Margins in pharmaceutical powder processing are low and production conditions are complex. This has led to a shift of manufacturing capacities to lower-cost markets. With this development in mind, how can supply bottlenecks be avoided? And what does it take to revive local production? Of course, equipment suppliers can’t master these challenges on their own. However, they can contribute their expertise and technological solutions to change things for the better.

Pharmaceutical powders are the basis of many essential antibiotics and ensure comprehensive medical care. For example, penicillin or cephalosporins are used in pneumonia or tonsillitis therapies. They are often administered by means of infusions to avoid the gastrointestinal tract and increase the effect of the drug. Purified water is added to the powder shortly before the infusion is administered.

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A shift in the production environment
What sounds simple actually requires a very complex manufacturing process. The powders need to be kept far away from machine operators during the filling process, as they otherwise might be exposed to potentially toxic dust. Hence, active ingredients and batches must be strictly separated from one another. As far as penicillin is concerned, the filling specifications are particularly strict: the FDA requires pharmaceutical manufacturers to isolate filling machines and equipment. They must provide separate air supply and filtration. Moreover, regular tests for residues of the drug are required. Often, the only possibility to comply with all regulations and keep operators safe at all times is using separate factories, leading to secluded facilities with separate offices and other rooms for different shifts.

These safety requirements lead to large financial investments that not every antibiotics manufacturer can afford. Increasingly demanding audits were one of the driving cost factors. Hence, the antibiotics production capacities were migrated to Asia some decades ago, as a study on the security of supply of antibiotics by Pro Generika (conducted by Roland Berger) states. For example, China starts subsidizing antibiotic production in the 1980. This soon led to economies of scale, which enabled manufacturers to produce large quantities of antibiotics at low prices. At the same time, the Western world experienced a rise in costs in the production of generics, with expiring patents opening up completely new fields of business.

Covid-19: a new situation
The situation today has changed a lot compared to a few years ago. On the one hand, the fight against Covid-19 has taken a very important place in the agenda of many pharmaceutical manufacturing companies. On the other hand, it has shown how vulnerable our current supply chains are. Regional dependencies are as obvious as they have maybe never been before. Taking Covid-19 as an example and extending it to further life-saving medication, it is clear that we have been and are still facing a global shortage. Referring to our antibiotics example, we must acknowledge that physicians in some regions must prescribe broad-spectrum antibiotics more frequently in the event of supply bottlenecks. This, in turn, increases the risk of patients developing resistance.

To counteract this development and to ensure more stable availability on the market, antibiotic manufacturers, physicians, and pharmacists’ associations, as well as politicians are calling for a global redistribution of production capacities. An example from Europe shows, how industry and politics work together to solve the problem: The Austrian government is supporting the only site in Western Europe (the Novartis generics division Sandoz based in Kundl) that both produces and fills antibiotics with extensive investments. At the same time, other countries are starting to invest in similar programs (such as Phlow in the U.S.) or three companies in India.

The extended role of machine manufacturers
At the moment, it is difficult to predict whether other countries and manufacturers will follow this strategy. However, setting up similar programs would certainly help a regional market availability of antibiotics in different continents. Apart from suitable production sites, programs like this require extensive knowledge of the pre-requisites for antibiotic powder production and fill-finish operations, as well as efficient equipment that meets all regulatory requirements and is geared towards high efficiency. Of course, machine manufacturers cannot solve the challenges on their own. But they can contribute their long-term knowledge and existing technological solutions to change things for the better.

While liquid pharmaceuticals are known for their challenges regarding filling operations, pharmaceutical powders add an additional level of complexity due to their consistency. The finely ground active ingredients generate dust easily. Hence, machine operators must be protected from these potentially toxic ingredients—and the other way round to prevent cross-contamination. So, what is needed? For example, dust-tight barriers and a sealed air supply with efficient and powerful filter systems are needed in the filling area. As an example, a UDAF ventilation system cleans and tempers the circulating air of the filling area and regulates humidity. At the same time, cleaning is complex and essential with powders: the fine dust particles could settle anywhere within the machine. What helps: an open design, easy accessibility, and CIP-SIP for cleaning the product in-feed system.

Size does matter!
Every inch is important in filling operations: the larger the filling area, the higher the costs for containment, filtration, temperature control, operation, maintenance, and cleaning. Powders are usually filled in cleanroom class B, hence a cost-efficient and space-saving filling system is sought after. As an example, a vertical design with good accessibility and the possibility of wall mounting with maintenance options outside of the filling area offer enormous advantages. Additionally, the dedusting and cooling space is reduced as soon as the filling area is separated from the infeed and outfeed. Now how to save even more space? The answer is a modular design that offers drug manufacturers the flexibility to choose between different filling and weighing modules. But a KPI that is far more important is, of course, cost.

Here, time plays a decisive role. The faster format parts can be changed and the fewer product-contacting parts there are to clean, the faster a new batch can be initiated – and the more costs are saved. As an example, the AFG 5000 from Syntegon processes up to 480 vials per minute. A specially developed transport system that varies between continuous and intermittent transport makes it possible. While the vials enter the system continuously, the transport system precisely adjusts the speed as they progress to the individual workstations such as filling, weighing, or stoppering to avoid delays in the workflow. The vertically circulating transport system avoids idle times or jams. The carrier systems transport the vials to the respective workstations safely and quickly. As soon as the vials have been stoppered and are discharged, the shuttles return to the infeed in fast mode and are ready for the next transport. The 100% in-process control avoids any unnecessary product loss—a further important advantage to produce cost-sensitive antibiotics.

A positive outlook
Whoever wants to be on the safe side, is strongly advised to cooperate with a leading machine manufacturer when looking for a particular fill-finish system. Syntegon has more than 250 machines sold globally and has been supporting customers in pharmaceutical powder filling for more than 60 years. The Syntegon experts are continuously passing on their extensive experience, for example in the powder lab in Crailsheim, Germany, where they support pharmaceutical manufacturers in selecting the ideal filling system, determining the optimum setting parameters, or carrying out basic tests. The goal is to combine maximum safety for operator, product, and patient with optimum efficiency—and thus contribute the equipment prerequisites for a regional antibiotic production strategy.

It is not yet foreseeable whether other countries will follow the mentioned examples. But there is hope: some national projects, like in Austria, Italy, the U.S., or India to promote local drug production, including antibiotic powders, with public funds have already been initiated. The Corona pandemic has increasingly shown how dependent global supply is on individual regions—and could now serve as a kind of “wake-up call” to accelerate these initiatives. 

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Markus Heinz is Product Manager Vial Liquid & Powder at Syntegon Technology, a leading global process and packaging technology provider. He can be reaching at markus.heinz3@syntegon.com or visit www.syntegon.com for more information.