Understanding Traditional Approaches

Traditionally, pharmaceutical companies have employed several methods to assess the hazard levels of drug Active Pharmaceutical Ingredients (APIs). These methods include defining Occupational Exposure Bands (OEBs), using Occupational Exposure Limits (OEL) to estimate Acceptable Daily Exposures (ADEs), and categorizing molecules based on properties like genotoxicity or steroidal nature. However, these approaches often fall short as they don't consider all toxicological data, leading to potentially inaccurate hazard assessments.

Calculation of API Toxicity Scores

The emergence of ADE as a scientific metric offers a more accurate method for assessing toxicological risks. ADE considers comprehensive toxicological data from pre-clinical and clinical development stages. To effectively compare the hazard levels of APIs, we propose converting ADE values into a Toxicity Score using the following formula:

Toxicity Score = -Log10 (ADE in grams/day)

For example, consider the following API Toxicity Scores calculated from their respective ADE values:

• Valsartan: ADE = 0.00033 grams/day, Toxicity Score = 3.481
• Moxifloxacin: ADE = 0.022 grams/day, Toxicity Score = 1.658
• Donepezil Hydrochloride: ADE = 0.00017 grams/day, Toxicity Score = 3.770

These scores provide a clearer, logarithmic scale-based comparison of API hazards, facilitating more informed decision-making in manufacturing processes.

Practical Applications of API Toxicity Scores

API Toxicity Scores can significantly impact several key pharmaceutical manufacturing decisions:

• New Product Introduction: Integrate products with similar toxicity scores to streamline controls and mitigate cross-contamination risks.
• Setting Periodic Verification Frequency: Adjust the frequency of verification programs based on toxicity scores, with lower scores requiring less frequent checks.
• Dedicated vs Shared Equipment: Use toxicity scores to decide on the need for dedicated manufacturing facilities for high-hazard APIs.
• Product Changeover Sampling: Guide the frequency of analytical sampling based on the toxicity scores, adhering to the latest EMA guidelines.
• Extent of Cleaning Validation: Tailor cleaning validation efforts to the risk level indicated by the API Toxicity Scores, ensuring safety and compliance.

Transitioning from a binary to a continuous measurement system for API hazards allows for more nuanced, scientifically grounded decision-making in pharmaceutical manufacturing. By adopting the API Toxicity Score approach, companies can enhance safety, efficiency, and regulatory compliance.

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