Pharmaceutical Development with Focus on Paediatric formulations

1. 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

2. Pharmaceutical Development with Focus on Paediatric formulations Presented by: Dr A J van Zyl Technical Officer Head of Inspections HSS/PSM/QSM vanzyla@who.int

3. 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

4. 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 - 436 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)

5. 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

6. 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 Impact on the patient? Death by GMP: MH Anisfeld. GMP Review. Vol 4 No 4 2006

7. 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

8. 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

9. 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)

10. Prequalification Programme: Priority Essential Medicines

12. Steps in prequalification Expression of Interest Product dossier SMF Assessment Additional data and information

13. Steps in prequalification Expression of Interest Product dossier SMF APIs FP Assessment Inspections CRO Additional data and information Corrective actions

14. Steps in prequalification Expression of Interest Product dossier SMF Assessment Inspections Additional information and data Corrective actions Compliance Compliance Prequalification Monitoring

15. 7th Invitationto manufacturers of antituberculosis medicinesto submit an Expression of Interest (EOI) for product evaluation to theWHO 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 + 150 mg; tablet 150 mg + 150 mg • - Ethambutol + Isoniazid, tablet 400 mg + 150 mg • - Ethambutol + Isoniazid + Rifampicin, tablet 275 mg + 75 mg + 150 mg • - Ethambutol +Isoniazid +Pyrazinamide +Rifampicin tablet 275mg +75mg +400 mg +150mg

16. 7th Invitationto manufacturers of antituberculosis medicinesto submit an Expression of Interest (EOI) for product evaluation to theWHO 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 + 150 mg + 60 mg • - Pyrazinamide, tablet 150 mg

17. 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

18. www.who.int/prequal

19. Assessment procedure- Product dossiers • 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

20. Assessment procedure- Product dossiers 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 (www.fda.gov/cder/ogd) • 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

21. Assessment procedure- Product dossiers • 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.

22. Guidance for applicants

23. Assessment procedure- Product dossiers • 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

24. Assessment procedure - inspections • 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

25. Assessment procedureProduct dossiers received

26. Assessment procedure- Product dossiers

27. 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

28. Inspections 2006

30. 2.2.2 Parma. developmentTB 4FDC tablets ProductsB A 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) Quality of the products not known “bleeding”

31. Standards • International consultation process • The WHO Expert Committee – review and adopts • Executive Board • World Health Assembly • Printed in respective TRS and WHO web site

33. Prequalification Programme: Priority Essential Medicines USP BP Ph. Eur. Ph. Int.

36. Prequalification Programme: Priority Essential Medicines

37. New York Times 2007

38. 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)

39. 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

40. 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

41. Prequalification Programme: Priority Essential Medicines First inspections - Number of non-compliances in each area

42. 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

43. Prequalification Programme: Priority Essential Medicines

44. Prequalification Programme: Priority Essential Medicines 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 . . .

45. Prequalification Programme: Priority Essential Medicines Not only "bad news" …

47. Publications 2005/2006 • Updated prequalification web site launched in November 2006: http://who.int/prequal/ • Articles: • 1. Prequalification of medicines. WHO DrugInformation, 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. Ongoingmonitoring of antiretroviral products as part ofWHO’s Prequalifi cation Programme. Journal ofGeneric Medicines, 2006, 3(2):96–105.

48. Transparency: WHO Public Reports (WHOPIRs and WHOPARs) Part 2: Summary and conclusion of the inspection. Summary: