Case Study: How to Ensure Safety While Manufacturing Highly Potent APIs

Highly potent active pharmaceutical ingredients (API) require careful attention to safety and handling during formulation and manufacturing. This blog explores the process required for manufacturing a highly potent API for an ophthalmic indication, based on a case study involving loteprednol etabonate, a topical corticosteroid used to treat eye inflammations.

What are Highly Potent APIs?

Highly potent APIs elicit strong biological activity at minimal concentrations. They are defined as substances that are biologically active at approximately 150µm/kg in humans. Their high potency brings therapeutic advantages, but also introduces risks during manufacturing due to potential exposure.

The Challenge: Safe Manufacture of Highly Potent APIs 

Exposure to highly potent APIs must be carefully managed during production. This calls for specialized facilities, protective measures, and expert handling for the safety of both workers and the environment.

A long-term client tasked Altasciences with manufacturing a nanomilled suspension of a loteprednol etabonate intermediate for an ophthalmic application. Loteprednol etabonate, a corticosteroid, requires stringent safety protocols due to its classification as a highly potent API. We developed the drug from R&D to commercialization, maintaining our high standard of safe handling and processing procedures throughout the project.

Key Steps in the Process

1. Safety Protocols and Hazard Control: 

To manage the inherent risks of HPAPIs, we followed industrial hygiene protocols. We anticipated potential hazards and recognized and evaluated all potential exposure events to mitigate risk. Identifying exposure events early on—particularly for the dispensing of the API into the vehicle—enabled our experts to implement appropriate containment measures.

2. API Identification: 

Compound potency is classified via the Occupational Exposure Limit (OEL) or Operational Exposure Band (OEB), when little information is available. The classifications range from 1 to 4, with lower classification values indicating more potent compounds, which require greater levels of containment and safety precautions at the manufacturing site. 

Based on available toxicological data, we were able to identify loteprednol etabonate as an OEB 3 compound. Known to be a reproductive toxin and harmful to aquatic life, it required careful containment measures during production.

3. Engineering and Administrative Controls: 

The cornerstone of safe HPAPI manufacturing lies in strict controls and the use of personal protective equipment (PPE). Our staff wore double nitrile gloves, full-body protective suits, respirators, and safety goggles. Engineering controls, such as airlocks and pressure-controlled rooms, further minimized the risk of airborne contamination and cross-contamination.

Production took place in a Grade C cleanroom—a completely isolated unit that keeps airborne particulates down. These isolated suites feature containment systems for negative pressure controls to limit exposure, and for monitoring and verifying effectiveness of the containment strategies. With airlocks around the manufacturing and laboratory areas, staff could safely gown and de-gown. Furthermore, laminar flow systems were utilized to filter the air, reducing the risk of disrupting airborne particles. When handling loteprednol etabonate, additional containment strategies were applied to reduce aerosolization. 

4. Product Disposal: 

We disposed of all waste and material generated from the manufacturing loteprednol etabonate at regulated chemical treatment facilities. Proper documentation and disposal protocols ensured compliance with environmental and safety standards.

Altasciences’ Commitment to Excellence

We have decades of experience handling highly potent APIs, from formulation to manufacturing. We can manage highly potent API projects from start to finish within our own facility, with analytical, manufacturing, and cGMP warehouse capacity. With segregated Grade C and D cleanrooms, specialized training for operators, and state-of-the-art containment systems, even the most potent compounds can be handled safely. At the beginning of each highly potent API program, operators receive refresher training on the specifics of engineering controls and safety measures required for handling the API in question.

Are you working on a highly potent API? Contact us today to get your program on track.