Ultra-Potent pharmaceuticals: Verifying containment

TOXICOLOGY OF ULTRA POTENT PHARMACEUTICALS
Over the past twenty or so years, it has been a recurring theme within the pharmaceutical industry that active pharmaceutical ingredients (APIs) are becoming more and more potent and toxic. The potency of these APIs is generally indicated by the occupational exposure limit (OEL) which is defined as the airborne concentration of a chemical substance that a worker can be safely exposed to for a 40-hour work week, over a working lifetime. The methodology used in deriving these values for APIs was initially published in 1988 by Sargent and Kirk (1), and has been repeatedly refined over the years, but the basic premise remains the same:

• Find the adverse effect that the API has in human or animal studies.
• Define the lowest dose of the API that causes the effect or the highest dose that does not cause the effect (point of departure, or POD).
• Apply adjustment factors, accounting for variability of effects and other uncertainties, to lower the POD to an effect that is believed to be safe for workers repeatedly exposed to the API.
• Divide by the amount of air inhaled during a work shift to express the value as an airborne limit.

It is not unusual for APIs to have OELs that are below 1 µg/m3 but an increasing number of ultra-potent APIs have OELs in the 1-10 ng/m3 range. In fact, a handful of OEL values have been derived that are less than 1 ng/m3. Ultra-potent APIs are often associated with anti-neoplastic drugs but may also be associated with peptide hormones and antibody-drug conjugates (ADCs). Although the entire ADC may not be an ultra-potent API, the warhead (Figure 1), which has been conjugated to an antibody specific for the tumour type, is typically ultra-potent. The concept of an ADC, which allows targeted delivery of the warhead, allows the use of the ultra-potent warhead which would otherwise not be tolerated by the patient. As OEL values appear to become lower, many question the reasons why this might be occurring and have blamed this phenomenon on overly cautious toxicologists applying increasingly higher adjustment factors resulting in lower OELs out of an abundance of caution. In fact, this use of high adjustment factors (previously referred to as uncertainty factors) is more likely to be due to the high degree of uncertainty in extrapolating adverse effects seen in the clinic or animal studies to levels believed to be safe in healthy workers.