Twenty-five years of the WHO vaccines prequalification programme (1987-2012): lessons learned and future perspectives.

The World Health Organization (WHO) vaccines prequalification programme was established in 1987. It is a service provided to United Nations procurement agencies to ensure that the vaccines supplied through these agencies are consistently safe and effective under conditions of use in national immunization programmes. This review describes the purpose and aims of the programme, its evolution during 25 years of existence, its added value, and its role in the context of the WHO strategy to ensure the global availability of vaccines of assured quality. The rationale for changes introduced during the implementation of the programme is provided. The paper also discusses the resources involved, both human and financial, its performance, strengths and weaknesses and steps taken to maximize its efficiency. This historical perspective is used to inform proposed future changes to the service.

Introduction

WHO prequalification aims to ensure that selected diagnostics, medicines, vaccines, immunization-related equipment and devices for high burden diseases meet global standards of quality, safety and efficacy, in order to optimize use of health resources and improve health outcomes. It consists of a transparent and scientifically sound assessment process that in conjunction with other procurement criteria is used by United Nations (UN) and other procurement agencies to make purchasing decisions regarding specific commodities (diagnostics, medicines and/or vaccines). Prequalification (PQ) is a procurement term [1] which refers to limiting a global public tender to fewer than the total number of possible suppliers.

The vaccines prequalification programme was established in 1987. It was conceived as a service provided by the WHO to the Supply Division of its sister agency the United Nations Children's Fund (UNICEF). Its primary purpose was to ensure that the vaccines purchased by UNICEF and other UN procurement agencies would be consistently safe and effective under conditions of use in national immunization programmes. It started as a modest project, based on the testing of vaccine lots; review of summary lot protocols and also on inspection of the manufacturing facilities. As demand increased and needs evolved, the procedure was revised to strengthen its capacity to assess quality, safety and efficacy of the candidate vaccines for purchase through the UN agencies. The revisions of the procedure were triggered by changing needs and were introduced in the majority of cases based on recommendations by groups of experts (the ad hoc committee on vaccines prequalification). Every revision was further either endorsed or noted by the WHO Expert Committee on Biological Standardization (ECBS) prior to its implementation and publication as part of the WHO Technical Report Series (TRS) or as a Vaccines Department document.

The problem

The WHO Constitution was adopted by the International Health Conference held in New York from 19 June to 22 July 1946, signed on 22 July 1946 by the representatives of 61 States [2] and entered into force on 7 April 1948. Amendments adopted by the Twenty-sixth, Twenty-ninth, Thirty-ninth and Fifty-first World Health Assemblies (resolutions WHA26.37, WHA29.38, WHA39.6 and WHA51.23) came into force on 3 February 1977, 20 January 1984, 11 July 1994 and 15 September 2005 respectively. Those amendments are incorporated in the present text [3].

According to the article 2 of the Constitution, WHO's mandate is to “develop, establish and promote international standards with respect to food, biological, pharmaceutical and similar products”. WHO Member States rely on WHO for expertise and guidance in the regulation, safety and quality assurance of medicines through development and promotion of international norms, standards, guidelines and nomenclature.

In view of this mandate expert committees were established to develop and promote appropriate quality standards in the areas of pharmaceutical and biological products, including vaccines. The ECBS was established and has met annually since 1947 [4] and is responsible for assisting the WHO secretariat in the development and establishment of written and physical standards for biological products.

One of the challenges faced by WHO in the field of biological products was to ensure that vaccines used both domestically and globally would meet the appropriate standards of quality, safety and efficacy. This was an issue of particular concern taking into account the specific characteristics of vaccines which are used mostly as preventive medicines in healthy populations and in many cases in newborns and healthy infants.

After the Expanded Programme for Immunization (EPI) was started in 1974, vaccines were supplied either by multinational manufacturers or national vaccine producers. Increasingly, products were bought by UN procurement agencies – UNICEF and the Pan American Health Organization Revolving Fund (PAHO RF) [5] [6].

These agencies were conscious of the need to ensure the quality, safety and efficacy of the products they procured and distributed. The following was noted in an EPI Newsletter [7].

“PAHO/WHO screen manufacturers offering vaccines for EPI use and, where possible, review protocols of the specific lots submitted for sale.”

Much emphasis was initially placed on the national testing of vaccines or the use of WHO or PAHO testing centres [8]. At its 84th meeting in June 1980, the PAHO Executive Committee urged all Member States to strengthen their respective laboratories for vaccine testing [9].

In 1987, UNICEF established an agreement with WHO to request its involvement in assessing the acceptability, in principle, of vaccines for purchase through this agency. Through this agreement, WHO supported UNICEF by providing advice on the quality, safety and efficacy of vaccine candidates for purchase.

The prequalification procedure: early days

Based on this request, WHO published in 1987 its first set of requirements for prequalification [10], supplemented the following year by a modification applicable exclusively to BCG vaccine [11], because of the requirement as published in the TRS for annual clinical trials to establish the consistency of production of this vaccine. The early process focused on review of consistency of production (generally by review of summary lot protocols and by testing, but supplemented with clinical trials for BCG), and an inspection to the manufacturing site(s). In some cases a small file was provided by manufacturers to give information about the production process, strain development and involvement of NCA and NCL in the oversight of the product.

This started to be known as the WHO prequalification procedure. Through this evaluation process, WHO limited the number of suppliers of a specific vaccine to fewer than the total possible candidates. This reduced population of suppliers of “prequalified vaccines” was further subject to a final “selection or qualification” that is carried out by UNICEF based on procurement principles and using a tender process that ends up in granting an award.

The service provided by WHO to UNICEF, eventually was extended to the PAHO RF, and with time it became a standard service provided to any UN procuring agency including WHO Headquarters and all regional offices.

In addition to securing a standard quality for vaccines for global supply, there was a need to ensure regulatory systems at national level had the infrastructure and capacity to oversee the quality, safety and efficacy of products used within their territories. This was particularly important for countries with domestic production of vaccines and for those procuring vaccines directly through international bidding.

WHO's ECBS published in 1981 its first guideline on national control of vaccines, recommending the establishment of a “national control authority” (now called national regulatory authority) [12] for all countries, with responsibilities that may differ according to their capacity and need. A national control authority was recommended to be empowered to establish or recognize requirements for acceptability of products, establish standard preparations for biological testing, license manufacturers of biological products, and establish the necessary infrastructure to implement the requirements. At this point, most of the emphasis was placed on the testing related activities.

The Forty-fifth World Health Assembly in 1992 resolved that all vaccines used in national immunization programmes should meet WHO requirements (WHA45.17), thus reinforcing former guidelines as a credible goal for all countries.

Strategic approach to strengthening national regulatory capacity for vaccine regulation

WHO has further refined its guidance towards the development and strengthening national regulatory capacity by introducing and defining the key concept of “vaccines of known good quality”.

According to WHO, a vaccine is of known good quality [13]1 provided that:

The national regulatory authority independently controls the quality of the vaccine in accordance with the six specified functions defined by WHO, and

There are no unresolved confirmed reports of quality-related problems.

Implicitly, this requires that the NRA of the vaccine producing country be functional when assessed against international standards for vaccine regulation.

Comprehensive regulatory oversight of vaccines requires a regulatory system and six basic functions [14], [15]. These functions are: (1) Marketing authorization and facility licensing; (2) Pharmacovigilance including Adverse Events Following Immunization (AEFI); (3) NRA lot release; (4) Laboratory access; (5) Regulatory inspections; and (6) Authorization and monitoring of clinical trials.

To support countries to build appropriate regulatory capacity WHO developed a strategy to prioritize capacity building on the NRA's essential functions depending on the source of the vaccine (Fig. 1) [16]. This allowed with limited resources to focus on the most relevant functions. In this respect, countries purchasing vaccines through UN agencies were recommended to perform only two functions: marketing authorization and pharmacovigilance including Adverse Events Following Immunization (AEFIs). The other four functions are secured by the WHO prequalification system which ensures continued regulatory oversight by the NRA in the country of origin and compliance with WHO requirements, UN tender specifications and with the specific needs of national immunization programmes in user countries.

Fig. 1

NRA regulatory functions prioritized by vaccine source [16].

Non-producing countries procuring vaccines directly through international tenders are recommended to fulfil two additional functions: lot release and laboratory access. This means that they need to release each lot of vaccine to be used in the country through critical review of the summary lot protocols provided by the manufacturer with the shipment, and need to have access to a qualified laboratory capable of testing the vaccine products in case of need. There is no need to establish a laboratory in each vaccine procuring country so that it can be accessed when needed. The remaining two functions are secured by the NRA of country of origin.

The highest priority countries for capacity strengthening remain the vaccine producing countries, some of which may be exporters while others focus on the domestic supply of vaccines. These countries should fulfil the six functions.

Based on this prioritization mechanism and with producing countries as the highest priority, WHO developed in 1995 a 5 step capacity building programme to strengthen NRAs [16] that relies on:

Establishment of benchmarks to objectively and reliably assess a national regulatory system for vaccines,

A review, led by WHO, by a team of international experts to conduct the assessment of a national regulatory system. The assessment is performed by using an assessment tool with indicators and sub-indicators for each regulatory function,

Identification of gaps and weakness, and development of an Institutional Development Plan (IDP) to address the gaps,

Provision of technical input and support through learning and training to build capacity in line with the needs identified through the IDP, and

Monitoring progress and re-assessment of the performance of the regulatory system at regular intervals.

Development of a NRA assessment tool

The capacity building programme started in 1996 and was built on existing regulatory authorities with expertise to regulate drugs [17], [18]. The first NRA assessment tool was developed in 1997 with inputs from many countries (38 in the first round) (J.B. Milstien personal communication), and between 1997 and 2004 the tool was revised 4 times. During the same period, 68 assessments were conducted and 1200 staff trained [19], [20]. At the same time, the Global Training Network (GTN) was established by WHO involving collaborating centres around the world that provided training courses to bridge the gaps identified during the NRA assessment process. Further revisions of the tool were conducted in 2007 and 2011.

Thus, WHO established a dual and parallel system to secure the global supply of vaccines of assured quality; on one hand the prequalification procedure ensured the quality of vaccines distributed internationally through UN agencies, while the capacity building programme worked towards strengthening the regulatory capacity at country level.

The vaccines prequalification programme: its evolution

After the initial publication of the vaccine prequalification procedure in 1987, this was further revised in 1988 and reissued in 1989 [21]. This later edition took into account the need for the national regulatory authority of the country where the vaccine was produced to exercise its regulatory functions.

In 1996 the procedure was further developed [22] to allow for three significant changes:

Increase in importance to Good Manufacturing Practices (GMP) compliance. Previous versions of the procedure were more focused on testing the quality rather than seeking built in quality.

Submission of a defined summary file or dossier which would provide documented information on the production process and quality control as well as information supporting the claims of both clinical safety and efficacy of the vaccine.

Increase in the participation and role of the national regulatory authority (NRA) of the manufacturing country.

Independent testing of final vaccine lots by WHO contracted laboratories remained a requirement as a means to confirm consistency of final product characteristics. The site visit to the manufacturing site became a more systematically defined part of the procedure.

Table 1 compares the different versions of the prequalification procedure and shows its main features. It shows the changes introduced over time, from 1987 to date in order to strengthen it and to make it correspond more with emerging needs and with current regulatory trends and expectations [10], [21], [22], [23], [24], [25].

Table 1

Evolution of the WHO prequalification procedure for vaccines: 1987–2010.

	Characteristic	1987	1989	1997	2002	2005	2010
Pre-conditions for acceptance of submissions
	None required but concept of reliance on NRA already present
	Functionality of NRA as pre-requisite for submission
	Requires MA in country of origin or EMEA Scientific Opinion (Art. 58)
	WHO recommendations or guidelines are available
	Candidate vaccine present on list of priority products for prequalification
	Candidate vaccine meets mandatory characteristics for Programmatic Suitability for Prequalification (PSPQ) (Ref)
Assessment procedure
Technical evaluation of quality, safety and efficacy	Copy of licensure by NRA in country of origin and other documents.
	Requires submission of Product File containing limited information
	Requires submission of Product Summary File (PSF) with defined format and contents (10 Chapters)
	Acceptance of Common Technical Document (CTD) as alternative to PSF
	Strengthened requirements for demonstration of clinical efficacy and safety
	Requires application letter in advance to actual submission of PSF
	Pre-evaluation meetings between manufacturer and WHO-PQ and NRA
	Screening of files for compliance in format and contents prior to formal review
	Increased focus on the suitability of product characteristics to the target NIP
	Compliance with PSPQ mandatory characteristics
	Deviation from critical characteristic triggers referral to PSPQ standing committee
Consistency	Independent testing of samples, review of release certificates and SLP
Inspection/site visit/site audit	Inspection: focus on production, quality control and records
	Inspection: team of experts, one WHO staff plus one representative from NCL
	Site visit: additional focus on Quality Assurance and GMP
	Site visit: team of experts on each area, WHO staff, representative of NRA and UN agency representative may elect to join
	Written report sent to manufacturer. Improvements may be required before decision
	Debriefing sessions to manufacturer held on daily basis and on final day
	Availability of reports of recent inspections conducted by NRAs may be used to streamline the audit by WHO
	Ad hoc committee on PQ to advise on final outcome of the evaluation when needed
	Consultation meeting with responsible NRA to discuss regulatory status of the vaccine and to agree on future information sharing (nature and mechanism)
	Collaboration arrangements are signed with NRA for information sharing

A milestone in the development of the prequalification process was the decision taken in 2000 to require the NRA in the producing country to be functional as a prerequisite for acceptance of submissions from manufacturers from that country. This change was endorsed and stated in the 2002 version of the procedure. This single change to the procedure had the greatest impact on the WHO efforts to strengthen capacity for vaccine regulation in developing countries.

An important example of adjustments made to the procedure to address emerging needs is implementation of a mechanism to define and assess suitability of product characteristics for the target immunization programmes. This is a key feature that distinguishes PQ from a normal registration procedure or licensing mechanism by the NRA of the producing country. While the NRA focuses its review for registration on the specific needs of its own population, the prequalification emphasizes the review of data related to efficacy of the product in the target population, using the WHO recommended immunization schedules (which may differ from those recommended in the country of origin) and in co-administration with other vaccines recommended in the NIPs schedule. PQ also focuses on the programmatic suitability of the product for the target user countries. For example, vaccines filled in non-auto disable pre-filled syringes are not acceptable for prequalification due to the risk of re-use and unsafe disposal. The Programmatic Suitability for Prequalification (PSPQ) [26] describes characteristics that are suitable and those that are unsuitable for national immunization programmes in UN supplied countries. The submission of a product deviating from a critical characteristic is referred to a standing committee composed of programme experts and regulators. They review relevant information and to make a recommendation to the WHO PQ secretariat on whether the product can proceed or not to prequalification evaluation. The PQ process also ensures that the UN tender specifications are met.

The PQ procedure includes different options (Table 2) aimed at guiding the evaluation process in different situations, such as the use of the fast track option for emergency situations, or streamlining the procedure in the case of vaccines which have followed the EMA Scientific Opinion regulatory pathway [27]. These provisions are also aimed at accelerating the timeframe for prequalification, increasing efficiency, transparency and communication to stakeholders, as well as the need to efficiently respond to increased demand, and to assess novel.

Table 2

Measures to strengthen the procedure: period 1987–2013.

Characteristic	1987	1989	1997	2002	2005	2010
Measures to improve the procedure
Cost of inspection/site visit/site audit paid by manufacturer
Inclusion of confidentiality and non-conflict of interest clauses
Provision for evaluation of products formulated and filled by a manufacturer purchasing bulk material from a prequalified source
Establishes criteria to consider waiving the site visit
Establishes a funding mechanism based on fees for service to the manufacturers
Validity of the prequalification two years
Validity of prequalification is between two and five years depending on performance
Prequalification and reassessment scope and frequency based on risk analysis
Includes special considerations for fast-track procedure in emergency situation or case of acute shortage of vaccine
Strict timelines for evaluation (target 12 months without counting time taken by manufacturer to provide responses to questions or corrective actions)
Includes special considerations for accepting submissions before license is granted
Includes special considerations for accepting submissions of vaccines that have been licensed in countries different from that of manufacturer
Introduces a streamlined procedure for evaluation of vaccines regulated by stringent regulatory authorities and defines basis for selection of the authorities. Evaluation process based on review of reports provided by the NRA
Introduces a streamlined procedure for evaluation of vaccines which were granted a positive Scientific Opinion by the CHMP (Art. 58)
Special considerations for vaccines produced in multiple sites or different countries
Improved communication and transparency through upgraded web list and other published documents (rationale for PQ, statements on investigation of AEFIs and complaints, points to consider for manufacturers)

Fifteen years ago, the programme had very limited funds, fully provided by UNICEF by levying a small percentage on each purchase order. In order to increase the capacity of the programme, and expand its portfolio, an agreement was reached with UNICEF and vaccine manufacturers to drop this percentage and to charge a fee directly to manufacturers for the service that was provided. Fees are revised at regular intervals to reflect increased costs. This funding mechanism has supported the programme to the present time. The programme is also sustained by ad hoc contributions from donors (UNICEF, Bill and Melinda Gates Foundation, USAID and some national governments such as the Netherlands), which have been essential to increase staffing and to support the post-prequalification monitoring activities.

Post-prequalification activities (Table 3) enable the monitoring of the performance of vaccines shipped to countries and for WHO to rapidly react in cases of non-compliance. This post-prequalification work is almost entirely supported through UNICEF funding and contributions from PAHO and other Regional Offices.

Table 3

Post-prequalification activities to monitor performance of the prequalified vaccines: period 1997–2013.

Characteristic	1987	1989	1997	2002	2005	2010
Post-prequalification activities
All lots released by NRA, release certificates to be provided upon request
Retention samples for testing by WHO contracted laboratories upon request
Reporting of changes (variations)
Reporting of changes (variations) with guidance on what and when to report
Reassessments based on site visit and testing if needed
Reassessment based on fully updated PSF, testing and site visit
Provides criteria to define frequency and scope of reassessment requirements. Site visit can be waived if criteria are met, but at least one every five years
Frequency and scope of reassessments based on risk analysis
Random testing to monitor continued compliance with specifications
Introduces requirement for Prequalified Vaccines Annual Reports (PQVARs)
Monitoring and investigation of complaints and reports of AEFI
Recommendations for action in case of non-compliance

The procedure used for the prequalification of vaccines was used as a basis for the formulation of the medicines prequalification procedure and later for selected diagnostics. However, a different approach to prequalification was followed by the medicines programme. In this case, the functionality of the NRA is not required for the acceptance of a generic product from any particular country, if the manufacturer meets the defined standards of quality, safety and efficacy. In the case of vaccines, this approach is not considered feasible taking into account the complexity and inherent variability of biological products thus requiring a partnership with the NRA to provide lot-to-lot oversight. The different nature of the products assessed and the different level of risk (e.g.: generic medicines vs. biological products) are important scientific reasons for different approaches between WHO prequalification programmes [28].

In some instances the pressure on vaccine manufacturers to increase capacity leads to introduction of changes in the manufacturing processes aimed at increasing yields, purity or achieving other improved characteristics. Scaling up manufacturing, renovating or building up new facilities, new equipment and changes in processes may impact product characteristics, thus requiring approval by the NRA prior to the review by the PQ experts.

As for drugs, the procedure in place for the prequalification of diagnostics [29] does not require the functionality of the NRA. The main reason for this is the fact that in many countries where these diagnostics are produced, the NRAs are not yet developed enough to ensure their regulation. Similarly to the situation with generic medicines, the risk assessment analysis remains favourable to enable WHO prequalification in absence of a recognized functional NRA in the country of manufacture.

In spite of different approaches among the PQ programmes, especially with respect to the role played by the local NRA and the funding mechanism, the three programmes have very similar approaches with respect to the way in which the evaluation of products is performed: a review of a dossier, consistency testing of samples or performance evaluation and inspection/audit of the manufacturing facilities.

Current challenges facing the vaccines prequalification programme

Vaccines are one of the most successful and cost-effective health interventions. According to the State of the World's Vaccines and Immunization report (2009) “Immunization – even with the addition of the new, more costly vaccines – remains one of the most cost-effective health interventions.” The publication remarks that “more children than ever before are being reached with immunization: over 100 million children per year in the period 2005–2007. And the benefits of immunization are increasingly being extended to adolescents and adults – providing protection against life-threatening diseases such as influenza, meningitis, and cancers that occur in adulthood” [30].

According to data presented in the Global Vaccine Action Plan [31], the annual number of deaths among children under five years of age fell from an estimated 9.6 million in 2000 to 7.6 million in 2010, despite an increase in the number of children born each year. This is the result of improved access to clean water and sanitation, increased immunization coverage and the integrated delivery of essential health interventions.

Despite this progress, vaccine-preventable diseases remain a major cause of morbidity and mortality. Adoption of new vaccines by low- and middle-income countries has been slower than in high-income countries. In 2010, for example, only 13% of the total high income country birth cohort lived in countries that did not have pneumococcal conjugate vaccines in their immunization schedules. Of the total low-income country birth cohort, 98% lived in countries that did not have pneumococcal conjugate vaccines in their schedules [31].

In January 2000, the Global Alliance for Vaccines and Immunization (GAVI) was launched with the aim to fund vaccines for children in the world's 70 poorest countries. Its mission is to save children's lives and protect people's health by increasing access to immunization in the world's poorest countries. By pulling together the expertise and support of global key players in immunization – WHO, UNICEF, the World Bank, the Bill & Melinda Gates Foundation, donor governments, developing countries, international development and finance organizations and the pharmaceutical industry, the access to vaccines in national immunization programmes in developing countries has increased in recent years bridging the gap in immunization coverage for basic vaccines, accelerating the introduction of novel vaccines and fostering research and development of vaccines targeted to diseases endemic in developing countries [32].

The GAVI focuses its efforts on low and lower middle income countries and prioritizes a number of vaccines for introduction. Their current portfolio of priority vaccines includes the following: human papilloma virus (HPV), measles rubella, measles second dose, meningococcal A conjugate (Men A), pentavalent (diphtheria-tetanus-pertussis, hepatitis B, Haemophilus influenzae type b), pneumococcal conjugate, rotavirus, and yellow fever [32].

GAVI prioritized vaccines that are supplied to eligible countries through the UN centralized procurement mechanisms require prequalification as a condition for purchase.

Acceleration or increase of vaccine access leads to an increased demand for prequalification both by requiring expansion of the portfolio (types of vaccines assessed) as well as securing enough supply sources for each vaccine used in immunization programmes.

With the availability of licensed vaccines used to prevent and control 25 vaccine preventable diseases, it is now time to show commitment to achieve the full potential of immunization. The collective recognition of this opportunity has led the global health community to call for a Decade of Vaccines, in line with the requests made in resolution WHA 61.15 on the global immunization strategy. “The vision for the Decade of Vaccines (2011–2020) is of a world in which all individuals and communities enjoy lives free from vaccine-preventable diseases. The mission of the Decade of Vaccines is to extend, by 2020 and beyond, the full benefit of immunization to all people, regardless of where they are born, who they are or where they live.

The Global Vaccine Action Plan reiterates existing goals and sets new goals for the decade, proposes six strategic objectives and the actions that will support their achievement” [31].

Increasing number of vaccines are being produced in developing countries due to mergers, acquisitions, outsourcing of vaccine production steps including filling, freeze drying and labelling [33], [34]. In this context, the prequalification programme addresses an extensive portfolio of vaccines [35] of variable complexity, some of them produced in multiple sites in single or different countries. Work towards expanding the supply base to secure availability of traditional, under used and recently introduced vaccines for global supply entails exploring potential suppliers from countries with recently declared functional NRAs. These candidate manufacturers usually do not have experience with exporting vaccines and are therefore not familiar with the international standards of quality required by the WHO prequalification programme. The NRAs of the countries where these vaccines are manufactured are also new to the required standards and regulatory expectations; sustainable prequalification represents thus a challenge for them as well as for WHO.

Table 4 updates previous published information [20] and show a steady increase in the types of vaccines included in the prequalification portfolio and the number of suppliers. The percentage of suppliers from emerging economies showed rapid increase until 2006 and has now diminished relative to the total, most likely due to the prequalification of a significant number of novel vaccines developed and initially produced by developed country manufacturers. Suppliers have been categorized as from emerging economies when their products are regulated by NRAs from countries in this category.

Table 4

Sources of prequalified vaccines.

Year	No. of vaccine types	Number of suppliers	% from emerging economies
1986	6	13	13
1996	13	18	37
2006	24	22	55
2012	33	27	48

Another current challenge is sustainability of supply which is critical to vaccine security for national immunization programmes. In this respect, the role of the prequalification programme is even more important in the post-prequalification phase than before prequalification is granted. The continuing monitoring of quality and performance of prequalified vaccines in use in the target countries is an important component of the activities of the programme. This implies testing of vaccine lots shipped to countries to ensure that the vaccines continue to meet the established specifications (both WHO recommended and UN tender-related), review and approval of variations introduced to the manufacturing process or quality control methods, monitoring and investigation of reports of adverse reactions and of complaints. Table 5 shows the increase in post-prequalification related activities between 2009 and 2012.

Table 5

Evolution of post-prequalification, and other PQ, activities.

Post PA and other PQ activities	2009	2010	2011	2012
Reassessments	11	12	10	12
Annual reviews	6	21	74	53 (448)
Testing	124	159	183	105
Complaints/other issues of concern	3	13	16	15
AEFIs	7	7	7	14
Meetings with manufacturers	62	80	71	119
Meetings with NRAs/other stakeholders	33	86	64	109

Changes to the prequalification procedure introduced in the last revision adopted by ECBS in 2010 and implemented since February 2012 [25] aim at addressing these challenges: decreasing time taken for prequalification; improving assistance provided in response to complaints from the field and reports of AEFIs; and improving transparency and communication to stakeholders and public as well as maximizing the efficient use of resources. Particularly relevant is the introduction of a streamlined procedure for the evaluation of vaccines produced in selected countries with NRAs that are considered stringent (Australia, Belgium, Canada, EMA, France, Italy and USA), and that agree to collaborate with WHO by providing the assessment reports, inspection reports, and test results for the candidate products. These authorities are also engaged in establishing continuing communication with the PQ programme in case problems are identified in the quality, safety or efficacy of the prequalified vaccines under their jurisdictions.

It is expected that increased reliance in the work performed by these NRAs will free capacity at the PQ secretariat to focus increased attention on vaccines that have been recently licensed and prequalified and are produced by less experienced manufacturers in countries with less robust NRAs. Usually, such products require a closer monitoring due to need for scaling up production, improvement of product characteristics and other needs that may entail significant changes in the production process or QC methods used.

Performance of the vaccines prequalification programme

The staffing of the programme in 2013 consists of one programme manager, six professionals and four support staff. Four of these professionals are quality experts (focused on performing quality reviews), one is a clinical expert (for clinical reviews) and one is a testing expert (sample testing). Three secretaries provide all the administrative support; two are trained in and responsible for the logistics of receiving, keeping and shipping vaccine samples for independent testing in the WHO contracted laboratories.

This small secretariat works in close collaboration with, and with the contribution of, NRAs worldwide, eight from industrialized countries and seven from emerging economies. These NRAs donate staff time to contribute to the programme in the quality evaluation of the candidate vaccines. However, for the evaluation of the clinical data a network of independent clinical experts is used. The evaluation of manufacturers in terms of GMP is secured by contracting independent experts, although some NRAs also make in kind contributions of national experts.

A network of 12 laboratories worldwide secures the testing needs of the programme [36]. Independent testing of vaccine samples remains a challenge, particularly for novel vaccines where the expertise to perform the required tests rests with a very limited number of laboratories, and in some cases is restricted to the National Control Laboratory (NCL) of the producing country. Securing a minimum level of expertise worldwide to perform relevant tests independently from the manufacturers remains one of the objectives of the prequalification programme. Work with manufacturers has been initiated to foster establishment, through methodology transfer to at least one laboratory in addition to the NCL responsible for lot release. Additional work has been initiated with view at harmonizing test methodologies between the different WHO contracted laboratories in cases where this is relevant.

As part of the assessment of the performance of the prequalification process, in April 2012 the PQ Programme commissioned a survey with a specialized company addressed to vaccine manufacturers to measure the quality of service provided by the programme.

The objectives of the survey were to look at the quality of service design (process) and service delivery (people) particularly in the context of file review and site audits, with a view to identifying areas for improvement. The survey participants included manufacturers with one or more prequalified vaccines.

A list of 81 potential contacts was developed with intervention of regulatory affairs professionals (for the file review aspects) and of quality assurance professionals (for the site audit aspects). There was a 54% response rate with 23 of 29 companies providing completed response to the survey. PQ service was measured on a 7 point scale (SERVQUAL) [37] with two additional questions to describe the expectations from manufacturers: minimum level of service (minimum level of service performance acceptable to the manufacturer from any major regulatory agency) and desired level of service (the level of service performance that a regulatory agency should deliver). These two additional measures provide a range of acceptable level of service quality.

The main findings of the survey were the following:

Vaccine manufacturers consider that the service provided by the WHO vaccines prequalification programme is within the range of an acceptable level of performance compared to agencies that review and approve vaccine products.

In no area in the study is the PQ programme performing significantly below manufacturers’ minimum expectations.

Overall, the programme is especially strong in those aspects of service that build applicant's confidence and increase their comfort level with the overall process.

Major strengths identified were the following:

Providing the same reviewers throughout the file evaluation

Clarity of questions asked during the site audits

Auditors who handle confidential data/information in a way that makes applicants feel safe

Providing direct access to team leader to address technical questions or deficiencies

Providing timely announcement of audits

Agency rationale for the list of priority vaccines

Major areas for improvement identified by manufacturers were the following:

Concern about overall time required for prequalification and process time inefficiencies (overall elapsed time, knowing when to expect a response).

Sample testing is an area in which the programme is performing at minimum level of expectations.

Suggestions from the manufacturers for process improvement were the following:

Implementing fixed timelines for review and response.

More up-front collaboration between applicants and the WHO-PQ to develop a shared understanding of requirements and deliverables.

Sample testing performed in parallel with the Product Summary File (PSF) review.

Suggestions from the manufacturers for delivery improvement were the following:

Improved communications and follow up.

Timely feedback/reporting.

Consistency in GMP interpretation.

Some of these areas for improvement have been addressed through changes introduced in the procedure in the 2010 version [25] by implementation of a streamlined procedure for products originating in countries with experienced NRA/NCLs, by waiving the requirement for testing in cases where the NCL in those producing countries have confirmed production consistency through independent testing and agrees to share their results with WHO, by tightening the monitoring of timelines taken to complete the different steps of the procedure (through an internal monitoring tool), by encouraging meetings between manufacturers and WHO-PQ secretariat in advance to submissions and during evaluation to improve communication and to develop a shared understanding of requirements and deliverables. Furthermore, the secretariat publishes points to consider type documents to provide clear guidance to manufacturers on PQ expectations in different areas or aspects of the process [38], [39], [40]. Three additional documents are currently under development. These are addressing important and current issues: variations, validation of manufacturing process and risk analysis in case of deviations [unpublished].

In spite of the efforts to improve the performance of the programme to meet manufacturers and country expectations, a few constraints remain to be addressed. The most important one has to do with the lack of capacity at global level for testing novel vaccines. This lack of capacity is important not only at the time of evaluation of candidate vaccines but even more during the introduction phase of such vaccines into immunization programmes. The aspiration of manufacturers of having their vaccines tested in parallel with the file review is difficult to realize unless methodology transfer to the relevant and other NCLs is ensured in advance to registration and prequalification submissions, which is not always achieved.

Another area highlighted by manufacturers as requiring some improvement was related to consistency in interpretation of GMP requirements. An ongoing review of the GMP audits performed by the team will allow implementing a corrective action plan aimed at achieving a greater alignment in the way GMP requirements are enforced.

Looking into the future

The programme perceives itself as an interim mechanism required to secure vaccines of assured quality for countries while appropriate procurement expertise and regulatory capacity for vaccines is developed. Ideally, regulatory capacity will increase over time up to a point where the programme will become irrelevant. At least three fundamental conditions are required to make of this goal a reality: strong regulatory capacity in all exporting countries; sufficient regulatory capacity in the receiving countries; and decentralized procurement mechanisms (direct procurement by countries or groups of countries).

Currently, of the 90–100 countries served by UNICEF, the majority have limited or no regulatory expertise for vaccines. The situation is different in countries served by the PAHO Revolving Fund, where several have been satisfactorily evaluated with respect to their regulatory capacity. In any case, devolving the responsibility of assuring the quality of imported vaccines to each and every NRA from low and middle income user countries is an unrealistic short or mid-term expectation in most regions of the world.

The WHO Region of the Americas (PAHO/AMRO) is perhaps the exception to the rule, since several countries of the Region have well developed regulatory capacity. Since PAHO acts also as an important UN purchasing agency through its Revolving Fund [41], this region could consider accepting for purchase products that have been registered by a functional authority in the region and which are commercialized in the country that has granted the marketing authorization. However, such an approach has several challenges to replicate the service that is currently offered by the prequalification programme. For example:

There would be no guarantee that a single standard of quality, safety and efficacy is applied, i.e. WHO recommended requirements for vaccines.

The clinical data reviewed may be applicable to the population of the country granting the registration but not necessarily elsewhere.

Review of data related to immunization schedules and co-administration with other vaccines may also be restricted to the policies in use in the country granting the registration.

Vaccine presentation issues may not have been considered

Finally a very important constraint of such approach would be the lack of a mechanism to deal with the post-marketing activities, including management of complaints, reports of AEFIs, monitoring of continued compliance, approval of variations, etc.

An alternative option, potentially more widely applicable, could be to make use of pooled expertise based on a collective effort. Several WHO regions have established networks of regulators aimed at information sharing, strengthening regulatory capacity, harmonization of standards and procedures and ultimately as a long term goal achieving mutual recognition of work done by others in the network. There are also regulatory networks established as part of trade agreements between countries. Use of networks can be envisaged as a way to pool expertise to assess vaccines that are priority for a specific region. This approach has the advantage of leveraging expertise from different countries, wherever this is stronger, agreement on a common standard to be applied, sharing resources between the participating countries and establishing a collaborative and consensual mechanism for decision making. This approach may allow focusing on the specific needs of NIPs in the region in terms of clinical data, immunization schedules and programmatic characteristics. The network could and should monitor and investigate complaints and Adverse Events Following Immunization at least within their territory.

The EMA represents an example of a well-functioning regulatory network.

Decision making by the network regulators may well be valid for procurement of vaccines within the region but may not be automatically extrapolated or acceptable to other regions.

An important aspect to consider in any scheme alternative to the current PQ is the procurement mechanism. If the vaccine supply to low, low middle income and middle income countries continues to be managed through centralized procurement, diversification of decision making, of standards used, and decentralized management of complaints and AEFI may be difficult to deal with and not suitable for the procurement agencies. In addition, such diversification would also impact and increase workload for manufacturers who would have to deal with several independent authorities and their individual requirements.

Currently, there are a few regional procurement mechanisms in place that are independent from UN, i.e. for Gulf countries [42]. A regional regulatory network associated to a regional procurement mechanism may work for a particular region.

A complete elimination of global PQ functions would necessarily require to be linked to a decentralization of procurement to regional level with reliance on a regional regulatory network decision making body. This will require increased regional procurement expertise. This approach carries the risk of creating a fragmented market, increased prices unless a low cost supply is locally available, higher transaction costs, loss of global suppliers. Market fragmentation might negatively impact on product innovation and supply.

If a future replacement mechanism, whatever it is, is not fully accepted by user countries, it could end in a shift to products manufactured in countries with stringent NRAs, or conversely only from emerging manufacturers, leading to a potential loss of market diversity and potentially also price implications.

With the current procurement mechanism being centralized, it is the view of the authors that a network approach would be the most feasible approach provided that a minimum of functions is maintained at WHO level as a centralizing body partnering with both the evaluating network and the procurement agencies. The role of WHO would be to ensure suitability of clinical data and product characteristics at global level and more importantly to address in a consolidated manner the post-marketing functions.

Continuing work is required from WHO and partners to further strengthen regulatory capacity and expertise globally, and there is a need to test any alternative approach to PQ in at least one region to assess its feasibility. Proper transitioning of functions from PQ to national regulators would require the development of a road map with clear milestones and expected timeframes for implementation.

Conclusions

The WHO prequalification programme for vaccines has continually developed and evolved over a 25 year-period. Currently 127 vaccines are prequalified. These are used in 134 countries and approximately 64% of the global birth cohort is immunized with prequalified vaccines. The prequalification “seal of approval” is a powerful driver not only of public health but also of industrial policy development in countries that wish to supply international markets. Reliance of the NRA of record in the manufacturing country has also provided a powerful incentive to develop regulatory capacity. The prequalification service provided by WHO is however considered to be an interim solution as national capacity for procurement and regulatory processes is built. As the programme enters the next period of its evolution, plans are being developed and articulated for an eventual phased transition to increased country responsibility, perhaps through a collaborative effort between Regulatory Networks and WHO.