„Better safe than sorry“

When pro­ducing highly potent or toxic prod­ucts, cus­tomized bar­rier tech­nology is required in order to pro­tect product, oper­ator and envi­ron­ment. Bern­hard Brugger, aseptic and con­tain­ment expert at Harro Höfliger, is talking about the challenges.

Is it cor­rect to speak about con­tain­ment instead of bar­rier technology?

Brugger: No, even if the two are often equated. The generic term is bar­rier tech­nology. If we talk about product pro­tec­tion, we are in the field of asep­tics. How­ever, if we look at oper­ator and envi­ron­mental pro­tec­tion, we are talking about the issue of con­tain­ment. Con­fu­sion is also caused by the fact that in the German-speaking coun­tries the term con­tain­ment only refers to the enclo­sure, whereas in the Eng­lish-speaking coun­tries it means the entire process, including han­dling and inter­face difficulties.

Is Harro Höfliger active in both fields?

Yes, with a great deal of com­mit­ment since the estab­lish­ment of our depart­ment in 2008. After all, highly active ingre­di­ents, for example, in cancer therapy or in hor­mone treat­ments are used more and more fre­quently. Inde­pen­dent market researchers expect an annual average growth of the HPAPI-market (High Potency API) of almost 15 per­cent between 2015 and 2022. So, there is a lot of poten­tial. On the other hand, increas­ingly com­plex active ingre­di­ents are processed, which often cannot be ter­mi­nally ster­il­ized and there­fore have to be processed aseptically.

What kind of aseptic issues do you address?

There are clear guide­lines for aseptic machines like the FDA guid­ance “Sterile Drug Prod­ucts Pro­duced by Aseptic Pro­cessing“ or the EC-GMP guide­lines. Basi­cally, it is about the aseptic pro­cessing of sterile prod­ucts. Germs, viruses and spores, in other words, all sorts of con­t­a­m­i­nants have to be kept away from the product. We imple­ment iso­la­tors, open and closed RABS (Restricted Access Bar­rier System) with inte­grated lam­inar flow sys­tems. Due to rapid transfer ports or active and pas­sive mouse-holes, inter­faces no longer con­sti­tute a problem. Nat­u­rally, we have also mas­tered com­plex processes with strict tem­per­a­ture or humidity con­trol require­ments, as well as under an inert gas atmos­phere. For example, we imple­mented a system in which cryo pel­lets are filled under a nitrogen atmosphere.

A wooden mock-up (left) is used to sim­u­late oper­a­tion. The find­ings are imple­mented on the machine (right).

What role do people play in this?

A double role – because people are the main dis­rup­tive factor on the aseptic side. Just think of germs and par­ti­cles such as skin dander, clothing abra­sion or sweat drops. On the other side, when pro­cessing highly active ingre­di­ents, con­tain­ments are required to pro­tect us from these substances.

How do you deter­mine the pro­tec­tive measures?

An impor­tant, but not the only aspect is the OEL-limit (Occu­pa­tional Expo­sure Limit) that has been estab­lished and must be met. Many ques­tions have to be answered first. What prop­er­ties does the product have? How long does the oper­ator work on the machine per day? What is the con­cen­tra­tion of the active ingre­dient in the final product? What external inter­faces are involved in the process? What inter­ven­tion methods does the oper­ator need? Only when all these fac­tors are known, can we deter­mine the prob­a­bility of expo­sure and design the con­tain­ment solution.

What tools do you use?

Nat­u­rally, we use all modern tools such as com­puter-aided design (CAD), com­pu­ta­tional fluid dynamics (CFD) and vir­tual reality. In addi­tion we build wooden mock-ups of the entire machine. This is nec­es­sary to sim­u­late oper­a­tion. Together with our cus­tomers, all con­ceiv­able process steps are sim­u­lated, including setup, trou­bleshooting, and cleaning. These trial sequences often take sev­eral days. Then we work out the ergonomic details. With this method and using real­istic weights, oper­a­tors can test the system through glove ports and judge whether this is man­age­able in their daily work routine.

Bern­hard Brugger, Depart­ment Leader Design & Devel­op­ment Iso­la­tors & Con­tain­ment Sys­tems at Harro Höfliger,

pre­vi­ously spent his study time in the clean­room. His long-term expe­ri­ence gath­ered at the Fraun­hofer-Gesellschaft paved his way in asep­tics and con­tain­ment. After having worked in var­ious posi­tions in the industry – always close to the topic – he came to Harro Höfliger in 2008 where he founded the bar­rier tech­nology depart­ment. Today he man­ages a team of nine employees. 

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Photos: Harro Höfliger