Considerations in the sterile manufacture of polymeric microneedle arrays

Abstract

We describe, for the first time, considerations in the sterile manufacture of polymeric microneedle arrays. Microneedles (MN) made from dissolving polymeric matrices and loaded with the model drugs ovalbumin (OVA) and ibuprofen sodium and hydrogel-forming MN composed of "super-swelling" polymers and their corresponding lyophilised wafer drug reservoirs loaded with OVA and ibuprofen sodium were prepared aseptically or sterilised using commonly employed sterilisation techniques. Moist and dry heat sterilisation, understandably, damaged all devices, leaving aseptic production and gamma sterilisation as the only viable options. No measureable bioburden was detected in any of the prepared devices, and endotoxin levels were always below the US Food & Drug Administration limits (20 endotoxin units/device). Hydrogel-forming MN were unaffected by gamma irradiation (25 kGy) in terms of their physical properties or capabilities in delivering OVA and ibuprofen sodium across excised neonatal porcine skin in vitro. However, OVA content in dissolving MN (down from approximately 101.1 % recovery to approximately 58.3 % recovery) and lyophilised wafer-type drug reservoirs (down from approximately 99.7 % recovery to approximately 60.1 % recovery) was significantly reduced by gamma irradiation, while the skin permeation profile of ibuprofen sodium from gamma-irradiated dissolving MN was markedly different from their non-irradiated counterparts. It is clear that MN poses a very low risk to human health when used appropriately, as evidenced here by low endotoxin levels and absence of microbial contamination. However, if guarantees of absolute sterility of MN products are ultimately required by regulatory authorities, it will be necessary to investigate the effect of lower gamma doses on dissolving MN loaded with active pharmaceutical ingredients and lyophilised wafers loaded with biomolecules in order to avoid the expense and inconvenience of aseptic processing.

Successful application of large microneedle patches by human volunteers

“…While the earliest work was rightly centred on the fundamental science of delivery and understanding of the resulting physiological effects, recent years have seen enhanced emphasis on translation to patient benefit and commercial return, with several notable companies making progress towards commercialisation. Indeed, a number of studies examining patient usability (Birchall et al, 2011, Donnelly et al, 2014a, Vicente-Pérez et al, 2016), scaled-up manufacture and quality control testing (Larrañeta et al, 2015, Larrañeta et al, 2016b, Lutton et al, 2015b), sterile production (McCrudden et al, 2015a) and regulatory considerations (Lutton et al, 2015a) have now been published. MN with applications in improving skin appearance are now available commercially, though it is notable that these are not approved drug products (McCrudden et al, 2015b).…”

Microneedle characterisation: the need for universal acceptance criteria and GMP specifications when moving towards commercialisation

“…Dissolving microneedles [31], whereby the MNs are made from drug-loaded, dissolving polymeric matrices, could be classed with other dissolving or disintegrating drug products, such as tablets. The likes of hydrogel-forming [21] or metal [19] microneedles, where the arrays are removed from the skin intact after drug delivery, may be classed alongside other parenteral products or medical devices.…”

Tip-loaded dissolving microneedles for transdermal delivery of donepezil hydrochloride for treatment of Alzheimer’s disease

“…In previous study, microneedles were sterilized using ethylene oxide gas or gamma radiation [41,42]. A sterilization process for DPH tip-loaded microneedles needs to be considered for clinical use in order to provide effective treatment as well as to ensure the economy and convenience of the process.…”