Aseptic phar­ma­ceu­ti­cals: Open to new approaches

They have got what it takes to rev­o­lu­tionize the phar­ma­ceu­tical market: Bio­phar­ma­ceu­ti­cals as well as gene- and cell-based ther­a­pies are raising the fight against infec­tious dis­eases, cancer and autoim­mune dis­eases to a new and promising level. But filling the sub­stances is chal­lenging. Harro Höfliger has answers.

Since the suc­cessful use of mRNA vac­cines against COVID-19, aware­ness of biotech­no­log­ical med­ica­tions has spread beyond the circle of experts. The phar­ma­ceu­tical industry has been increas­ingly using highly effec­tive and patient spe­cific ther­a­peutic approaches for years in the fight against diseases.

Since 2012, EMA (Euro­pean Med­i­cines Agency) and the US FDA (Food and Drug Admin­is­tra­tion) have approved sev­eral gene ther­a­peu­tics that can be used to adjust genetic defects in order to cure dis­eases. In the next three years the FDA expects around 800 new licenses. The sen­si­tive prod­ucts, often even living cells, are gen­er­ally admin­is­tered intra­venously, and are extremely chal­lenging to handle. They not only require aseptic pro­duc­tion but also sterile filling in bags, syringes or vials.

“Our motto ‘the product deter­mines the process’ is right on the nail here. We devote all of our exper­tise to the devel­op­ment of aseptic pro­duc­tion processes.” Chris­tian Kol­lecker, Director Aseptic Tech­nolo­gies at Harro Höfliger

Harro Höfliger has been dealing for years with the chal­lenges of the bridge between flex­ible pri­mary pack­aging and the demanding pro­duc­tion require­ments for aseptic bag filling. Chris­tian Kol­lecker, Sales Director Aseptic Tech­nolo­gies at Harro Höfliger, explains: “Our motto ‘the product deter­mines the process’ is right on the nail here. We draw on our full know-how for devel­oping aseptic pro­duc­tion processes. Together with our part­ners we develop com­pletely new machine plat­forms to offer our cus­tomers unique and indi­vid­u­ally con­fig­urable solutions.”

New ter­ri­tory? Only partly!

In designing aseptic equip­ment, Harro Höfliger’s process and machine devel­opers can draw on their know-how and expe­ri­ence with many issues.

Julian Grossman, Sales Man­ager Aseptic Tech­nolo­gies at Harro Höfliger, explains: “We’re already exclu­sively building spe­cialty machinery. Every machine dif­fers from project to project, even if only min­i­mally at times. This is even more evi­dent in the aseptic sector. It’s almost impos­sible to estab­lish stan­dards. In this sector our estab­lished approach of col­lab­o­rating closely with cus­tomers to develop a holistic solu­tion indi­vid­u­ally designed for their needs is unavoidable.”

Fun­da­men­tally, the processes in devel­oping an aseptic machine are no dif­ferent from those already estab­lished at Harro Höfliger. Addi­tion­ally, it is essen­tial in this product sector to ensure that the sterile product – here the active ingre­dient and, for example, the bag it is filled in – remain sterile throughout the entire filling process.


Chris­tian Kol­lecker describes just some exam­ples that devel­opers have to bear in mind: “It must be pos­sible to bring in all prester­il­ized com­po­nents from out­side, i.e. the ‘dirty’ area, so that they remain sterile within the machine. It is also nec­es­sary to deter­mine which cleaning and decon­t­a­m­i­na­tion pro­ce­dures are required to guar­antee sterility throughout the entire process. The decon­t­a­m­i­na­tion media also require mod­i­fi­ca­tion of the machine design. They are mostly liquid or gaseous and would lead to cor­ro­sion at edges open down­wards after a single cleaning cycle. Nat­u­rally, the machine oper­ator may only reach into the machine through spe­cial glove systems.”

A resounding suc­cess through know-how


Harro Höfliger proved that these require­ments can be met as early as 2018, when it devel­oped an aseptic filling and sealing line for prester­il­ized IV bags for a biotech com­pany in Hong Kong which is spe­cial­ized in prod­ucts for vet­eri­nary med­i­cine. Com­pletely sterile processes were needed for filling the highly sen­si­tive bioac­tive ingredients.

Besides an active open RABS tech­nology (Restricted Access Bar­rier System), this machine also used the ‘one-time docking’ prin­ciple for the first time. In this the IV bags are filled using an aseptic triple filling head. The con­nec­tion to the filling nozzle is kept in place throughout all gas purging, evac­u­a­tion and filling processes until the transfer from the machine. This min­i­mizes the risk of par­ticle entry and keeps the residual oxygen con­tent of the bag low.

An inte­grated, laser-based Wilco HSA (Head Space Analysis) module pro­vides an in-line mea­sure­ment of the oxygen con­tent. A high-pre­ci­sion mea­sure­ment of mass flow using the Cori­olis effect is per­formed during liquid filling by a sensor which ensures that each infu­sion bag has been filled to exactly the right amount.


All fill media are sup­plied in a sterile manner by aseptic rotary dis­tri­b­u­tion. The opening is tightly sealed by radio fre­quency welding to min­i­mize the heat transfer to the active ingre­dient. An inte­grated CIP/SIP system (Cleaning in Place/Sterilization in Place) ensures per­fect cleaning after each batch.

Chris­tian Kol­lecker sum­ma­rizes: “In this project we imple­mented a lot of things which stricter reg­u­la­tions would soon make stan­dard prac­tice for sev­eral of our cus­tomers. And this showed us what the impor­tant things were for aseptic machines: Short throughput times and high process reli­a­bility by inte­grating process ana­lyt­ical tech­nology wher­ever pos­sible and necessary.”

Safely filled


The spe­cial­ists at Harro Höfliger focus on filling prester­il­ized bags. Kol­lecker explains: “Nat­u­rally, we can also fill syringes and vials, but the large, long-chain mol­e­cules of biotech prod­ucts often form highly vis­cous solu­tions that have to be diluted to larger vol­umes. Infu­sion bags have clear advan­tages here.”

The experts espe­cially have a wealth of expe­ri­ence with filling prester­il­ized bags. As Gross­mann knows, the devil here is again in the details: “Dealing with the new sub­stances is new ter­ri­tory for us as well. Whether it is living cells or so-called lyophilized pow­ders that emerge like cotton candy, we have to develop the right filling method for each substance.”

To deliver good solu­tions to cus­tomers quickly, Harro Höfliger relies on flex­i­bility through mod­u­larity. Kol­lecker explains: “We develop pre­fab­ri­cated mod­ules which can be quickly inte­grated into flex­ibly con­fig­urable machine plat­forms. This moves away from classic mechan­ical engi­neering and brings us closer to our cus­tomers as system providers.”

“We, too, are entering unchar­tered ter­ri­tory when it comes to dealing with these new sub­stances. Be it living cells or lyophilized pow­ders – we have to develop the right filling method for each sub­stance.” Julian Gross­mann, Sales Man­ager Aseptic Tech­nolo­gies at Harro Höfliger

Whether in bags, syringes or vials – anti­sep­ti­cally pro­duced and filled active ingre­di­ents are the future. And Harro Höfliger is well placed for this. Chris­tian Kol­lecker is con­fi­dent: “We have a good overview and are able to visu­alize a cus­tomer process fully with Harro Höfliger tech­nology. What our cus­tomers get from us in the aseptic sector is a fully-inte­grated system for their spe­cific require­ments – from a lab­o­ra­tory machine to a com­mer­cial pro­duc­tion line.”

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Photos: Janine Kyofsky, Illus­tra­tion: Bernd Schifferdecker