Scale Up for Pandemic
Figure 9. Scale-up process for manufacturing 20,000 units per lot using two automated lines.
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A pilot-scale patch production line has been custom built specifically for making LT, as well as other vaccine antigen dry
patches. The pilot-scale facility can produce 20,000 units per lot using an automated continuous-based dryer and laminator
or packaging equipment. Briefly, the formulated LT blend is dispensed onto circular patch matrixes, which have been previously
bonded to an occlusive backing film web roll (Figure 9). The LT-dosed, patch matrix and backing web is continuously fed into
a drying oven at a set speed. The resulting dried patch web is then fed into a patch assembly machine and is laminated (sandwiched)
between an adhesive overlay and a release liner. The assembled patch is finally inserted in a foil pouch, which is purged
and sealed under nitrogen. The final design of the patch product is shown in Figure 6.
The patch manufacturing processes described above are inherently scalable to meet pandemic flu needs. Capacity can be increased
many-fold by widening the patch film web and dryer. Moreover, by increasing the dryer length, the speed of the patch web could
be increased during oven drying. Finally, extra lines of the automated dryers and laminator or packaging equipment can be
added to increase output capacity. Scale-up planning is currently under way to identify critical design parameters to produce
and stockpile 150 million LT-IS patches within a six month period.
Summary
A dose sparing strategy for vaccines is being developed with an adjuvant (immunostimulant) skin patch. This strategy uses
E. coli heat-labile enterotoxin protein (LT) as an adjuvant, and application of the dry LT-IS patch over the vaccine injection site.
Preclinical and clinical trials have demonstrated proof-of-concept for the LT-IS patch. Extensive formulation development
work has been carried out to identify a stable dry formulation matrix for LT as well as for vaccine antigens. Based on ongoing
stability studies, the dry LT-IS patch is stable for 22 months at 2-8° C and up to 6 months at 25 ° C. Moreover, it was shown
to be stable against multiple thermal cycles between -20 ° C and 40 ° C (two days per cycle), demonstrating that the LT-IS
patch can tolerate temperature excursions during shipping and distribution. We have found that maintaining a low water activity
in the patch is critical for ensuring product quality and eliminating microbial growth. The formulation characteristics of
the dry LT-IS patch, including its inherent stability, and its use as a dose sparing strategy by which a smaller dose of injected
vaccine can produce an effective immune response, make the patch an excellent candidate for mass production and for stockpiling
in the event of a flu epidemic. We anticipate that the LT-IS patch will become part of the regular medical arsenal for combating
infectious diseases such as seasonal influenza and pandemic flu.
Acknowledgement
The authors wish to thank Ms. Wanda Hardy for assistance with manuscript preparation.
Jee Loon Look, PhD, is the director of formulation and process development at Iomai Corporation, Gaithersburg, MD, 301.556.4500, jlook@iomai.com
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References
1. HHS pandemic influenza plan. US Dept. of Health and Human Services. 2005 Nov. Available from: http://
http://www.hhs.gov/pandemicflu/plan/
2. Webby RJ, Webster RG. Are we ready for pandemic influenza? Science 2003 Nov 28;302(5650):1519–22.
3. Wood, JM. Developing vaccines against pandemic influenza. Philos Trans R Soc Lond. B. Biol. Sci. 2001;356(1416):1953–60.
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