This little known part of WHO is effective and has teeth that can bite rapidly⁽¹⁾

Established in 2001, the UN Prequalification Project is an action plan for expanding access to medicines for the hardest hit by HIV/AIDS, Tuberculosis and Malaria while ensuring front-line quality assurance in every step of the medicines supply chain.

The prequalification team within the Department of Medicines Policy and Standards in WHO handles those aspects of the project that ensure safe and efficacious drugs of good quality. The team prepares a list of prequalified medicines that meet certain pre-determined criteria. Drug procurement agencies can then refer to such a list while placing their orders.

Working with a small, quiet and committed group the prequalification team has been successfully addressing the problems of substandard and counterfeit medicines that waste resource, lead to treatment failure, and greatly erode patient confidence and goodwill. With this article, we bring to our readers the reasons for and the remit of the prequalification project and how it operates.

The challenges

The triple menace: HIV/AIDS, tuberculosis (TB) and malaria

Annually, more than six million people die of HIV/AIDS, TB and malaria, compounding the effects of poverty and social inequities in many developing countries. HIV/AIDS has destroyed communities, health-care systems and put a shadow upon the future of entire countries. In poor countries, six million people with HIV/AIDS need immediate antiretroviral therapy. Less than eight per cent get it.⁽²⁾

There is a clear need for programmes to improve access to medicines in these sectors. But, for improved access to bear real benefits, all these programmes have to ensure access to medicines of sound quality, safety and efficacy.

Accelerated access and quality assurance

Efforts to accelerate access to pharmaceutical products used in the treatment of these major impact diseases through negotiation and generic competition, have highlighted the importance of building quality assurance into procurement systems for pharmaceutical products and diagnostics. Currently, about 20% of countries have well developed and operational medicines regulation⁽³⁾; the rest have either no or limited capacity to adequately regulate the safety, efficacy and quality of medicines circulating in their markets.

In the absence of a quality assurance system, public health agencies risk sourcing substandard, counterfeit and contaminated pharmaceutical products leading to product recalls, waste of resource and mone, with added health risks to patients. While strengthening regulatory systems remains WHO's priority and will continue as part of ongoing health-care initiatives, there is an immediate need to address current gaps in the quality and supply of medicines for major impact diseases.

Treatment failure and risk of resistance

Substandard medicines could result in treatment failure and resistance while exposing patients to the potential risks of chemical impurities. The high failure rate in quality control tests for the antimalarial chloroquine tablets in some sub-Saharan African countries in a recent WHO study highlights this. Only 58% of the medicines tested had an acceptable level of chloroquine content and only 25% had acceptable dissolution properties. The study authors have suggested that poor quality chloroquine may be among the causes of the high rate of resistance in these countries.⁽⁴⁾

Treating patients with poor quality medicines may result in low content of active ingredient and/or low bioavailability leading to drug under-dosage, thus potentially promoting the development of resistance. A system needs to be in place to ensure good manufacturing and clinical practices.

Good Manufacturing Practices (GMP): lack of compliance

In some countries, illegal manufacturing, distribution (including uncontrolled sales in market places and on streets) and smuggling of medicines are widespread. Even manufacturers who fail to comply with good manufacturing practice (GMP) requirements can still produce medicines for domestic use and for export, no doubt greatly undermining the quality of medicines circulating in the market.

Issues of bioequivalence

Increased availability of medicines can translate into improved access only if these medicines are affordably priced. Quite often, competitive prices are realized through multi-sourcing of products. In those instances where multi-source, generic products are being introduced, it is important to ensure that these generic products are interchangeable with the innovator products in being pharmaceutically and therapeutically equivalent.

An impartial process, that critically evaluates all generic product 'claims' for meeting quality specifications and inspects the manufacturing facility, can ensure that multi-source products are of good quality and therapeutically equivalent to the innovator products.

In short, the WHO commitment to scaling up access to medicines for major-impact diseases is of little relevance to public health if quality, safety and efficacy issues are ignored. The UN Prequalification Project was thus born for ensuring quality, efficacy and safety of priority medicines.

Organization of the overall Prequalification Project

The project is organized and managed by WHO on behalf of the United Nations; UNICEF, UNFPA, UNAIDS are key UN partners with the support of the World Bank. WHO provides the technical and scientific support for quality assurance of medicines and works in close cooperation with qualified assessors and inspectors from national drug regulatory authorities as well as national quality control laboratories of developed countries (e.g.,

Australia, Canada, EU Member States, Switzerland). Qualified experts from other countries also contribute

(e.g., Brazil, Indonesia, South Africa, Uganda, United Republic of Tanzania).

Objectives of the WHO prequalification exercise

The WHO prequalification process aims to:

1. Propose a list of prequalified products as manufactured in sites that meet WHO norms and standards.

2. Follow-up products and manufacturing facilities for quality issues.

3. Ensure that requalification and update of the original approved list is carried out periodically and that variations and changes are correctly controlled.

4. Help national drug regulatory authorities to build capacity in assessment, inspection and control of medicines for priority diseases.

Applying for prequalification

Products identified as being of public health significance are listed on the Prequalification Project web site under "Invitations for Expression of Interest (EOIs: http://mednet3.who.int/prequal).(5) These products are generally selected from the WHO Model List of Essential Medicines. Any manufacturer or supplier of such a product is eligible for assessment in the Prequalification Project by applying (with product dossier etc.) in conformity with WHO guidelines.

The process of prequalification

A team of WHO appointed assessors drawn from national competent authorities will assess the product data as submitted in the dossiers by the interested manufacturers. Additionally, samples may also be analysed for quality control and compared with specifications as provided in the dossier. The manufacturing site(s) and the clinical site (see bioequivalence studies below) listed in the product dossier are inspected on all aspects of Good Manufacturing Practices (GMP) and Good Clinical/Laboratory Practices (GCP/GLP), respectively, by a team appointed by WHO. Normally GMP inspections take a minimum of three consecutive days. In all, the entire process, from receipt of the dossier to prequalification of the product takes about two to four months provided the product dossier is complete at the time of submission and the mentioned sites are up to standards when inspections are due. Frequently however, additional data are requested by the assessors and/or the mentioned sites need to be upgraded to meet requirements. In such cases the time for prequalification of a product may be considerably longer.

Requalification

Manufacturers are required to apply for requalification of their products three years following prequalification. Requalification involves reassessment of the product data as provided in the original product dossier and reinspection of the relevant site(s) for continued compliance.

Bioequivalence studies

In case of multisource (generic) products, therapeutic equivalence is mostly demonstrated through a bioequivalence study carried out by an independent organization, company, academic institution, research organization or laboratory. Where bioequivalence studies are conducted through contract research organizations (CROs), the CRO study also needs to be inspected as per WHO guidelines.

Outcomes

The immediate outcomes of the WHO prequalification process include the list of prequalified products for treating priority diseases, harmonization of quality requirements for international procurement organizations and strengthening of collaboration between WHO, other UN agencies, related organizations and drug regulatory authorities.

Earlier last year the prequalification process came under some criticism when several antiretroviral drugs were 'de-listed' due to non-compliance with good clinical and laboratory practices (see the prequalification web site for the findings at these inspections, including an additional draft guidance for Contract Research Organizations conducting bioequivalence studies).(5) Two of the products have since been put back on the list after the manufacturer carried out new bioequivalence studies and demonstrated that these two drugs were bioequivalent to and, therefore, as effective and safe as the originator products. Thus, while the de-listing might affect the number of drugs to choose from in the immediate sense, the process always aims to safeguard the patients' well-being. Equally, it shows that here is an impartial system to enforce quality-driven measures, even when dealing with established manufacturers. It is obvious that the prequalification process exists to ensure that "some of the most important drugs are being made safely available in the parts of the world where they are most needed".(1)

References:

1. Editorial, The Lancet, Volume 364, Number 9448, 2004.

2. The 3 by 5 initiative web site: http://www.who.int/3by5/about/en/

3. WHO Policy Perspectives on Medicines: Effective medicines regulation: ensuring safety, efficacy and quality, November 2003, World Health Organization.

4. The quality of antimalarials. A study in selected African countries. Geneva, WHO, 2003.

5. WHO Prequalification Project web site: http://mednet3.who.int/prequal/