Prequalification of RH medicines

WORKSHOP ON QUALITY ASSURANCE OF REPRODUCTIVE HEALTH
MEDICINES IN ETHIOPIA
Addis Ababa, Ethiopia, 12-13 June 2014
Elilly Hotel, Addis Ababa, Ethiopia
Wondiyfraw Z. Worku
Technical Officer, Prequalification Programme- Medicines, WHO
1
WHO Prequalification of RH medicines and
collaborative registration
2
Outline
 Introduction
 Objectives/outputs
 Prequalification process
 Collaboration
 Key achievements
 Challenges
3
WHO Prequalification
 A United Nations Programme managed
by WHO
Prequalification of medicines
Prequalification of vaccines
Prequalification of diagnostics
 The three product streams have recently
been merged to achieve synergies
4
Prequalification of Medicines
 Started in March 2001 as a Pilot Project: Focus on HIV/AIDS
 Partners included WHO, UNICEF, UNFPA, UNAIDS and
supported by World Bank
 Quickly expanded to include Tuberculosis, Malaria,
Reproductive Health, Influenza and others
 Funded by donors – mainly UNITAID and Bill and Melinda
Gates Foundation
5
Prequalification of Medicines - Objectives
 Contributing to achievement of Millennium
Development Goals (MDG) 4, 5 and 6 through
 Contribution to the United Nations priority goal of addressing
widespread diseases in countries with limited access to
quality medicines
 In cooperation with National Regulatory Agencies and
partner organizations, make quality priority medicines
available for the benefit of those in need
6
Therapeutic areas
 Therapeutic areas invited are:
HIV/AIDS
Malaria
Tuberculosis
Reproductive Health (RH)
Influenza
Acute diarrhoea in children (zinc)
Neglected Tropical Diseases (NTDs)
 Potentially other categories of products, if there is the need
7
RH products on the current EOI (5th)…
 Implantable contraceptives:
 two-rod levonorgestrel-releasing implant, each rod containing 75 mg of
levonorgestrel (150 mg in total); etonogestrel, implant, 68 mg of
etonogestrel
 Oxytocics:
 oxytocin, injection 10 IU, 1-ml; mifepristone 200 mg tablet (only to be
used in combination with misoprostol) ; misoprostol 200 microgram tablet
 Prevention and treatment of eclampsia:
 magnesium sulphate, injection 500 mg/ml, in 2-ml and 10 ml ampoule
8
RH products on the current EOI (5th)
 Oral hormonal contraceptives:
 Ethinylestradiol/desogestrel 30 µg/ 150µg tablets;
Ethinylestradiol/levonorgestrel 30 µg/150 µg tablets; levonorgestrel 30µg
tablets; levonorgestrel 750 µg tablets (pack of 2), 1.50 mg tablets (pack of
1); norethisterone 350µg tablets; norgestrel 75µg tabs
 Injectable hormonal contraceptives:
 medroxyprogesterone acetate, depot injection 150 mg/ml, in 1-ml vial;
medroxyprogesterone acetate/estradiol cypionate 25 mg/5 mg injection;
norethisterone enanthate, injection 200 mg; norethisterone
enanthate/estradiol valerate 50 mg/5 mg, injection
9
Why prequalify medicines?
 Quality needs to be built into the product, not be tested in.
 Provide quality products for UN procurement, but also other partners
(Global Fund, interested NGOs and country procurement).
 Lack of well established drug regulatory systems (50% have varying capacity
and level of development, 30% minimal or limited regulation)
 Increasing demand for generics, several players, substandard products on
the market
 Lack of quality assured medicines can have serious consequences – e.g.
ineffective treatment, drug resistance, side effects etc
10
RH Medicines- some potential issues
 Oral contraceptives
 Potent- very low content per tablet- potential content uniformity problems - requires extra
vigilance in control of in put materials and manufacturing processes
 Low soluble APIs- BE necessary
 Some of the APIs (e.g. EE) are moisture sensitive
 Injectable contraceptives
 Sterile products- pose greater manufacturing and safety risk
 Suspensions- content uniformity, resuspendability /syringeability- pose greater manufacturing
challenge
 Oily injections- pose greater manufacturing challenge
 Oxytocics
 Sterile products- Oxytocin
 Stability issues- Oxytocin
 Stability and content uniformity issues- Misoprosol tablets
11
RH Medicines- some potential issues…
• Manufacturers' storage conditions for Oxytocin inj
 Samples from 15 manufacturers
•
•
•
•
•
3x 2-8ºC
1x 2-15ºC
7x below 20/25/30ºC
1x above 0ºC
3x not available
Effective regulatory and QA system is essential to ensure that RH
and other medical products are of appropriate quality and
safe/effective.
12
Oxytocin quality survey-Ghana- PQM, USP
13
Key outputs

Published list of prequalified medicinal products (FPPs)
 Used principally by UN agencies, including UNFPA, UNAIDS and
UNICEF, and any other agency or organization involved in bulk
purchasing of medicines, to guide their procurement decisions

Published list of prequalified APIs
 Can be used by FPP manufacturers to assure the quality of APIs
 Can be used by NMRAs who wish to verify the standard of APIs that
have been used to manufacture nationally registered medicines

Published list of prequalified QC laboratories
 The list may be used by any organization to ensure that testing for
quality monitoring is done to an acceptable standard
14
PQP vs national approval procedures
15

Only certain therapeutic areas/products are invited in PQ

PQ is voluntary

Not a national marketing authorisation (but some countries may use
it for this purpose).

Fees introduced on 1 Sept 2013 (for new dossiers, major variations)

Assessments and inspections done by multinational teams

Assessment and inspection outcomes are publicly available
(WHOPARs and WHOPIRs)

Technical assistance and regulatory support possible
Prequalification process
Expression
of Interest
Assessment
Product dossier
+ SMF
Inspections
Additional information
and data
Corrective
actions
Acceptable
Compliance
Prequalification
Maintenance and monitoring
16
Screening
 Confirmation of eligibility (listed on the EOI)
 Review of data in the Application Forms and Dossiers
- Mainly a qualitative review to confirm presence of data
- Some selected quantitative checks done e.g. duration of
stability studies, number of batches used etc.
 Ensure Administrative and Technical Completeness
 A screening checklist is used.
17
Dossier assessments
 Quality and Efficacy/safety parts of dossier assessed in
parallel (usually bioequivalence data)
 Several rounds of communication with applicants
 API section of dossier can be supported by prequalified API,
CEP, APIMF or full API data.
 QA step at the end of the assessment process
 Product listed (prequalified) once all requirements are met
and Letter of prequalification issued to applicant.
18
Dossier assessments…
 WHO, ICH and specific PQP guidelines and the International
Pharmacopoeia/recognized pharmacopoeias are applied:
 Guideline on Preparation of product dossiers (PDs) in Common
Technical Document (CTD) Format
 Guideline on submission of documentation for a multisource
(generic) finished pharmaceutical product (FPP): Quality part
 All the relevant guidelines and forms published on WHO
PQP web site
 Maintenance (variations, requalification) done in-house and
during assessment sessions
19
Administration of dossier assessments



20
Assessors
 In-house and external (90%), mostly from SRAs (subject to
availability). Total assessor pool 50+.
Assessment sessions every 2 months in Copenhagen for 5 days
 Dossiers are assessed by at least 2 assessors (Q and BE
separate), each report is reviewed by a more senior assessor;
≈35 assessors/session.
 Assessors from developing countries constitute ≈ 40%
 A unique opportunity for assessors from all over the world to
work together
 Frequent manufacturer meetings and Teleconferences
Assessments in-between sessions (WHO HQ)
Inspections
 The evaluation of a medicine for prequalification includes
inspection of FPP and API manufacturing sites, and
CROs, i.e. no dossier, no inspection
 Inspections conducted by an SRA are taken into account
when planning inspections
 WHO reserves the right to inspect all manufacturers and
clinical sites listed in a product dossier - to assess
compliance with WHO GMP, GCP and GLP
 The need for inspections of API sites and CROs are
decided on a case by case risk basis.
21
Inspections…
 Inspections are conducted by a team
 A WHO inspector leads the team
 A co-inspector from another Regulatory Authority
(usually a PIC/S member)
 An inspector from NMRA of the country of manufacture
is invited as observer (host country).
 Inspectors from developing countries may be included
in the team as observers for training purposes
(potential recipient of PQ products)
22
Number of inspections performed 2005-2013
23
Prequalification of SRA approved products
(innovator or generic)
 Assessment and inspections by a stringent regulatory
authority (SRA) are recognised
 SRAs are 1) ICH member, 2) ICH observer or 3) RA
associated with an ICH member through a legally binding,
mutual recognition agreement.
 Abbreviated process for prequalifying medicines approved
by an SRA (no duplication)
 Variations handled by the SRA
 Also limited to defined priority medicines (EOIs)
24
Products prequalified 2007- 2013
70
60
NTD
Diarrhea
Influenza
RH
Malaria
TB
HIV
50
40
30
20
10
0
2007
25
2008
2009
2010
2011
2012
2013
Prequalified medicines as at 31 December
2013
- Prequalified generics and innovators
as of December 31 2013: 371 products
- Total listed as of December 31 2013
(including those listed based on
USFDA-PEPFAR/EMA Article 58/HC
approvals): 472 products
Countries that have submitted and had products prequalified: Belgium (6); Canada (16), China (11);
France (16); Germany (8); Greece (6); Hungary (1); Iceland (2); India (222); Japan (1), Kenya (1);
Republic of Korea (1); Latvia (1); Netherlands (8); Pakistan (1); Romania (7); Russia (1), South Africa
(9); Spain (7); Switzerland (17); United Kingdom (31); USA (3); Zimbabwe (2).
Countries of manufacture of prequalified products: Australia; Belgium; Canada; China; Finland;
France; Germany; Hungary; India; Italy; Kenya; Korea; Latvia; Morocco; Netherlands; Pakistan;
Romania, Russia, South Africa; Spain; Switzerland; Uganda; United Kingdom, USA; Zimbabwe.
26
Status of RH Prequalification as of May 2014
1.
Oral hormonal contraceptives
Ethinylestradiol + desogestrel, tablet 30 micrograms +150 micrograms
Ethinylestradiol + levonorgestrel, tablet 30 micrograms + 150 micrograms
Levonorgestrel, tablet 30 micrograms
Levonorgestrel, tablet 750 micrograms (pack of two)
Levonorgestrel, tablet 1.5 mg (pack of one)
Norethisterone, tablet 350 micrograms
Norgestrel, tablet 75 micrograms
Number of
individual FPPs
prequalified
4
6
1
3
1
2
0
Number of individual FPPs
under assessment
0
0
0
0
1
0
0
2. Injectable hormonal contraceptives
Medroxyprogesterone acetate, depot injection 150 mg/ml, in 1-ml vial
Medroxyprogesterone acetate + estradiol cypronate, injection 25 mg + 5 mg
Norethisterone enanthate, injection 200 mg
Norethisterone enanthate + estradiol valerate, injection 50 mg + 5 mg
1
0
1
0
0
0
0
0
1
1
2
0
0
0
1
1
0
1
0
0
3. Implantable contraceptives
Two-rod levonorgestrel-releasing implant, each rod containing 75 mg of
levonorgestrel (150 mg in total)
Etonogestrel, implant, 68 mg of etonogestrel
4. Oxytocics
Oxytocin, injection 10 IU, 1-ml
Mifepristone, 200 mg tablet (only to be used in combination with misoprostol)
Misoprostol, 200 microgram tablet
5. Prevention and treatment of eclampsia
Magnesium sulphate, injection 500 mg/ml, in 2-ml and 10 ml ampoule
27
Why the low numbers of PQ RH products?
 Rigorous GMP requirements - separate, dedicated
facilities for RH products; should be classified as
containment facilities (minimise risk of exposure, crosscontamination). Safety issues.
 Few API/FPP suppliers with SRA experience
 Lack of incentives from procurers
 Need for BE studies (low water solubility APIs)
 PQP has introduced accelerated procedure for accepting
RH product dossiers since March 2012
28
PQP - Transparency
 Product pipeline (FPPs) on PQP website
 WHOPARs and WHOPIRs (where found to be
compliant) are published on the PQP website in
response to a World Health Assembly resolution
(2004)
 Notices of Concern or Notices of Suspension may
be issued and published if there are serious noncompliances requiring urgent attention
29
Products under assessment (on website)
30
QCLs Prequalification Procedure
 Established in 2004 - for QC laboratories in Africa only
 3rd Invitation for Expression of Interest published in September
2007 (current)
Without regional limitation
 Scope - chemical and microbiological testing of medicines (vaccines,
biologicals not included)
 Participation of a QC laboratory is voluntary
Any laboratory (private or governmental) can participate
Free of charge
 Priority in the assessment is given 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
31
Potential benefits of PQ for QCLs
 Possibility to provide testing services to UN agencies and
other organizations - financial profit
 Recognition as being WHO listed laboratory
 Facilitated discussions with manufacturers/customers in case
of non-compliant results
 Learning process improving the standards of laboratory work
 In case of national QCLs of a developing country, possibility
to be assisted by WHO expert consultants and participate in
WHO organized trainings
32
Prequalified/interested QCLs
(31 December 2013)
33
33
Extensive collaboration:
working with regulators … for regulators
 PQP is recognizing work done by stringent regulatory authorities
 Prequalification of SRA approved innovators and generic products – abridged
procedure
 US FDA tentative approvals (PEPFAR) – PQ list (USFDA PARs)
 European Medicines Agency (EMA) – Art 58 - PQ list
 Canadian access to medicines regime (CAMR) – PQ list
 PQP is recognizing PIC/S, EU and USFDA inspection reports
 PQP assessments and inspections include SRA, PIC/S and dev country NMRA experts
 International API inspection collaboration (USFDA, EMA, TGA, EU, EDQM)
 Joint inspections (EMA, EDQM, MHRA, USFDA, ANSM etc). Joint inspections with EAC
since 2010
 Collaboration in handling GMP related crises (SRAs, dev country NMRAs)
34
New activities in WHO to facilitate access to
quality medicines
 African Medicines Registration Harmonization Initiative (AMRHI) –
pilot in East Africa (EAC) – several partners, WHO providing
technical support (assessments/ registration, GMP, IMS, QMS)
 Joint assessment WHO PQT-EAC (Kenya, Tanzania, Zanzibar,
Uganda, Rwanda and Burundi)
• Prequalification and national registration as close as possible in
time (successful pilot in 2010 with times to national registration
reduced by 50% in EAC countries). Another joint assessment
being concluded, involving 2 RH products.
 Collaborative registration procedure (accelerated registration pilot
project; started June 2012)
 Joint inspections (with EAC since 2010)
35
Collaborative registration of Prequalified products
in countries
 PQD generic products are expected to be registered in the recipient
countries
 In order to facilitate timely registration at the country level, WHO has
issued a procedure where by national agencies can access full
assessment and inspection reports as written by WHO assessors and
inspectors (instead of repeating full assessment at the national level)
 Requires certain obligations on part of WHO, Applicant Company and
National agency.
 The national agency is free to make their own decision on registration
 It is voluntary
36
WHO Collaborative registration procedure
 Procedure drafted with wide consultation and adopted by WHO Expert
Committee in October 2012. Approved by WHO Executive Board in May
2013.
 Pilot testing ongoing from June 2012 with currently 18 NMRAs
participating
•
•
•
•
•
•
•
•
37
Armenia
Botswana
Ethiopia
Ghana
Georgia
Kenya
Kyrgyzstan
Madagascar
•
•
•
•
•
•
•
•
•
Malawi
Mozambique
Namibia
Nigeria
Tanzania (incl. Zanzibar)
Uganda
Ukraine
Zambia
Zimbabwe
Steps: NMRA agreement
Interested NMRAs agree
to participate in the procedure
and designate focal persons
PQP lists interested NMRAs
on its website and gives focal
persons access to
restricted-access website
38
Steps: Registration
NMRA and PQP informed about the applicant’s
interest to follow this specific procedure
Prequalified product dossier is submitted to NMRA
Applicant informs PQP about national submission
and
gives consent to information sharing
NMRA confirms its interest to participate in
the procedure for this specific product
PQP shares assessment and inspection
reports with NMRA (within 30 days from
request)
NMRA reviews PQP material and decides within 90
days on national registration and informs PQP about
its decision (copy to applicant)
39
Steps: Post registration
Variations
PQP informs NMRAs
about important variations
NMRAs inform PQP about
variations and decisions leading to
inconsistency with PQP conditions
De-registrations and de-listings
WHO PQP informs NMRA about
withdrawals, suspensions or de-listings
of prequalified medicinal products
40
NMRAs inform PQP about
national de-registration
Collaborative registration procedure – as of 29 April
2014
 20 submission completed
 Covering 14 products all produced in India (9 ARVs, 1 RH, 3 Malaria, 1 TB)
registered in 7 countries (Zimbabwe, Namibia, Kenya, Ghana, Nigeria,
Tanzania and Uganda),
 8 submissions completed within 60 days, another 8 in < 90 days,
 Pilot shows accelerated national registration is possible
 To become regular PQP procedure soon
41
Capacity building- NMRA

Seminars and workshops
 General – PQP procedures and WHO requirements
 Annual PQP assessment training
 Problem or product specific ; HIV/AIDS, TB, antimalarial or RH products
 Pharmaceutical development/paediatric dosage forms
 Training of NRA staff and manufacturers frequently combined
 International experts frequently involved
 Support is given to training organized by others
 Focus on "training of trainers“

Within the assessment/inspection process, advisory meetings, review of protocols

“Inclusive” (assessments, inspections), 3-month rotational post at WHO HQ (n=20;
Zimbabwe, Uganda, Tanzania, Ethiopia, Kenya, Ukraine, Zambia, Botswana, Ghana,
DR Congo, China)

Technical assistance to eligible manufacturers
42
Technical assistance- Manufacturers
 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
43
Technical assistance to applicants 2006 to 2013
 More than 140 technical assistance missions have been
organized and delivered
44
Challenges
 Funding
 Mainly donor funded (UNITAID and Bill and Melinda Gates foundation)
 Recently started charging nominal fees
 Quality of submissions
 Most PQ applicants are located outside of SRA countries
• Less experienced applicants (some are SRA naive)
– Require repeated rounds of assessment and inspection
– The need for technical assistance
 Lack of applications for certain invited medicines
 Lack of incentive to manufacturers
45
web site: http://www.who.int/prequal/
46
Further information:
http://www.who.int/prequal/
Email: [email protected]
47
Thank you
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