| Slide 1 of 63 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 63 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 63 April 2008 In this presentation… Prequalification Programme Assessment of products and manufacturers –Standards Information on generic ARVs, TB and Malaria products Innovator and generic products Agreement with USA FDA for exchange of information Companies participating in WHO prequalification –Companies that succeed and fail Capacity building Incentives for manufacturers

| Slide 4 of 63 April 2008 Prequalification Programme: Priority Essential Medicines Quality concerns - India 96 samples (chloroquine and antibacterials) collected in Nigeria and Thailand - >36% failed pharmacopoeia standards (Shakoor O et al, 1997) Rajasthan DCA - substandard medicines in 13% to 18% of samples (1996 and 2001) ( Arlington, VA: Management Sciences for Health. 2003) Delhi - 53 samples, 86% were substandard or counterfeit (Iyengar J. A, Asia Times. 2002) Maharashtra out of 1026 manufacturers reported non compliant with Schedule M and unwilling to upgrade (Deshmukh R. Mumbai Mirror 2005) One out of four tablets sold in the market in UP reported as fake (Singh RK. Bitter pill: one out of four drugs in UP is fake. HT Nation. Mumbai. 2006)

| Slide 5 of 63 April 2008 Prequalification Programme: Priority Essential Medicines Quality – China Little information available in public domain Fake artesunate: –38% ('01); 53% ('03) - in Myanmar –89% - Laos –Wellcome trust: 22 of 27 locations (in 15 - only fakes) (Lancaster IM 2006) Strict control on compliance implemented and enforced –07/07: "former head was executed for accepting bribes to approve untested medicine" –Now "vowed to overhaul the agency, institute a recall system and strengthen drug regulations" (Chicago Tribune, 11 July 2007) –GMP again under revision

| Slide 6 of 63 April 2008 Prequalification Programme: Priority Essential Medicines Also a problem in industrialized countries 1999 to 2000, Schering Plough USA had to recall about 59 million metered dose asthma inhalers –17 children died - no active ingredient 2003, TGA (Australia) recalled products of Pan Pharmaceuticals Ltd –219 products (local market) and 1650 for exports recalled and cancelled 2007, Roche recalled all batches of ARV Viracept –contamination with genotoxic substance Death by GMP: MH Anisfeld. GMP Review. Vol 4 No Impact on the patient?

| Slide 7 of 63 April 2008 Prequalification Programme: Priority Essential Medicines The prequalification program is an implemented action plan for expanding access to medicines for patients with: - HIV/AIDS - Tuberculosis - Malaria -Ensures quality, efficacy and safety of medicines procured using international funds (e.g. GFTAM) Now also Reproductive Health Products and Avian Flu

| Slide 8 of 63 April 2008 Prequalification Programme: Priority Essential Medicines  Partners and role players include: UNICEF, UN Population Fund (UNFPA), UNAIDS and with the support of the World Bank; Roll Back Malaria, Stop TB (Global Drug Facility), HIV/AIDS Department, UNITAID and the Gates Foundation  Role of WHO: Managing and organizing the project on behalf of the United Nations. Provides technical and scientific support Ensures that international norms and standards are applied GMP, GCP, GLP, quality control  Assessors and Inspectors: Mainly from National DRAs of ICH and associated countries, and PIC/S

| Slide 9 of 63 April 2008 Prequalification Programme: Priority Essential Medicines In WHO - PQ team has its own Quality Assurance system:  Quality Assurance and Safety: Medicines (QSM)  Organization chart, job descriptions  Standard Operating Procedures (SOPs)  General Procedure for Prequalification  Manuals and guidelines  Norms and standards (product dossiers, manufacturers etc)

| Slide 10 of 63 April 2008 Prequalification Programme: Priority Essential Medicines Program Manager Head: Inspections Inspector Head: Dossier assessments Assessor Liaison Quality Control Technical Assistance Admin Support

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| Slide 12 of 63 April 2008 Expression of Interest Product dossier SMF Additional data and information Assessment Steps in prequalification

| Slide 13 of 63 April 2008 Steps in prequalification Expression of Interest Product dossier SMF Additional data and information Corrective actions Assessment Inspections APIs FP CRO

| Slide 14 of 63 April 2008 Expression of Interest Product dossier SMF Compliance Additional information and data Corrective actions Compliance Assessment Inspections Prequalification Monitoring Steps in prequalification

| Slide 15 of 63 April th Invitation to manufacturers of antituberculosis medicines to submit an Expression of Interest (EOI) for product evaluation to the WHO Prequalification Programme June 2007: Interested manufacturers are encouraged to submit documentation for recommended dosage forms and strengths, as specified below, of medicinal products in the following categories. 1. Single ingredient first-line antituberculosis medicines - Ethambutol, tablet 400 mg - Isoniazid, tablet 300 mg - Pyrazinamide, tablet 400 mg - Rifampicin, capsule 150 mg; 300 mg -Streptomycin, powder for injection 1g (vial) 2. Fixed dose combination products of first-line antituberculosis medicines - Isoniazid + Rifampicin, tablet 75 mg mg; tablet 150 mg mg - Ethambutol + Isoniazid, tablet 400 mg mg - Ethambutol + Isoniazid + Rifampicin, tablet 275 mg + 75 mg mg - Ethambutol +Isoniazid +Pyrazinamide +Rifampicin tablet 275mg +75mg +400 mg +150mg

| Slide 16 of 63 April th Invitation to manufacturers of antituberculosis medicines to submit an Expression of Interest (EOI) for product evaluation to the WHO Prequalification Programme 3. Single ingredient second-line antituberculosis medicines - Amikacin, 250 mg/ml (vial 2 ml, 4 ml); powder for injection 1g (vial) - Capreomycin, powder for injection 1g (vial) - Cycloserine, capsule 250 mg - Ethionamide, coated tablet 125 mg; 250 mg - Kanamycin, powder for injection 1g (vial) - Levofloxacin, tablet 250 mg - Moxifloxacin, tablet 400 mg - Ofloxacin, tablet 200 mg; 400 mg - Prothionamide, coated tablet 250 mg - P-aminosalicylic acid, granules 4g - P-aminosalicylic sodium, granules 100 g 4. Scored solid dosage formulations for children, preferably dispersible - Ethambutol, tablet 100 mg - Isoniazid, tablet 50 mg; 100 mg - Isoniazid + Rifampicin, tablet 60 mg + 60 mg; tablet 30 mg + 60 mg - Isoniazid + Pyrazinamide + Rifampicin, tablet 30 mg mg + 60 mg - Pyrazinamide, tablet 150 mg

| Slide 17 of 63 April 2008 In this presentation… Prequalification program Assessment of products and manufacturers –Standards Information on generic ARVs, TB and Malaria products Innovator and generic products Agreement with USA FDA for exchange of information Companies participating in WHO prequalification –Companies that succeed and fail Capacity building Incentives for manufacturers

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| Slide 19 of 63 April 2008  Innovator product: Abbreviated procedure Approved by stringent authorities like EMEA and US FDA Trust scientific expertise of well-established DRAs Submit: Assessment report from Drug Regulatory Authority (DRA), WHO Certificate of Pharmaceutical Product (CPP), Batch certificate Update on changes Assessment procedure- Product dossiers

| Slide 20 of 63 April 2008 Generic Product Generic product: 1. To contain the same active ingredients as the innovator drug 2. To be identical in strength, dosage form, and route of administration 3. To have the same indications for use 4. To meet the same batch requirements for identity, strength, purity and quality 5. To be manufactured under the same strict standards of GMP required for innovator products. 6. To be bio-equivalent Prequalification requirements for generics –Fully in line with major regulatory agencies –See also FDA requirements for generic drugs ( What if not generics –Full data to prove safety (including preclinical toxicology) and efficacy has to be presented Not all non-innovator products in prequalification pipeline can be defined as generics –no innovator may be available Assessment procedure- Product dossiers

| Slide 21 of 63 April 2008  Multisource (generic) products  Submit: Full dossier with all the data and information requested (quality; safety and efficacy) Quality: (Information on) Starting materials (API, exipients) Finished product Specifications, stability data, formulation, pharmaceutical development, (QBD), manufacturing method, packaging, labelling etc Efficacy and safety: Bio-equivalence study / clinical study report (WHO and ICH) Commercial sample Requested, but not always analysed before prequalification. Assessment procedure- Product dossiers

| Slide 22 of 63 April 2008 Guidance for applicants

| Slide 23 of 63 April 2008  Assessment of product dossiers  Ongoing  and  Copenhagen assessment week: Teams of professionals from national Drug Regulatory Authorities (DRA): Including Brazil, China, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Uganda, UK, Zimbabwe 8 to 20 assessors - at least every two months at UNICEF in Denmark Every dossier is assessed by at least four assessors. An assessment report is issued - signed by assessors Letter summarizing the findings and asking for clarification and additional data if necessary Assessment procedure- Product dossiers

| Slide 24 of 63 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 25 of 63 April 2008 Assessment procedure Product dossiers received

| Slide 26 of 63 April 2008 Assessment procedure- Product dossiers

| Slide 27 of 63 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 28 of 63 April 2008 Inspections 2006

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| Slide 30 of 63 April Parma. development TB 4FDC tablets FPPs (packed products) Unpacked tablets (control) After 5 days at 40°C/75% RH After 5 days at 40°C/75% RH + Light S. Singh, Int. J. Tuberc. Lung. Dis., 7, 298 (2003) Products B A Quality of the products not known “bleeding”

| Slide 31 of 63 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

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| Slide 33 of 63 April 2008 USP BP Ph. Eur. Ph. Int. Prequalification Programme: Priority Essential Medicines

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| Slide 36 of 63 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 37 of 63 April 2008 New York Times 2007

| Slide 38 of 63 April 2008 Prequalification Programme: Priority Essential Medicines HIV/AIDS products Started 2001 – largest pool of generic antiretroviral dossiers Initially, many problems including: Manufacturers lacked knowledge and experience in international standards Only 2 monographs in pharmacopoeia and official reference standards Often no specifications, no bioequivalence studies, no stability data, no data on API manufacturing and profile Fixed Dose Combinations (FDCs)

| Slide 39 of 63 April 2008 Anti-tuberculosis products Relatively "older" products Low profit margins Mainly manufactured in developing countries Mainly purchased by governments Limited number of API and FP manufacturers –first and second line products Lack in stability data (e.g. Schedule M) FDCs Lack of bioequivalence studies No clear comparator product or product no longer the same Incompatibilities... Prequalification Programme: Priority Essential Medicines

| Slide 40 of 63 April 2008 Prequalification Programme: Priority Essential Medicines Anti-malaria products Recommended treatment – artemesinin combinations –resistant malaria Mainly products (single component) from Asia (China) Lack of specifications –initially no pharmacopoeia monographs (excluding CP) - now Ph. Int. Lack of safety and efficacy data Innovator products? Generics – few in ICH countries Limited regulatory experience in ICH region FDCs and bi-layer tablets

| Slide 41 of 63 April 2008 Prequalification Programme: Priority Essential Medicines First inspections - Number of non-compliances in each area

| Slide 42 of 63 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 43 of 63 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 44 of 63 April 2008 Generally, in all three groups: In addition to non compliance with standards (e.g. GCP, GMP), also: Products not controlled (appropriately registered) in countries of manufacture Products produced only for export purposes Most manufacturers can overcome these problems if motivated. However, it may take a lot of time... Prequalification Programme: Priority Essential Medicines

| Slide 45 of 63 April 2008 Prequalification Programme: Priority Essential Medicines Not only "bad news" …

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| Slide 47 of 63 April 2008 Publications 2005/2006 Updated prequalification web site launched in November 2006: Articles: –1. Prequalification of medicines. WHO Drug Information, 2005, 19:1. –2. WHO and its Prequalification Programme: an Overview. WHO Pharmaceuticals Newsletter, 2005, No. 2. –3. Dekker TG, van Zyl AJ, Gross O, Tasevska I, Stahl M, Rabouhans ML, Rägo L. Ongoing monitoring of antiretroviral products as part of WHO’s Prequalifi cation Programme. Journal of Generic Medicines, 2006, 3(2):96–105.

| Slide 48 of 63 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:

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| Slide 51 of 63 April 2008 Increased transparency about the "pipeline"

| Slide 52 of 63 April 2008 Recognition scientific assessment based on information exchange (Confidentiality agreement between US FDA and WHO Prequalification) Same approach will soon apply for EU Art58 and Canadian JCPA procedure Prequalification Programme: Priority Essential Medicines

| Slide 53 of 63 April 2008 In this presentation… Prequalification program Assessment of products and manufacturers –Standards Information on generic ARVs, TB and Malaria products Innovator and generic products Agreement with USA FDA for exchange of information Companies participating in WHO prequalification –Companies that succeed and fail Capacity building Incentives for manufacturers

| Slide 54 of 63 April 2008 Prequalification Programme: Priority Essential Medicines Companies participating in prequalification ICH regionOther regions GlaxoSmithKline Abbott Roche Bristol Myers Squibb Merck Sharp & Dohm Boehringer Ingelheim Gilead... Cipla Ltd Ranbaxy Ltd Aurobindo Aspen Pharmaceuticals Strides Ltd Hetero Drugs Ltd...

| Slide 55 of 63 April 2008 Companies that succeed and fail Compliance with standards Exposed to international environment Local requirements similar or the same as international or stringent national requirements Willing or motivated to comply even if local requirements are less stringent Business incentive – share of the market Prequalification Programme: Priority Essential Medicines

| Slide 56 of 63 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 57 of 63 April 2008 Prequalification Programme: Priority Essential Medicines

| Slide 58 of 63 April 2008 Prequalification Programme: Priority Essential Medicines Capacity building Assessors - Copenhagen Assessors – rotational post Inspectors – local DRA Indirect – local manufacturer and CRO Inspectors – recipient country

| Slide 59 of 63 April 2008 Prequalification Programme: Priority Essential Medicines Capacity building Assessors - Copenhagen Assessors – rotational post Inspectors – local DRA Indirect – local manufacturer and CRO Inspectors – recipient country Technical Assistance - Independent -

| Slide 60 of 63 April 2008 Prequalification Programme: Priority Essential Medicines - Acceptance - Facilitate registration - GFTAM - UnitAID - GDF

| Slide 61 of 63 April 2008 Prequalification Programme: Priority Essential Medicines €£¥$€£¥$

| Slide 62 of 63 April 2008 Since 2005 annual reports; 2006 annual report on the web

| Slide 63 of 63 April 2008 Thank you