Here at Affygility Solutions, we frequently engage in conversations with pharmaceutical professionals from all over the world regarding dedicated facilities and the underlying concepts of permissible daily exposures (PDEs), acceptable daily exposures (ADEs), and occupational exposure limits (OELs) for active pharmaceutical ingredients (1). Often, we field questions that are similar in nature and unfortunately just unsupported information, which I will call myths. These myths are as follows:
- Isn’t there some magical unicorn database or computer program available on the Internet that will provide both the OEL and ADE for free? Sorry there isn’t, so you can stop wasting your time searching for one right now. There’s several reason why this “free database” doesn’t exist. These reasons are as follows: i) two groups of professionals establish OELs and ADEs, either toxicology professionals internal to a pharmaceutical company or expert consultants. Neither have the time or desire to work for free and most get paid extremely well. Researching and preparing the necessary documentation to support an OEL/ADE takes time and effort. Don’t be naive and discount the value of an informational product or service just because it’s not a hard tangible item (like a tablet press); and ii) the number of potential employees exposed to APIs in relatively small when compared to the number of employees exposed to general industrial chemicals (methanol, xylene, etc.). Governmental agencies, such as OSHA and UK’s HSE, tend to focus their efforts on programs that will have the largest impact. Occupational exposures to APIs won’t get much attention from governmental agencies unless it impacts the health of a large number of employees. In addition, OSHA doesn’t even have the resources or political clout to even update their existing permissible exposure limits. Now, with the advent of the ADE/PDE requirements for multi-product pharmaceutical manufacturing facilities, these values have the potential to impact patient populations (which will be a much larger population than a worker population), so ADE and PDEs will get attention from the applicable regulatory agencies, but there are just too many API compounds for governmental agencies to devote resources to deriving the ADE and PDE for you. Even if they did, you wouldn’t agree with their numbers anyway. Finally, you should also remember that the PDE, ADE, or OEL has the potential to impact multi-million dollar (or rupee) decisions. Do you really want to base that decision on some unsupported, “free” number that you found on the Internet? Get your numbers from credible sources.
- If you have two OELs or ADEs for the same compound, the lower number must be correct or a better number. Wrong. A lower number might be right – or it might be wrong. You would have to critically review the OEL/ADE monograph documentation to make that determination (this is why having just a “number” is a worthless and dangerous practice). Lower OEL/ADE numbers might exist because someone selected a difference point of departure, or more commonly, the person calculating the OEL or ADE was not confident in their own technical abilities so they overcompensated by using larger uncertainty factors than what is necessary. It could also occur because an OEL/ADE for the compound was established when the compound was early in development and uncertainty was high. Remember, unnecessarily low OELs or ADEs cost a pharmaceutical company money, in terms of unnecessary engineering controls, elaborate work practices, or elaborate cleaning practices. The documentation for an OEL or ADE must present a reasonable scientific argument to support the number.
- Once an OEL or ADE is established for a compound, it will never change. Nope, not true. As a compound moves through the pharmaceutical development process, I would expect the OEL/ADE to change. In addition, sometimes adverse health effects appear that did not show up in clinical trials. Therefore, the OEL and ADE must be revised.
- OELs and ADEs are a bright line between safe and unsafe. OELs and ADEs are NOT precise numbers. They are protective, but not precise. OELs and ADEs are an extrapolation of a known dose (NOAEL, NOEL, lowest daily dose, etc.) to an unknown dose that is believe to be protective over a long period of exposure. The more uncertainty factors you use, the greater the extrapolation, and the fatter the pencil will be. A difference between an OEL of 200 vs. 233 ug/m3 is a meaningless rounding difference. Don’t overthink things and try to argue this point, you’re wasting your time. Unfortunately, regulatory agencies don’t help us out much here with their foolish practices of saying that if you’re just barely over an OEL, you’re in violation.
- The equations for both OELs and ADEs look pretty simply, I can do these calculations myself. You can try, but unless you’re an expert with the advanced education, training and experience, you will have a tough time defending yourself to regulators or an attorney when you get it wrong. In addition, the EMA is requiring a CV summary of the person preparing the PDE. Good luck defending your number if you don’t have the relevant training, education, and experience on your CV.
- An OEL that is presented on a material safety data sheet is always correct. Nope. Many are wrong. Some are really wrong. In addition, the SDS may be a legacy version and never get revised with a new number once new data is available. Furthermore, here at Affygility Solutions, we have seen the practice of one company copying incorrect information from one SDS to the next SDS, resulting in dozens of safety data sheets for APIs with incorrect information. Vet out your sources!
- OELs and ADEs must be certified. Nope, no requirement to be certified. We hear this often from companies in the developing world, “We need certification.” Certification in what? In addition, certifications of any kind by private companies are meaningless. Only certifications by independent accreditation organizations based on a consensus based standard have any worth.
- All I need is the OEL and ADE number. Give me the number for free. A number without documentation and cited references is not credible or the approach is not verifiable and won’t survive the rigor of a regulatory inspection. You won’t get an OEL or ADE monograph for free.
- I’ve taken a webinar, seminar, workshop, or bootcamp on potent compound safety and OEL/ADE setting, doesn’t that make me qualified to do this work myself? Not going to happen. There are NO overnight experts in any field. Taking webinars, seminars, workshops and bootcamps are all good things, but all they do is provide you with an awareness level of understanding, so you know the right questions to ask. See this article.
- If the SDS says that the OEL is “not available”, or that it is “not listed” by OSHA, ACGIH, or AIHA, then it must be “non-hazardous.” Repeat after me, “not available” does not equal “non-hazardous.” We have seen many SDSs that have the OEL listed as “not available” and these were for highly potent compounds.
So, there are my top 10 myths regarding PDEs, ADEs, and OELs. If you need a credible OEL or ADE for an active pharmaceutical ingredient, please check out our OEL Fastrac with ADE catalog. Now with over 1900 compounds. If your compound is not listed, please contact us about creating one for you.
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(1) For the purposes of this blog post, we will assume that PDEs and ADEs are analogous.