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| Slide 1 of 63 April 2008
Pharmaceutical Development with Focus on Paediatric formulations
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
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
| Slide 3 of 63 April 2008
In this presentation… 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
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)
| Slide 5 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
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
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?
| Slide 7 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
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
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 descriptionsStandard Operating Procedures (SOPs)General Procedure for PrequalificationManuals and guidelinesNorms and standards (product dossiers,
manufacturers etc)
| Slide 10 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
Program Manager
Head :Inspections
Head: Dossier assessments
LiaisonQuality Control
Technical Assistance
Inspector AssessorInspector Assessor
Admin Support
| Slide 11 of 63 April 2008
| Slide 12 of 63 April 2008
Expression of InterestProduct dossier
SMF
Additional data and information
Assessment
Steps in prequalification
| Slide 13 of 63 April 2008
Steps in prequalification
Expression of InterestProduct dossier
SMF
Additional data and information Corrective actions
Assessment Inspections
APIs
FP
CRO
| Slide 14 of 63 April 2008
Expression of InterestProduct dossier
SMF
Compliance
Additional informationand data Corrective actions
Compliance
Assessment Inspections
Prequalification Monitoring
Steps in prequalification
| Slide 15 of 63 April 2008
7th Invitationto manufacturers of antituberculosis medicines
to 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
| Slide 16 of 63 April 2008
7th Invitationto manufacturers of antituberculosis medicines
to 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
| Slide 17 of 63 April 2008
In this presentation… 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 18 of 63 April 2008
www.who.int/prequalwww.who.int/prequal
| 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 dossiersAssessment procedure- Product dossiers
| Slide 20 of 63 April 2008
Generic Product
Generic product: 1. To contain the same active ingredients as the innovator drug2. To be identical in strength, dosage form, and route of administration3. To have the same indications for use 4. To meet the same batch requirements for identity, strength, purity and quality5. 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 dossiersAssessment 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 dossiersAssessment procedure- Product dossiers
| Slide 22 of 63 April 2008
Guidance for applicantsGuidance 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 dossiersAssessment 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 - inspectionsAssessment procedure - inspections
| Slide 25 of 63 April 2008
Assessment procedureProduct dossiers received
Assessment procedureProduct 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
| Slide 26 of 63 April 2008
Assessment procedure- Product dossiersAssessment 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
| 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 - inspectionsAssessment procedure - inspections
| Slide 28 of 63 April 2008
Inspections 2006Inspections 2006
0
5
10
15
20
25
Inspection sites
India
China
Belgium
France
Switzerland
Canada
Malaysia
Kenia,Cameroon
USA
South Africa
| Slide 29 of 63 April 2008
| Slide 30 of 63 April 2008
2.2.2 Parma. developmentTB 4FDC tablets
2.2.2 Parma. developmentTB 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)
ProductsB 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
| Slide 32 of 63 April 2008
| Slide 33 of 63 April 2008
min0 1 2 3 4 5 6
Norm.
0
50
100
150
200
DAD1 A, Sig=270,4 Ref=360,100 (D:\2\AMR_EA\29070415.D)
1.7
28 -
Is
onia
zid
5.4
78 -
E
tham
buto
l HC
l
USPBP
Ph. Eur.Ph. Int.
Prequalification Programme: Priority Essential Medicines
Prequalification Programme: Priority Essential Medicines
| Slide 34 of 63 April 2008
| Slide 35 of 63 April 2008
| Slide 36 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
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
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
Prequalification Programme: Priority Essential Medicines
| Slide 40 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
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
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
Nu
mb
er
of
ob
serv
atio
ns
All Major
All 687 282 238 207 164 156 108 104 97 62 48 36 22 14
Major 301 107 79 95 59 77 54 26 50 29 27 10 12 3
Prod QC Rec Smp Doc Wgh Val PackPack Mat
Micro
HVAC
H2OCl val
Fin gds
| Slide 42 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
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
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
Prequalification Programme: Priority Essential Medicines
| Slide 45 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
Prequalification Programme: Priority Essential Medicines
Not only "bad news" …
| Slide 46 of 63 April 2008
| Slide 47 of 63 April 2008
Publications 2005/2006Publications 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.
| Slide 48 of 63 April 2008
Transparency: WHO Public Reports (WHOPIRs and WHOPARs)
Transparency: WHO Public Reports (WHOPIRs and WHOPARs)
Name of manufacturerAurobindo Pharma Limited, Unit - VIII
AddressSurvey N° 13Gaddapotharam (Village), IDA- Kazipally, Jinnaram (Mandal),Medak District, Andhra Pradesh- 502319India
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:
| Slide 49 of 63 April 2008
| Slide 50 of 63 April 2008
| 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
Prequalification Programme: Priority Essential Medicines
| Slide 53 of 63 April 2008
In this presentation… 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
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 . . .
| 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
Prequalification Programme: Priority Essential Medicines
| Slide 56 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
Prequalification Programme: Priority Essential Medicines
| Slide 57 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
Prequalification Programme: Priority Essential Medicines
| Slide 58 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
Capacity buildingAssessors - Copenhagen
Assessors – rotational post
Inspectors – local DRA
Indirect – local manufacturer
and CROInspectors – recipient country
| Slide 59 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
Capacity buildingAssessors - Copenhagen
Assessors – rotational post
Inspectors – local DRA
Indirect – local manufacturer
and CROInspectors – recipient country
Technical Assistance -Independent-
| Slide 60 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
Prequalification Programme: Priority Essential Medicines
- Acceptance
- Facilitate
registration
- GFTAM
- UnitAID
- GDF
| Slide 61 of 63 April 2008
Prequalification Programme: Priority Essential Medicines
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 youThank you
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