The High Cost of Uncertainty and Modifying Factors

When establishing occupational exposure limits (OEL) for active pharmaceutical ingredients the equation that is often used is the one that was published in by E.V. Sargent and G.D. Kirk (1988), and presented with slight modification by B.D. Naumann and P.A. Weideman (1995).  This equation is as follows:

occupational exposure limit for pharmaceuticals



OEL = Occupational Exposure Limit
NOAEL = No Observable Adverse Effect Level (mg/kg)
BW = Body Weight (kg) and typically either 70 kg for males or 50 kg for females
UFc = Uncertainty Factor Composite
MF = Modifying Factor
V = Volume of air breathed in an 8-hour work shift.  10 m3 is typically used.
S = The time to achieve a plasma steady state.
α = The present of the compound absorbed.

As stated in the above articles, when establishing occupational exposure limits for an active pharmaceutical ingredient, the occupational toxicologist performing the risk assessment will review the pre-clinical and clinical data to determine the critical effect that serves as the basis for the establishment of an occupational exposure limit. Typically, the critical effect used is a no-effect level for the pharmacological action of the drug in humans.

uncertainty factors occupational exposure limits

Since the majority of the above factors (NOAEL, BW, V, S, and α) are either set values (BW and V) or values that can be obtained from the pre-clinical/clinical data, the largest source of variations between occupational exposure limits is the uncertainty factors. The combined uncertainty factors can range from 1 to well over 1,000, and the largest increases in uncertainty factors come from simply the lack of data.  If for a minute we consider the impact that this has on the OEL, it means that depending upon the uncertainty factors used, an example OEL can range from 1 mg/m3 to 0.001 mg/m3 or less, and if using a traditional control banding approach this can cause variations of placement into a specific band by 3 or more bands.  As indicated by Maier (2010), the United States Environmental Protection Agency has held that 3000 should be the maximum uncertainty factor for four categories of uncertainty, and if additional uncertainties are present, then the dataset should be considered inadequate for a risk assessment.  In addition, Maier (2010) states as exposure controls increase to afford more exposure protection; costs increase dramatically, employee productivity decreases, and the level of ergonomic hazard to employees can increase substantially.  At Affygility Solutions, it has been our experience with contract manufacturing organizations (CMOs) and contract research organizations (CROs) that the cost difference from handling a Category 2 potent compound to a Category 3 potent compound can range from 40 to 100 percent more.  Then when you start discussing costs for handling Category 4 or 5 potent compounds the cost increases are even more dramatic.

What uncertainty factors should be considered?

While I could go on forever, regarding the various uncertainty factors, the main ones to consider are 1) Interindividual variability, 2) Interspecies extrapolation, 3) LOAEL to NOAEL extrapolation, 4) Subchronic to chronic extrapolation, 5) route to route extrapolation, and 6) Modifying factors.  For a more detailed discussion on these factors, I would suggest reading the Naumann and Weideman article, or register to attend our webinar series on Advanced Topics in Potent Compounds.

Keeping uncertainty factors in check

So how can innovator companies and virtual pharmaceutical companies keep these uncertainty factors in check?  First, communicate early with your prospective CMO/CRO.  In order to prepare an accurate cost estimate, they will need to determine what exposure control band that the compound will need to be handled.  Second, make sure that the CMO/CRO is aware of all the toxicology data that you have available on the specific compound.  Data speaks loudly, and lack of data causes uncertainty factors to increase dramatically, as the uncertainty factors increase the OEL decreases and thus, the costs increase.  Third, just like making any major decision, if you receive a potent compound classification report and the occupational exposure limit seems unreasonably low, get a second opinion.  At Affygility Solutions, we have seen OELs vary as much as a factor of 1000.  Finally, as the dataset for the specific active pharmaceutical ingredient becomes more complete, communicate that additional information to your CMO/CRO.

The goal of establishing an occupational exposure limit for an active pharmaceutical ingredient is to ensure employee protection, but establishing occupational exposure limits with overly conservative uncertainty factors can create hazards as well.  In order to place a compound into the correct exposure control band or establish a reasonable occupational exposure limit, the occupational toxicologist needs data to work with, without data, uncertainties and costs will increase.

If you have any questions regarding the calculation of occupational exposure limits for active pharmaceutical ingredients, or the use of uncertainty factors, please contact Affygility Solutions.


About Dean Calhoun

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Dean is the President and CEO of Affygility Solutions. Affygility Solutions provides environmental, health and safety software, potent compound safety, industrial hygiene, containment validation services to the pharmaceutical, biotechnology, and medical device industry. "Dean's Google+ Profile"

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