The Cal­i­fornian bio­phar­ma­ceu­tical com­pany Zosano Pharma is one of the pio­neers in the field of intra­cu­ta­neous drug admin­is­tra­tion using MAPs (microarray patches) as an alter­na­tive to oral delivery. These microneedle sys­tems pen­e­trate the upper­most skin layer, allowing a more rapid absorp­tion of active ingre­di­ents into the blood­stream than with oral ad­ministration. Zosano has devel­oped its own device, a pro­pri­etary intra­cu­ta­neous microneedle system.

Prior to appli­ca­tion, the patch ring assembly is snapped onto the hand­held, reusable applicator.

“The core of our tech­nology con­sists of almost two thou­sand drug-coated tita­nium micronee­dles,” explains Hayley Lewis, Senior Vice Pres­i­dent of Oper­a­tions at Zosano Pharma. “The patch is about the size of a two-euro coin and is applied to the skin using a reusable hand­held appli­cator. To make the appli­ca­tion as con­ve­nient and safe as pos­sible, the microneedle patch is mounted in two polymer rings. The patient snaps the outer ring onto the appli­cator. Once pressed down­ward, the appli­cator applies the patch with a pre­cisely defined energy onto the skin, while the ring ­assembly remains attached to the applicator.”

Novel processes and pre­cise mechanics

In the upper­most layer of the cutis, the epi­dermis, the drug coating is recon­sti­tuted and quickly avail­able for absorp­tion. “Our triptan-coated patch for the acute treat­ment of migraine, for which we filed an NDA to the FDA at the end of 2019, can be removed and dis­posed of after just 30 min­utes. Wear times of our system are con­sid­er­ably shorter than those of tra­di­tional trans­dermal sys­tems, which also have the draw­back that delivery of the active ingre­dient is typ­i­cally slow, as well as inef­fi­cient,” says Hayley Lewis.

Man­u­fac­turing an inno­v­a­tive device such as the intra­cu­ta­neous microneedle system required a series of novel processes. One of the chal­lenges was to find a dip coating tech­nology for applying tiny amounts of for­mu­la­tion on each microneedle. This is where Harro Höfliger, with their expe­ri­ence in the field of microneedle sys­tems and dosing processes in micro quan­ti­ties, came in as a partner for devel­op­ment and scale-up. Hayley Lewis: “A microneedle is only about 340 µm in height – pre­cise mechanics and high-end con­trol sys­tems are essen­tial for coating accu­racy and uni­for­mity. Our first joint mile­stone was a lab­o­ra­tory-scale coater for proof-of-prin­ciple (PoP). ­Harro Höfliger has scaled up the prin­ciple of a rotating drum that cre­ates a thin liquid for­mu­la­tion film for higher output.”

“Harro Höfliger and Zosano are both pio­neering this new tech­nology.”Hayley Lewis, Senior Vice Pres­i­dent of Oper­a­tions at Zosano Pharma

The fully auto­matic line from Harro Höfliger not only coats up to 12 prod­ucts per minute in a low bioburden envi­ron­ment. It also car­ries out the final assembly of the devices and pack­ages them indi­vid­u­ally in heat-sealed, nitrogen-purged foil cups. The sub­assembly of adhe­sive backing, inner ring and array are loaded in tubular con­tainers. These con­tainers are fed by a walking beam con­struc­tion to a robotic system where the parts are de-loaded and pre­pared for fur­ther processing.

A sep­a­rate robotic system dis­trib­utes the com­po­nents to four coating sta­tions where the arrays are dipped sev­eral times into the for­mu­la­tion film at a con­trolled depth, and speed. A high-res­o­lu­tion camera then checks for integrity of the micronee­dles and uni­for­mity of the coating. After coating, each sub­assembly is pressed into the outer ring. The final assembly is then trans­ferred to a cus­tomized SSP2 machine for forming, filling and sealing of alu­minum packaging.

Dis­cover fur­ther details of the fully auto­matic machine:

The sub­assembly of patch, inner ring and microneedle ele­ment are loaded in tubular containers.

A robot system dis­trib­utes the com­po­nents to the coating stations.

The micronee­dles are coated by a rota­tion drum that cre­ates a thin liquid for­mu­la­tion film.

A high-res­o­lu­tion camera checks for integrity of the nee­dles and uni­for­mity of coating.

After forming, a retainer is sealed into the cups into which the device is inserted with the cor­rect ori­en­ta­tion, fol­lowed by printing the cover foil, purging with nitrogen, sealing and punching. Quality and trace­ability play a major role: The prod­ucts are dis­charged on four lanes – one for each coating station.

“Harro Höfliger has an extremely tech­nical and dili­gent approach to processes and chal­lenges. We’ve come a long way together, and it has been a deep, col­lab­o­ra­tive expe­ri­ence,” says Hayley Lewis. “We’re both pio­neering this new tech­nology and have evolved in our under­standing of it. It’s always been a dia­logue, never a one-way conversation.”

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Photos: Zosano Pharma, Graphic: shutterstock.com/Tatiana Barinova