1. WHO Technical Briefing Seminar
03 – 07 November 2014
WHO Prequalification Team – Need and contribution
Wednesday, 5 November 2014
13:35 – 15:45
Lembit Rägo, EMP/RHT
Acting Coordinator,
WHO Prequalification Team
Presented by
Deusdedit K. Mubangizi
Group Leader, Inspections
WHO Expert Committee on Specifications, Oct 2010

2. Role of PQT – towards MDGs Reorganisation of PQ Programmes
WHO Prequalification Team: Programme for Priority Health products and Technologies
In this presentation:
Role of PQT – towards MDGs
Reorganisation of PQ Programmes
How PQT works - operating principles
Selected focus on few areas:
Inspections
Prequalification of QCLs
Collaborative registration of WHO-PQ products
Capacity building
Frequent misunderstandings about WHO-PQ
Selected outcomes/achievements
WHO Expert Committee on Specifications, Oct 2010

3. WHO Prequalification Programme for Priority Health products and Technologies
Action plan of UN for expanding access to selected priority medicines
Objective
To ensure quality, efficacy and safety of Health products and Technologies procured using international funds (e.g. GFTAM, UNITAID, UNICEF) to serve patients in developing countries
Components
Evaluation of Quality, Safety and Efficacy of prioritised Health products and Technologies, inspections of manufacturers and monitoring of the products after their prequalification
Prequalification of quality control laboratories
Building capacity of regulators, manufacturers and quality control laboratories

4. WHO-PQ contributes to the Millennium Development Goals (MDGs):
Eight international development goals that 192 United Nations member states and at least 23 international organizations have agreed to achieve by the year 2015
Reduce child mortality
Improve maternal Health
Combat HIV/AIDs, Malaria and other diseases
WHO Expert Committee on Specifications, Oct 2010

5. Role of WHO prequalification
Facilitate access to safe, appropriate priority diagnostics, medicines & vaccines
Support two of WHO's six core functions:
setting norms & standard/promoting their implementation
providing technical support, catalysing change & building institutional capacity.
Contribute to achieving four of WHO's impact goals:
reduce under-five mortality
reduce maternal mortality
reduce the number of people dying from AIDS, tuberculosis and malaria
eradicate polio.

6. Reorganization: single PQ programme for further impact & restructured regulatory units
Consolidated prequalification programme aiming at:
Enhanced management & operations
e.g. quality management system
e.g. administrative efficiencies, incl. financial management
Better relationship with stakeholders
e.g. single voice when dealing with national regulatory authorities
e.g. increased transparency around processes and outcomes
Cross-product stream learning
e.g. extension of ERP process to new product categories
e.g. bigger pool of external experts and testing laboratories
e.g. PQDx benefit from medicines and vaccines experience to improve efficiency
Flexibility
transition business-as-usual PQ activities to NRAs
WHO PQ moves into new therapeutic areas (e.g. non-communicable diseases) and/or new product types (e.g. biologicals)
Improved regulatory support ― pharmacovigilance, norms & standards ―to PQ processes

7. Structure of Department of Essential Medicines & Health Products
Essential Medicines and Health Product [EMP]
Policy, Access and Use [PAU]
Regulation of Medicines and other Health Technologies [RHT]
Technologies Standards and Norms [TSN]
Regulatory Systems Strengthening [RSS]
Prequalification Team [PQT]
Safety and Vigilance [SAV]
Public Health, Innovation and Intellectual Property [PHI]

8. Structure of the Prequalification Team
Coordinator’s office
Vaccines Assessment
Medicines Assessment
Diagnostics Assessment
Inspections
Technical Assistance/Labs
Administrative team

9. How does PQT work? In the short term:
assessing product dossiers,
inspecting manufacturing & testing sites, organizing quality control testing of vaccines & medicines,
evaluating performance of diagnostics & verifying that products are suitable for use in destination countries,
facilitating regulatory approvals
In the medium- and long-term by building capacity of manufacturers & regulators

10. Two routes to medicines prequalification
Invitation for
expression of Interest
Medicine not
assessed by SRA
Medicine assessed
by SRA
Dossier and SMF
submitted for assessment
Valid for innovators and generics
SRA registration
(assessment and
compliance check)
WHO assessment
and inspections
organized
Simplified review
Prequalification
Compliance
Acceptance
WHO Expert Committee on Specifications, Oct 2010

11. Overview of prequalification of diagnostics

12. Steps of the Vx PQ procedure
Official request and response
Meetings with manufacturers
Product summary file (PSF)
Initial testing of vaccine samples
WHO site audits
Report and outcome of the assessment
Principles:
Reliance on the National Regulatory Authority responsible for the regulatory oversight of the vaccine.
Prerequisites:
The National Regulatory Authority responsible for the product is "functional" as per assessment performed using the WHO established indicators.

13. PQT Operating principles
Acts independently
Strives for innovation
e.g. Expert Review Panel (1st for medicines, now for Dx)
e.g. PQ of APIs
e.g. Reducing time to national registration of medicines through joint assessments
e.g. actively advising manufacturers how to develop unique paediatric formulations
e.g. early implementation of BE study waivers for medicines to ease the regulatory burden for manufacturers
e.g. Collaborative registrations for medicines and vaccines
e.g. advisory visits and technical assistance for Dx innovators
Seeks collaboration to enhance impacts, optimize resources, share expertise
e.g. joint assessments and joint inspections with NRAs
e.g. fast-track procedure for diagnostics registered by SRAs
Is pro-active
e.g. assists manufacturers and NMRAs
e.g. monitors needs of stakeholders
Seeks incremental improvements that can be sustained
e.g. reduced timelines to PQ
e.g. continuous process to review and refine technical guidance

14. WHO-PQT-Rx: Target Inspection Timelines
First inspection: 6 months from dossier acceptance for assessment or from site confirms it is ready.
Routine inspection: ± 3 months from due date.
Notification: 1 – 2 months before inspection.
Onsite days: 3 – 5 days.
Report: 30 days from last date of inspection.
CAPAs: 30 days from receipt of report (max 2 rounds, comprehensive, on CDs and not hard copies)
Closing of inspection: 6 months from inspection.
Follow-up inspection: 6 months from inspection
Validity of compliance: 1 to 3 year from inspection date

15. STATISTICS: INSPECTIONS 2013 FPP SITES 34 API SITES 22 CRO SITES 11
17/09/2018
STATISTICS: INSPECTIONS 2013
FPP SITES 34
API SITES 22
CRO SITES 11
QCL SITES 16
TOTAL 83
NEW 32
REINSPECTION 51
COMPLIANT 49
AWAITS CAPAs 12
NOT COMPLIANT
PRE-AUDITS 6
TOAL

16. 17/09/2018
DATE REPORT SENT
Total
2883
Number 81
Average 36
Minimum
Range: 0 – 148 days
Maximum
148
First Quartile, Q1 15
Median, Q2 28
Median: 28 days
Target: 30 days
Third Quartile, Q3
42.5
2013: New Sites
COMPLIANT
AWAITS CAPAs
NOT COMPLIANT
TOTAL
FPP SITES 16 6 1 9
API SITES 7 2 3 23 8 12
2013: Re-inspections
COMPLIANT
AWAITS CAPAs
NOT COMPLIANT
TOTAL
FPP SITES 18 13 5
API SITES 15 6 3 33 8

17. NEW SITES: Days from acceptance to first date of inspection
17/09/2018
NEW SITES: Days from acceptance to first date of inspection
FPP+API
Total
2284
Number 23
Average 99
Minimum 13
Rage: 13 – 263 days
Maximum
263
First Quartile, Q1 33
Median, Q2 87
Median: 87 days
Target: 180 days (6 months)
Third Quartile, Q3
145
FPP
1387 16 27
Range: 27 – 261 days
261
30.75 70
Median: 70 days
127.25
API
897 7
128
Range: 13 – 263 days 69
130
Median: 130 days
189

18. RE-INSPECTIONS: Days from acceptance to first date of inspection
17/09/2018
RE-INSPECTIONS: Days from acceptance to first date of inspection
FPP+API
Total 92
Number 33
Average 3
Minimum
-136
Rage: -136 – 175 days
Maximum
175
First Quartile, Q1
-23
Median, Q2 1
Median: 1 day
Target: 180 days (6 months)
Third Quartile, Q3 27
FPP
-208 18
-12
Range: -136 – 105 days
103
-53 -4
Median: -4 days 26
API
300 15 20
-48
Range: -48 – 175 days -6
Median: 3 days 29

19. Inspections: Worrying Trends
Media is awash with NOCs, warning letters, import alerts, statements of non-compliance, complaints, recalls, etc.
Data integrity and falsification
unbalanced focus on QC (quality built in – not tested in).
« Show-case » and « shadow » industries.
« Knee-jerk » responses to inspection observations.
Many « Awaits CAPAs » on routine inspection:
poor maintenance of quality systems
work hard to pass first inspection and then go on holiday

20. Prequalification of QCLs: Objectives
Increase the access to services of QCLs that
Meet recommended standards for testing of medicines, and
Are committed to test medicines for UN agencies
Contribute to capacity building of national QCLs in developing countries (strengthening of health systems)
Technical assistance
Trainings
Guidelines 20

21. QCL Prequalification procedure
Established in 2004 in cooperation with UN agencies
Procedure published in 2004, revised in 2007 and 2011
Participation of a QC laboratory is voluntary
Any laboratory (private or governmental) can participate
Scope - chemical and microbiological testing (including LAL test) of medicines (vaccines, biologicals not included)
Based on the following principles
Evaluation of information submitted by the laboratory
On site inspection
Monitoring of performance of prequalified laboratory

22. QCL Invitation for Expression of Interest
Previous invitations limited to QC laboratories in Africa, currently no regional limitation
3rd EOI published in September 2007
Priority in the assessment is given to
National QC laboratories and laboratories providing testing services to the governments
QC laboratories in areas where UN agencies identify the need for quality testing

23. QCLs: Steps of the procedure
Expression of interest
Currently free of charge
Submission of laboratory information file
Guidelines for preparing LIF available
Quality Manual can be submitted (amended as necessary)
Evaluation of submitted information
Assessment of laboratory's potential to pass successfully the inspection
Compliance  WHO organizes an inspection
Gaps  For a national QCL in a developing country, WHO may organize a pre-audit/ technical assistance 23

24. QCLs: Steps of the procedure
Site inspection
Planned and coordinated by WHO
2-3 days, external inspectors experienced in QC appointed (preferably from MRA)
Representative of MRA of the country where the QCL is located is invited
Compliance with WHO recommended standards
WHO Good Practices for Pharmaceutical Quality Control Laboratories
WHO Good practices for pharmaceutical microbiology laboratories
WHO Good manufacturing practices – parts relevant to QCLs
Focus on the overall quality system in the laboratory and chemical and microbiological testing, not on individual methods only 24

25. QCLs: Steps of the procedure
Site inspection (cont)
Report communicated to the laboratory
If corrective actions to be taken by the laboratory, final decision is made after their evaluation
Audit report from another authority (e.g. EDQM)
Compliance with WHO standards is evaluated and WHO inspection may not be necessary
ISO accreditation encouraged and considered but does not cover GMP aspects
If compliant, laboratory is included in the published list and WHOPIR is published
Prequalification does not guarantee future contracts for testing for UN agencies, competitive tendering usually organized 25

26. QCLs: Steps of the procedure
Monitoring after prequalification
Re-inspections at a frequency based on risk assessment
At least once every 3 years
Evaluation of results from participation in proficiency testing
WHO External Quality Assurance Scheme (EQAAS), ANSM network of Francophone African countries
Brief report requested to be submitted annually
Summary of services provided to UN agencies, number of analysed samples, methods used, complaints received
Changes with significant impact to the laboratory (key personnel, facility, equipment) and update LIF
WHO may suspend or withdraw a laboratory from the list when there is evidence of noncompliance 26

27. Prequalified/interested QCLs (October 2014)
17/09/2018
Prequalified/interested QCLs (October 2014) 27 27

28. Prequalified QCLs (October 2014)
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)
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)
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)
Eastern Mediterranean
Morocco, LNCM (2008)
Pakistan, Getz Pharma (2014)
Western Pacific
Vietnam, NIDQC (2008)
Singapore, TÜV (2009)
China, NIFDC (2012)

29. QCLs in the procedure – by status
17/09/2018
QCLs in the procedure – by status
(October 2014) 29 29

30. QCLs in the procedure – by region
17/09/2018
QCLs in the procedure – by region
(October 2014) 30 30

31. Capacity building for QCLs
Technical assistance provided to national medicines QCLs in developing countries
46 since 2006 (14 in 2013, 7 in 2014)
Focus on implementation of quality system, microbiology testing/lab design
Training
Training in HPLC (organized with ANSM in March 2013, Tunisia)
6 Workshops on laboratory quality control of reproductive health products (organized with UNFPA in in Tanzania, Namibia, Ghana, Thailand, Fiji, Djibouti)
WHO Interregional Seminar of QCLs involved in Prequalification in South Africa, October 2014 (training focused on observations marked in red)
WHO External Quality Assurance Assessment Scheme (EQAAS) – Dr Sabine Kopp 31

32. 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 on a national QCLs in a developing country, possibility to be assisted by WHO expert consultants and participate in WHO organized trainings

33. Collaborative registration of WHO-prequalified products
To be used, prequalified medicines must be authorised for use (registered) by national regulatory authorities.
In many countries that are recipients of prequalified medicines, regulatory systems are either weak or lack capacity to manage effectively queuing applications, delaying accessibility of essential medicines.
PQT strives to facilitate the process in co-operation with involved manufacturers and regulators.

34. Principles of WHO Collaborative Procedure
Voluntary for manufacturers and NMRAs and does not interfere with national decision making process and regulatory fees
WHO-PQT shares with interested regulators detailed outcomes of its assessment and inspections to support their decision making in exchange for accelerated registration process
Product and registration dossier in countries are 'the same' as approved by PQP. Co-operation among PQ holder (manufacturer), NMRA in interested country and PQT overcomes confidentiality issues, ensures information flow and product identity
'Harmonized product status' is monitored and maintained
Microbiological training, Nov 2011, Jordan

35. Principles of the process1)
Being asked by PQ holder (manufacturer), PQT shares full PQ assessment and inspection outcomes with NMRAs participating in the scheme and provides advice to facilitate national regulatory decisions (registrations, variations, withdrawals).
- Applicable only for medicines assessed/inspected by PQP
PQ holder provides consent with information sharing
Data and product are 'same' as prequalified
- Voluntary for manufacturers and NMRAs and does not interfere with national decision making process and regulatory fees.

36. Principles of the process2)
It is up to discretion of participating NMRAs how to benefit from shared information. However, participating NMRAs commit to adopt registration decision within 90 days from having available full PQP assessment and inspection outcomes. NMRAs have the right to
decline to adopt procedure for individual medicines
decide differently from PQP, but keep PQP informed and clarify reasons for deviation.

37. Principles of the process3)
Communication continues in post-approval period to be assured that product does not 'disconnect' from prequalification status
variations are synchronized
de-listings and/or de-registrations are communicated 4)
Participating NMRAs (countries) and registered products are posted on PQP website

38. 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 PQP
Manufacturer informs PQP about national submission and
gives consent with information sharing
Participating NMRA confirms its interest to participate in procedure for specific product
PQP shares with participating NMRA
outcomes of assessment and inspections
Template documents for each step.
Participating NMRA reviews WHO PQP outcomes, decides within 90 days decides upon the national registration and informs PQP about its decision
Microbiological training, Nov 2011, Jordan

39. Steps of the procedure: post-registration
Variations
NMRAs inform PQP about
variations and decisions leading to
inconsistency with PQP conditions
PQP informs NMRAs
about important variations
Post-PQ and post-registration actions
WHO PQP informs NMRA about
withdrawals, suspensions or de-listings
of prequalified medicinal products
NMRAs inform PQP about
national de-registration

40. Medicines: pilot initiated in June 2012, now operational process
20 participating NMRAs from 19 countries
Africa
Botswana
Burkina Faso
DR Congo
Ethiopia
Ghana
Kenya
Madagascar
Malawi
Mozambique
Namibia
Nigeria
Sierra Leone
Tanzania
Uganda
Zambia
Zanzibar
Zimbabwe
Europe/Asia
Armenia
Georgia
Kyrgyzstan
Ukraine
Microbiological training, Nov 2011, Jordan

41. 38 registrations in 8 countries:
Zimbabwe 9 Nigeria 5
Tanzania 7 Uganda 4
Ghana Kenya 1
Namibia 5 Botswana 1
21 different prequalified products for treatment of HIV/AIDS, TB, malaria and contraceptives
7 companies involved,
6 from India

42. 28 (74%) approved within 4 months 18 (47%) approved within 3 months
Right-click graph, “Edit data” to see full information

43. 72 Expressions of interest received
DID NOT PROCEED:
Registered or advanced through normal route
HA498 Mozambique The product was in advanced stages of being registered
MA078 Ghana No - MCAZ assessment already underway – reviewing additional data; MCAZ offered procedure- Jun/Jul 2013
MA079 Ghana No, MCAZ assessment completed
HA498 Uganda MCAZ assessment completed
TB230 Zimbabwe 8 May: In principle yes - awaiting add'l info from Hetero;
HA153 Zimbabwe National assessment already advanced
HA152 Zimbabwe National assessment already advanced
HA448 Zimbabwe Info from Sultana, 4 Feb 2014: Product already registered by another local applicant
Not on STG
HA508 Zimbabwe Not on national STG
HA508 Uganda Not on national STG
Not as PQd
RH038 Zambia NRA would have agreed to use RH013 shared info, but Famy care decided to follow normal route.
RH013 Zimbabwe Replaced by HA521
RH013* Zimbabwe Stopped clock - Namrata, 7 March 2014: will follow up on resubmission ; No re-application as at 28 Feb 2014; As per L Gwaza status update 22 July: Applicant to resubmit the dossier with same information as prequalified
Not accepted (13): 8 already registered or at advanced stage of normal evaluation; 3 not in line with prequalification data; 2 not in national TG

44. Win-win outcomes for all stakeholders
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
NMRAs
Availability of WHO assessment and inspection outcomes to support national decisions and save internal capacities
Opportunity to learn from PQP assessors and inspectors
Demonstrating NMRA efficiency
Having assurance about registration of 'the same' medicine as is prequalified
Quality control by same methods and specifications
WHO
Prequalified medicines are faster available to patients
Feed-back on WHO prequalification outcomes
Ultimate beneficiaries are patients !!! ……..Improved Access.

45. Outcomes and experience
National registrations are achieved faster
Product and registration dossier in countries are 'the same' as approved by PQP.
'Harmonized product status' is monitored and maintained
Co-operation among PQP holder (manufacturer), NMRA in interested country and PQP is necessary to overcome confidentiality issues, assure information flow and product identity.
Avenue for learning and regulatory collaboration
Success factors:
Effective communication and good administrative practice
Involvement and training of local representatives
Dossiers in line with PQ
Microbiological training, Nov 2011, Jordan

46. Revision of the Procedure and extension to vaccines
New developments
Revision of the Procedure and extension to vaccines
Draft in the first round commented by vaccine manufacturers
Extended pilot for vaccines under preparation
WHO Expert Committees involved
Scheduled meeting with participating countries
Analogous process considered for in vitro diagnostics
Similar model under preparation for facilitated registrations of medicines approved by SRAs
Applicable both for innovators and generics
Process constructed in collaboration with associations of industry, relevant SRAs and companies

47. Capacity building - objectives
Good quality submissions for PQ supported by compliance with "good practices"
platform for improvement of drug development, manufacturing, documentation and quality control
Fast regulatory approvals of PQ medicines in recipient countries
technical education of regulators as a platform for strengthening expertise, regulatory efficiency and networking
Reliable quality monitoring
technical education of staff of QCLs to strengthen expertise, effectiveness of quality monitoring and networking
PQP standards and PQP example support strengthening of regulatory systems and capacity of manufacturers in general
Next we will have a short session on Self-inspection.
We then turn to the topic of Personnel. Personnel should be seen by the pharmaceutical manufacturer as its most valuable resource. It is sometimes its most difficult one to manage. Inspectors need to be sure that there are sufficient human resources, with people who have the correct qualifications and acceptable levels of experience. An important issue for you to check is the conflict of interest that can arise if Quality Control is not properly independent of Production. For this reason a full day is required for this subject.
This will be followed by a half-day session on Equipment. If you would like to have any particular piece of equipment discussed please write its name down and hand it to me at the end of this module. If possible we will discuss the item during the Equipment module.
We shall then spend a full day on Premises. Here we are going to be looking at some of the fundamental issues, including the effect of the external environment, on a company’s ability to manufacture products in the appropriate conditions.
This will be followed by a half-day session on Materials. Experience has shown that many problems arise as a result of the selection of unsuitable or impure materials. Many developing countries have financial constraints that work against using materials of the right quality.

48. Key capacity building approaches
1) Training activities of different set-up
2) Technical
assistance &
consultancy
3) Provision of information,
standards and regulatory
expertise

49. Seminars and workshops
Trainings of NRA staff and manufacturers frequently combined
Microbiological training, Nov 2011, Jordan

51. Selected key outcomes to date
Expanded public health programmes:
e.g. immunization…both vaccines and devices/equipment to support them
e.g. HIV/AIDS treatment programmes (9.7 million in low- and middle-income countries accessing treatment)
Strengthened regulatory systems:
e.g. national capacity to regulate (due to hands-on assessment training, observation of inspections, training workshops)
e.g. harmonized application of standards (due to training, collaborative assessments, accelerated registration)
Quality-assured production of appropriate products:
more manufacturers producing more quality-assured priority products in more low- and middle-income countries
products appropriate for use in low-income settings and/or for specific population groups
Cost of a year’s supply of 1st-line ARVs decreased from more than US$ 10,000 per person in 2000 to less than US$ 100 for the least expensive WHO recommended regimen in 2011, while the cost of today’s most affordable 2nd-line regiment has fallen from its original US$ 1,200 to US$ 300 per person per year.
First PQed vaccine from China in 2013.
Increasing number of PQed APIs and FPPs.

52. Contribution to increased access to quality medicines, for example:
Key achievements
Contribution to increased access to quality medicines, for example:
in 2012, 8 million people living with HIV and in need of treatment were receiving treatment, around 6.5 million of whom were taking WHO-prequalified antiretrovirals (ARVs);
and sales of WHO-prequalified artemisinin-based combination antimalarials exceeded 180 million individual treatment courses in 2010)
UNAIDS. World AIDS Day Report Geneva, UNAIDS, 2012.
WHO. World Malaria Report, Geneva, World Health Organization, 2011.

53. Frequent misunderstandingsNO
Manufacturers/manufacturing sites are prequalified
PQP issues WHO GMP certificates
PQ substitutes national authorization (registration) in recipient countries
Prequalification gives right to succeed in tenders
PQP provides direct financial support
All medicines used in treatment of HIV/AIDS and tropical diseases are invited for PQ
Expert review panel is a substitute to prequalification

54. 谢谢！ HOW TO CONTACT US ధన్యవాదాలు
WHO Expert Committee on Specifications, Oct 2010