Review your potent compound safety handling practices and determine your gaps. Obtain occupational exposure limits for your active pharmaceutical ingredients.
Unlike traditional hazardous substances, active pharmaceutical ingredients (API) are designed to have an effect on the human body. As stated by Dr. Joe Nieusma, Senior Occupational Toxicologist for Affygility Solutions, "If an operator provides a pathway of exposure to an active pharmaceutical ingredient, it will have its intended effect."
In a traditional workplace setting, occupational exposures to hazardous substances are regulated by a variety of governmental agencies such as the Occupational Safety and Health Administration (OSHA) in the U.S. or the Health and Safety Executive (HSE) in the U.K. Additionally, other organizations such as ACGIH and NIOSH provide occupational exposure guidance for hazardous substances.
Unfortunately, a review of these standards reveal only a limited number of APIs with established occupational exposure limits (OELs). Furthermore, examination of the Food and Drug Administration's (FDA) National Drug Code (NDC) Directory reveals over 71,000 prescription drugs that have been assigned a NDC number.
While there is certainly some duplication of APIs due to different formulations and dosage strengths, the number of APIs that exist is still easily in the tens of thousands of unique compounds. Many of these compounds meet the definition of a "potent compound" and would have OELs much lower than traditional hazardous substances. Just because a potent compound lacks an OEL does not mean that it is harmless. Potent compounds must be managed differently than traditional hazardous substances.
New compounds enter a company’s development pipeline through a variety of channels: compounds can be identified through drug discovery technologies, can be in-licensed from other companies, or may become a generic drug coming off patent expiration. Once a compound enters a company’s development pipeline, it will need to be reviewed for appropriate hazard information.
This review should be conducted by an occupational toxicologist with the training and experience in evaluating potent compounds. Potent compound evaluations conducted by inexperienced personnel often lead to increased exposure risk due to overlooking critical toxicology information or to expensive over classification of the potent compound.
Once a potent compound evaluation has been completed, the company will need to determine the appropriate combination of engineering controls necessary to prevent occupational exposure. The appropriate combination is typically determined through the use of a control banding strategy such as those discussed by Naumann.
As compounds advance through a company’s development pipeline, the potent compound evaluation must be periodically reviewed as new data from pre-clinical studies and clinical trials become available. It is critical that pharmaceutical EHS professionals develop and maintain solid lines of communication with the drug development departments, and that these departments are trained in the basics of potent compound safety. The management of a company’s potent compound safety process is an ongoing effort, not a means to an end.
After many discussions with contract manufacturing organizations (CMOs) with potent compound experience, Affygility Solutions estimates that an overly conservative OEL or over classification of a potent compound will cost a company 60 to 100 percent more to have it processed.
As discussed by Maier (2010), for compounds with limited dose-response information, the use of default uncertainty factors can easily overwhelm what is actually known about a compound and play a greater role in the risk assessment than scientific knowledge. This will then result in an unjustifiably low OEL which would require significant amounts of controls.
With increased controls, costs increase significantly and worker productivity is reduced. Potent compounds need to be evaluated correctly or it will cost your company money. If you have OELs for your potent compounds, develop a thorough understanding of what uncertainty factors are being used and why.
Quite often I will meet with new clients and request the results of previous industrial hygiene studies. And just as often I will be presented with a stack of total dust monitoring sample results and the client will say "See, they are all well below the total dust limit!"
What's missing here is the knowledge that the limit of detection/limit of quantification (LOD/LOQ) for the total dust method is 10 µg/filter. With a LOD/LOQ at this level, this approach is only reliable for potent compounds with an occupational exposure limits (OEL) just over 10 µg/m3 based on an 8-hour sampling duration. Total dust monitoring methods won’t provide the data you need to ensure protection against occupational exposure to highly potent compounds.
In the pharmaceutical industry, the respiratory protection factor of most powered air-purifying respirator (PAPR) and air-line respirators is rated as 1000. What this means is that the respirator is rated to provide protection to 1000 times the OEL.
In poorly controlled pharmaceutical operations, airborne concentrations of potent compounds can be well into the mg/m3 range. For example, if you have an operation with airborne concentrations of a potent compound at 1.5 mg/m3 (1,500 µg/m3) and an OEL for that compound of 500 ng/m3 (0.5 µg/m3), your operation has exceeded the protection factor of the PAPR by 300 percent.
EHS professionals in the industry must ensure that they have reliable industrial hygiene data to support the protection factor of any respiratory protection used, and that it is adequate for protection against occupational exposure to highly potent compounds.
Over the past several years Affygility Solutions has been performing containment validation studies. As expected, clients are often surprised to find out that the results of the containment validation monitoring are not "non-detectable" for every sample.
In the majority of cases, the reasons for increased airborne concentrations are not due to poor design of the containment device, but due to poor work practices. Evaluate your company’s containment devices and make a determination as to what categories of potent compounds you can reliably handle.
As most EHS professionals know, RISK = HAZARD × PROBABILITY. The hazard of a specific potent compound is based on its toxicological characteristics. The probability of exposure to the potent compound is based on a number of other factors, including: quantity handled, physical form, frequency of handling, etc.
EHS professionals in the pharmaceutical industry frequently develop risk assessment matrices to determine the overall risk for handling specific potent compounds. Based on the outcome of these potent compound risk assessments, additional controls will be implemented or enhanced to lower the risk of handling the potent compound.
If you have additional questions on occupational exposure to potent compounds, occupational toxicology, or industrial hygiene in the pharmaceutical or biotechnology industry, please contact Dean M. Calhoun, CIH at 303-884-3028, or firstname.lastname@example.org.