PHARMA DEVELOPMENT WORLD HEALTH ORGANIZATION.ppt

PHARMACEUTICAL DEVELOPMENT

1. | 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

2. | 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
[email protected]

3. | 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

4. | 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 - 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. | 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

6. | 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 4 2006 Impact on the patient?

7. | 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

8. | 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

9. | 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)

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

11. | Slide 11 of 63 April 2008

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

13. | 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

14. | 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

15. | Slide 15 of 63 April 2008
7th 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 + 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. | Slide 16 of 63 April 2008
7th 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 + 150 mg + 60 mg
- Pyrazinamide, tablet 150 mg

17. | 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

18. | Slide 18 of 63 April 2008
www.who.int/prequal

19. | 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

20. | 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 (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
Assessment procedure- Product dossiers

21. | 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

22. | Slide 22 of 63 April 2008
Guidance for applicants

23. | 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

24. | 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

25. | Slide 25 of 63 April 2008
Assessment procedure
Product dossiers received
0
10
20
30
40
50
60
70
HIV/AIDS
2005 2006
2007
0
2
4
6
8
10
12
14
16
18
Tuberculosis
2005 2006
2007
0
1
2
3
4
5
6
Malaria
2005 2006
2007

26. | Slide 26 of 63 April 2008
Assessment procedure- Product dossiers
0
10
20
30
40
50
60
70
80
90
Total number of dossiers
2005 2006
2007
0
10
20
30
40
50
60
70
80
90
100
Dossiers evaluated 2007
HIV
TB
Malaria
ReproductiveH

27. | 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

28. | Slide 28 of 63 April 2008
Inspections 2006
0
5
10
15
20
25
Inspection sites
India
China
Belgium
France
Switzerland
Canada
Malaysia
Kenia,
Cameroon
USA
South Africa

29. | Slide 29 of 63 April 2008

30. | Slide 30 of 63 April 2008
2.2.2 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”

31. | 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

32. | Slide 32 of 63 April 2008

33. | Slide 33 of 63 April 2008
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Prequalification Programme: Priority Essential
Medicines

34. | Slide 34 of 63 April 2008

35. | Slide 35 of 63 April 2008

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

37. | Slide 37 of 63 April 2008
New York Times 2007

38. | 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)

39. | 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

40. | 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

41. | Slide 41 of 63 April 2008
Prequalification Programme: Priority Essential
Medicines
First inspections - Number of non-compliances in each area
0
100
200
300
400
500
600
700
800
Area of manufacturing
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42. | 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

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

44. | 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

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

46. | Slide 46 of 63 April 2008

47. | Slide 47 of 63 April 2008
Publications 2005/2006
Updated prequalification web site launched in November
2006: http://who.int/prequal/
 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.

48. | Slide 48 of 63 April 2008
Transparency: WHO Public Reports
(WHOPIRs and WHOPARs)
Name of manufacturerAurobindo Pharma Limited, Unit - VIII
AddressSurvey N° 13
Gaddapotharam (Village), IDA- Kazipally,
Jinnaram (Mandal),
Medak District, Andhra Pradesh- 502319
India
Postal addressSame as above
Telephone number+91 8458 277115
Fax number+91 8458 277114
Summary of activities of manufacturer (e.g.
manufacturing, packing) .
Indicate dosage forms and type of products
(e.g. tablets; cephalosporin containing
products)
Manufacturing and control of anti-retroviral
active ingredients, including but not
restricted to the manufacturing process of
Zidovudine and Efavirenz..
Date of inspection:14 & 15 March 2006
Project:Prequalification Programme
Part 2: Summary and conclusion of the inspection.
Summary:

49. | Slide 49 of 63 April 2008

50. | Slide 50 of 63 April 2008

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

52. | 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

53. | 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

54. | Slide 54 of 63 April 2008
Prequalification Programme: Priority Essential
Medicines
Companies participating in prequalification
ICH region Other 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 . . .

55. | 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

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

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

58. | 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

59. | 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-

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

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

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

63. | Slide 63 of 63 April 2008
Thank you