PQP-overview & update January 2011 1 Prequalification of Medicines Overview & update Wondiyfraw Z. Worku WHO Prequalification of Medicines Programme Assessors.

PQP-overview & update January 20111

Prequalification of Medicines Overview & update

Wondiyfraw Z. Worku

WHO Prequalification of Medicines Programme

Assessors training, Copenhagen

January 2011


Agenda

• PQP and its activities• Paths towards prequalification• PQ process flow • Some numbers and achievements• Our future and challenges• Summary


UN Prequalification Programme for Priority Essential Medicines

• A UN action plan since 2001 to expand access to priority essential medicines for– HIV, Malaria, TB, – RH, selected Influenza products and Zinc products for Acute

diarrhoea

• To ensure quality, safety and efficacy of medicines procured using international funds– Propose a list of prequalified products and manufacturers

meeting international norms and standards



– Also since recently, to propose list of prequalified APIs and their manufacturers

– Ensure that international norms and standards are applied at all the steps of the Prequalification Programme.

• Help the national medicine regulatory authorities to build up capacity in assessment, inspection and quality control meeting international norms and standards.

• Develop local possibilities of manufacturing and clinical studies by offering customized technical assistance.



• Principally for generic products • Similar programmes run by WHO:

– Prequalification of Vaccines• http://www.who.int/immunization_standards/vaccine_quality/pq_system/en/index.html

– Prequalification of diagnostic products• http://www.who.int/diagnostics_laboratory/evaluations/en/

http://www.who.int/immunization_standards/vaccine_quality/pq_system/en/index.html


Why PQ?

• Many of the UN and other procurement agencies lack sufficient means to ensure safety, efficacy and quality of procured medicines and other medical items.

• Many of the receiving and exporting countries do not have/did not have well established regulatory system.

• Increasing demand for generic medicines-several players- substandard products– A number of reports on sub standard Anti Tb and Malaria

products

• Need for common-international standard.


Similarities with NMRAs

• Like NMRAs, the prequalification programme performs

- Dossier assessments

- Inspections

- Quality control testing (mostly through post approval sampling)

- Also post approval pharmacovigilance activities (through sister units within EMP/QSM)


Differences from NMRAs

• Priority therapeutic areas• Assessments and inspections by international experts• Marketing authorization is not issued.• Prequalification of APIs• Prequalification of quality control laboratories• Provides technical assistance to applicants• No fees


Prequalification activities• Prequalification of medicinal products and APIs

– Review of quality and safety/efficacy documentation– Inspection of manufacturing sites and CROs

• Prequalification of quality control laboratories– To identify suitable laboratories for quality testing of products

procured using international funds– Also for quality survey of products

• Technical assistance and capacity building– Help manufacturers to meet dossier and GMP requirements– To build capacity of national medicine regulatory authorities


Organogram

Program Manager

Head :Inspections

Head: Dossier assessments

LiaisonQuality Control

Technical Assistance

Inspector AssessorInspector Assessor

Admin Support


Paths for inclusion of a product in the list of prequalified products

• Prequalification of multisource generic products – Full review and inspection by PQP

• Prequalification of innovators– Approval based on marketing authorization issued by an NMRA in

ICH region and associated countries

• Prequalification of generic products approved by SRA– Approval based on SRA marketing authorization– For established generic products

• Recognition of temporary approvals / scientific opinions – USFDA PEPFAR approval/tentative approval– EMA article 58– Hcnda Access programme


The assessment process• Coordinated by Dr. Matthias Stahl,

– Quality assessors

– BE assessors

– Clinical assessors

– Support staff

• Six full time in-house and one rotational assessor. • More than 50 temporary advisors (pool of external

assessors)• Six sessions per annum (every other month) here in

CPH. • More than 30 assessors per session.


International standards for prequalification

• Primarily WHO guidance documents and standards – PQ main generic and variation guidelines– The WHO Bioequivalence and bio waiver guidelines– The WHO Stability guideline– International Pharmacopoeia– WHO GMP and GCP Guidelines

• ICH guidelines • Other guides issued by SRAs such as USFDA and EMA• Other recognized pharmacopoeias

– BP, EP, JP, USP


Process flowApplication for prequalificationDossier, Samples & SMF

ScreeningApplicant

GMP

Review of GMP Certification,

Inspection reports, Site Master Files (SMF).

Informationrequested

Application accepted for assessment

Assessment

Accepted Accepted

Applicant

ManufacturerInspection

Corrective and preventative actions

Final decision on prequalification

Listing on WHO website

VariationsComplaints

Random samplingRequalification



Expression of interest (EOI)

WHOPIR

WHOPAR


Invitation for Expression of interest (EOI)

• A list of medicines invited for prequalification– Priority public health medicines – We can only accept product dossiers for medicines included in

this list

• List prepared by WHO clinical experts (HIV, TB, Malaria, RH, Influenza, Zinc) – Based on inclusion in treatment guidelines and/or WHO model

list of essential medicines

• Revised as needed to capture new developments


WHOPAR and WHOPIR

• PQ transparency – As per WHA Resolution WHA57.14, dated 22 May 2004 – Also the pipeline (dossier status sheet)

• WHOPAR– Assessment history– Discussion on the review outcomes– Approved SmPC, PIL and labels– Prepared by team of experts (Clinical, BE and Quality assessors)

• WHOPIR– For FPP, API, CRO and QC lab inspections – Scope and dates of inspection– Summary of observations and findings– Conclusion


Variations

• Part of the prequalification status maintenance activity• To ensure that changes will not negatively impact the

product in terms of quality, safety and efficacy• Guideline primary based on the EU guide

– Discussions ongoing on possible revision

• Mostly handled by in-house assessors– Growing activity as the number of prequalified products has

increased– Time lines shortened


Requalification

• Every 5 years or when requested, as per PQ procedure• Guideline adopted by the WHO Expert Committee in

2009• Verification of acceptability of the product in terms of

– current norms and standards– consistency of the product quality

• First set of products have been identified and applicants are requested to submit the necessary data


Prequalification of APIs• Procedure approved by the WHO Expert Committee in 2009

– Separate from the APIMF procedure• GMP compliance is mandatory• Does not require submission of the corresponding FPP dossier• A separate list of prequalified APIs and their manufacturers will be posted on our

website– Same guideline- PQ Generic guide

• Launched in October 2010 (as pilot programme)– Initially for those APIs for which we already have approved APIMFs– Will soon be expanded to invite other APIs included in our EOI

• Expected to be of importance to NMRAs and procurement agencies


Major achievements in 2010

• Revision of our main guideline for multi source generic products– To harmonize requirements and formats with other regulators

(adoption of CTD)– To provide further details to requirements– Revision of development, process validation and stability

requirements for prequalification

• Growing number of PhInt monographs • Improvement in internal handling of variations• High number of prequalified products despite declining

submission


Major Achievements 2010, contd• Undertook manufacturer survey • First manufacturers meeting took place in July 2010 • Studies to determine the value of PQ to manufacturers (ongoing)• Joint assessment of one HIV and one second line TB product

dossiers with EAC countries – Capacity building and promotion of regional harmonization– Facilitating national registration– No duplication of efforts– Incentive for manufacturers

• Two products manufactured by Varichem were prequalified


List of products included in WHO prequalified products list

Prequalified products

75%

12%

7% 3% 3%HIV

TBMalaria

RHInfleunza

• Prequalified generics and innovators as of December 31st 2010: 252 products (assessed and inspected by PQ)• Total listed as of December 31st 2010 (including those listed based on USFDA/EMA/HCnda approvals): 350 products

0

5

10

15

20

25

30

35

40

45

50

2007 2008 2009 2010

HIV TB Malaria RH Influenza USFDA


Inspections

0

5

10

15

20

25

30

35

2005 2006 2007 2008 2009 2010

FPP

API

CRO

QCL


Prequalified / interested quality control laboratories

83

10

3

16

3

22

8

24

11

29

17

30

0

5

10

15

20

25

30

35

40

45

50

2004 2005 2006 2007 2008 2009 2010

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) Kenya, MEDS (2009) Singapore, HSA (2009) Singapore, TÜV (2009) Canada, K.A.B.S.

Laboratories (2010) Ukraine, CLQCM (2010) Ukraine, LPA (2010) Peru, CNCC (2010) Uruguay, CCCM (2010) Bolivia, CONCAMYT

(2010)


Quality survey of Antimalarial medicines in Sub-Saharan Africa

2010

• To evaluate quality of ACTs and Sulfadoxine/Pyrimethamine

• Cameroon, Ethiopia, Ghana, Kenya, Nigeria, Tanzania

• To estimate quality at different points of the distribution system

• To identify possible causes for any findings

• To propose possible strategies and implementation plans to address the problems identified by the study


Collected samples by products935 samples

516

26

1 1185

327

362

30Artemether/LumefantrineArtesunate/AmodiaquineDihydroartemisinin/Piperaquine PhArtemisinin/Piperaquine PhArtemisinin/Naphthoquine PhArtesunate/MefloquineArtesunate+SPP

Artesunate+SP

Sulfadoxine/PyrimethamineSulfamethoxypyrazine/ Pyrimethamine


Results

3

80

73

111

2

68

12

12

1

12

17

7

0%

20%

40%

60%

80%

100%

PQ total Non-PQtotal

AL PQ AL non-PQ

A&A co-pPQ

A&A co-pnon-PQ

Non-compliant Compliant

83 samples of PQ products

– AL (Novartis, Ajanta, Ipca)

– A&A co-pack (Cipla, Guilin, Ipca)


Quality survey of anti TB medicines

• Armenia, Azerbaijan, Belarus, Kazakhstan, Ukraine, Uzbekistan– Countries with high multidrug-resistant and extensively drug-

resistant TB

• Rifampicin caps, Isoniazid tabl/inj, Rifampicin/Isoniazid tablets, Kanamycin inj powder, Ofloxacin tabl/infusion


9

45

15

17

43

1

41 67

6

32

2 12

0%

20%

40%

60%

80%

100%

Non-compliant Compliant

Results

291 samples from 33 manufacturers and 90 sampling sites


Results continued

• 38 samples of WHO-prequalified products

• Isoniazid/Rifampicin tablets– 75/150mg, Lupin India (18), Sandoz Private India (17)– 30/60mg (2) and 60/60mg (1) Macleods Pharmaceuticals India

• None of WHO-prequalified products failed to comply with specifications


Technical assistance to applicants

• More than 60 technical assistance missions have been organized and delivered

213

210

3

8 7

21

14

4

8

0

5

10

15

20

25

30

2006 2007 2008 2009 2010

Technical assistances organized by PQP

REG

GPCL

GCP

GMP


Trainings

• More than 65 trainings have been delivered

4

9

4

11

4

12

5

16

4

0

2

4

6

8

10

12

14

16

18

20

2006 2007 2008 2009 2010

Trainings organized or supported by PQP

PQP supported

PQP organized


Trainings (contd)

• More than 3130 assessors, inspectors and manufacturers have been trained

165

198

10357

263

301

568

396

282

4944

793

203

130

73

0

200

400

600

800

1000

1200

2007 2008 2009 2010

Participants in trainings organized or co-organized/supported by PQP

Others

QCL staff

Regulators

Manufacturers


Rotational post within WHO PQP team

• A full time P3 position, on rotational basis (one participant every three months)

• A unique arrangement for assessors from national medicine regulatory authorities (developing countries)

• Opportunity for further development in regulatory skills and exposure to the WHO Medicines area of work

• Several assessors from Ethiopia, Kenya, Tanzania, Uganda, Zimbabwe, Zambia and Ukraine have participated.


The future

• Additional therapeutic areas may be included• Prequalification of API continued• Requalification continued• Revision of our variation guide• Continue with capacity building and harmonization

activities including joint assessments• Continue with our technical assistance missions


Challenges• Declining number of submissions• Slow progress with respect to RH, TB and Malaria

dossiers• Increasing demand vs limited capacities

– Additional therapeutic areas– Prequalification of APIs– Additional support to procurement agencies (risk assessment for interim

procurement decisions)

• Increasing demand for technical assistance– From initial dossier compilation to prequalification– GMP compliance


Info rich & user friendly website

• Notice of concerns & related info

• Prequalification lists

• Procedures & Guidelines

• Prequalification of APIs

• Inspection info • Trainings and

meetings• Public

assessment and inspection reports

www.who.int/prequal

http://www.who.int/prequal


Summary• Prequalification of priority essential medicines

– Promoting access to safe, effective and quality medicines– Prequalification of APIs and – Prequalification of quality control laboratories– Provides technical assistance to applicants– NMRAs capacity building

• International standards are applied• Assessment and inspections by international experts• Mainly for multisource generics and innovator products approved

in ICH region • Has issued a revised CTD based guideline for multisource

pharmaceutical products– Can serve as resource document for NMRAs

• Active participation in regional regulatory harmonization efforts – Joint assessments

• Complete information on the web, transparent– www.who.int/prequal

http://www.who.int/prequal


Thank you

PQP-overview & update January 2011 1 Prequalification of Medicines Overview & update Wondiyfraw Z. Worku WHO Prequalification of Medicines Programme Assessors.

Documents

prequalification programme

pqpoverview update

quality of procured

priority essential medicines

prequalification pq

efficacy of medicines

generic medicines

agenda pqp