Konstantinos Apostolou, R&D senior manager, Adragos Athens discusses the HPAPI sector and how it's one of the fastest-growing areas in pharma.
The highly potent active pharmaceutical ingredient (HPAPI) sector is one of the fastest-growing areas in the pharmaceutical industry, fuelled by the need to meet the growing demand for novel targeted treatments.
The high-potency drug market size was valued at $185.5 billion in 2024 and is predicted to reach $520 billion by the year 2034, with more than a quarter of drugs on the market today being classed as highly potent.
HPAPI-based drugs have shown significant promise in treating a range of disease indications, with oncology drugs notably dominating the current market. Data show that 60% of such treatments in development today involve highly potent ingredients. Additionally, HPAPI drugs are also being used to target a range of diseases, including asthma, diabetes, and central nervous system disorders.
As the development of new drugs becomes more precise and targeted, the industry is witnessing a general increase in higher potency levels, and consequently, a rise in drugs for clinical microdosing that exhibit properties with containment requirements as low as nanogram levels. The challenges of containment and handling such products mean that organisations involved in the development, manufacturing, and formulation of these drugs must ensure that their strategies, equipment, and operating procedures are suitable for each project.
The challenges of working with HPAPIs
Despite the significant therapeutic benefits HPAPI drugs can have for patients, their toxicity presents numerous obstacles and risks during development and manufacturing. Operator exposure to such highly potent compounds is one of the greatest risks associated with this, and therefore, stringent containment measures and personal protective equipment are crucial, especially as the health risks are still under evaluation during the development phase.
Currently, there is a lack of standardisation of HPAPI classification and containment across the pharmaceutical industry, meaning each company must have its own set of guidelines for handling materials at the relevant development stage. This lack of harmonisation across the regulatory landscape demands continuous reassessment of employed strategies to ensure approaches remain robust and effective throughout the product lifetime.
A secondary challenge of development and manufacturing of HPAPI is the small volumes necessary, along with the typical low dose of the products, which can make the testing and validation of contaminant measures a significant challenge. As a result, such activities can be time-consuming and costly, as rigorous testing and validation of small batches to ensure safer operation and handling may prove problematic.
Strategies to overcome HPAPI production challenges
To overcome the production challenges, a multi-faceted approach and accurate hazard assessment from early development stages are essential. A risk mitigation strategy can indicate potential risks and how to pre-emptively introduce appropriate measures to ensure safety. This can lead to a smooth transition to the next development phase and reduce potential delays and minimise costs.
To this end, a thorough assessment of the potency and toxicity of the HPAPI is needed to understand the occupational exposure limits (OEL) for each molecule based on the available information. If full toxicology assessments are not available, then assumptions will need to be made based on the analysis of the molecule and comparisons to known compounds with similar structures. With more data, a more specific strategy will be possible, but in the absence of this, it is important to build in a number of safety and uncertainty factors into the assessment to ensure a safe handling approach is adopted.
From this information, the operational exposure banding (OEB) for the molecule is determined to develop a containment strategy. Using OEB, the HPAPI is assigned to a band depending on the risk to human health, and appropriate engineering controls such as containment equipment and ventilation systems, as well as administrative protocols, and necessary levels of personal protective equipment are introduced. By employing advanced equipment and sophisticated analytical approaches, organisations can achieve a more accurate representation of toxicity risks associated with highly potent active pharmaceutical ingredients (HPAPIs), leading to more meaningful categorisations. These include informed assessment of the toxicological risk and employment of quantitative structure-activity relationship (QSAR) models that can predict the toxicity of new chemical entities based on their structural properties, allowing for early categorisation of potential risks. Together, these technologies enable more targeted control strategies that are tailored to the specific hazards of each HPAPI, ultimately enhancing workplace safety while ensuring compliance with regulations.
To maximise the safety of operators, the use of robotic liquid handling systems allows the precise manipulation of HPAPIs without human exposure, ensuring consistent handling and minimising risk. In combination with real-time wearable exposure sensors, which provide immediate data on the levels of HPAPIs in workers’ environments, companies can accurately monitor exposure and quickly adapt safety protocols as needed.
Collaborative approach
Achieving a successful development method that considers safety from concept to commercialisation relies on strong cross-disciplinary collaboration between research, development, and manufacturing personnel. By integrating a quality-by-design (QbD) approach, all safety measures can be implemented across the production pipeline, from small-scale research and development through to large-scale manufacturing. In addition to ensuring operator safety, an approach that is built on collaboration will streamline the process, with smooth transitions between each stage designed to reduce delays and expedite product delivery.
The future of highly potent materials
With so much emphasis in the development pipeline on drugs that are highly potent, the landscape will continue to evolve, driven by the increasing need for novel and high-precision treatments. These shifts include:
- The use of sophisticated drug delivery systems such as nanoparticles, liposomes, and micelles. Combining high potency with targeted delivery maximises the efficacy of the treatment;
- The increase of biological HPAPIs such as antibody-drug conjugates (ADCs), which exploit the specificity of antibodies to deliver cytotoxic payloads directly to target cells;
- The integration of artificial intelligence and machine learning to optimise manufacturing processes, and ensure greater efficiency and quality control;
- The adaption of regulatory frameworks to address the unique challenges associated with HPAPI production, facilitating innovation while maintaining patient safety.
Effectively navigating HPAPIs
Overall, the development and manufacture of HPAPIs pose several challenges, including safety risks to operators, the lack of regulatory standardisation, and the need for specialised equipment and facilities. Overcoming these challenges requires comprehensive hazard assessment, accurate potency and toxicity determination, and the implementation of appropriate engineering controls, administrative protocols, and personal protective equipment. By adopting a multi-disciplined approach that considers safety from concept to commercialisation, pharmaceutical companies can ensure the safe and efficient development and manufacturing of HPAPI products.