Safely Scaling High Potency API Manufacturing

Editor’s Take: HPAPI manufacturing takes more than containment—it requires a partner that can manage scale-up, tech transfer and future production needs without compromising safety or quality.

As demand for highly potent active pharmaceutical ingredients (HPAPIs) continues to accelerate, pharmaceutical companies face an increasingly important question: how do they find a contract development and manufacturing organization (CDMO) with both the technical capability to manufacture HPAPIs and the commercial expertise to bring them to market successfully?

The distinction is becoming more significant as the global HPAPI contract manufacturing market continues to grow, driven largely by expanding oncology pipelines. Under pressure to bring innovative therapies to these patients faster, pharmaceutical companies are looking for manufacturing partners capable of supporting programs from early development through to commercial supply.

While discussions around HPAPI manufacturing often focus on containment technologies or facility design, long-term success depends on managing a broader set of challenges. In practice, pharmaceutical companies should be aware of four interconnected risks that can hinder a drug program: the risks of exposure, the risk of improper scale-up, ineffective tech transfer and being unprepared for future change.

These risks are tightly interconnected. Decisions made during development can influence scale-up outcomes years later, while exposure risks from facility and process design can jeopardize future readiness. Understanding these risks and their interactions is now essential for companies seeking a CDMO partner capable of commercializing their HPAPIs.

Risk 1: Exposure

The defining characteristic of an HPAPI is its ability to exert a therapeutic effect at extremely low doses. While this potency creates significant clinical value, it also introduces substantial occupational health and safety challenges for all operators during manufacturing.

For CDMOs, managing HPAPI exposure risk begins with defining occupational exposure limits (OELs). These provide a quantitative framework for determining the maximum acceptable concentration of an API in workplace air.

OELs and OEBs

HPAPI potency can also be defined 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. However, because OEB systems lack standardization, OELs are generally regarded as the more reliable basis for CDMO risk assessment and containment strategies.

The next challenge for any CDMO lies in translating these defined exposure limits and/or bandings into practical manufacturing controls that can be consistently applied throughout development and commercial production. This is achieved through multiple overlapping layers of protection, from strict facility design to protective equipment requirements:

• At the primary level of containment, closed systems, isolators and contained transfer technologies can minimize opportunities for potent materials to escape into the manufacturing environment.

• At the secondary level, negative-pressure rooms, airlocks and carefully controlled airflow patterns can help prevent material migration beyond designated production areas.

• Finally, at the tertiary level of containment, operator procedures, gowning protocols and environmental monitoring can provide an additional safeguard to ensure containment remains effective during routine operations.

Beyond direct manufacturing, exposure risks are also present during maintenance and cleaning of equipment, as well as material sampling. For this reason, leading CDMOs, the ones most efficient at commercializing their APIs, increasingly evaluate entire process lifecycles rather than focusing solely on production steps.

Regulators also continue to place emphasis on science-based risk management. The ICH Q9(R1) Quality Risk Management guidelines, for instance, revised in 2023, state the benefits of a “proactive” policy of identifying, evaluating and controlling manufacturing risks. CDMOs should therefore design containment strategies that protect personnel and generate evidence of their ongoing effectiveness through monitoring and documentation.

No one action can eliminate exposure risk across all levels of manufacturing. To do their utmost to protect their operators, CDMOs must integrate engineering, procedural and behavioral controls into a robust, simultaneous containment strategy.

Risk 2: The challenge of scale

Even once a CDMO has established such a containment strategy, there is no guarantee the same protocols will suffice at commercial scale. Scaling up to this kind of operation involves increasing API batch sizes, which can amplify the impact of small process variations on critical quality attributes. As batch sizes increase, manufacturing systems are exposed to new physical and operational demands:

• Dust generation may rise, placing greater pressure on airflow systems and filtration capacity.

• Scaling up batches can alter flow properties and granule characteristics, affecting blending performance, compression behavior and overall process consistency.

• Cleaning operations also become more complex as equipment grows in size and introduces additional surfaces, interfaces and potential residue-retention points.

In HPAPI manufacturing, these challenges are amplified by the need to maintain strict containment alongside product quality and process efficiency.

CDMOs should address these challenges through enhanced process understanding and predictive modelling tools. By identifying scale-sensitive variables in advance, manufacturers can optimize process parameters before large-scale production begins, reducing the likelihood of delays, investigations or corrective actions later in development.

Risk 3: Ineffective tech transfer

As products progress through development and approach commercialization, manufacturing activities are often transferred between facilities. Although this transition is a routine part of pharmaceutical production, HPAPIs introduce additional layers of complexity due to their containment and safety requirements.

Five considerations for successful technology transfer:

1. Familiarity with the transition process

Reproducibility begins with comprehensive process knowledge. Critical information, including exposure limits, formulation data, process parameters, sampling plans and equipment requirements, must be fully understood before implementation at the receiving site can begin.

2. Facility assessments

CDMOs must evaluate whether the receiving facility can achieve the same containment performance and process outcomes as the original site. This assessment extends beyond routine manufacturing activities to include cleaning, maintenance and material handling operations, all of which may present exposure risks if not properly managed.

3. Equipment checks

Facility infrastructure, airflow systems, equipment configuration and cleaning strategies must be aligned to the specific needs of the product. In some cases, existing equipment may require modification to achieve target containment levels or process performance expectations.

4. Inter-site communication

Just as physical infrastructure is moved, so too should organizational knowledge. Successful projects often depend on close collaboration between technical teams, operators, engineers, quality specialists and environmental health and safety personnel. Capturing practical knowledge from the sending site can be just as important as transferring formal process documentation.

5. Batch evaluation

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.

Failure to manage technology transfer systematically can have consequences that extend well beyond project timelines. Poorly executed site transfers can introduce variability, delay regulatory approvals and ultimately jeopardize commercial supply.

Pharmaceutical companies would therefore be best placed by partnering with an experienced CDMO, one with proven experience in transferring HPAPI processes across facilities, while maintaining containment, reproducibility and regulatory compliance.

Risk 4: Being unprepared for the future

The demands placed on HPAPI manufacturers continue to evolve. Increasingly complex therapies, rising production requirements and heightened regulatory expectations are encouraging CDMOs to explore new technologies, particularly automation, digital and artificial intelligence (AI) technologies, that can improve both control and efficiency.

Automation

One area attracting significant attention is automation. Modern robotic handling systems can perform activities such as material charging and sampling with minimal operator intervention, reducing potential exposure while improving consistency and repeatability. As robotic capabilities continue to improve, opportunities for automation within high-containment environments are likely to expand further.

Digital technologies

Real-time, digital environmental monitoring systems are already providing continuous visibility into critical containment parameters, while integrated data platforms and electronic batch records enhance traceability and operational oversight.

AI

AI and advanced analytics may also play a growing role in the future of HPAPI manufacturing. As more operational data becomes available, manufacturers will be better positioned to predict process behavior, identify emerging risks and optimize manufacturing performance proactively rather than reactively.

The value of these technologies extends beyond compliance. Greater visibility into process performance allows manufacturers to identify trends, detect deviations earlier and make more informed operational decisions. Over time, this data-driven approach can support continuous improvement initiatives and help strengthen process robustness.

More broadly, beyond just adopting new technologies, future readiness is about building adaptable manufacturing operations that remain efficient across technological, regulatory and market upheavals.

Looking beyond containment

When evaluating a CDMO’s HPAPI capabilities, pharmaceutical companies should, first and foremost, assess its containment capabilities. But this security parameter should be seen as part of a bigger picture.

The organizations best positioned to support the next generation of highly potent therapies will be those capable of managing all four outlined risks simultaneously: protecting operators from exposure, maintaining performance during scale-up, preserving process integrity during transfer and embracing technologies that strengthen future competitiveness.

As the HPAPI market continues to expand, success will belong to the CDMOs that can translate development knowledge into reliable commercial manufacturing while maintaining the highest standards of safety, quality and operational excellence.

Joining Recipharm in 2022, Lidia’s role is MSAT & New Productions Head. Before joining Recipharm, she worked at Roche for many years in various technician roles, including Drug Product Technical Lead, and 10 years with the company as a Process Transfer and Validation Technician.