by Sy Gebrekidan (Merck), Debra Kristensen (PATH), Osman Mansoor (UNICEF), Gisele Corrêa Miranda (Fiocruz), Robert Steinglass (JSI), and Simona Zipursky (WHO) In 2009, the Vaccine Presentation and Packaging Advisory Group (VPPAG) published its first generic preferred product profile (gPPP) for vaccines intended for use in public-sector immunization programs in low-resource settings. Informed by these recommendations, the World Health Organization (WHO) issued guidelines for Programmatic Suitability of Vaccine Candidates for Prequalification in the same year. Since then, several manufacturers have changed the presentation or packaging of their vaccine products to be more responsive to developing-country constraints. For immunization programs in developing countries, getting vaccines safely and reliably to children in remote areas is a serious challenge. Exposure to excessive heat or freezing temperatures can compromise the potency of certain vaccines, and in low-resource settings it may be difficult to transport and store vaccines at the appropriate temperature. The addition of new vaccine formulations or presentations to these already stretched systems can generate further problems. Traditional cold chain systems lack the capacity to handle the much larger number of vaccines that exist today (though a number of timely new initiatives promise expansion and improved maintenance), while many new vaccines are presented and packaged in a way that can create serious management difficulties for countries with poor infrastructure. Strengthening national immunization systems and providing support to health workers tasked with delivering vaccines will help to address many of these challenges. However, in environments with limited resources, protecting every child with lifesaving vaccines may not be possible without also improving the design and presentation of vaccines themselves. In fact, many supply chain problems can be best addressed at the earlier stages of vaccine development, where decisions relating to formulation, packaging, labeling, and presentation can make vaccines more suitable for distribution, storage, and use in low-resource environments. However, without effective dialogue with stakeholders in developing-country immunization programs, it can be difficult for vaccine manufacturers to take these perspectives into account. Established in 2007, the VPPAG has become an important forum for discussion between the private and public sector on how vaccine products can be designed to suit the needs of developing countries. The VPPAG generic preferred product profile and workplan published by the VPPAG summarizes the agreed upon recommendations for vaccine producers and developers on formulation, presentation, labeling, and packaging of new vaccines for use by public-sector programs in developing countries. In recent years, manufacturers have demonstrated the adoption of these recommendations early in the vaccine development process. Several companies have also redesigned vaccine products to meet these recommendations in second- and third-generation products. Adherence to the product requirements of WHO Quality, Safety and Standards is essential for prequalification; alignment to the recommendations provided in the gPPP will help to ensure maximum market penetration and user acceptability in developing country settings. One such recommendation in the gPPP states that vaccine product should ideally be in a format that “minimizes volume and weight of secondary and tertiary packaging, as well as the need for repackaging for in country supply chain distribution.” Following increased dialogue with vaccine manufacturers and developers, as well as the publication of the gPPP, several first-generation WHO-prequalified vaccine products have successfully been redesigned to decrease their volume per dose footprint, often helping to mitigate the need for increased space for cold storage and transport. For example, Pfizer (formerly Wyeth) updated their first-generation pneumococcal vaccine Prevnar® (licensed in 2007 and originally designed for high-income markets) from a prefilled glass syringe to a single-dose vial presentation (licensed in 2009) for developing-country use. The change in packaging and presentation reduced the cold chain space per dose required from 55.9 cm3 to 12 cm3. The four-fold reduction in volume now helps countries mitigate the need to invest in new refrigeration equipment to accommodate new vaccines. In 2012, in response to recommendations provided by the VPPAG, the vaccine manufacturer Crucell also reduced the packaging size for their Quinvaxem® pentavalent vaccine from 13.1 cm3 to 10.3 cm3 per dose. These small changes in packaging increased the vial capacity of tertiary packaging (that is, the boxes used for shipment) by 17 percent, leading to more cost-effective shipping. The gPPP advises that manufacturers should “provide vaccines, whenever possible, in ‘ready-to-use’ presentations that do not require the mixing of components.” It also states that vaccines should be provided “in formats to minimize number of steps and potential for error during preparation and administration.” Following feedback from health workers that GlaxoSmithKline’s (GSK) first-generation lyophilized rotavirus vaccine, Rotarix®, was difficult to reconstitute and consumed a significant amount of cold storage space, the vaccine manufacturer changed their lyophilized rotavirus vaccine (licensed in 2004) requiring 156 cm3 per dose to a ready-to-use liquid presentation in an oral applicator (licensed in 2007) requiring 85.3 cm3 per dose. GSK further developed a plastic tube presentation (licensed in 2010) requiring only 17.1 cm3 of space per dose to store and transport. Another recommendation of the gPPP states that vaccine products should “maximize vaccine heat stability to improve effectiveness and enable higher temperature storage.” This trade-off in formulation and thermostability is challenging to achieve. However, GSK’s evolution of Rotarix® resulted in the meeting of developing country demands surrounding ease-of-use and small packaging volume, without compromising thermostability of the product (both products have a vaccine vial monitor 14 [VVM14]). The gPPP also states: “Vaccines packaged in prefilled injection devices should have both space-saving and auto-disabling features.” In response to this, Crucell has been developing a new presentation of its Quinvaxem® fully-liquid pentavalent vaccine in a compact, prefilled, single-use, autodisable device (cPAD). The company has introduced a novel secondary packaging design to minimize storage volume of Uniject™ cPAD devices to equal the volume per dose of a single-dose vial format. The innovative resealable tray being developed by Crucell contains 20 Uniject™ injection systems and has been shown to fit comfortably in WHO-prequalified vaccine carriers. Twelve of these trays (containing a total of 240 devices) can be contained within a single carton. By comparison, just 50 single-dose vials of Quinvaxem® can be contained in a carton of comparable size. Discussions with VPPAG members from WHO and PATH were important in advising Crucell in the development of their new presentation. “VPPAG is a great way of establishing contact with the public sector,” explained Dr. Olga Popova, Head of Global Vaccine Policy at Crucell. “We talked to many stakeholders and got to understand the most important delivery problems facing developing countries. For us, it’s critical that advisory groups keep their doors open to industry so that knowledge can be shared and decisions can be well-informed and endorsed. If we have a question, we need to be able to ask the right people at the right moment of the development process.” By working with the VPPAG and other immunization stakeholders to better understand country needs and constraints, vaccine manufacturers can make their vaccines more suitable for distribution, storage, and use in low-resource environments. Doing so has the potential to address some of the most pressing vaccine storage and distribution problems faced by immunization programs in developing countries. Learn more about the VPPAG by reading the following article in the January 2013 edition of the WHO Bulletin: http://www.who.int/bulletin/volumes/91/1/12-110700.pdf Note: The statements, views, and opinions presented in this article do not necessarily reflect the opinions of Merck & Co., Inc.
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