Let us rewind back to 1988: the world dances to the songs of Michael Jackson. The World Wide Web known as the Internet expe­ri­ences its first virus epi­demic. The first dig­ital camera is pre­sented, which – what a sen­sa­tion! – offers storage space for up to ten photos. And Harro Höfliger receives the first order for the HH20 assembly machine, which is to be deliv­ered to Macclesfield.

In the course of more than 30 years, the syringe design for AstraZeneca’s suc­cessful product has been mod­i­fied sev­eral times.

The machine auto­mat­i­cally opens the pre-assem­bled syringes, checks the depot length and pres­ence, inserts the del­i­cate implant con­taining the active ingre­dient, closes the syringes and trans­ports them to the removal point. 20 high-quality syringes per minute are pro­duced in this way – a major step for­ward com­pared to the pre­vi­ously purely manual production.

Inserting the brittle depot man­u­ally into a syringe was a tricky, time-con­suming oper­a­tion. 24 pre-­assem­bled syringes arrived in a tray to the “Grade A” lam­inar air­flow cab­inet. The oper­ator removed a single syringe, sep­a­rated the top and bottom halves, mea­sured the depot in a tem­plate, inserted it into the bottom half of the syringe using for­ceps, reassem­bled the syringe, closed and sealed it in a table mounted jig. The wrap-around self-adhe­sive label was also applied by hand. The syringe was then passed to the next sta­tion for hand inser­tion into a pouch and sub­se­quent final sealing.

The chal­lenge of aseptic production

The product at that time was still an oncology product of former British chem­ical giant ICI (Impe­rial Chem­ical Indus­tries). The implant releases the active sub­stance over a period of around four weeks as it dis­solves within the body. Wolf­gang M. Rauch, founder of Rau­pack Ltd., which was to become a 100 per­cent sub­sidiary of Harro Höfliger in 2012, recalls ini­tial talks with ICI in the summer of 1988. “We man­u­fac­tured a rig for sep­a­rating and sorting the approx­i­mately 10 mm long depots and pre­sented a suc­cessful sta­tion in autumn.”

This was a mile­stone because it was the first aseptic project in Harro ­Höfliger‘s his­tory and it was to lay the foun­da­tion for today‘s pro­found know-how in the field of sterile pro­duc­tion. With the HH20, the oper­ator loaded the tray and all 24 syringes were auto­mat­i­cally removed and processed one ­after the other. Fol­lowing on from the suc­cess of the HH20 Syringe Filling & Assembly Machine, Harro Höfliger went on to develop an auto­mated pouch filling and sealing system, a car­toner with a feeding and sealing sta­tion and an auto­mated labelling system: a com­plete turnkey line was created.

This is how the HH20 and HH60 lines worked:

The HH20 allowed pro­duc­tion of 20 syringes per minute. The trays were pre­sented to the machine by the oper­ator and each syringe was auto­mat­i­cally removed, opened and passed on to sub­se­quent operations. 

Assembly of the syringe shield. Harro Höfliger con­verted all HH60 lines to incor­po­rate tech­nology for the pro­tected needle syringe to coun­teract the hazard of needle-stick injury.

Rau­pack drew up the require­ment spec­i­fi­ca­tions for ICI and later the first val­i­da­tion and qual­i­fi­ca­tion doc­u­men­ta­tion. Here, too, Harro Höfliger broke com­pletely new ground. In close coop­er­a­tion with ICI, the nec­es­sary doc­u­men­ta­tion was devel­oped for pre­sen­ta­tion to the reg­u­la­tory author­i­ties. “When he saw the doc­u­men­ta­tion package, com­pany founder Harro ­Höfliger’s com­ment was that it weighed nearly as much as the equip­ment itself. He said that his com­pany was in the busi­ness of building machines, not paper moun­tains,” recalls Dr. Neil Calder of HH Pack­aging Sys­tems Ltd. with a smile. “Little did we know back then, how impor­tant the val­i­da­tion and qual­i­fi­ca­tion package would become to sup­plying equip­ment into the phar­ma­ceu­tical industry.”

When ICI trans­ferred all of its phar­ma­ceu­tical busi­ness to the Zeneca Group in 1993, Harro ­Höfliger had already sup­plied four HH20 lines. In 1999, when Zeneca merged with the Swedish com­pany Astra, the number of machines had increased by sev­eral more lines.

State-of-the-art

In view of the ever stricter reg­u­la­tory require­ments for aseptic pro­duc­tion, and as the product was increasing world­wide sales, AstraZeneca and Harro Höfliger were faced with the chal­lenge of devel­oping a new, faster gen­er­a­tion of equip­ment. A walk-in lam­inar air­flow unit was devised.

In 1992 the HH60 was born, a state-of-the-art line for fully auto­matic filling, assembly, labelling, pouching, and pack­aging tar­geting 60 syringes per minute. It took into account modern aseptic pro­cessing, reducing the risk of micro­bial con­t­a­m­i­na­tion by sep­a­rating the oper­ating staff from crit­ical areas of man­u­fac­ture. A total of four HH60 lines have been sup­plied to AstraZeneca and these turnkey lines have gone on to pro­duce mil­lions of filled syringes.

Over three decades, the syringe design has been mod­i­fied sev­eral times due to reg­u­la­tory require­ments. One example is the syringe shield, which is designed to coun­teract the hazard of needle-stick injury. All HH60s were suc­cess­fully con­verted to incor­po­rate this new technology.

The next gen­er­a­tion of the turnkey line for filling, assem­bling, pouching, sealing and labelling of the syringes will fea­ture closed bar­rier tech­nology with VHP decontamination.

30+ years of partnership

Harro Höfliger is also involved in the next gen­er­a­tion of equip­ment to sup­port pro­duc­tion at Mac­cles­field. This involves a new state-of-the-art line, including closed Restricted Access Bar­rier System (cRABS) tech­nology, incor­po­rating inte­grated decon­t­a­m­i­na­tion with vapor­ized hydrogen per­oxide (VHP). Auto­matic inline 100% leak testing of the “final sterile bar­rier sealed pouch” will be car­ried out to ensure that the line meets the highest stan­dard of sterile pro­duc­tion for years to come.

Harro Höfliger in con­junc­tion with AstraZeneca are striving to ensure that patients all over the world con­tinue to be sup­plied with Zoladex.

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Photos: Helmar Lünig