Here at Affygility Solutions, we frequently interact with hundreds of pharmaceutical manufacturing companies throughout the world. Based on this interaction, here are some of the key challenges that they have with implementing (health-based exposure limits) HBELs:

• Companies not understanding what a HBEL is and how to use it. Many companies don’t understand what is the regulatory intent (i.e., reducing the risk of cross-contamination and therefore protecting patient safety). Having written HBEL monographs (a.k.a. PDE reports) is only one part of the risk management process. The more challenging (and expensive) part is ensuring adequate segregation or installing additional containment, verifying containment through SMEPAC testing, implementing improved procedures, improving cleaning processes, and implementing more sensitive analytical methods. In addition, companies in some areas of the world are not familiar with concepts of containment validation, surrogate monitoring, and occupational hygiene monitoring. The vendor for the isolator may initially perform surrogate monitoring after installation of an isolator, but years later, the pharmaceutical manufacturer may never repeat the surrogate monitoring or repeat it if the process or scale changes. A comprehensive strategy for evaluating airborne, surface cross-contamination, and mechanical transfer should be developed (purchase the ISPE Risk-MaPP Baseline Guide for more detailed information). Implementing a cross-contamination prevention program takes a team effort and change is hard for people. Implementing a cross-contamination prevention program is not a simple buy a HBEL monograph and check off the box activity.
• Companies basing their risk assessment solely on the HBEL value and not considering the process, scale, physical state, dosage form, existing engineering and administrative controls, etc. in the risk assessment. For example, a large-scale milling step of a low-potency compound may be a higher risk of cross-contamination than small scale packaging step for a coated tablet batch for a high-potency compound. Risk assessments should be performed for each unit operation in the production process.
• Basing HBEL monograph purchasing decisions solely on price. Companies often don’t plan appropriately; therefore when it comes to compliance issues they have budget challenges and base HBEL monograph purchasing decisions solely on low price. We have seen many “cheap” providers of monographs, even though they are supposedly “certified,” make the following errors or tricks to mislead you into believing that you’re getting a quality report:
  • Using the wrong point of departure (PoD) by ignoring human clinical data. Just because the toxicologist can find a NOAEL value in the literature from an animal model, doesn’t mean that the NOAEL will always be the best PoD. This is especially true if you have human clinical data. Having a wrong HBEL value can cause either of two problems: 1) you create a cross-contamination risk; or 2) you spend a lot of time/money/effort on engineering controls that aren’t needed. Writing a proper HBEL monograph requires good critical thinking skills, it is not simply finding a NOAEL value and plugging it into the PDE equation and spitting out a value.
  • Overlooking conflicting data such as “mixed” genotoxicity results
  • Using outdated data
  • Using limited data sources or only “free” data sources, thus missing important toxicology data
  • Not understanding the limitations of the threshold of toxicological concern (TTC)
  • Over aggressive use of F factors or adjustment factors, thus driving cleaning
    limits so low that you get frequent cleaning failures
  • Inserting a lot of “useless” filler material, such as CVs inserted in every report, lengthy table of contents, a detailed glossary, and lengthy tables of irrelevant data that is not useful in determining the HBEL.
• Companies have a challenging time with deriving PDEs for data poor molecules. There are approaches that you can use, but it takes a skilled toxicologist to do this and sometimes expensive in silico software to perform structure-activity relationship modeling.

As always, if you have any questions regarding health based exposure limits suchs as permitted daily exposure (PDE) limits, acceptable daily exposure (ADE) limits, or occupational exposure limits, please contact us.