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WHO Drug Information Vol. 25, No. 3, 2011 WHO Prequalification of
Ensuring quality medicines: a decade of prequalification
Reflections from A. J. van Zyl, First Programme Manager for the
WHO Prequalification of Medicines Programme In March 2001, United Nations partners operating procedures (SOPs). Prequalifi- initiated a project, managed by the World cation (PQ) was based on existing WHO Health Organization, to facilitate access norms and standards approved by the to quality medicines used in the treat- ECSPP. In those cases where WHO did ment of HIV/AIDS. Partnering with WHO not have guidelines, relevant guidelines were UNICEF, UNAIDS, and UNFPA. The from ICH were used. A web site was also World Bank also supported this project. established to disseminate PQ vision, The first manager for the programme was mission, procedures, guidelines, training appointed by WHO on a six-month con- material, results and information (1).
tract to establish, implement and manage the pilot project. The project was prin- The initial focus was to prequalify medi- cipally funded by donations and grants cines used in the treatment of HIV/ from Member States. AIDS. It was estimated that the number of people needing antiretroviral (ARV) Objectives of the WHO Prequalification of therapy in 2003 was in the range of Medicines Programme (PQP) were to: 100 000 with an ARV therapy coverage of only around 2%. It was further 1. Propose a list of prequalified products estimated that less than 10% of people manufactured in sites that meet WHO in most African countries had access to norms and standards.
ARV treatment (2). Figure 1 shows the number of deaths per 100 000 in the US 2. Follow-up on products and manufactur- population in the period 1982–1993 (3).
ing facilities for quality issues.
3. Ensure that prequalification and update Later on, due to the pressing need for of the original approved list is carried quality medicines in other disease areas, out periodically and that variations and the project was expanded to include changes are correctly controlled.
products used in the treatment of tubercu- losis (TB) and malaria. 4. Assist national drug regulatory autho- rities to build capacity in assessment, Prequalifying medicines is achieved inspection and control of medicines for through an extensive evaluation pro- priority diseases.
cedure that consists of assessment of product data and information that are In designing the project, a quality sys- voluntarily submitted by interested appli- tem was established consisting of a cants and manufacturers expressing their Procedure for Prequalification that was interest to participate in the project. This adopted by the WHO Expert Committee is followed by inspection of manufactur- on Specifications for Pharmaceutical ing and testing sites. No fees have been Preparations (ECSPP), various guide- charged by WHO since the beginning of lines, norms and standards, and standard prequalification but this practice is under WHO Prequalification of Medicines Programme WHO Drug Information Vol. 25, No. 3, 2011 Figure 1: USA deaths per 100 000 population in the period 1982– 1993
National Vital Statistics * Provisional Data review. Sites are inspected to verify data The organization chart in 2011 comprises: submitted in the product dossiers and to assess compliance with WHO good • one PQP manager manufacturing practices (GMP), good clinical practices (GCP) and other appro- • one head of inspections with five in- priate guidelines.
• one head of assessments with seven Reasons for initiating the PQ pilot project was concern about low quality products circulating in the international market, • eight support staff the prevalence of spurious products and • one person each for liaison, capacity also as a result of the recommendation building and training, and sampling and in a report from a group of independ- monitoring (which includes prequalifica- ent experts. The report found that many tion of quality control laboratories). procurement organizations had no, or very limited, quality assurance systems in Expansion of the programme after 2006 place to ensure that good quality products was possible due to the financial support from the Bill & Melinda Gates Foundation. Today, the programme is largely financed by UNITAID but is seeking a broader In terms of staff appointments, the PQP team slowly grew from one manager in 2001 to a manager plus one coordina- External assessor group
tor for assessments and one assistant From the initial one staff member with six during the first two years. One inspector external assessors present at the assess- was seconded from the French medi- ment meeting in June 2001, the group cines regulatory agency in 2003, and in has grown over the past ten years to subsequent years the team expanded to include on average seven internal as- include one manager, a coordinator for sessors and more than 20 external assessments and three inspectors. assessors at a group session. WHO Drug Information Vol. 25, No. 3, 2011 WHO Prequalification of Medicines Programme Complaints on prequalified products Data and specifications are submitted that are received in PQP are logged and and assessed by teams of assessors investigated by the inspectors. Inspec- from national medicines regulatory autho- tors and assessors must comply with the rities and WHO staff. Data and specifi- confidentiality and conflict of interest rules cations include but are not limited to the active pharmaceutical ingredient (API), formulae, manufacturing process, stability Inspectors publish a quarterly newsletter (appropriate packaging and suitable for available on the PQP web site as well the intended market) and bio-equivalence as submitting articles to the WHO Phar- data (for generic products). maceuticals Newsletter and WHO Drug Information (see "Further reading" on Group assessment sessions are held every two months at the UNICEF offices in Copenhagen. Requirements for product data and information have also Field sampling and testing projects have intensified over the years. In 2011, the been carried out by PQP in order to moni- recommendation is that manufacturers tor the quality of medicines (both WHO- should submit a dossier in the common prequalified and non-WHO prequalified) technical document (CTD) format (4–6). procured by UN agencies (8). Through To build capacity in developing countries, cooperation with medicines regulatory a unique three-month rotational post was authorities (MRAs), these projects also established in the area of dossier assess- contribute to national quality control of ment in 2006. Since then, 14 developing medicines, to strengthening of health country regulators from nine countries systems and capacity building. Samples have benefited from the arrangement.
are collected by MRA staff and tested at WHO-prequalified laboratories and During assessment, multisource (generic) results are published. Several reports and drug products are expected to satisfy the publications in scientific journals have be- same quality standards as those appli- come available over the ten-year period.
cable to the originator/reference product. In addition, assurance has to be provided Brief overview
that they are clinically interchangeable After the initial establishment of the with equivalent originator products (4). project in 2001, the first list of prequalified products was published in March 2002. The inspection unit operates in accor- The project expanded to include prequali- dance with an established quality system fication of quality control laboratories and consisting of documented SOPs, formats tuberculosis and malaria medicines in for reports and letters, a training pro- 2003–2004. Due to inspection findings of gramme and related aspects as recom- non-compliance with GCP, some products mended in guidelines (7). Inspections were withdrawn from the list in 2004. In are performed at the facilities of finished order to improve patient compliance and product manufacturers, API manufac- ease of dosing, fixed dose combinations turers, quality control laboratories and were developed. PQP was instrumental in clinical sites including contract research providing the corresponding guideline. As organizations (CROs). Feedback on the the applicant of a prequalified medicinal implementation of norms and standards product invariably makes changes to a is given to the relative unit in WHO and supplied product during the product's life recommendations are made for the cycle, a variation guideline was also de- development of new GMP guidelines (or veloped to ensure appropriate oversight revision of existing ones) as appropriate. of such changes.
WHO Prequalification of Medicines Programme WHO Drug Information Vol. 25, No. 3, 2011 Table 1: Summary of main events
Year Event
March: Appointment of first Manager for PQ (Dr AJ van Zyl). First expression of interest (EOI) published. Procedure for prequalification adopted by ECSPP.
First assessment of product dossiers and inspections.
First list of prequalified products published - March.
Global publicity - New York Times and Wall Street Journal (9).
Procedure for Prequalification of Quality Control Laboratories. Expand inspections to include API manufacturers. Donor: Bill and Melinda Gates Foundation Expand inspections to include CROs. WHO withdraws products form the List of PQ products due to non-compliance with GCP (10).
Start the Programme of prequalification of quality control laboratories (restricted to Africa).
Annual report published. Fixed Dose Combination guideline TRS 929, 2005.
Annual report published. Facilitate a new guideline for Contract Research Organizations.
Publication of the Variations guideline TRS 943 Annex 6. Facilitate development of the guideline on comparative dissolution for biowaiver applications.Development, adoption and publication of a Model Quality Assurance System for Procurement Agencies, TRS 937, 2006.
Donors: Bill and Melinda Gates Foundation and UNITAID.
Annual report published. Appointment of the second Manager for PQP (Dr R Kiivet).
Appointment of the Head of inspections, and Head of Assessments.
Suspension of Viracept (Roche). Launching the PQP web site in Chinese.
Implementation of the bio-waiver procedure. Contract PricewaterhouseCoopers to develop a business plan. First NOC issued by PQP - Sandoz SA.
First suspension of products - Sandoz SA. NOS issued Wyeth Pakistan.
First training workshop on pharmaceutical development with focus on pediatric formulations.
Third Manager for PQP appointed (Mr A Gould). First inspection newsletter published NOC issued to Matrix. Undertake a manufacturer survey.
Establish a joint assessment programme with EAC. Establish a collaborative procedure for inspections. Start inspections for comparative dissolution (bio-waiver applications).
Prequalify the first influenza product. Issue NOC - BBRC. Implement the prequalification of API procedure and first EOI published. Manufacturer's meeting in Copenhagen .
List 3 products in the list of prequalified APIs. Manufacturers' meeting in Geneva.
Issue NOC to Themis and Amsal. Publication on malaria medicines quality survey.
Confidentiality agreement with EDQM signed.
As the PQP become successful, it was Drug Administration (FDA), PQP and the extended to include HIV/AIDS, TB and Quality Assurance and Safety: Medicines malaria, reproductive health products, Unit of WHO and in 2011 between the zinc sulphate for the treatment of diar- European Directorate for the Quality of rhoea in children, products used in treat- Medicines (EDQM) and WHO.
ment of influenza and diethylcarbamazine Within the biopharmaceutical classifica- tion system, PQP assisted in the devel- Mutual confidentiality agreements were opment of a guideline on comparative signed in 2005 between the US Food and dissolution for biowaiver applications.
WHO Drug Information Vol. 25, No. 3, 2011 WHO Prequalification of Medicines Programme Due to cases of non-compliance identi- the PQP web site in Chinese followed, as fied during inspections at CROs, it was well as implementation of the biowaiver decided to facilitate the development of procedure. All NOC and NOS were also an additional guideline for CROs to assist published. In keeping interested parties in better understanding the application of informed of the activities of PQP, an in- GCP for bioequivalence studies.
spection newsletter was regularly pub- lished as well as articles in publications. Due to reporting of low quality repro- To further ensure transparency and better ductive health products and problems serve clients, PQP undertook a manufac- in procuring good quality products, PQP turer's survey in 2009. expanded its scope and included repro- ductive health products within the PQP in In an effort to expedite registration of cooperation with UNFPA.
prequalified products, prevent duplication, and promote harmonization, PQP estab- In September 2008, the USA issued an lished and implemented a joint assess- import alert against Ranbaxy, a phar- ment programme with the East African maceutical company based in India. As Community (EAC) for product dossiers there were several of their products listed and a collaborative procedure for inspec- in PQP, a joint inspection with Canada, tions (joint inspections and recognition Australia and the United Kingdom was of inspection reports among regulators). undertaken at Ranbaxy to investigate Both initiatives deserve more in depth impact. At that time, to respond to World clarification. It is anticipated that activities Health Assembly Resolution 57.14 and will be described in more detail in future the request by Member States and inter- national procurement organizations to enhance transparency, PQP published a With an increasing number of product first Notice of Concern (NOC) for manu- dossiers containing comparative disso- facturing sites. Provision was also made lution data, the inspection unit began for issuing Notices of Suspension (NOS) inspections at sites to verify reliability of for products. Resolution 57.14 requested dissolution data and GMP compliance WHO, among other actions to "ensure (biowaiver applications). that the prequalification review process and the results of inspection and assess- A major step forward in assisting MRAs to ment reports of the listed products, aside obtain information on the quality of APIs from proprietary and confidential informa- and API manufacturing sites, was imple- tion, are made publicly available". mentation of the procedure for prequalifi- cation of APIs in 2010. This procedure is As a consequence, publication of WHO based on the assessment of API Master Public Inspection Reports (positive Files (also known as a Drug Master Files) outcomes of site inspections) and WHO and inspection of the sites.
Public Assessment Reports (positive outcomes of dossier assessment) and the In further attempting to ensure the quality list of prequalified products provides the of products purchased, a model qual- public and regulators with extensive infor- ity assurance system for procurement mation on the PQ evaluation of products agencies was developed. This guideline was adopted by the ECSPP and the Interagency Pharmaceutical Coordina- The structure of PQP changed in 2007 tion group (IPC) and is used by different with the appointment of a new Pro- organizations including the World Bank.
gramme Manager, appointment of a Head Following publication of the first Expres- of Inspections, and a Head of Assess- sion of Interest for HIV/AIDS products, ments. In the same year, the launching of more than 90 product dossiers were WHO Prequalification of Medicines Programme WHO Drug Information Vol. 25, No. 3, 2011 Table 2: Number of inspections by site, per year
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010 2011*
APIs 1 2 11 8 6 11 7 5 15
FPPs 6 23 20 22 18 19 26 27 27 38 26
QC labs 1 7 3 1 10 8 9 6
CROs 6 13 17 13 14 10 7 7
Total 6 23 21 31 42 47 46 62 52 59 53
* Up to 15 July 2011 received for assessment in the first group cess; question/problem resolution during assessment session in Copenhagen. The assessment; consistency of membership number of product dossiers submitted for in the team of assessors throughout the assessment has varied from year to year, process, and local/national representation and between disease groups. in on-site inspection teams. Most manu- facturers view PQP GMP requirements Since 2001, more than 60 training as more stringent than those of the US workshops have been organized or co- FDA or European Medicines Agency. The organized in countries including Austria, findings from this survey indicate that Belgium, Brazil, China, Estonia, India, pharmaceutical manufacturers consider Kenya, Pakistan and Tanzania. Twenty PQP to be a well-designed, well-executed quality control laboratories (QCLs) have programme. PQP assessors and inspec- been prequalified and four sampling and tors are meeting or exceeding manufactu- testing projects have been undertaken. rer expectations for service delivery in all In 2008, PricewaterhouseCoopers was appointed to assist in the development Table 2 reflects the number of inspections of a business plan. Recommendations by site, over the years, including for APIs, for improvement were made and it was finished pharmaceutical products (FPPs), calculated that the return on investment in CROs and quality control laboratories.
PQ was 170.1 in the period 2009–2013. By 21 June 2011, a total of 253 finished products had been prequalified by WHO. Outcomes of the manufacturer survey This included 190 HIV/AIDS products, carried out in 2009 (11) were presented 31 TB; 17 malaria; seven influenza, and to a manufacturers' meeting in Copenha- eight RPH products.
gen in April 2010 and at the PQP Annual Stakeholders meeting in 2011. The report Conclusion
concluded that both PQP assessors and The establishment and implementation of inspectors are meeting or exceeding a prequalification procedure for pharma- manufacturer expectations for service ceutical products, especially in the area delivery. The structure of PQP generally of HIV/AIDS, has significantly facilitated delivers levels of service at, or above, access to quality medicines. Moreover, it those expected by manufacturers. has also triggered harmonization between quality assurance policies of various However, the service process is falling organizations involved in procurement of short of manufacturer expectations with medicines for the developing world such respect to review/reply time for product as the Global Fund to Fight AIDS, Tuber- dossiers; opportunities for in-person com- culosis and Malaria, UNFPA, UNITAID, munication during the assessment pro- WHO Drug Information Vol. 25, No. 3, 2011 WHO Prequalification of Medicines Programme Table 3: Number of products and quality control laboratories
2001 2002 2003 2004 2005 2006 2007 2008 2009 2010
0 61 13 13 17 33 13 29 24 24 TB 0 0 6 2 0 0 5 5 7 5
RPH 0 3 5
Zn sulphate 0 0
DEC 0 0
Total 0 61 19 17 18 35 21 40 44 36
QC labs
Several publications reflect the increase lable. Where only 13% of patients were in number of patients on antiretroviral able to afford therapy in 1996, the num- treatment over the last decade, as well as ber increased to 44% in 2003. The most the reduction in price of these medicines common ARV regimen was 3FDC (lami- (see figure 2 below) (12). For example, in vudine, stavudine, nervirapine) which was 2005 it was reported that the cost of high- administered to 56% of patients receiving ly active antiretroviral therapy (HAART) HAART (13). This is supported by the decreased from US$ 778 per month in Global Fund's quality assurance policy 1996 to US$ 100 per month in 2000, and (supporting procurement of prequalified further to US$ 33 per month in 2003 after products) and Global Fund reports on the first generic ARVs were made avai- procurement in countries (14).
Figure 2: Number of people receiving ARV therapy
North Africa and Middle East East, South and South-East Asia Europe and Central Asia Latin America and the Caribbean Sub-Saharan Africa People receiving antiretroviral therapy (in m 05 WHO Prequalification of Medicines Programme WHO Drug Information Vol. 25, No. 3, 2011 According to a report from Médecins 3. US deaths per 100 000 population in the sans Frontières (MSF), the price of FDC period 1982–1993 at http://commons.wikime- lamivudine + nevirapine + stavudine per patient per year dropped significantly from 2000–2001 and from 2008–2009. 4. World Health Organization. Marketing authorization of pharmaceutical products with The originator cost was US$ 10439 in special reference to multisource products. 2000, US$ 727 in 2001, US$ 331 in 2008 WHO/DMP/RGS/98.5 9 (1989).
and US$ 531 in 2009. The corresponding generic product cost was US$ 2767, US$ 5. World Health Organization. Report of the 295, US$ 87 and US$ 80 in the corres- Expert Committee on Specifications for Phar- ponding years. The price dropped by 99% maceutical Preparations. Guidelines on sub- from 2001 to 2010 (15, 16).
mission of documentation for prequalification of innovator finished pharmaceutical products approved by stringent regulatory authorities. The majority of products on the list of Annex 11. Technical Report Series, No. 961, prequalified medicines are multisource/ generic products. Generic manufacturers are the main suppliers of essential medi- 6. World Health Organization. Report of cines in developing countries: 67% of the Expert Committee on Specifications for medicines produced in India are exported Pharmaceutical Preparations. Guidelines on to developing countries. Also, according submission of documentation for a multisource to PEPFAR – 73% of ARVs delivered in (generic) finished product: general format: preparation of product dossiers in common focus countries are generic medicines technical document format. Annex 15. Techni- cal Report Series, No. 961, 2011.
7. World Health Organization. Report of The prequalification programme has fa- the Expert Committee on Specifications for cilitated access to quality medicines and Pharmaceutical Preparations. Quality systems created a mechanism for better medi- requirements for national good manufactur- ing practice inspectorates. Annex 8. Technical cines at better prices. This was made Report Series, No. 902, 2002.
possible by partners, donors, participat- ing industry and the kind assistance of 8. World Health Organization. Expert Commit- assessors and inspectors from many tee on Specifications for Pharmaceutical Pre- national medicines regulatory authorities. parations. Guidelines for sampling of pharma- WHO PQP would like to express a sin- ceutical products and related materials. Annex cere thank you to all involved as well as 15. Technical Report Series, No. 961, 2011.
supporting staff in PQP and within WHO. 9. McNeill, DG. New List of Safe AIDS Drugs, The writer further wishes to thank all staff Despite Industry Lobby. The New York Times. members in WHO and in particular PQP 20 March 2002 at http://apps.who.int/prequal/ for their cooperation in the programme Press&Media/ Prequalification Update and their contribution to the writing of this 10. Alyman LK, McNeill, DG. UN Agency Drops Two Drugs for AIDS Care Worldwide.
The New York Times, 16 June 2004, at http:// 1. World Health Organization. Prequalification cation Update. of Medicines Programme at http://www.who.
11. Interclarity Research and Consulting Inc. at http://apps.who.int/prequal/trainingre- 2. Antiretroviral therapy coverage in sub- Saharan Africa at http://www.who.int/hiv/data/ tations/Day_1/PQPSurvey.pdf and http://apps.
survey.pdf and http://apps.who.int/prequql/ WHO Drug Information Vol. 25, No. 3, 2011 WHO Prequalification of Medicines Programme info_applicants/qclabs/monitoring_documents/ 3. Survey of service quality provided to manu- facturers. Volume 24, No. 4, p. 293 (2010).
12. WHO, UNICEF, UNAIDS. Towards uni- 4. WHO initiates pilot prequalification of active versal access: scaling up priority HIV/AIDS pharmaceutical ingredients. Volume 24, No. 4, interventions in the health sector. Progress p. 297 (2010).
report 2009, p.55 at http://apps.who.int/pre- 5. Collaborative participation of national inspectors in WHO prequalification. Volume 13. Kumarasamy N et al. The changing natu- 24, No. 3, p. 201 (2010).
ral history of HIV disease: before and after the introduction of generic antiretroviral therapy in 6. Inspection news report. Volume 24, No. 3, southern India. Clinical Infectious Diseases, p. 205 (2010).
7. Inspection of finished pharmaceutical pro- 14. The Global Fund to Fight AIDS, Tubercu- duct manufacturers. Volume 24, No. 2, p. 87.
losis and Malaria at http://www.theglobalfund.
8. Facts and figures for 2009. Volume 24, 15. Medecins sans Fontières (MSF). Untan- No. 1, p. 3 (2010). gling the web at http://www.msfaccess.org/ 9. Prequalification of quality control laborato- ries. Volume 23, No. 4, p. 300 (2009).
16. Medecins sans Fontières (MSF). Examples of the importance of India as the 10. WHO medicines prequalification: progress "Pharmacy of the developing World" (2007) at in 2008. Volume 23, No. 1, p. 201 (2009). 11. WHO Prequalification: GMP deviations 17. The US President's Emergency Plan for and suspension. Volume 22, No. 3, p. 203 AIDS Relief (PEPFAR) at http://www.pepfar.
12. WHO prequalification: progress in 2007. Volume 22, No. 2, p. 79. 1. Dekker TG, van Zyl AJ, Gross O et al. WHO Pharmaceuticals Newsletter
Ongoing monitoring of antiretroviral products as part of WHO's Prequalification Project. J 1. Inspection of manufacturing sites for active Generic Med 2006;3:96-105
pharmaceutica ingredients within the WHO Prequalification of Medicines Programme. 2. Caudron JM et al. Substandard medicines Number 1, p. 12 (2011).
in resource-poor settings: a problem that can no longer be ignored. Tropical Health and 2. Collaborative participation of inspectors International Health Journal 2008;13(8):1062.
from medicines regulatory authorities (MRAs) in inspections coordinated by the 3. Strauch S, Jantratid E, Stahl M et al. WHO Prequalification of Medicines Pro- The biowaiver procedure: its application to gramme. Number 3, p. 12 (2010).
antituberculosis products in the WHO Prequa- lification Programme. J Pharm Sci 2010:DOI 3. WHO Prequalification of Medicines Pro- 10.1002/jps.22349;Wiley Online Library at gramme: Inspection of finished pharmaceuti- cal product manufacturers to increase quality of medicines. Number 2, p. 16 (2010).
WHO Drug Information
1. Facts and figures for 2010. Volume 25, No.
4. Prequalification of quality control laborato- 2, p. 101 (2011).
ries. Number 1, p. 22 (2010).
2. Inspection of API manufacturing sites. 5. Inspections of bio-equivalence studies. Volume 25, No. 1, p. 24 (2011).
Number 4, p. 11 (2009).

Source: http://2012.atmindex.org/sites/www.accesstomedicineindex.org/files/who_prequalification_of_medicines_programme.pdf

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