Products –Bio-equivalence studies –QC labs Inspection findings Summary and conclusion Pharmaceutical Development with Focus on Paediatric formulations

| Slide 22 of 59 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 23 of 59 April 2008 Prequalification Programme: Priority Essential Medicines Inspections have to cover all aspects including: Receiving of material through all stages (storage, sampling and testing, weighing, production, packaging, finished product testing, storage and release) Utilities e.g. water and HVAC

| Slide 24 of 59 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 25 of 59 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 26 of 59 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 27 of 59 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 28 of 59 April 2008 Airflow Problems Air deflected off scale!

| Slide 29 of 59 April 2008 Prequalification Programme: Priority Essential Medicines Quality Risk Management Risk assessment Risk communication Risk control Risk review

| Slide 30 of 59 April 2008

| Slide 31 of 59 April 2008 Know the process: E.g. for tablet production Weighing – Sieving – Mixing – Granulation and drying – Milling – Blending – Compression – Coating – Packaging. Also storage and in-process control Specific aspects: temperature and relative humidity Contamination; mix-ups Premises; equipment; documentation; personnel; validation and qualification; personnel flow, material flow etc Cleaning Assessment procedure - inspections

| Slide 32 of 59 April 2008 Prequalification Programme: Priority Essential Medicines India, China, Belgium, France, Canada, Malaysia, South Africa, Switzerland, United States, Cameroon, Ghana, Kenya, Madagascar, Niger, Uganda... Findings: Compliance in some cases Non-compliance in many cases Full inspection report reflecting observations Corrective action – verified before final conclusion

| Slide 33 of 59 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 34 of 59 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 35 of 59 April 2008 Different products in the same area including penicillin Lack in maintenance Inappropriate layout and finishing Lack in validation and qualification utilities and processes Cross-contamination and mix- ups Falsification of data Inappropriate sampling of materials and lack of testing before use No proof of sterility of products including validation of equipment and process Not following stability protocol Cleaning validation lacking Prequalification Programme: Priority Essential Medicines

| Slide 36 of 59 April 2008 Prequalification Programme: Priority Essential Medicines GMP compliance – India Review of 30 inspection reports for GMP Manufacturers in prequalification interested in international supply Assessed against WHO GMP Period 2001 to 2004

| Slide 37 of 59 April 2008 Prequalification Programme: Priority Essential Medicines Average numbers of non-compliances observed per site in each year ( ).

| Slide 38 of 59 April 2008 Prequalification Programme: Priority Essential Medicines First inspections - Number of non-compliances in each area

| Slide 39 of 59 April 2008 Prequalification Programme: Priority Essential Medicines APIs - ICH Q7 I. QUALITY MANAGEMENT A. Principles (2.1)., B. Responsibilities of the Quality Unit(s) (2.2). C. Responsibility for Production Activities (2.3)., D. Internal Audits (Self Inspection) (2.4). E. Product Quality Review (2.5). II. PERSONNEL A. Personnel Qualifications (3.1)., B. Personnel Hygiene (3.2). C. Consultants (3.3).

| Slide 40 of 59 April 2008 Prequalification Programme: Priority Essential Medicines APIs - ICH Q7 III. BUILDINGS AND FACILITIES A. Design and Construction (4.1)., B. Utilities (4.2). C. Water (4.3)., D. Containment (4.4). E. Lighting (4.5)., F. Sewage and Refuse (4.6). G. Sanitation and Maintenance (4.7). IV. PROCESS EQUIPMENT A. Design and Construction (5.1)., B. Equipment Maintenance and Cleaning (5.2). C. Calibration (5.3)., D. Computerized Systems (5.4).

| Slide 41 of 59 April 2008 Prequalification Programme: Priority Essential Medicines APIs - ICH Q7 VI. MATERIALS MANAGEMENT A. General Controls (7.1)., B. Receipt and Quarantine (7.2). C. Sampling and Testing of Incoming Production Materials (7.3). D. Storage (7.4)., E. Re-evaluation (7.5). VII. PRODUCTION AND IN-PROCESS CONTROLS A. Production Operations (8.1)., B. Time Limits (8.2). C. In-process Sampling and Controls (8.3). D. Blending Batches of Intermediates or APIs (8.4)., E. Contamination Control (8.5).

| Slide 42 of 59 April 2008 Prequalification Programme: Priority Essential Medicines APIs – Deficiencies include: Annual Product Review – lack in review Insufficient qualification and validation Failure to provide documented evidence of sufficient control of the warehouse where starting materials, semi-finished product as well as finished products (including returned materials) were stored. E.g.; –temperature and relative humidity (to be stored below 30 degrees Celsius), inappropriate use of devices to monitor, office type ACs used

| Slide 43 of 59 April 2008 Prequalification Programme: Priority Essential Medicines APIs – Deficiencies include: No separation between batches of material to prevent any possible mix-up of batches, Insects in the area Nitrogen used to flush materials - no samples taken and no quality control tests performed There was no procedure (SOP) or record for the cleaning of the tank (ABC123) and transfer lines (TFL123) for AAA used during processing.

| Slide 44 of 59 April 2008 Prequalification Programme: Priority Essential Medicines GCP – Bio-equivalence studies GCP and GLP recommendations Also the additional recommendations to CROs Problems experienced in developed and developing countries Team of inspectors – clinical part and bio-analytical part

| Slide 45 of 59 April 2008 Prequalification Programme: Priority Essential Medicines Clinical Sites Volunteer selection and participation Ethics committee operations Clinic and bio-analytical laboratory Archives Pharmacy CRFs Source data –including chromatograms, ECGs

| Slide 46 of 59 April 2008 Example of findings in a Clinical Trial Two patients reported as voluntarily withdrawals were already dead Original CRFs disappeared Though the patient had died 8 days before - continued entries for dosing and no ADE between visits Entries in CRF for 46 visits every 2 wks after death. Radiologist report described “No changes” - Autopsy record “calcified focus of TBC found in the top part of the right lung” Prequalification Programme: Priority Essential Medicines

| Slide 47 of 59 April 2008 WHO Prequalification and Bio-equivalence studies Source data…

| Slide 48 of 59 April 2008 WHO Prequalification and Bio-equivalence studies Example CRFs destroyed on site due to "monsoon" CRFs destroyed in archives due to "fire" CRO: "CRFs and source data (chromatograms) given to the sponsor"; Sponsor: " CRFs and source data (chromatograms) archived by the CRO"

| Slide 49 of 59 April 2008 WHO Prequalification and Bio-equivalence studies Example Two of the ECGs shown to the inspectors, bearing different subject numbers and initials, were found to be identical. Other ECGs bearing different subject numbers and initials appear to have been recorded from a single subject. Out of 95 ECGs copied by the inspectors, 43 appear to have been recorded from the same and single subject during a single session E.g. Project XXX: –screening, subjects #01, 02, 04, 06, 07, 08, and 11, 14, 19, 22, 23, 24, 25; –follow-up, subjects #02, 03, 04, 05, 06, 07, 08, 09, 10, 11, 12, 13, 15, 16, 19, 20, 21, 22, 24; E.g. Project YYY: –screening, subjects #01, 02, 06, 07, 08, 09, 10, 11, 12, 19, 20. –follow-up, subjects #01 to 07, 10, 12 to 16, 18, 19, 21, 23 to 27

| Slide 50 of 59 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 51 of 59 April 2008 Transparency: WHO Public Reports (WHOPIRs and WHOPARs) Aurobindo Pharma Limited, Unit - VIIIName of manufacturer Survey N° 13 Gaddapotharam (Village), IDA- Kazipally, Jinnaram (Mandal), Medak District, Andhra Pradesh India Address Same as abovePostal address Telephone number Fax number Manufacturing and control of anti-retroviral active ingredients, including but not restricted to the manufacturing process of Zidovudine and Efavirenz.. Summary of activities of manufacturer (e.g. manufacturing, packing). Indicate dosage forms and type of products (e.g. tablets; cephalosporin containing products) 14 & 15 March 2006Date of inspection: Prequalification ProgrammeProject: Part 2: Summary and conclusion of the inspection. Summary:

| Slide 52 of 59 April 2008 Quality Control Laboratories Initially for Africa, now globally (EOI) 4 prequalified laboratories Inspections focus on GMP and Good Practices for national Control Laboratories Inspections now in Asia Covers Management, Materials and equipment, and Safety Prequalification Programme: Priority Essential Medicines

| Slide 53 of 59 April 2008 Since 2005 annual reports; 2007 annual report on the web

| Slide 54 of 59 April 2008 Prequalification Programme: Priority Essential Medicines Summary of inspections in 2007

| Slide 55 of 59 April 2008 Prequalification Programme: Priority Essential Medicines By product…in 2007

| Slide 56 of 59 April 2008 New developments New Draft Guidelines (Hormone) Reproductive health products (sex hormones) Comments invited… Prequalification Programme: Priority Essential Medicines

| Slide 57 of 59 April 2008 New developments Notice of Concern (NOC) –similar to "warning letters" From 1 June 2008 –negative outcomes to be published –Major and critical non-compliances –On the PQ web site Prequalification Programme: Priority Essential Medicines

| Slide 58 of 59 April 2008 Summary and conclusion Inspections improve compliance Identify gaps Risk management Contribute to development: –Norms and standards, monographs, reference substances, legislation Quality of medicines – for patients' benefit Prequalification Programme: Priority Essential Medicines

| Slide 59 of 59 April 2008 Thank you