1 qa /qc including issues related to gf policies and prequalification :general principles truls...

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QA /QC including issues related to GF policies and prequalification :general

principles

Truls Eriksen

Technical Officer

HIV/AIDS and STI

WHO Western Pacific Regional Office

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Overview of presentation

• Introduction

• Determinants of quality/QA

• GFATM policy on QA

• WHO prequalification project

• QC

• Conclusion

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What is quality?

• Fitness for purpose

• Fulfilling of needs

• Compliance with specifications

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What is quality assurance?

• QA is the sum total of the organized arrangements made with the object of ensuring that medicinal products are of the quality required for their intended use;

• “Quality assurance is about getting it right “

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Determinants of Product QualityDeterminants of Product Quality

• Active ingredients

• Inactive ingredients

• Packagingimmediate and external

• Labeling./packet inserts/

Product information

• Handling and storage conditions

• Product manufacture

• Equipment and maintenance

• Plant environment

• Manufacturing process

• Quality control program

• Product formulation

Product=specific medicine manufactures at a specific siteProduct=medicine in container with label, packaging insert and information

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Product Selection

Procurement

Storage/distribution

Use

Prod.Specs.

Prequalification

Tender contract

Monitoring of supplier performance

GSP,GDP

Inspections/licensing

QAStorage/handling

GMP, inspection and licensing

Evaluation of product dossier

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Critical Elements in QA for ProcurementCritical Elements in QA for Procurement

• Product selection

• Supplier prequalification

• Product certification

• Contract specifications

• Inspection of shipments

• Laboratory testing

• Appropriate storage, transport, dispensing, and use procedures

• Product monitoring/ reporting system

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Guide to the Global Fund’s Guide to the Global Fund’s Policies onPolicies on Procurement and Supply Procurement and Supply ManagementManagement

Building on:

Interagency Guidelines: Operational Principles for Good Pharmaceutical Procurement. WHO, Geneva, 1999.WHO/EDM/PAR/99.5.

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Guide to the Global Fund’s Guide to the Global Fund’s Policies onPolicies on Procurement and Supply Procurement and Supply ManagementManagement

Before May 2005:

Products bought using GF must be:

WHO prequalified; or

Approved by Stringent Regulatory Authority; or

Approved by National Regulatory Authority

After May 2005:

WHO prequalified; or

Approved by Stringent Regulatory Authority

Quality standard has been raised !!

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Guide to the Global Fund’s Policies Guide to the Global Fund’s Policies onon Procurement and Supply Procurement and Supply ManagementManagementQuality assurance refers to the management activities required to ensure that the medicines (or other health products) that reach patients are safe, effective and acceptable to the patient.

These activities may include, but are not limited to, (drug) registration, pre-qualification and quality control.

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Pharmaceuticals procured with Global Fund resources are subject to authorization by the National Drug Regulatory Authority (NDRA) in the country in which they are used, following its standard practices for drug registration (or other forms of authorization, such as authorizations for special use) for pharmaceutical products.

Guide to the Global Fund’s Policies onGuide to the Global Fund’s Policies on Procurement and Supply Management Procurement and Supply Management

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Multi-source pharmaceutical products are off-patent products that have a prior history of safe and efficacious use.

Multi-source pharmaceutical products tend to be available from a wide range of manufacturers around the world.

For such multi-source products, there are no additional requirements other than verification of compliance with quality standards must be conducted in accordance with relevant requirements of the NDRA in the recipient’s country.


Multi-source pharmaceutical productsMulti-source pharmaceutical products

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Products that are available only from a single supplier, normally the originator company, are referred to as single source products.

If in addition to the single supplier there are a limited number of other suppliers, the product is referred to as a limited-source product.

Many of the antiretrovirals and antimalarials belong to the latter category.


Single and limited-source pharmaceutical productsSingle and limited-source pharmaceutical products

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Grant funds may be used to procure a single- or limited-source pharmaceutical product provided that such product meets one of the following standards:

a) Have been found to be acceptable by the UN Procurement Quality and Sourcing Project (also known as the WHO Prequalification Project ); or

b) Have been authorized for consumption in their country by a stringent regulatory authority

c) Have been authorized by the NDRA in the recipient’s country, provided that this clause shall only apply until April 30, 2005.



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Countries with stringent regulatory Countries with stringent regulatory authorities authorities

Pharmaceutical Inspection Cooperation Scheme (PIC/S) participating regulatory authorities

Australia Greece Norway Austria Hungary Portugal Belgium Iceland Romania Canada Ireland Singapore Czech Republic Italy Slovak Republic Denmark Latvia Spain Finland Liechtenstein Sweden France Malaysia Switzerland Germany Netherlands United Kingdom

European Union Member States, Japan and United States

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After April 30, 2005, Grant funds may only be used to procure single- or limited-source pharmaceutical products that meet the requirements of the two standards set out in a) and b), provided that:.

(1) Contracts entered into by the Principal Recipient on or before April 30, 2005 with suppliers for products that qualified for purchase under clause c) may be honoured until such contracts expire or otherwise terminate. (2) After April 30, 2005, the Principal Recipient may not enter into any new contracts, nor extend any existing contracts, for the supply of products that would have qualified for purchase under clause c) prior to April 30, 2005.

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NDRA marketing authorization (registration) for new productsNDRA marketing authorization (registration) for new products

For products that have

•passed the WHO Prequalification Project review, or

•have been authorized by stringent regulatory authority

DRA’s are encourages to expedite registration by accepting the above

•Fast track registration

•Provisional registration

•Waive registration

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2 Equivalent products

Number of equivalent

products under option (a) or (b)

Recommendation

(a), (b)End Option (c) on

30 April 2005

(i) In pipeline of Option (a) or (b) + Manufactured in a facility compliant

with GMP following inspection by WHO

or stringent regulatory authority

2 Equivalent products

If products unavailable, PR informs Secretariat and then:

* Product defined as: chemical + strength + formulation** Unavailability defined as: inability of the manufacturer to supply a sufficient quantity of finished product within 90 days from date of order.

The PR is required to notify GF if procuring under (i) or (ii) which should be time-limited until products under option a) and b) are available



Evidence of application submitted and GMP compliance

Evidence of GMP compliance

IF NOT, THEN

(ii) Manufactured in a GMP-compliant manufacturing facility

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Use of option i) or ii)Use of option i) or ii)

QC of samples is required and GF will contract an

independent third-part to conduct random quality analysis

In general QC should be carried out for quality monitoring

Laboratories used must meet the following criteria

1. Be “prequalified”

2. ISO17025 or EN45002 Accreditation

3. Acceptance by stringent regulatory authority

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WHO Prequalification WHO Prequalification ProjectProject

• I. Assessment of products dossiers i.e. quality specifications, pharmaceutical development, bioequivalence etc. : teams of professionals from national drug regulatory authorities: Brazil, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Zimbabwe ...

• II. Manufacturing site inspections: teamwork of inspectors: WHO representative (qualified GMP inspector), inspector from well-established inspectorate (Pharmaceutical Inspection Convention Scheme countries) and national inspector(s): Canada, France, Italy, Switzerland, The Netherlands …

• Quality control analysis - upon need but not always necessarily before prequalification and supply, increasingly as part of follow-up

http://mednet3.who.int/prequal

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HIV/AIDSHIV/AIDSAs of June 2005:

88 HIV/AIDS products

53 ARVs

34 originator products (30single, 4FDCs)

19 generic products (15 single, 4 FDCs)

14 2nd line ARVs

8 paediatric formulations

35 other products for HIV-care (non-ARV)

6 originator products

29 generics hiv_suppliersJune05.pdf

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WHO Prequalification WHO Prequalification Project MalariaProject Malaria

As of 2005:

Malaria products:

2 products only:

Artesunate 50 mg tablets

Arthemeter/Lumefantrine 20/120mg tablets

mal_suppliers.pdf

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WHO Prequalification Project WHO Prequalification Project MalariaMalaria

However, 25 products are currently being evaluated

4 artemether capsules/tablets

7 artemether inj.

5 artesunate tablets

3 artesunate rectal

3 artesunate+ amodiaquine tablets

3 artesunate+sulfadoxine+pyrimethamine tablets

1 Dihydroartemesinine/piperaquine phosphate tablets

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TBTBAs of 2005:

TB products:

7 products only:

tub_suppliers.pdf

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WHO Prequalification WHO Prequalification Project-withdrawalsProject-withdrawals

Withdrawals from of products because of :

non-compliant with international standards of Good Clinical Practice and Good Laboratory Practice

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WHO Prequalification WHO Prequalification Project-withdrawalsProject-withdrawals

WHO's advice to countries is that, in principle, patients should suspend the use of de-listed medicines and switch to other prequalified products.

The risk of withholding treatment is higher than that of providing medicines whose bioequivalence is not proven but which have demonstrated quality and safety. A switch to non-prequalified products is not recommended, as their quality has not been documented by WHO.

However, if it is difficult to obtain alternative prequalified products immediately, it is recommended that patients continue the use of de-listed products.

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Quality Control (QC)

• Part of quality assurance• Testing to confirm compliance with

specification• QC useful in monitoring product quality during

storage/distribution/use• Screening for Counterfeit medicines

• Quality needs to be built into a product during design, formulation and manufacture

• Can not “test quality into a product”

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Product Selection

Procurement

Storage/distribution

Use

Prod.Specs.

Prequalification

Tender contract

GSP,GDP


QAStorage/handling


GMP, licensing

Evaluation of product dossier

QCQC

QC

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QC of “new” ARVsQC of “new” ARVsWHO Monographs:

•Didanosine

•Indinavir sulfate

•Nelfinavir mesilate

•Nevirapinhe

•Ritonavir

•Saquinavir

•Saquinavir mesilate

WHO Draft monographs for comment:

•Stavudine

•Lamuvidine

•Nelfinavir mesilate tablets

•Nelfinavir mesilate oral; powder

• Saquinavir mesilate capsules

The Int. Chem. Ref substances required for the monograph for Didanosine and Nevirapine are available. Those required for the other monographs are in preparation and notification will be given (on this website) when they are available

http://www.who.int/medicines/library/qsm/IntPharmARV/QAS_124_Lamivudine_monograph.pdf

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Counterfeit ARVsCounterfeit ARVs

• Information Exchange System• Alert No. 110• Counterfeit triple antiretroviral

combination product (Ginovir 3D)• zidovudine (200 mg), lamivudine (150 mg)

and indinavir (40 mg).• detected in Côte d’Ivoire

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WHO Definition of a counterfeit medicine

• A product that is deliberately and fraudulently mislabeled with respect to source and/or identity. Counterfeiting can apply to both generic and branded products. Counterfeit products may include:– products with the correct ingredients– with wrong ingredients– without ingredients– with incorrect quantities of active ingredients– with fake packaging

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Counterfeit malaria medicines

• Recent reports of counterfeit antimalarials :– Chloroquine– Quinine– Sulphadoxine-pyrimethamine (Fansidar TM)– Metakelfin TM

– Mefloquine– Halofantrine– Primaquine– Artesunate– Intramuscular artemether– Dihydroartemisinin ?

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Fake artesunate in mainland SE Asia 2000-1

• 38 % of shop bought artesunate counterfeit, containing no active drug

Paul Newton, Welcome Foundation

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Repeat artesunate survey 2002-3• In the same areas, by Dondorp et al.• 188 artesunate samples• 58 % ‘artesunate’ blisterpacks contained no

artesunate. All labelled as made by ‘Guilin Pharma’

• 9 % of mefloquine was substandard and probably fake

• No counterfeit artesunate injection or oral artemether, dihydroartemisinin were found

Paul Newton, Welcome Foundation

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Genuine Hologram Fake Artesunate Type 2

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Rapid Alert System on Rapid Alert System on combating counterfeit drugscombating counterfeit drugs

http://218.111.249.28/ras

http://218.111.249.28/ras

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Rapid Alert System• Information System for reported cases• Repository of reports and response data• Alert mechanism enhancing process flow• Platform for communication & collaboration

Objectives:• To transmit alerts on counterfeit medicines• Support professional assessment• Improve national & international smart partnership & networking• Reduce the incidence of counterfeit medicines• Increase awareness of the problems

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Conclusion - Quality can be assured Conclusion - Quality can be assured through: through:

Prequalification of products/manufacturers

WHO Prequalification Project

Prior registration in countries with stringent regulatory authority

National Registration by DRA (fast track)

Maintaining product quality through:

Proper storage (GSP)

Proper distribution (GDP), dispensing and use

Monitoring of quality through out the distribution chain

1 qa /qc including issues related to gf policies and prequalification :general principles truls...

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procurement quality

limitedsource product

supply management slide

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multisource products

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global funds policies

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