Innovating Particle Characterization of High Potency Active Pharmaceutical Ingredients (HPAPI): The Latest Approach Balancing Safety and Cost Efficiency

Introduction

Among pharmaceutical developments, “High Potency Active Pharmaceutical Ingredients (HPAPI)” have been garnering particular attention in recent years. This refers to active components that exhibit potent pharmacological effects and therapeutic efficacy even in microgram levels. These are primarily used in anti-cancer agents, hormone therapies, and targeted therapies for specific diseases, characterized by demonstrating high effectiveness in small quantities [1].

Market Expansion

Against this backdrop, the market for HPAPI continues to expand [2-3]. A major factor is the progress in research and development of next-generation pharmaceuticals like antibody-drug conjugates (ADC) and molecular targeted drugs. Currently, over two-thirds of HPAPIs are used for anti-cancer purposes, and future demand is expected to increase. While general pharmaceuticals face price competition, HPAPI requires advanced manufacturing techniques and strict safety management, making it a crucial area for enhancing corporate competitiveness. Conversely, due to their potent effects, even minimal exposure during manufacturing and handling can seriously impact workers’ health, necessitating strict controls [4-5].

Handling and Solubility Challenges

In the manufacturing field, “Containment” technology is essential to balance safety and quality [6]. This involves systems to prevent the leakage of active components to the outside and minimize worker exposure. HPAPI is classified according to its toxicity level with “OEB (Occupational Exposure Band)”, and for high-risk substances like OEB4 or OEB5, strict measures such as isolators, enclosed transport systems, and CIP/SIP mechanisms are required for cleaning and sterilizing without disassembling the equipment.

Moreover, many HPAPI are poorly soluble in water, making precise control of particle size and shape crucial for medical performance [6-7].

Challenges in Particle Analysis

HPAPI requires cautious handling, but during development stages, “particle shape and size evaluation analysis” must also progress simultaneously. The challenge here is balancing safety, cost, and analysis efficiency. The traditionally used laser diffraction method (LD) is excellent for measuring particle size but cannot grasp particle shape. Additionally, it requires relatively large sample amounts and large equipment, significantly increasing costs. On the other hand, manual image analysis using microscopes can handle small samples but is time-consuming and labor-intensive for evaluating numerous particles, posing challenges in ensuring reproducibility.

New Method: Combined Approach of WD-TESO and APIA

A new approach appearing in application notes to solve these challenges is the method combining “WD-TESO (Wet Dispersion and Thinly Encapsulated Sample Observation)” and “APIA (Automated Particle Image Analysis)” [8]. This method involves dispersing a small sample in liquid and thinly encapsulating it on glass slides for observation. A significant advantage is the substantial improvement in safety since samples do not scatter externally. Furthermore, by combining automated image analysis, it efficiently quantitatively evaluates not just particle size but also shape and distribution.

Features

A notable point of this method is its speed and cost. Compared to traditional methods, analysis time is reported to be shortened to one-tenth to twentieth, and costs are reduced to about one-tenth. This dramatically improves throughput (processing capacity) of analysis, allowing many data to be obtained in a short period.

Practical Deployment

This method is particularly effective during the early clinical development stages. The ability to comprehensively obtain particle characteristic data even with limited API amounts allows for efficient development. Besides, the automatically acquired image data are highly objective, smoothing in-house information sharing and useful in technology transfer and communication with CMOs.

Furthermore, its advantage is that it can be introduced into existing environments without depending on large-scale containment facilities. Automation reduces workload and human errors, enhancing data reliability. Consequently, it enhances development efficiency and reproducibility with limited resources.

Overall, the integrated method of WD-TESO and APIA is a powerful approach that contributes to the efficiency and risk reduction in HPAPI development by balancing safety, cost-efficiency, and reliability at a high level.

References

• [1]B.Y. Shekunov, P. Chattopadhyay, H.H.Y. Tong, A.H.L. Chow, Particle size analysis in pharmaceutics: principles, methods and applications, Pharm. Res. 24 (2007) 203–227, https://doi.org/10.1007/s11095-006-9146-7.
• [2] NovaOne Advisor, High Potency Active Pharmaceutical Ingredients Market, NovaOne Advisor, 2025. https://www.novaoneadvisor.com/report/high-potenc y-active-pharmaceutical-ingredients-market. Last Updates April 22. 2025.
• [3] Mordor Intelligence, High-potency API contract manufacturing market, Mordor Intell. (2025). https://www.mordorintelligence.com/industry-reports/high-potenc

[4]C. Challener, Challenges to formulation development for highly potent APIs, Pharmaceut. Technol. 46 (2022) 24–27.

• [5]A. Scott, High potency API manufacture: too risky for new entrants? Chem. Week 167 (2005) 31–36.
• [6]O. Lazzaro, Choosing containment strategies for highly potent APIs, Pharmaceut. Technol. 9 (2016) 66–69.

[7] C. Cynthia, Enabling technologies advance poorly soluble highly potent APIs, Pharmaceut. Technol. 43 (2019) 20–2

[8] Sasakura, D. (2026). Cost-effective particle characteristics for highly potent active pharmaceutical ingredients using particle image analysis with thinly encapsulated sample observation methods. Journal of Drug Delivery Science and Technology, 116, 107905.