World Health Organization Activities Focus on Prequalification of Medicines

Dr A J van Zyl (WHO) | 19 April 20231 |

World Health Organization ActivitiesFocus on Prequalification of Medicines

André van Zyl (M. Pharm, Ph.D, Ph. D)

Head of Inspections

Quality Assurance and Safety: Medicines (QSM),

Department of Essential Medicines and Pharmaceutical Policies (EMP),

Health Systems and Services (HSS)

WHO, Geneva

[email protected]


World Health OrganizationWorld Health Organization

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Head quarters located in GenevaHead quarters located in Geneva


Essential Medicines and Pharmaceutical Policies

Medicines information, access, rational use,

traditional medicine, INN, quality and safety (norms and standards including

Pharm. Int. and.…

www.who.int/medicines


Prequalification


Prequalification of Medicines ProgrammePrequalification of Medicines Programme The UN Prequalification Programme is ensuring that medicines procured with international funds are of

assessed and inspected quality, efficacy and safety.

The Prequalification Programme is an IMPLEMENTEED action plan for expanding access to priority essential medicines in the following four areas:

- HIV/AIDS - Tuberculosis - Malaria - Avian Flu - Reproductive Health A UN Prequalification Program of Quality Control Laboratories exists to facilitate the quality control of the

prequalified products.


Expression of Interest

Compliance

Additional informationand data

Corrective actions

Compliance

Assessment Inspections

Medicines Prequalification ProcessMedicines Prequalification Process

Prequalification

Monitoring

Product dossierSMF


Assessment of the product dossier i.e. quality specifications, pharmaceutical development, stability, bioequivalence…

Copenhagen assessment week• 15 to 20 assessors during one week at least every two months • Every dossier is assessed by at least four assessors including one

senior assessor for the second assessment• An assessment report is issued• Letter summarizing the findings and asking for clarification and

additional data if necessary; sent first by e-mail to the applicant followed by surface mail

Variations - Done in house and during Copenhagen-week

Prequalification of Priority Essential Medicines Organisation (1)



Inspections of manufacturers:- Finished Products (FPP)- Active Pharmaceutical Ingredient (API) and also - Contract Research Organizations (CRO, which carry out

clinical/bioequivalence studies)

Team of inspectors - WHO representative (qualified GMP inspector)- Inspector from well-established inspectorate- National inspectors invited to be part of the team but have no

decision making power (different GMP standards, potential conflict of interest)

-Inspector of potential target countries (and other countries in need for capacity building) as observer, for capacity building purpose.




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”


Assessment

What is required?– 1. Details of the product– 2. Regulatory situation in other countries– 3. Active pharmaceutical ingredient (s) (API)– 3.1 Properties of the active pharmaceutical ingredient(s)– 3.2 Sites of manufacture – 3.3 Route(s) of synthesis– 3.4 Specifications

– API described in a pharmacopoeia:– API not described in a pharmacopoeia:

– 3.5 Stability testing


Assessment

What will be required (2)?– 4. Finished product– 4.1. Formulation– 4.2. Sites of manufacture – 4.4. Manufacturing procedure – 4.5 Specifications for excipients– 4.6 Specifications for the finished product– 4.7 Container/closure system(s) and other packaging– 4.8 Stability testing


Assessment

What will be required (3)?– 4.9 Container labelling– 4.10 Product information– 4.11 Patient information and package inserts– 4.12 Justification for any differences to the product in the

country or countries issuing the submitted WHO-type certificate(s)

– 4.13 Interchange-ability (bio-equivalence studies)– 4.14 Summary of pharmacology, toxicology and efficacy of

the product


Assessment

Key numbers for 2008– 40 products prequalified (21 in 2007) – 92 dossiers submitted (90 in 2007)– 732 assessment reports (463 in 2007)– 52 inspections (45 in 2007)

For each prequalified product there were:• 5-15 assessment reports• 1 or more inspections• 2 years total time on average to get prequalified (the clock stops for PQ when

request for additional information/corrective actions is sent to the applicant)


2005 2006 2007 2008

HIV 67 42 25 42

TB 17 9 17 12

Malaria 3 5 7 9

R Health - - 10 4

87 56 59 67

Product dossiers accepted for evaluation


As of 31 January 2009 :

68 products for treatment of HIV/AIDS and related diseases

41 products for treatment of tuberculosis

17 products for treatment of malaria

11 reproductive health products

Total 137

Currently under evaluation in WHO Prequalification Programme

Currently under evaluation in WHO Prequalification Programme


Transparency – dossier status information on the web


Inspections…Inspections…

.What about inspections?

.Why do inspections?

…"We are already approved by FDA, TGA, MHRA…"

.What about inspections?

.Why do inspections?

…"We are already approved by FDA, TGA, MHRA…"


Quality concerns - India 96 samples (chloroquine and antibacterials) collected in Nigeria and Thailand - >36%

failed pharmacopoeia standards (Shakoor O et al, 1997)

Delhi - 53 samples, 86% were substandard or counterfeit (Iyengar J. A, Asia Times. 2002) 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)

Quality concerns - China

Strict control on compliance implemented and enforced– 07/07: "former head was executed for accepting bribes to approve untested medicine"

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)

Quality issues….Quality issues….


Poor quality has an impact on the patient

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

Quality issues….Quality issues….


GMP compliance – Majority of generic products world wide sourced from India

Review of 30 inspection reports for GMP

Focus on manufacturers for international supply

Assessed against WHO GMP

Period 2001 to 2004

Included the "top 45" group of companies

GMP issues….GMP issues….


GMP compliance – India

Review of 30 inspection reports for GMP

Focus on manufacturers for international supply

Assessed against WHO GMP

Period 2001 to 2004

Included the "45" group of companies

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Number

Rec.Store

Sampling

Weighing

PMS

FGS

Production

Packaging

QC

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Validation

Cl Validation

Documentation

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First inspections - Number of non-compliances in each area

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Area of manufacturing

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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

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Top 5 (all)Top 2 (major)


WHOPICSIndiaChina

4.Qualification and validation20Validation and Process validation

4.1In accordance with GMP, each pharmaceutical company should identify what qualification and validation work is required to prove that the critical aspects of their particular operation are controlled.

4.2The key elements of a qualification and validation programme of a company should be clearly defined and documented in a validation master plan.

(defined in Annex 15 – not included here)

4.3Qualification and validation should establish and provide documentary evidence that:


57Validation of manufacturing processes included

(a )the premises, supporting utilities, equipment and processes have been designed in accordance with the requirements for GMP )design qualification or DQ(;



Inspections - statistics in 2008 vs 2007

A total of 52 inspections were carried out in 2008: (45 in 2007)

– 27 (26) FPP manufacturers– 11 (6) active pharmaceutical ingredient (API)

manufacturers– 14 (13) contract research organizations (CROs)

In 2008 three inspectors in-house (plus manager)


Deviations, changes

In process controls

Product quality review

Contamination, cross contamination and mix ups

Validation and qualification work was often incomplete

Process validation lacking or unreliable results

Qualification e.g. HVAC, water (not to current standards)

GMP issues...GMP issues...


New York Times 2007


WHO Prequalification and Bio-equivalence studiesWHO 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, 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



Authenticity of chromatograms and peak areas?

Identical chromatograms with different identities

Integration reports of identical chromatograms showed different peak areas, even though peak integration parameters were identical

Identical chromatograms had different peak areas but the same area percent

min0 1 2 3 4 5 6

Norm.

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DAD1 A, Sig=270,4 Ref=360,100 (D:\2\AMR_EA\29070415.D)

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Examples

Half of the CRFs "missing"

Source data destroyed accidently by fire or "monsoon"

Sponsor claims the data were kept by the CRO, and the CRO claims the data were kept by the sponsor

All data and retention samples destroyed as the product "expired" – even though the submission is still under evaluation


Prequalification Programme:Transparency - WHOPIRs and NOCs

Prequalification Programme:Transparency - WHOPIRs and NOCs

These are published in response to the WHA Resolution WHA57.14 of 22 May 2004, which requested WHO, among other actions:

– "3. (4) to ensure that the prequalification review process and the results of inspection and assessment reports of the listed products, aside from proprietary and confidential information, are made publicly available;"

A WHO Public Assessment and Inspection Report (WHOPAR and WHOPIR) reflects a positive outcomes

A Notice of Concern (NOC) is a letter reflecting areas of concern where the non-compliances require urgent attention and corrective action by the manufacturer or research organization.


Transparency – Inspection outcomes on the web


CRO inspection findingsCRO inspection findings


Not only bad news or problems…Not only bad news or problems…


Currently prequalifed products (31 January 2009):

164 for treatment of HIV/AIDS and related diseases

18 for treatment of tuberculosis (10 prequalified in 2007-08)

14 for treatment of malaria (9 prequalified in 2007-08)

Total 196

List of WHO Prequalified Medicinal ProductsList of WHO Prequalified Medicinal Products


Training activities in 2008

In Brazil, China, Ghana, India, Indonesia, Iran, Jordan, Morocco, Nicaragua, Pakistan, Tanzania …

More than 500 participants - staff of regulatory authorities and pharmaceutical manufacturers

Topics:– Development of dossiers for submission– Assessment of bioequivalence (interchangeability) of medicines– Pharmaceutical Development of Paediatric Formulations– GMP, Quality and Bioequivalence of malaria ATC products– GMP, Quality and Bioequivalence of RHPs– Pharmaceutical Development of Paediatric Formulations

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11

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2006 2007 2008

PQP supported

PQP organized


QCL Prequalification trendsQCL Prequalification trends

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16

4

22

8

24

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35

2004 2005 2006 2007 2008

QCLs Prequalified QCLs Interested

Prequalified QCLs:

South Africa, RIIP+CENQAM (2005)

Algeria, LNCPP (2005)

South Africa, Adcock Ingram (2007)

Morocco, LNCM (2008)

Kenya, NQCL (2008)

India, Vimta Labs (2008)

France, CHMP (2008)

Vietnam, NIDQC (2008)


Sampling and testing projects in 2008Sampling and testing projects in 2008Sampling and testing projects in 2008Sampling and testing projects in 2008

Quality survey of antimalarials (ACTs and sulfadoxine-pyrimethamine)– Cooperation with NDRAs in Cameroon, Ethiopia, Ghana, Kenya, Madagascar, Nigeria, Senegal,

Tanzania, Uganda– 936 samples collected and screened by Minilab, 299 selected for full testing in laboratory (testing

ongoing)– Assessment of quality of product information (Labelling and PIL)

Quality monitoring of products funded by UNITAID – Pilot phase (paediatric and second-line antiretrovirals) in cooperation with NDRAs in Kenya,

Tanzania, Uganda, Zambia– 378 samples collected and tested in laboratory (testing ongoing)– Assessment of quality of product information (Labelling and PIL)

Quality survey of anti-TB medicines in Eastern Europe– Cooperation with NDRAs in Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, Uzbekistan;

Focused on Rifampicin, Isoniazid, Rifampicin/Isoniazid, Ofloxacin, Kanamycin (360 samples planned)


Technical Assistance - PolicyCriteria for the products in relation to which technical assistance is considered:

Inclusion in the list of expression of interest

High value for Public Health purposes

Poor representation on the Prequalification list

Manufacture has applied for PQ (exemptions can be made upon justified requests for technical assistance from regional offices) danger

Criteria for the experts:

Excellent qualifications and long standing experience in the area where expertise is required

Absence of conflict of interest

Total intellectual independence from the prequalification programme, no participation in inspections or assessments.


New PQ procedure for APIs in 2009

Until now - evaluation of API source and manufacturer mostly the responsibility of finished product manufacturer

Not all NDRAs inspect API manufacturers, and seldom a full evaluation of API dossier

Often - API source considered "confidential" information

Oct 2008 WHO Expert Committee on Specifications for Pharmaceutical Preparations adopted PQ procedure for active pharmaceutical ingredients (APIs)

New approach similar to CEP (EDQM) – assessment of API Master File and site inspection for GMP compliance (ICH Q7)


The purpose of the prequalification programme is to list medicinal products of good quality - that are safe and effective – in the interest of public health in resource-limited countries.

The products should be submitted with technical data proving the quality of API and finished product together with necessary data on safety and efficacy (quality submissions in demand)

WHO wishes to gratefully acknowledge the assistance and help provided in 2008 by our many partners in and outside WHO, donors and many other individuals and organizations

Especially grateful to the staff from National Drug Regulatory Authorities of: Australia, Austria, Brazil, Canada, China, Estonia, Ethiopia, France, Germany, Ghana, Hungary, Italy, Kenya, Netherlands, Poland, Singapore, South Africa, Spain, Sweden, Switzerland, Tanzania, Uganda, Ukraine, United Kingdom, and Zimbabwe …


Thank you for your

attention

World Health Organization Activities Focus on Prequalification of Medicines

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