Regulatory Capacity Building and

Accelerating Approvals of prequalified products

PQT Annual Quality Training Workshop

Copenhagen, May 2016

Rutendo Kuwana,

Technical Officer WHO Prequalification Team, Medicines Technical Assistance and Laboratories 1

Overview

• Capacity building and technical assistance • Initiatives to accelerate national registration of

prequalified products • PQT in quality assurance of prequalified products

2

WHO PQT Regulatory Capacity Building

Objectives Strengthening of regulatory functions of recipient and source-country NMRAs to; • Provide suitable regulatory oversight (dossiers and GMP) • Facilitate accelerated approvals of PQd medicines • Reliable quality monitoring

PQT builds capacity in general: – PQT technical expertise is used in support of capacity building of

regulators, quality control laboratories and manufacturers – WHO/PQT standards and PQT example support strengthening of

regulatory systems and manufacturing capacity

Focus on regulators in: – Recipient Countries of PQd medicines – Major producing countries without stringent regulatory oversight. – Other countries with specific needs

Key capacity building approaches

Training activities

Technical assistance & consultancy

Provision of information, standards and regulatory

expertise

Seminars and workshops • General: PQ procedures and WHO requirements • Technical, to reflect identified needs, e.g.:

− Product specific: HIV/AIDS, TB, antimalarial or RH products − Pharmaceutical development/paediatric dosage forms − Quality of APIs, Stability testing − Manufacture of sterile medicines − Bioequivalence testing and GCP − Dissolution and water determination, microbiological testing, HPLC

analyses, quality management system

Training Individualized and collective (seminars and workshops

• Training of regulators integrated into core PQT activities – NMRA assessors in PQ assessment Teams

– NMRA inspectors in PQ inspections Teams

– NMRAs professionals in quality monitoring of medicines

– Rotations of assessors and inspectors from NMRAs

– Joint problem solving

– Joint assessments

– Collaborative registrations

– Informal training audits of manufacturers, QCLs and CROs

Technical assistance • Provision of expert consultants to

– Manufacturers – Quality control laboratories

• Assistance focuses on – GMP, GCP or GLP compliance – Data development and compilation of

dossier Technical assistance is separated from the

assessments and inspections 8

Technical assistance to applicants

9

Conditions for provision of technical assistance

Manufacturers: • Participation in the Prequalification of Medicines

Programme • Capable and willing to improve • Located in a developing country Products: • Inclusion in the EOIs • High public health value • Poorly represented in the prequalified list.

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Accelerating Registration of WHO prequalified and SRA approved products

Cutting the regulatory burden to Access to Medicines

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Source http://www.rsapharmaceuticallistservices.com

9-16 Years 1-2 years Generics Introduction

Pharmaceutical Product Life Cycle

Regulatory approval times in Africa after approval by ‘stringent regulatory authority’ (data collected by Gates Foundation)

Source: Gates Foundation Regulatory Strategy Study (2009-2012) 13

Generics 6 months to 6 years!

Strategies used to cope with increasing regulatory demands

• Concentration on priority issues most relevant for public health

• Benefiting from information available from trusted parties

• Co-operation with partners in order to increase regulatory capacity

– Facilitated by use of comparable standards and administrative requirements

– Co-operation can be formal or informal

WHO-PQT collaborative registration process

Key PQT Objectives in information sharing

• Need to facilitate availability of WHO

prequalified medicines by acceleration of national registrations

• Provide assurance that nationally registered medicine is the same as prequalified

• Propose a model for regulatory co-operation and information sharing

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• Voluntary for manufacturers and NMRAs.

• Should not interfere with national decision making process and registration fees.

• Interested NMRAs sign confidentiality undertaking

• NMRA strive to register in 90 days.

• Product and registration dossier in countries 'the same' as approved by PQT.

• WHO-PQT shares with regulators detailed outcomes of its assessment and inspections to support their decision making in exchange for accelerated registration process.

• 'Harmonized product status' is monitored and maintained.

Principles of WHO Collaborative Procedure

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• Decide on use of the process for individual products

• Conclude differently from WHO PQT - if justified. – Recognize – Verify – Organize Risk Based second review and

inspections – Consider PQT reports in own decision making – Use as quality assurance of national assessment

and decision

Options for participating regulators

Manufacturer informs PQT about national submission and

gives consent with information sharing

Participating NMRA confirms its interest to participate in procedure for specific product

PQT shares with participating NMRA outcomes of assessment and inspections

Participating NMRA reviews WHO PQT outcomes, decides within 90 days decides upon the national registration and informs PQT about its decision

Steps of the procedure: registration

PQ product is submitted for national registration to NMRA participating in the procedure

NMRA is informed about the interest to follow PQT

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Steps of the procedure: post-registration

PQT informs NMRAs about important variations

NMRAs inform PQT about variations and decisions leading to inconsistency with PQT conditions

WHO PQT informs NMRA about withdrawals, suspensions or de-listings

of prequalified medicinal products

NMRAs inform PQT about national de-registration

Variations

De-registrations and de-listings

Win-win outcomes for all stakeholders (1)

• Manufacturers – Harmonized data for PQ and national

registration – Facilitated interaction with NMRAs in

assessment and inspections – Accelerated and more predictable registration – Easier post-registration maintenance

• Procurers

– Faster start of procurement and wider availability of PQ medicines

– Assurance about 'the same' medicine as is prequalified (website)

Win-win outcomes for all stakeholders (2)

NMRAs – Having data well organized in CTD – Availability of WHO assessment and inspection outcomes to

support national decisions and save internal capacities – Having assurance about registration of 'the same' medicine as

is prequalified – or understanding the deviations – Quality control by same methods and specifications – Easier post-registration maintenance – Demonstrating NMRA efficiency – Opportunity to learn from PQT assessors and inspectors – Having a model process for mutual co-operation

WHO – Prequalified medicines are faster available to patients – Feed-back on WHO prequalification outcomes

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Participating NMRAs

One or more medicines registered One or more submissions pending No submissions yet

As at 1 March 2016

0 10 20 30

Nigeria (May-13)Zambia (Jul-14)

Zimbabwe (Nov-12)Mali (Feb-16)

Botswana (May-14)Tanzania (Oct-13)Namibia (May-13)

Ghana (May-13)Ethiopia (Apr-14)Ukraine (Jan-14)Uganda (Nov-12)

Philippines (Jan-16)Mozambique (Apr-15)

Malawi (Sep-15)Kenya (Dec-12)

DRC (Feb-16)Madagascar (Jan-15)Kyrgyzstan (Sep-14)Cameroon (Jan-15)

Burkina Faso (Dec-14)Senegal (Jul-15)

Côte d'Ivoire (Feb-16)

Registered: 110Pending: 85

Pipeline of applications in countries

No products registered or in-process yet: Armenia, Burundi, Georgia, Sierra Leone, Zanzibar

As at 1 March 2016

Country (when started): submissions

Growing acceptance by manufacturers and NMRAs

50

22

20

17

1

Therapeutic categories of registered medicines

HIV/AIDS

TB

Malaria

Reprod.HealthNeglectedTrop. Dis.

15

36

56

3 6 12 14 2

0

10

20

30

40

50

60

2013 2014 2015 2016

Registrations Countries

As at 1 March 2016

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Time to registration (2013-2015, n=107)

Including regulatory time and applicant time

26

13

22 20

5

9

5 3 2 2 1 0 0 1 0 1 0 0

5

10

15

20

25

30

Regi

stra

tions

Time to registration (days) As at 1 March 2016

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Revision of the Procedure – Some steps of the process improved based on accumulated

experience – Extension of the process to Vaccines approved by the WHO Expert

Committees

– Analogous process considered for in vitro diagnostics

Similar model of the procedure piloted to facilitate registrations of medicines approved by SRAs – Applicable both for innovators and generics – Process constructed in collaboration with associations of industry,

relevant SRAs and companies

http://www.who.int/prequal/info_applicants/collaborative_registration.htm

Recent developments

Collaborative registrations of medicines approved by SRAs

Process and supporting documents

– Agreed between WHO PQT and IFPMA

– Upon manufacturer & SRA agreement, manufacturer to share detailed outcomes of full assessment and inspection reports with the National Medicines Regulatory Authorities (NMRAs)

– Submission of a Common Technical Document (CTD) dossier adapted for collaborative registrations

– NMRAs strive to provide approval within 90 days

– WHO to facilitate the process between all parties

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Collaborative registration of ‘SRA’ approved medicines Pilot scheme

+ + +

• EMA as a reference authority agreement to be SRA reference country for pilot (Q4 2014)

• 11 NRAs involved to date

• Geographical spread of participating NRAs: ZAZIBONA + DRC, EAC & French speaking Africa

• Submissions synchronized in two different waves

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Phase I of Pilot Process

3 MOS.

Namibia Granted

within 90-day target

MOS. 4 Cote d’Ivoire

Positive opinion granted within 4 mos. + 1 mo.

MA granted MOS. 7 Botswana &

Burkina Faso Granted in

approx. 7 mos.

MOS. 6 Kenya &

Tanzania Granted in approx. 6

mos.

Phase I of Pilot Process (Cont’d)

Approvals

MOS. 10.5 Zimbabwe

Granted in approx. 10.5

mos.

MOS. 9.5 Zambia

Granted in approx. 9.5

mos.

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Pilot Phase II

• Bedaquiline Fumarate 100mg tablets (Sirturo) - Janssen, EMA as a reference authority)

9 participating countries – Burundi, Cameroon, Ethiopia, Ghana, Kenya, Nigeria, Rwanda, Tanzania and Uganda

• Pyronaridine tetraphosphate/artesunate 180/60mg tablets (Pyramax) - Shin-poon, reference to EMA - Art 58

• Medroxyprogesterone acetate (DMPA) suspension 104mg/0.65ml in blister for injection (Sayana Press) - Pfizer, MHRA (UK) as reference authority)

WHO PQT Facilitated Work-sharing

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Zazibona – ‘look to the future’

Initiative Pilot of collaborative registration procedure in

four mutually co-operating regulatory authorities

Zambia, Zimbabwe, Botswana and Namibia

Testing the applicability of collaboration in exchange of assessment and inspection reports on generic medicines (not submitted for WHO-PQT) among NMRAs in participating countries

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Zazibona - perspective

Regulatory collaboration in exchange of assessment and inspection reports • to reduce regulatory workload • to accelerate registrations of needed products • to develop mutual confidence in regulatory

collaboration • to test the mechanism of co-operation among

regulatory authorities for potential use by others • to improve information sharing and/or networking

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Agreed steps

• Agreement of HoA backed by MoH on pilot of mutual collaboration and HoA interaction

• Quarterly meetings of assessors to support AR sharing and develop experience

• BE (comparator, sourcing, BW) and stability conditions

• DMFs, pharmacopoeias, product information, communication platform

• Meeting with inspectors to agree on exchange of inspection reports and inspection planning

• Regular interaction among assessors, inspectors and HoA to cultivate joint work

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Zazibona Process Flow

Application

OK Rapporteur

Screening OK

AR + 1 LoQ from

rapporteur

discussion

1cLoQ + national Q

assessment

Response time 1

2cLoQ + national Q

Response time 2

discussion

Zazibona position

Registration decisions

Feedback on final

registrations

Proposed position

AR + 2 LoQ from

rapporteur

Final AR from rapporteur

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Outcomes • Harmonized assessment criteria and documents,

suggestions for harmonization of guidelines • Defined a worksharing process with max 180 days

Zazibona regulatory time

• Worksharing results: – 61 primary consolidated assessment reports – 55 AR ready for sharing with others – 9 positive opinions - 6 products registered in approx 9

months – 10 withdrawals and 7 rejections (BE not demonstrated)

– 38 pending positions waiting for applicant´s response

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Prequalification of QCLs • Established in 2004 (WHO, UNICEF, UNAIDS, UNFPA, UNITAID,

supported by World Bank) - for QC laboratories in Africa only

• 3rd EOI published in September 2007 (amended 2011) – Without regional limitation – http://apps.who.int/prequal/info_applicants/eoi/EOI-

QCLabsV3rev1.pdf

• Scope - chemical and microbiological testing (including LAL test) of medicines (vaccines, biologicals or toxicological tests not included)

• Voluntary – Any laboratory (private or governmental) can participate – Free of charge

• Priority to – National QC laboratories and laboratories providing testing

services to the government – QC laboratories in areas where UN agencies identify the need for

quality testing

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40 Prequalified QCL (April 2016) • Africa • South Africa, RIIP+CENQAM (2005) • Algeria, LNCPP (2005) • South Africa, Adcock Ingram (2007) • Kenya, NQCL (2008) • Kenya, MEDS (2009) • Tanzania, TFDA (2011) • Zimbabwe, MCAZ (2014) • Uganda, NDA QCL (2015)

• Americas • Canada, K.A.B.S. Laboratories (2010) • Peru, CNCC (2010) • Uruguay, CCCM (2010) • Bolivia, CONCAMYT (2010) • Brazil, FUNED (2011) • Mexico, CCAYAC (2013) • Brazil, INCQS (2014)

• South-East Asia • India, Vimta Labs (2008) • India, SGS (2011) • Thailand, BDN (2012) • India, Stabicon (2013) • India (IPL) (2015)

• Europe • France, CHMP (2008) • Ukraine, CLQCM (2010) • Ukraine, LPA (2010) • Belgium, SGS (2011) • Netherlands, Proxy (2011) • Portugal, INFARMED (2011) • Russia-Moscow, FSBI (2012) • Belarus, RCAL (2012) • Portugal, Laboratorios Basi (2013) • Russia-Rostov on Don, FSBI (2014) • Germany, InphA (2014) • Netherlands, Synergy Health Utrecht

(2014) • Switzerland, Intertek (2014) • Belgium (SCM-DGO 2015) • Ukraine SSRL (2016)

• Eastern Mediterranean • Morocco, LNCM (2008) • Pakistan, Getz Pharma (2014) • Iran FDCL (2016)

• Western Pacific • Vietnam, NIDQC (2008) • Singapore, TÜV (2009) • China, NIFDC (2012)

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Geographical Spread - 80 QCLs

Status Laboratory

Type

AFRO

AMRO

EMRO

EURO

SEARO

WPRO

Total

Prequalified

National 5 6 1 7 2 2 23

Commercial 3 1 1 7 3 1 16

Sub-Total 8 7 2 14 5 3 39

In Process

National 17 3 7 3 1 1 32

Commercial 4 1 1 1 2 0 9

Sub-Total 21 4 8 4 3 1 41

Combined

Total 29 11 10 18 8 4 80

% Prequalified 28% 64% 20% 78% 63% 75% 49%

% National 76% 82% 80% 56% 38% 75% 69%

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Pipeline QCLs - AFRO Laboratory Reference

Year of Application

Years since application

Technical Assistance Provided

Benin - LNCQM 2006 9 0 Burkina Faso - LNSP 2006 9 1 Cameroon - LANACOME 2005 11 2 Cote d'Ivoire - LNSP 2006 9 0 Ethiopia - DQC+TL 2005 11 3 Ethiopia - JuLaDQ 2013 2 n/a Ghana - CePAT 2014 2 n/a Ghana - FDA QCL 2005 11 1 Guinea - LNCQM 2006 9 0 Madagascar - AMM-LCQM 2005 11 3 Mali - LNS 2004 11 0 Mauritania - LNCQM 2013 2 1 Mozambique - LNCQM 2010 6 0 Namibia-NMRC-QSL 2011 5 2 Niger - LANSPEX 2006 9 0 Nigeria - NAFDAC QCL 2014 2 1 Senegal - LNCM 2004 11 0 Seychelles - NDQCL 2013 2 0 Tanzania - MUHAS 2012 3 n/a Uganda - Chemiphar 2011 4 n/a Zambia - ZAMRA QCL 2013 2 1

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QCL Technical Assistance Peer Audit Scheme

• Established 2015 • Peer evaluation process amongst NQCLs using WHO

norms and standards as a basic requirement. • Capacity building process for QCLs which aim to be

prequalified

• train auditors from both prequalified and pipeline laboratories

So Far • 4 conducted in 2015 (Ghana, Armenia,

Nigeria and Madagascar) • 2 conducted so far in 2016 (Egypt, Zambia).

Planned for 2016 – Not less than 5

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How it works • Participation is voluntary. • Audits performed only in national QCLs that

applied for PQ. • Auditors from national, university/NGO and/or

independent commercial QCLs, either prequalified or undergoing the WHO prequalification procedure.

• An audit team of 3-4 persons, with at least; – 1 expert appointed by WHO – 1 staff-auditor from a prequalified QCL – 1 staff-auditor from a QCL in PQ pipeline

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Current Quality Monitoring Surveys

• HIV/AIDS medicines quality survey - started Q3 2015. Samples from 5 countries (Burkina Faso, RD Congo, Nigeria, Rwanda and Zambia). Testing ongoing.

• Anti-Malarials quality survey - starting 2016. Protocol under development to include generation of spectral library (NIR and Raman) for FPP.

Contact PQT Technical Assistance and

Laboratories

Dr Milan Smid smidm@who.int Mr Rutendo Kuwana kuwanaru@who.int