PREQUALIFICATION General overview and procedures and practical implications of WHO PQ, FDA registration, registration with PICs member countries for procurement.

PREQUALIFICATIONGeneral overview and procedures

and practical implications of WHO PQ, FDA registration, registration with PICs member countries for procurement agencies

involved in procurement

Maija Hietava M.Sci.Pharm

Quality Assurance and Safety: Medicines, Medicines Policy and Standards, Health Technology and Pharmaceuticals Cluster

Tel: +41.22.791.3598 Fax: +41.22.791.4730World Health Organization

E-mail: [email protected]

Technical Briefing Seminar for Consultants on Procurement and Supply Management

for HIV/AIDS, TB and MalariaOrganized by WHO and AMDS Network

Copenhagen, Denmark 31 January 2006

2WHO - PSM

Department of Medicines Policy and Standards

Prequalification of essential medicines

The UN prequalification program is an action plan for expanding

access for the hardest hit by

HIV/AIDS

Tuberculosis

Malaria

for ensuring quality, efficacy and safety of medicines all the way

through the medicines supply chain.

3WHO - PSM


Why the prequalification is needed

Problems• Millions of people living with HIV/AIDS, tuberculosis and

malaria, have no or limited access to treatment• Procurement and supply of substandard and counterfeit

products in different countries• Weak/absent QA systems of medicines supply chain• Lot of money invested in procurement

no harmonized quality assurance system available for procurement organizations

Risks• Sourcing of poor quality products or even counterfeit

medicines risk to patients, treatment failure, resistance

4WHO - PSM


Challenges of prequalification

Demand for affordable antiretrovirals, anti-malaria drugs and anti-tuberculosis drugs is increasing

Numerous generic manufacturers offering products Challenges for UN family and procurement

agencies/organizations

5WHO - PSM


Substandard drugs is a big problem - antibiotics, antimalarials, antituberculosis antiretrovirals drugs included

Incorrect amount

17%

No active ingredient

60%Other errors7%

Incorrect ingredient

16%Percentage breakdown of data on 325 cases of substandard drugs - reported from around the world to WHO database

Is quality of pharmaceuticals a problem?

6WHO - PSM


Prequalification basic principles

Voluntary for participating manufacturers Legitimate - General procedure and standards approved through

WHO Expert Committee system involving all WHO Member States and WHO Governing bodies

Widely discussed • FIP Congress, Nice 2002 • Supported by ICDRA in 2002 and 2004, representing more than

100 national drug regulatory authorities Transparent (all significant information available on the web site

http://mednet3.who.int/prequal/ ) Open to both innovators and multisource/generic manufacturers No cost for applicants during pilot phase

7WHO - PSM


Expected outcome of prequalification

List of products and manufacturers/CROs• Meeting international norms and standards on quality, safety, and

efficacy (Q, S & E) Harmonization

• Co-operation, training, capacity building – NDRAs, WHO, NGOs Facilitate access to treatment

• Procurement mechanisms (e.g. tender, competition)• Ongoing monitoring of Quality, Safety & Efficacy • WHO commitment to developing

8WHO - PSM


Objectives

Propose a list of prequalified manufacturers and products of which the quality, efficacy and safety have been assessed, inspected and controlled to meet international norms and standards.

Gives assurance that international norms and standards are applied at all the steps of the prequalification and at the process itself.

Make possible and speed up access to good quality of medicines. Fast track process for listing can take as little as two months from the date of application.

9WHO - PSM


Objectives cont…

Follow-up and regular monitoring of the quality of manufacturers and products

Ensure re-qualification and update of the list of prequalified products and manufacturers as new products and manufacturers meet the standards

Ensure the appropriate control of variations and changes Develop the local capacity for quality production and clinical

studies. National regulatory authorities (DRA) are involved in dossier

assessment and inspections Producers receive invaluable specific technical feedback

Help the national DRA to build up capacity in assessment, inspection and control meeting international norms and standards

10WHO - PSM


How prequalification is organized Role of WHO: Managing and organizing the project on behalf of the

United Nations. • provide technical and scientific support and • guarantee that international norms and standards are applied all through the

process including assessment, inspection (GMP, GCP/GLP) and quality control Partners:

• UNICEF, UN Population Fund (UNFPA), UNAIDS and with the support of the World Bank

• Anti-malarial and anti-TB products: Roll Back Malaria and Stop TB (Global Drug Facility)

• US FDA tentative approvals – recognition based on information exchange (Confidentiality agreement)

Actors: Mainly assessors and inspectors of National DRAs as well as

National Quality Control Laboratories of PIC/S and ICH member countries

11WHO - PSM


Steps of prequalification

1. Expression of interest (EOI) from a prospective supplier interested in a voluntary participation in the program.

2. Receipt of the dossier at UNICEF in Copenhagen and the Site Master File in WHO Geneva. Explicative notes and guidelines are published on the WEB in

order to explain how to bring together a product dossier meeting the requirements for prequalification.

3. Screening of the dossier, "Quality" part, "Clinical" part and samples. possible inspection

4. Assessment of the dossier and writing of the assessment report and assessment letter.

5. Outcome of the evaluation communicated to supplier

12WHO - PSM


Steps of prequalification cont…

6.Inspection of the site (s) of manufacturing and follow-up inspection when necessary GMP compliant list of manufacturers

7.Inspection of the Research Laboratory or Contract Research Laboratory (CRO) where the bioequivalence study has been performed GCP compliant list of CROs

8.Conclusion and listing of the product in the prequalification list

9.Publication of the Public Assessment (WHOPAR) and Inspection (WHOPIR) Reports

10.Assessment of the variation when submitted, market survey, de-listing if necessary

11.Re-qualification after 3 years

13WHO - PSM


Assessment procedure Assessment of products dossiers

i.e. quality, specifications, pharmaceutical development, bioequivalence etc. • teams of professionals from national drug regulatory authorities (DRA):

Brazil, Canada, Denmark, Estonia, Finland, France, Germany, Hungary, Indonesia, Malaysia, Philippines, Spain, South-Africa, Sweden, Switzerland, Tanzania, Zimbabwe ...

• Copenhagen assessment week– 8 to 12 assessors together during one week at least every two

months at UNICEF in Copenhagen– Every dossier is assessed by at least two assessors. – An assessment report is issued; signed by two assessors– Letter summarizing the findings and asking for clarification and

additional data if necessary.• Letter is sent first by e-mail to the applicant followed by surface

mail

14WHO - PSM


Assessment procedure-Product dossiers

Innovator products• Assessment report from DRAs• WHO Certificate of Pharmaceutical Product (CPP)• Batch certificate• Update on changes.

Multisource products (generics)• Full dossier with data and information• Quality : information on starting materials and finished product including

API details, specifications, stability data, formulation, manufacturing method, packaging, labelling etc

• Efficacy: Bio-equivalence study or clinical study report• US FDA tentative approvals – recognition based on information

exchange (Confidentiality agreement)

Commercial sample

15WHO - PSM


Inspection procedure

Inspections Manufacturing site (FPP, packaging) Active pharmaceutical ingredient (API) Research laboratory/Contract Research Organization (CRO) Teamwork of inspectors

• WHO representative (qualified GMP inspector)• Inspector from well-established inspectorate (Pharmaceutical

Inspection Convention Scheme PIC/S countries)• National inspector(s): Canada, India, China, France, Italy,

Switzerland, South-Africa, Thailand…Quality control analysis - upon need but not always necessarily beforeprequalification and supply; increasingly as part of follow-up

16WHO - PSM


Prequalification of quality control laboratories

To increase the local capacity to control the quality of pharmaceutical products

Quality Control Laboratories in sub Saharan Africa as priority WHO norms and standards for QC laboratories Prequalification process

• Expression of Interest (EOI)• Laboratory Information File (LIF), evaluation• Inventory Audit – help/evaluate• Inspection with the team of inspectors• Prequalified laboratories list public in WHO web site (2 listed)• Reassessment system

17WHO - PSM


Training activities

In 2005 three comprehensive 5-day training courses on quality, GMP and BE for TB drugs and ARVs (Malaysia, China, Ukraine)

Course on quality, GMP and BE planned for Jan-06 (China)

Two GMP training courses for NDRA inspectors (South-Africa, China)

Recent GMP training course in Tanzania (with PQ participation)

Training of QC lab officials

Training of PQ staff and inspectors working for WHO in BE study inspections (January-February -06)

18WHO - PSM


Current status – December 2005

Started with HIV/AIDS products in 2001 – malaria and TB products joined later

Prequalified products (Dec 2005) Dossiers arrived • 105 HIV related medicines - 316 (Aug-05) 343 (Dec -05)• 8 anti-tuberculosis medicines - 156 165• 2 anti-malarial medicines - 48 49• 115 520 557

Ongoing assessments and follow-up• Products• Manufacturing sites • CROs

19WHO - PSM


Current status – Manufacturers of finished products

In the prequalification list: 15 sites of generics

Asia: 9 sites Europe: 4 sites Africa: 2 sites

20WHO - PSM


Ongoing monitoring and requalification

Samples taken after supply Routine inspections and additional inspections Changes and variations controlled

• Products and manufacturers Requalification (re-assessment) every 3 years World Health Assembly resolution: WHA57.14 of May 2004

Public reports requested• WHOPIRs (WHO Public inspection report) and WHOPARs (WHO Public

Assessment Report) are now on the prequalification web site• Increasing interest in WHO Public Inspection Reports (WHOPIR)

21WHO - PSM


PQ web site information for procurement

List of prequalified products List of manufacturers of manufacturers for APIs (Active

Pharmaceutical Ingredient) and FFPs (Finished Pharmaceutical Product), which are GMP compliant

List of GCP compliant Contract Research Organisations (CROs), bio-equivalence centers and research laboratories, which are GCP/GLP compliant

WHOPIRs (WHO Public Inspection Report) WHOPARs (WHO Public Assessment Report)

22WHO - PSM


Global Fund Quality assurance policy related to procurement

Practical implications of FDA registration, registration with PICs member countries for procurement

Grant funds to procure products meeting following standards (A) such product is acceptable under the WHO Prequalification Program; or (B) such product has been authorized for use by a stringent regulatory authority, FDA tentative

approvals; > 2 manufacturers option A or B applies AND the product is available (conditions defined) (C)* If the Principal Recipient determines that there is only one or no (< 2) equivalent

pharmaceutical product that meets the standards of either (A) or (B) or if the Principal Recipient determines that the products that meet these standards are unavailable (Defined as inability of the manufacturer to supply a sufficient quantity of finished product within 90 days from date of order), then Grant funds may be used to procure another equivalent pharmaceutical product, provided that such product is selected in accordance with the following, in order of priority:

Application submitted to the WHO Prequalification Program or to a stringent regulatory authority and product manufactured at a GMP compliant site; or

Product manufactured at the GMP compliant site (WHO or ICH or PIC/S**) (Random quality analysis of products being procured according to these criteria)

*(C) UNTIL 30 APRIL 2005: approval by the NDRA of the recipient country. ** ICH or PIC/S countries: see next slide

23WHO - PSM


New Policy, Global Fund

2 Equivalent products

Number of equivalent

products under option (a) or (b)

Recommendation

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

IF NOT, THEN

(ii) Manufactured in a GMP-compliant

manufacturing facility

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)

24WHO - PSM


Global Fund Quality assurance policy related to procurement

Practical implications of FDA registration, registration with PICs member countries for procurement

Access to a list of countries that belong to ICH or PIC/S:

http://www.theglobalfund.org/pdf/guidelines/List_of_Countries_ICH_PICS.pdf

25WHO - PSM


Countries with "stringent" regulatory authorities

PIC/S= Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme participating regulatory authorities (www.picscheme.org)

Australia Austria Belgium Canada Czech Republic Denmark Finland France Germany Greece Hungary Iceland Ireland Italy Latvia Liechtenstein Malaysia Netherlands Norway

Poland Portugal Romania Singapore Slovak Republic Spain Sweden Switzerland United Kingdom

ICH = International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use participating regulatory authorities (www.ich.org )

European Union* Japan United States

* Members include: Austria, Belgium, Cyprus, Czech Republic, Denmark, Estonia, Finland, France, Germany, Greece, Hungary, Ireland, Italy, Latvia, Lithuania, Luxembourg, Malta, Poland, Slovakia, Slovenia, Spain, Sweden, The Netherlands, United Kingdom

26WHO - PSM


Important about Quality of Pharmaceutical Products

Building in the quality

Starts during development phase documented evidence during the product life cycle that product used in bioequivalence studies (sometimes pilot batches) is the same as the marketed product (big production batches)

Reliable regulatory system and control for stability studies and product variations during the life cycle of a product (if changes are not controlled systematically, there could be a significant change during the product life cycle); capacity problems at the regulatory side

27WHO - PSM


Important in the regulatory assessment of GENERIC pharmaceuticals

There are requirements especially for Generics (requirements have not been harmonised yet)

Bioequivalence studies (not always a requirement as such)

Bioequivalence (guidance not harmonised yet)

Variations = changes in the product that may have effect on quality (not always strictly followed or controlled)

Stability studies (not always strictly followed or controlled)

Requirements are controlled by the authorities (capacity problems!)

And…..

28WHO - PSM


Important in the PQ process related to Quality and Efficacy

Dossier evaluation and Inspections (GMP = manufacturing and GCP for bioequivalence studies)

Go hand in hand in the PQ process

Sometimes "GMP compliance" alone does not tell the whole truth!!

Dossier assessment

InspectionsGMP/GCP

29WHO - PSM


This is misleading and/or misunderstood

WHO type certificate (by WHO Certification Scheme) is used worldwide

But it is not WHO certificate

GMP compliance??

National GMP requirements are not always those of WHO or stringent authority requirements

Does not tell everything about the product

30WHO - PSM


!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!This is correct!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!!

WHO Prequalification does not give GMP/GCP certificates, but the GMP/GCP compliant companies are listed in our web site

WHO GMP/GCP

CERTIFICATE

31WHO - PSM


Recent news and new challenges

2005 changes in GFTAM procurement policy – challenges for prequalification

Confidentiality Agreement with the US FDA

Recognition of US FDA tentative approval process for ARVs based on the scientific assessment done by FDA

Additional fields of cooperation with European Directorate of the Quality Medicines (responsible for European Pharmacopoeia)

Jointly funded post established with UNICEF to help managing the assessment weeks in Copenhagen from Sept 2005

Constant upgrading guidelines and guidance documents increasing workload

Building of the Quality system

Resources for 2006/2007

32WHO - PSM


Summary and conclusion

Good news; quality of generics exists Relatively large number of products and suppliers comply with the standards Many potential suppliers appreciating feedback and willing to improve Unique technical knowledge obtained of products, especially generic antiretrovirals

and antimalarials

Bad news: quality assurance has the price Only limited number of products have met the required standards Takes time to get into compliance

• Data to be generated, tests carried out• GMP upgrade needed

Bad quality generics may undermine the public confidence in generics

33WHO - PSM


Summary and conclusion CONT…

However… REMEMBER

Quality can not be assessed, tested or inspected into the product, BUT

has to be

built into the product

in all the steps …

development phase, production, QC, BE study etc. with the help of guidelines, regulatory requirements etc.!!

More technical help to manufacturers in developing countries is needed!!

34WHO - PSM


Summary and conclusion CONT…

No more poor quality medicines for poor people!

Equitable access to good quality, safe and effective medicines for all!

35WHO - PSM


http://mednet3.who.int/prequal/

36WHO - PSM


THANK YOU VERY MUCH FOR

YOUR ATTENTION!!

PREQUALIFICATION General overview and procedures and practical implications of WHO PQ, FDA registration, registration with PICs member countries for procurement.

Documents

safety of medicines

standards substandard

counterfeit medicines

treatment procurement

procurement organizations

prequalification program

quality of pharmaceuticals

resistance slide