Alkermes’ successful approach to commercialscal final dosage manufacture of drug product containing highly potent API

Project History
• Donor site capacity issue where the company was seeking an outsourcing manufacturing partner for commercial supply
• Product was classed as a highly potent compound and had an Occupational Exposure Limit (OEL) of 0.5 μg/m3, an Adverse Drug Event (ADE) level of 5μg/ day and exhibited teratogenic and exotoxic properties
• The product had a low Minimum Ignition Energy (MIE) of <3mJ
• Manufacturing required contained dispensing, high shear granulation with microwave drying, blending, compression and coating processes.

Why the Alkermes Athlone Site Located on a 40-acre site, with over 220,000 sq ft of dedicated cGMP grade facilities, this FDA/EMA inspected site had a proven manufacturing track-record with many products optimized and manufactured for partners for multiple territories. The facility had previous recent experience with the development, scale-up commercial manufacture of a highly potent product.

The Challenge
The manufacture of a Highly Potent Active Pharmaceutical Ingredient (HPAPI) compound can present many challenges due to the complex handling required for toxic substances. The successful and safe manufacture of HPAPIs require the availability of a highly skilled team of staff with the right experience, the proper evaluation and training procedures being in place and the use of state-of-the-art facilities.

When taking on a HPAPI for final stage manufacture, it was important to follow a systematic approach to handle potent drugs safely.

Other essential elements included the following: defined standard operating procedures, developing and managing a staff training program, using tools to evaluate and measure exposure, designing and developing containment and controls, developing systems to verify effectiveness and finally determining and assessing the environmental impact of the active substance and associated manufacturing.

Ensuring these steps were in place was particularly important due to the fact that the Alkermes Athlone site is a multiproduct facility. Concern relating to crosscontamination with other products being manufactured had to be considered.

The following steps were undertaken to ensure containment procedures were in place to manage the safe manufacture of the HPAPI product:

• Determination of OELs and compound categorization scheme
• Industrial Hygiene (IH) exposure assessment, control verification and sensitive IH analytical methods
• Engineering controls and maintenance
• General and specific handling guidance
• Procedures and training
• Medical surveillance.