Rob Abbenhuis, global head, corporate EHS and ESG, Ardena shares a risk-based approach to safe and efficient synthesis of HPAPIs.
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In recent years, drug discovery has seen a significant drive towards developing highly potent compounds, particularly in critical therapeutic areas like oncology, inflammatory diseases and antiviral treatments. These highly potent active pharmaceutical ingredients (HPAPIs) offer the promise of effective therapies, often at very low doses, but they come with a unique set of challenges.
While HPAPIs hold immense potential, their development in early stages is complicated by limited safety data and often unknown toxicology profiles. This inherent uncertainty means that new chemical entities are frequently designated as HPAPIs by default, requiring stringent control measures. The critical challenge then becomes how to efficiently synthesise sufficient drug substance to progress into clinical trials, all while ensuring protection for workers and the environment. Without a clear understanding of a compound’s full toxicological impact, traditional development pathways can be filled with delays and risks. This is where a rational, risk-based approach becomes essential for addressing the complexities of early HPAPI synthesis.
The unique challenges of early HPAPI synthesis
HPAPIs frequently exhibit potent pharmacological activity at low doses, which can translate to significant toxicological effects even at minute exposures. Unlike well-characterised substances, new drug candidates are treated as HPAPIs until their complete toxicology profile is conclusively established, a process that is both lengthy and expensive. The potential for unknown off-target effects further compounds this uncertainty, demanding an exceptionally cautious approach.
Given the potent nature and unconfirmed safety profiles of new substances, robust containment strategies and meticulous handling procedures are non-negotiable to protect personnel and the environment. However, this is complicated by the absence of universally standardised definitions for various toxicological terms and a lack of clear, unified guidelines for classifying new chemical entities and their specific handling requirements. This regulatory ambiguity necessitates an individual, compound-by-compound evaluation to derive appropriate safety and precautionary measures for manufacturing. Consequently, these multifaceted challenges can significantly impact development timelines, as generating comprehensive safety data and establishing appropriate synthesis protocols are critical, yet time-consuming, milestones for timely entry into clinical trial programs.
Implementing a rational risk-based approach in drug synthesis
To effectively address the uncertainties of early HPAPI development, a rational risk-based approach is indispensable. This strategy begins with a comprehensive review of all available safety, preclinical and physicochemical properties of the compound. The initial data form the foundation for a thorough risk assessment, which integrates insights from established databases and literature, such as the International Society of Pharmaceutical Engineers (ISPE) Risk-Based Manufacture of Pharmaceutical Products (Risk-MaPP) guidelines and the U.S. National Institute for Occupational Safety and Health (NIOSH) Hazardous Drug Alert. Crucially, this assessment informs the layout and design of the entire synthesis process, encompassing facility considerations, equipment selection, process flow and the formulation of a robust risk mitigation strategy — all meticulously planned before the first synthesis campaign begins.
A key aspect of this approach is its continuous and adaptive nature. As more clinical and safety-relevant data become available throughout the project lifecycle, the risk assessment is dynamically updated. This process ensures that the most efficient and cost-effective API synthesis methods are continually identified and adapted, always remaining compliant with stringent Environment, Health and Safety (EHS) standards and regulatory requirements.
The following concepts are central to defining acceptable exposure levels:
- Acceptable Daily Exposure (ADE) and Permitted Daily Exposure (PDE), which quantify the acceptable limits of cross-contamination (from dust, vapours, or equipment) in Europe and the USA, respectively.
- Occupational Exposure Limits (OELs), which define acceptable airborne concentrations to which workers may be exposed, considering specific exposure risks like inhalation or dermal contact.
- Occupational Exposure Bands (OEBs), based on the initial risk assessment, providing an exposure range associated with negligible risk for workers and ensuring that efficient precautionary measures are in place during synthesis, even when comprehensive toxicology data are still emerging.
ADE/PDE and OELs are established upon completion of a complete safety data package, while OEBs are critically employed during early development. The determination of these limits is always compound-specific, considering whether the compound exhibits a threshold value of toxicity or is toxic at any level.
Optimising HPAPI synthesis
Once the operative OEB for a compound is determined, the focus shifts to strategic process development. This involves a meticulous evaluation of potential synthetic routes, with the most suitable approaches defined by principles of efficiency, low exposure risk, scalability and robust analytical monitoring. Using a Quality by Design (QbD) framework, a parallel synthesis approach is often applied to accelerate development. This enables the early identification of Critical Quality Attributes (CQAs), allowing for the establishment of a safe and efficient design space. Building a deep understanding of operational parameter ranges is crucial, supporting process optimisation, successful scaling up and ensuring consistent quality and safety throughout synthesis.
In manufacturing, particularly with HPAPIs and compounds lacking complete toxicity data, each campaign is executed under stringent safety conditions, adhering to guidelines such as ICH Q11. This demands a delicate balance between effective safety measures, development timelines and investment, often guided by the extensive experience of toxicologists and highly trained operators. Hazard analysis and hygiene risk assessments dictate the necessity of segregation concepts, pressure cascading or containment technology, with the default adoption of these technologies proving highly effective in mitigating unknowns. Additionally, automated systems can continuously record process parameters, aiding in CQA design space development. Post-manufacturing, comprehensive cleanability assessments and validation, including swab, rinse and fluorescent dye testing, are critical to confirm the absence of cross-contamination, ensuring the integrity of multipurpose process equipment.
Paving the way for future therapies
The rapid advancements in biomedical sciences have shifted drug discovery towards addressing unmet medical needs, while also demanding substantially shorter development timelines. For future programs involving highly potent compounds, this presents a unique challenge: synthesising drug substance with only limited toxicological and pharmacological data, often under a predicted HPAPI classification. Overcoming this hurdle will require a delicate balance of stringent EHS protocols, regulatory compliance and the imperative for early entry into clinical trials to ensure rapid patient access. By adopting a rational risk-based approach, underpinned by dedicated manufacturing facilities, experienced personnel and QbD principles, organisations can establish an integrated platform. This facilitates safe and efficient synthesis from preclinical through clinical stages and builds crucial product and process knowledge for future scalability, transferability and manufacturing optimisation as more comprehensive safety data emerge.