High potency APIs (HPAPIs) are central to areas of pharmaceutical innovation such as oncology and precision medicine, with the market expected to grow at a rate of nearly 11% by 2030 .
These drug substances demand stringent controls throughout development and manufacturing due to their strong biological activity and the serious health risks they pose to those handling them. Containment and manufacturability are therefore core to the success of any HPAPI project.
However, as processes move from gram-scale development to kilogram-scale manufacturing, the volume of material increases, so does the risk associated with handling HPAPIs. Navigating this transition requires more than containment infrastructure alone. It depends on the integration of process chemistry, engineering, industrial hygiene and manufacturing expertise, supported by flexible containment technologies and robust occupational health programmes.
In this blog, we’ll uncover four common pitfalls that can hinder HPAPI manufacturing success, and discuss how they can be prevented with the right experience, infrastructure and process design.
1. Potency and risk classification
APIs are classified by occupational exposure banding (OEB), with those having an occupational exposure limit (OEL) of <1 µg/m3 generally considered highly potent. However, accurately defining exposure limits and control strategies for each API necessitates a combination of prior compound knowledge, toxicological data, in silico models and literature reviews.
During early-stage development, limited clinical and toxicological data may necessitate conservative potency assumptions. While protective, these assumptions can introduce operational complexity down the line if containment strategies are not effectively aligned to long-term manufacturing requirements. The right balance between speed and protection is essential.
Where this shows up in scale-up
- Project costs and timelines exceed initial projections due to overly conservative containment assumptions.
- Inadequate containment necessitates a redesign of engineering controls later in the process to avoid putting employees at risk.
- Manufacturing suites must be requalified following changes to containment strategy, creating project delays.
How to prevent it
Ensuring detailed potency classification and designing processes accordingly requires a structured and collaborative approach.
- Conduct extensive toxicological assessments early, engaging occupational toxicologists and industrial hygienists to define exposure limits.
- Use structured occupational exposure banding (OEB) frameworks to guide containment measures.
- Where clinical data is limited, use in silico modelling tools such as DEREK Nexus, SARAH Nexus, and other QSAR models to predict toxicological activity and guide early OEB classification based on potential health hazards.
- Align initial process design with long-term containment measures, ensuring feasibility at both the lab and plant scale.
2. Containment strategy
Containment requirements are not uniform and can vary significantly across unit operations within the same programme, depending on material potency and handling requirements. Both under- and over-containment present risks, either to operator safety and regulatory compliance or to process efficiency and cost.
The highest exposure risk generally occurs during steps such as weighing, charging, dispensing and final product packaging. These operations could involve limited open handling and increased material movement, making them especially challenging to control.
Where this shows up in scale-up
- Operational complexity and overly restrictive containment controls increase cycle times and lead to significant project delays.
- Bottlenecks occur at critical points like charging, distillation, isolation, drying or final product packaging.
- Engineering modifications occur mid-process due to misaligned containment strategies.
How to prevent it
An adaptive, risk-based containment strategy is critical for safety and efficiency.
- Perform detailed, step-specific risk assessments.
- Develop a right-sized containment strategy for each stage of development and manufacturing.
- Validate containment performance as the project progresses through ongoing verification and exposure monitoring.
- Establish cleaning protocols and validated maximum allowable carryover limits (MACO) and acceptable surface limits (ASL) for manufacturing suites, partnering closely with analytical teams to confirm full residue removal between campaigns.
- Where feasible, keep materials in solution for as long as possible during processing to minimise airborne inhalation risk.
- Leverage a flexible and multi-layered containment approach, including isolators, PPE, downflow booths and facility-level controls.
3. Facility design
For HPAPI manufacturing, especially as potency increases and exposure limits shrink, facility design is crucial for achieving safe and consistent containment.
Custom-built, dedicated facilities provide integrated capabilities that enable the safe and efficient processing of highly potent compounds. Facilities should be designed with containment in mind from the outset, incorporating features like process downflow booths with unidirectional HEPA-filtered airflow and high-containment isolator technology to control exposure.
Validation of containment by qualified industrial hygiene professionals is equally important. Standardised methodologies like SMEPAC (Standardised Measurement of Equipment Particulate Airborne Concentration) are applied to understand equipment performance under simulated operating conditions while using lower potency surrogate materials like naproxen sodium or lactose.
Where this shows up in scale-up
- Low OEL containment targets are difficult to consistently achieve without custom-built facilities.
- Inflexible asset configuration cannot support certain specialised unit operations.
- Misaligned infrastructure and process requirements create inefficiencies.
How to prevent it
Partnering with organisations that offer the infrastructure to meet the needs of different molecules ensures efficient and effective containment at every stage.
- Partner with facilities designed for high-containment manufacturing, validated through SMEPAC testing at required OELs.
- Confirm that multi-layered containment is integrated into facility design.
- Verify that containment equipment can support filtration, drying, hydrogenation and other complex operations where needed.
4. Training and knowledge transfer
HPAPI manufacturing requires specialised procedures for powder handling, equipment cleaning and emergency response. As a process scales, the introduction of new personnel and equipment paired with the handoff between development, engineering, QA and manufacturing teams can create gaps in knowledge and continuity for critical project information.
Where this shows up in scale-up
- Misalignment between development and engineering teams leads to inconsistencies from development to manufacturing.
- Deviations occur during initial large-scale batches, requiring impact assessments and corrective actions.
- Inadequate training in HPAPI handling and emergency procedures increases the risk of exposure and delays responses when deviations occur.
- Cycle times extend as teams require more time to adapt to and adjust containment controls.
How to prevent it
A full-lifecycle process perspective and consistent communication across teams enable more streamlined scale-up without lapses in knowledge.
- Work with experienced HPAPI development and manufacturing teams who have demonstrated success bringing projects from development to manufacturing.
- Ensure that CDMO partners protect employees who handle HPAPIs with certified occupational and environmental medicine physicians who support annual medical surveillance.
- Ensure that CDMO partners have HPAPI emergency response capabilities.
- Develop processes and maintain close collaboration and visibility across teams at every stage of the project with consistent communication and detailed documentation.
- Ensure direct access to the scientists and engineers who developed the process, rather than basic documentation, so that questions arising during scale-up can be quickly addressed by people with firsthand project knowledge.
- Validate that all personnel are trained in containment measures, standard operating procedures and emergency response protocols.
Enabling successful HPAPI scale-up with the right expertise and infrastructure
HPAPI process delays, cost overruns and other challenges are rarely caused by chemistry alone. More often, they arise from classification challenges, containment strategies, infrastructure limitations or knowledge gaps, particularly as processes transition from development to manufacturing.
The increasing prevalence of ultra-high potency compounds, often with genotoxic or clastogenic properties and extremely low OELs, adds to these challenges. Effectively addressing them requires a fully integrated, strategic and science-backed approach.
At Sterling, this integration is built into every HPAPI programme. We combine purpose-built facilities with flexible containment controls, dedicated teams and in-house industrial hygiene and occupational toxicology expertise to effectively bridge the gap between development and scale-up for HPAPIs. This ensures that containment strategies are not only designed effectively, but translated consistently from early development through to manufacturing.
With this coordinated approach, we can more quickly identify and resolve potential risks, scale projects more efficiently and provide customers greater confidence that their processes will perform as expected.
If you’re ready to learn more about how we can streamline the path to manufacturing in your HPAPI programme, contact an expert.
