Developing a vaccine that is stable at room temperature for 8 weeks

There is a pressing need to improve the storage stability of currently available vaccines, and achieving this could facilitate mass vaccination campaigns and increase vaccination coverage on a global scale — particularly to underserved and remote regions of the world. With the cost of coldchain maintenance high and its quality control difficult to ensure in developing countries, it is imperative that the stability of vaccines be improved. As such, we sought to develop a measles vaccine formulation that could be stored for a reasonable length of time at ambient temperature (25–50 °C), and be transported and administered both safely and conveniently.

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Following our research efforts, in collaboration with the international non-profit organization PATH, we formulated and developed an improved measles vaccine that is stable for at least 8 weeks at 37 °C.¹

Developing a stable formulation

Through formulation development and spray drying, we vastly improved the storage stability of the measles vaccine.

The growing need for auto-injectors

Spray drying the measles vaccine under mild conditions (i.e., low atomization pressure and drying temperature) was the key to maintaining the titre of the vaccine during processing. We utilized a nozzle that atomized the liquid vaccine into fine droplets at a relatively low pressure (compared with commercially available two-fluid nozzles) and the drying temperature was optimized accordingly; the choice of drying temperature is a fine balance between drying efficiently (i.e., at higher temperatures) and minimizing vaccine deactivation (i.e., at lower temperatures).

Delivering drugs through mucus

The stable formulations, which comprised all excipients that are approved for human use, consisted of a mixture of sugars (trehalose and sucrose) in potassium phosphate buffer as base excipients. We then incorporated our patented plasticisation technology to further enhance the storage stability of the measles vaccine. Other components that we found to stabilize the vaccine included Larginine, human serum albumin and a mixture of divalent cations.

Process challenges

The challenges we faced with the measles vaccine were the same as those encountered with other virus and bacteriabased vaccines, which we have worked on previously: to minimize the process loss; and to maintain the vaccine titre during storage.

The measles vaccine comprises live attenuated measles virus and, as such, we could not employ traditional spray drying conditions (i.e., high atomization pressure, high drying temperature, etc.); we observed process loss resulting in > 1 Log₁₀ in vaccine titre under traditional spray drying conditions. With optimization in atomization pressure, drying temperature and solution feed rate, we minimized the process loss to < 0.2 Log₁₀. The formulation components do have an impact on process recovery; with certain formulation mixtures, we were able to see no process loss from spray drying.

Formulation challenges

For formulation development, we started with our base composition of sugars and buffer. The resulting storage stability was not sufficient (> 1 Log ₁₀ loss after 1 week of storage at 37 °C). Thus, several other excipients were screened, but we limited the list of excipients to those that are approved for human use. We discovered that a mixture of divalent cations was effective in enhancing the storage stability of the vaccine, but interestingly, the salts were not effective individually. Furthermore, the stabilizing effect of the salts was pH and concentrationdependent.

We also examined the influence of a surfactant, but this was removed from our lead formulation because it was found to be incompatible with other excipients (i.e., human serum albumin). Surfactants are very effective in enhancing the product yield from the spray drying process, but their amounts need to be optimized — especially for an enveloped virus such as the measles virus; the surfactant can solubilize the viral envelope and breach its integrity, leading to virus inactivation.

Cost-effectiveness and safety

The improved storage stability of vaccines has a number of potential cost benefits — primarily because of the savings related to the ability to transport and store the vaccine without refrigeration at the end of the distribution system. Switching the vaccination route from injection to inhalation might also reduce costs; for example, dry powder vaccines can be administered using very low cost, disposable units. These prefilled units could facilitate immunization, decrease vaccine wastage, minimize required materials (e.g., no vials and syringes needed) and improve safety. A full cost/benefit analysis is warranted to compare single dose prefilled inhalation units with the existing freezedried, multidose vials and syringes used to deliver the measles vaccine. In terms of processing, the time required to freeze dry a vaccine formulation could be significantly longer, and thus more costly, than a spray drying process.

With regard to safety, by foregoing the injection route, the reuse of syringes and needles can be avoided, which contributes significantly to crosscontamination and infection.

If clinical trials demonstrate the vaccine to be safe and efficacious (previous studies have demonstrated similar efficacy for vaccines administered by injection and inhalation² ), then the cost and safety advantages for inhalation therapy, compared with injection, should merit its consideration.

The future

The feasibility of dry powder measles vaccines has been studied by other groups;³ but prolonged stabilization of this vaccine at conditions above room temperature has not been demonstrated to date. The perception within industry is to apply freeze drying; the majority of currently available vaccines (in the solid dosage format) are processed by lyophilization and most companies have the capacity to lyophilize. In that respect, spray drying is a new and 'unproven' technique for most manufacturers. We have, however, shown that spray drying can effectively stabilize a variety of vaccines, including rotavirus and adenovirus. Furthermore, in the current study, the storage stability of the measles vaccine was shown to be superior to those of commercially available measles vaccines in a lyophilized format. As such, spray drying is a potentially feasible manufacturing process that should be considered by vaccine manufacturers.

Although the most direct application of a vaccine in a dry powder format may be to administer the vaccine to patients by the inhalation route, the powder dosage presentation can simply be reconstituted from single or multidose vials and parenterally administered, or can be converted to other dosage formats, including capsules, tablets, thin films, and so on.

With the improved storage stability (and heat stability), our hope is that the vaccine can be made more readily available to those patients in developing countries that desperately need more stable and efficient vaccines.

References

1. S. Ohtake, et al., "Development of 37 °C stable, inhalable dry powder aerosols containing live measles vaccine," 2009 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition (Los Angeles, CA, USA, 8–12 November 2009).

2. R.L. de Swart, et al., Vaccine, 24, 6424–6436 (2006).

3. C. LiCalsi, et al., Vaccine, 17, 1796–1803 (1999).

Professor Ohtake's research was presented at the 2009 American Association of Pharmaceutical Scientists (AAPS) Annual Meeting and Exposition, 8–12 November 2009, Los Angeles (CA, USA).