By: Lidia Garcia Martin, MSAT & New Productions Head, Recipharm
Containment, Strategy, and Commercial Readiness in Modern Pharma
A growing proportion of pharmaceutical therapies is based on highly potent active pharmaceutical ingredients (HPAPIs) that can deliver therapeutic effects at very low doses. Manufacturing HPAPIs, however, requires specialized equipment and facilities with contamination-limiting capabilities, such as negative pressure rooms and air-handling units, that not every contract development and manufacturing organization (CDMO) can offer.
CDMOs with such capabilities, not to mention the expertise to organize them, are now increasingly prized by pharmaceutical companies looking to bolster their HPAPI catalog. But, amid a market surge in HPAPI contracting, how can drug developers know which CDMOs truly have high potency credentials, and which ones can scale up to the current demand?
Determining High Potency
HPAPIs tend to be defined using occupational exposure limits (OELs). These limits set the maximum acceptable concentration of an API in workplace air. As such, they directly inform a CDMO’s entire HPAPI workflow, from containment design to engineering controls, personal protective equipment (PPE) selection, and cleaning validation limits.
Some CDMOs may also define their potency with another method, occupational exposure banding (OEB), which groups substances into qualitative or semi-quantitative hazard categories based on potency and toxicology. Like an OEL, this definition can help keep API operators safe from exposure, but given that OEB systems lack standardisation, OELs are generally regarded as the more reliable bases for CDMO risk assessment and containment strategies.
Keeping It Contained
All HPAPI manufacturing relies on strict, multi-layered, and integrated containment strategies. This framework relies on three overlapping pillars of protection, ensuring that safety is maintained even if a single barrier is challenged:
1. Primary containment
The first line of defence is keeping potent materials enclosed at the source. This is achieved through closed-process isolators and enclosed transfer technologies, such as split butterfly valves or vacuum systems. Wash-in-place (WIP) technologies further reduce risk by minimising manual intervention during cleaning.
2. Secondary containment
To ensure airborne potent material does not migrate beyond designated manufacturing areas, facility infrastructure like negative-pressure rooms, airlocks and pressure cascades should establish predictable airflow patterns that draw air into, rather than out of, high-potency spaces.
3. Tertiary containment
The final layer governs behavior. Strict gowning protocols, including powered air-purifying respirators and double-gloving, serve as the last line of defence. Rigorous environmental and hygiene monitoring provides data-driven assurance that containment remains effective.
By integrating these layers, a CDMO builds a robust defence that prioritizes operator safety and product integrity. These strategies must align with EU GMP requirements and ICH risk-management principles.
With these safety and regulatory foundations secured, the next challenge is maintaining this same level of rigorous control as production scales up to meet commercial demand.
Scaling Up Safely
According to a recent report by Grand View Research, the global HPAPI contract manufacturing market, valued at $8.05 billion in 2024, is projected to grow at a compound annual growth rate of 10.98% from 2025 to 2030.1
This strong forecast largely rests on two factors: the many oncology applications of HPAPIs and the projected 77% global increase in new cancer cases between 2022 and 2050.2
To meet this rising demand, it is increasingly important for CDMOs to be able to support their clients’ HPAPI needs as they move from development-scale production to commercial levels. However, this is no simple task, and the challenges facing CDMOs while scaling HPAPI production are multifold:
Airflow demands
As batch sizes grow, dust generation increases, driving a corresponding rise in airflow requirements. Larger-scale operations impose greater demands on filtration systems, necessitating reassessment of both airflow capacity and filter performance to ensure exposure remains within established OELs.
CDMOs should therefore evaluate containment performance under worst-case operating conditions, rather than simply assuming particulate burden will scale proportionately with production. This is typically verified through airflow assessments and containment testing carried out prior to routine commercial production.
Behavioral changes
Scaling up batches can alter flow properties and granule characteristics, which subsequently impact downstream processes such as compression. At higher volumes, variations in mass and flow behaviour may influence tabletting forces and feed dynamics, often requiring adjustment of process parameters or the introduction of in-process monitoring to maintain consistent output.
CDMOs must understand these behaviors early, as changes in blend uniformity or granule density can result in content uniformity challenges if not properly managed. Predictive tools, such as Recipharm’s ReciPredict™, can assist at this stage by identifying scale-sensitive parameters in advance, enabling teams to optimise settings before transitioning to large-scale equipment.
Cleaning complexity
Cleaning requirements become more challenging as equipment increases in size and complexity. Expanded surface areas, additional contact points, and a higher number of interfaces introduce more opportunities for residue accumulation.
While toxicology-based acceptance limits remain constant across both new and old sites, demonstrating compliance at commercial scale often necessitates additional sampling points, modified cleaning cycles, or adjustments to WIP/clean-in-place (CIP) programs to ensure effective removal of potent materials. The greater number of valves, seals and interfaces also increases the importance of selecting worst-case scenarios when establishing cleaning validation strategies.
Maintaining Reproducibility Across Sites
As production scales, CDMOs may also need to transfer projects from development facilities to commercial ones. Far from a simple replication exercise, such a move requires CDMOs to rely on a carefully considered risk-management strategy with attention to the following steps:
1. Initial preparation and data consolidation
Any facility transfer should begin with the consolidation of all relevant information required to define the process and its containment needs. This typically encompasses OEL and permitted daily exposure (PDE) values, formulation details, critical process parameters, sampling strategies, and equipment specifications. Establishing clear exposure limits at this stage is crucial, as they form the basis for containment design, cleaning validation, and PPE selection at the receiving facility.
2. Evaluation of exposure risks and containment needs
CDMOs should then conduct a structured safety, health, and environment (SHE) risk assessment to identify potential exposure points throughout the transfer process, considering each unit operation and material handling step. This evaluation covers both routine activities and non-routine tasks such as maintenance and cleaning, which frequently present the greatest exposure risk. Importantly, this step determines whether the receiving site can achieve the defined OEL or PDE targets with its existing infrastructure or if modifications are required.
3. Process configuration at the receiving facility
Once containment requirements are established, the receiving facility should configure its process environment and, where necessary, adapt the transferred equipment to ensure that airflow, pressure differentials, and transfer mechanisms function effectively under operational conditions. Cleaning procedures must be validated to confirm that the site’s approach consistently meets the toxicology-based limits associated with the HPAPI. In parallel, quality control methods should be aligned to ensure that monitoring and analytical outputs remain consistent with those generated at the development site.
4. Process verification and operational stabilization
Finally, initial batches produced at the receiving facility should be evaluated to confirm that the HPAPI manufacturing process performs as intended under the new conditions. These runs provide practical evidence that both containment and process performance are stable, while also confirming that cleaning, monitoring, and procedural controls operate reliably during routine production.
Scaling Up with New Technologies
Robotic handling systems are nothing new in API production. But, until relatively recently, such equipment lacked the finesse to reliably handle materials as demanding as HPAPIs.
Now, thanks to advances in the field of commercial robotics, many CDMOs are testing the benefits automated handling equipment can bring to HPAPI production. One clear potential upside is safety. When carried out by robotic systems, activities such as feeding or sampling have little to no need for direct operator involvement, minimising a CDMO’s exposure risks. Efficiency, too, could be improved by a robot system’s accuracy and consistency.
New software and sensor systems can also provide CDMOs with vast oversight of their manufacturing. Real-time environmental monitoring helps provide continuous visibility of key parameters such as pressure, humidity, and airborne particulate levels, allowing sites to confirm that containment conditions remain stable during processing. Digital batch records further support operational control by improving traceability, and integrated data capture can provide a consolidated view of process performance, making it easier to track trends and demonstrate compliance during audits. All these systems also enable early detection of process variation, forming a basis for ongoing optimisation and continuous improvement across operations.
Positioning for the Future of High-Potency Manufacturing
As demand for HPAPIs continues to grow, the expectations placed on CDMOs will only intensify. Future success will depend on the ability to integrate robust containment strategies with scalable processes, while maintaining the highest standards of safety, quality, and regulatory compliance. These requirements call for deep technical expertise, proactive risk management, and a willingness to adopt emerging technologies that enhance both control and efficiency.
Those CDMOs that can consistently translate development insights into reliable commercial production will be best positioned to support the next wave of high-potency therapies. In doing so, they will play a critical role in accelerating drug development timelines and enabling broader patient access to innovative treatments.
About the Author
Lidia Garcia Martin brings over 18 years of experience in pharmaceutical manufacturing, specializing in technology transfer, process validation, and high-potency product introduction. She has held key technical leadership roles at global companies, driving innovation and ensuring compliance across complex manufacturing networks