David Fernández Bleda, global head EHS operations and Pere Hernandez, global EHS API projects manager, ESTEVE CDMO explore the human side of HPAPI safety.
ESTEVE CDMO
As pipelines shift toward more targeted and potent therapies, the number of highly potent APIs (HPAPIs) entering development continues to rise. HPAPIs now account for an estimated 12% of the pharmaceutical market and are growing at 9–12% annually, outpacing the broader sector and reshaping expectations for safe, reliable manufacturing.
Industry conversations often emphasise containment architecture, for example, isolators, closed‑system transfers, pressure cascades, and cleanroom design, as the foundation of HPAPI safety. These systems are indispensable, but their effectiveness ultimately depends on how they are designed, understood, and applied by the people who use them. Engineering controls and human factors are not separate domains; they work together, and safety breaks down when either is weak.
Effective HPAPI safety begins with an integrated risk assessment that considers the molecule, the process, the facility, and the people performing the work. These elements cannot be evaluated independently, as decisions in one area directly influence the effectiveness of the others. This integrated approach is particularly important in CDMO environments, where teams work across different molecules, potency levels, processes, and project requirements.
Human factors in HPAPI handling
Safe handling of HPAPIs depends as much on human behaviour as it does on engineering controls. Even in facilities equipped with advanced containment systems, the way people interact with those systems determines whether they perform as designed. Containment is not a passive barrier; it is a human‑operated control strategy, and its effectiveness can rise or fall based on day‑to‑day decisions.
Human factors influence containment performance in several concrete ways. The precision of material transfers affects airflow patterns inside isolators and hoods; small deviations in how an operator loads equipment, positions a drum, or handles a liner can disrupt the efficiency of the equipment maintaining the containment during the operation. Gowning discipline directly affects barrier integrity: a misaligned glove, an unsealed sleeve, or a rushed changeout can create breaches on the containment that engineering controls cannot compensate for. Even the timing of movements matters: rapid motions, unnecessary reach-ins, or opening doors at the wrong moment can create turbulence that defeats carefully engineered airflow.
Decision-making also plays a critical role. Personnel must recognise when a glove port feels different, when a flexible connection isn’t seated correctly, or when powder behaviour looks unusual. Containment systems rely on these real-time judgements; a willingness to pause, reassess, and escalate concerns is often the difference between a controlled operation and an exposure event. Engineering controls provide the structure, but human behaviour determines whether that structure is upheld.
Containment performance should not only be demonstrated during equipment qualification with surrogate testing. It should also be verified under real operating conditions, considering the equipment, the facility, and the way operators perform each activity. Regular industrial hygiene monitoring provides evidence that controls continue to perform as intended throughout routine operations.
Organisational culture shapes these behaviours. A culture that values caution, clarity, and collaboration encourages operators to speak up early, share observations, and treat deviations as learning opportunities rather than failures. In HPAPI operations, where exposure limits are extremely low and processes can be unforgiving, this culture is essential. Real‑world execution becomes just as critical as technical design because containment systems only work when people use them correctly, consistently, and with a clear understanding of the risks involved.
Building a culture of shared responsibility
A strong HPAPI safety culture is built on shared responsibility. Protecting employees, patients, and partners requires every individual, from operators to senior leadership, to understand the risks and their role in managing them. This begins with transparency: open communication about process changes, deviations, and uncertainties. When teams feel comfortable raising concerns, organisations can identify issues early and prevent escalation.
Accountability reinforces this transparency. Clear ownership of procedures, decisions, and corrective actions ensures that expectations are understood and consistently applied. In HPAPI environments, accountability is not about blame; it is about clarity, consistency, and reliability.
Equally important is empowerment. Operators must feel confident pausing work, requesting support, or escalating concerns without hesitation. Facilities handling potent compounds depend on this kind of psychological safety, where speaking up is seen as a strength rather than a disruption.
Training and competency
HPAPI handling requires sustained risk awareness and technical competency. Training must go beyond standard operating procedures to include an understanding of potency, exposure pathways, and the rationale behind containment strategies. Competency is reinforced through hands‑on practice, mentoring, and periodic reassessment to ensure operators maintain vigilance over time.
However, true competency in HPAPI operations does not develop in isolation. Learning should be intentionally cross‑functional, connecting operators with process development, engineering, EHS, quality, and manufacturing. This shared approach helps teams understand not only what a procedure requires, but why each control exists, how it was designed, and what risks it is intended to mitigate. When people understand the scientific and engineering basis for a control, they apply it more consistently and recognise earlier when something is off‑track.
HPAPI processes evolve as projects progress, so training cannot be static. Continuous updates are essential as equipment changes, new controls are introduced, or process parameters shift. Cross‑functional input ensures these updates reflect real‑world experience: lessons from deviations, unplanned interventions, and previous campaigns are fed back into training, SOP revisions, and process reviews. This creates a loop where operational insight strengthens engineering controls, and engineering clarity strengthens operator behaviour.
Consistency in safe handling, especially during weighing, transfers, and cleaning, ultimately depends on both technical knowledge and behavioural discipline. Connected learning across functions ensures that discipline is supported by shared understanding, common expectations, and a culture where everyone feels responsible for maintaining safe, compliant HPAPI operations.
The science of collaboration in HPAPI operations
Effective HPAPI operations rely on structured cross-functional collaboration. Dedicated project teams bringing together project management, process development, manufacturing, quality, engineering, EHS, and toxicology, ensure that the appropriate expertise is involved when risks, changes, and technical decisions are assessed. Early collaboration helps align containment assumptions, exposure limits, and process requirements before technology transfer and scale-up.
This model also supports transparent communication with the customer. Sharing project status, emerging risks, deviations, and proposed solutions enables safety considerations to be integrated into technical and business decisions while maintaining project momentum.
Connecting development stage knowledge with plant execution is essential. Processes that appear straightforward at a small scale can behave differently in larger equipment, requiring adjustments to controls, transfer methods, or cleaning strategies. Clear communication of process changes and containment requirements helps ensure that every function understands how its decisions affect operator safety.
When unexpected conditions arise, such as equipment deviations, process upsets, or unplanned interventions, joint decision‑making ensures that responses are both safe and scientifically sound. Cross‑functional collaboration reduces the likelihood of miscommunication and supports rapid, coordinated action.
Human factors across the HPAPI lifecycle
Human factors influence every stage of HPAPI development and manufacturing.
During development, early awareness of potency and containment needs helps shape processes before they are locked in, reducing the need for later redesign.
During technology transfer, knowledge must be transferred, not just documentation. Direct interaction between cross-functional teams helps preserve the tacit understanding behind process decisions, and containment assumptions. This shared understanding enables the receiving team to identify potential gaps before execution begins.
During scale‑up, risks change as batch sizes increase and operations become more complex. Teams must reassess exposure scenarios and adapt controls accordingly.
During commercial manufacturing, vigilance must be maintained. Routine operations can create a false sense of security, and organisations must guard against normalisation of risk.
What this means for pharmaceutical sponsors
For biotech and pharmaceutical sponsors, this integrated approach supports more reliable technology transfer, safer and more predictable scale-up, and earlier identification of operational risks. It also provides greater confidence that containment strategies will remain effective as the program progresses from development into routine manufacturing.
Preparing for the future
As HPAPI molecules become more potent and processes more complex, safe operations will depend on more than increasingly sophisticated containment technology. They will require organisations to connect scientific expertise, robust systems and empowered people throughout the product lifecycle.
At ESTEVE CDMO, this connection reflects ‘the science of collaboration’: cross-functional teams sharing knowledge, challenging assumptions and making coordinated decisions to protect employees, partners and the continuity of the molecule’s journey. When collaboration is structured and supported by scientific rigour, human factors become an integral part of reliable HPAPI performance.