As scale increases, so does risk

A dust particle, invisible to the human eye, dispersed in the air volume of a large concert hall: this is the order of magnitude of the maximum permissible concentrations that must be maintained in certain pharmaceutical production areas. In the lab, much still seems manageable. A few grams of substance, a reaction vessel, a fume hood, perhaps a glove box. The processes are manageable, the distances short, interventions controllable. But as soon as grams turn into kilograms, and kilograms into tons, the equation changes fundamentally. Scale-up—that is, the scaling of a production process from laboratory through pilot to industrial production scale—is not simply a matter of larger equipment; with it, the risk profile also changes.

For as the scale increases, flow conditions, heat transfer, mixing quality, and dust generation change. Above all, however, the number of process steps grows—and with it, the number of critical interfaces. What takes place in a single setup in the laboratory is distributed in production across a chain of reactions, filtration, washing, drying, grinding, sieving, mixing, dosing, tableting, coating, and packaging. Each of these steps can take place in a separate piece of equipment, often in different rooms or even different areas of the building. And every handoff potentially means: an opening in the system.

The most dangerous point: the transition

The key insight from practical experience is this: it is usually not the closed reactor that poses the greatest risk. Nor is it the filter dryer or the tablet press. The weak point almost always lies in between. Every material transfer, every decanting, every product change, and every cleaning step is a potential contamination event. In the laboratory, such transitions can often still be controlled manually. At the production scale, however, both the number of interfaces and the quantities of material handled multiply.

What appears in the lab to be a brief, acceptable instance of open handling adds up over weeks and months of multi-shift operation to constitute significant exposure. As the potency of the active ingredients increases, this becomes not only a technical problem but also a regulatory obligation.

Because the requirements are becoming more stringent. The amended German Hazardous Substances Ordinance of December 2024 explicitly prioritizes closed or, where possible, closed systems for carcinogenic, mutagenic, or reprotoxic substances—not only during production operations, but also during maintenance, cleaning, and retrofitting, provided this is technically feasible. This marks the first time that the entire plant lifecycle is consistently brought into focus.

Highly active ingredients are leaving their niche

It is no coincidence that this topic is gaining importance. More than 57 percent of the active ingredients newly approved between 2011 and 2020 fall into Occupational Exposure Band 3 or higher. At the same time, the global market for highly active pharmaceutical ingredients (HPAPIs) is projected to grow to more than $41 billion by 2028. For manufacturers, this means that highly potent active ingredients are no longer a special case but are increasingly becoming the industry standard.

POWTECH TECHNOPHARM: Where the problem becomes concrete

How the industry is responding to this is evident where technology, operational experience, and regulation converge—such as at the POWTECH TECHNOPHARM. The solutions to the interface problem have become highly specialized. Rapid transfer ports, double-flap valves, and closed liner systems are now among the key tools for avoiding open transfers.

At POWTECH TECHNOPHARM, among other venues , suppliers such as Air-Jet, Andocksysteme, ChargePoint Technology, Engelsmann, Hecht, Lugaia, Rubitec, and Zermec Pharma regularly solutions that address precisely this critical issue. These systems now achieve containment performance in the nanogram range. This is particularly relevant during scale-up, as transfer points become a key risk factor with each additional process step.

The challenge becomes even greater at the highest exposure classes. Here, the isolator is often considered the gold standard. These fully enclosed systems allow access via integrated glove ports and create a physical separation between operating personnel and the product. But even this technology has its limits. An isolator only works as long as operation, assembly, and maintenance remain within the reach of its interfaces. As throughput increases, this structural logic quickly becomes a bottleneck.

Several exhibitors at POWTECH TECHNOPHARM address the scaling limitations of traditional isolators with modular systems: Flexible layouts enable the integration of robotics for automated aseptic fill-and-finish processes, while validated VHP cycles handle decontamination. More compact, automated variants are specifically designed for sterility testing and small-batch processing and meet the requirements of GMP regulations, including 21 CFR Part 11.

Even seemingly minor process steps require specialized solutions. With its ST1 safety weighing booth, a1-envirosciences demonstrated how even weighing can be performed safely under OEB-5 conditions. And HET-Filter demonstrated that air handling technology remains an integral part of a robust containment concept: high-performance HEPA filters with very high filtration efficiency are indispensable, especially at the production scale.

The most elegant solution: fewer interfaces

Perhaps the most convincing solution to the transfer problem, however, is not a better interface—but fewer interfaces. Continuous manufacturing, i.e., continuous rather than batch production, takes precisely this approach. Instead of many discrete process steps with numerous handoffs, the product ideally remains in a closed material flow from raw material to finished dosage form. Fewer transitions mean fewer openings. Fewer openings mean less potential for exposure.

Regulatory support for this approach comes from the ICH Q13 guideline on continuous pharmaceutical manufacturing as well as the Emerging Technology Program of the U.S. Food and Drug Administration (FDA). However, the same principle applies here: a closed process is only as safe as its maintenance. Automated cleaning systems for piping, filter chambers, or valves are therefore increasingly becoming a must.

Knowledge remains the underestimated factor

Technology alone is not enough, however. Many scale-up projects fail not due to a lack of hardware, but because of unclear requirements. How is an active ingredient correctly classified? What exposure target value is realistic? What must a validatable containment concept look like? Which test methods are regulatory-compliant?

This is precisely where the knowledge transfer provided by APV, the Association for Pharmaceutical Process Engineering, comes into play. As the conceptual sponsor of POWTECH TECHNOPHARM, it combines scientific methodology with industrial application. At the EXPERT FORUM, operators, plant manufacturers, regulatory representatives, and experts from development and production come together.