Toxicology and safety considerations
In a recent state-of-the-art battery of toxicology studies, TBA demonstrated no signs of mutagenic toxicity or systemic toxicity
in rodents when doses for up to 28 d at levels reaching 109 times higher than any potential exposure from product (7). TBA
levels that have been observed in bio/pharmaceutical and consumer healthcare products are within the range observed in beverages
(ppb-ppt) including chlorinated drinking water, wine, and beer. Based on an in-depth review of the literature by the PDA Task
Force, these levels of TBA in beverages were not associated with any adverse events.
Several adverse-event analyses have been conducted by companies represented in the PDA TBA Task Force. The results of these
analyses do not indicate any causal relationship between TBA exposure and GI events. The "musty/moldy" odor associated with
products contaminated with TBA has been reportedly associated with acute, transient, gastro-intestinal adverse events (e.g.,
nausea, vomiting, and diarrhea). The rodent is incapable of vomiting, but is a good model for diarrhea. In the battery of
rodent toxicology studies noted above, there were no signs of diarrhea or any macroscopic or microscopic pathological effects
observed along the GI tract.
A potential exposure to TCP, TBP, or TCA in the 100 to 1000 ppt range in product would lead to an acceptable, de minimis (minimal effect) exposure based on the acceptable chronic exposure levels of TCP. An analysis of all of the above, toxicology
data, environmental exposure data, and adverse events reporting suggest that any human health risk associated with clinical
exposure to these ppt levels of TBA is inconsequential and presents a de minimus safety risk. TBA occurs naturally in our environment and human exposures to these ppt levels are not uncommon.
Risk management
A risk-mitigation plan for TBA/TCA tainting can be established by a pharmaceutical company at its manufacturing sites that
follows the International Conference on Harmonization (ICH) Q9 guideline principles (8). Details from this plan are available
in the PDA Technical Report for the following:
- Pharmaceutical and consumer healthcare facility pallet-inspection procedures
- Management of pallets in the supply chain
- Warehousing, storage control, and shipment procedures
- Components and raw materials inspection procedures
- Customer-complaint procedures.
Conclusion
Useful risk-mitigation steps identified by the PDA Task Force include not constructing pallets from TBP treated lumber, controlling
the moisture content of wood to levels not conducive to fungal growth, improved supply chain awareness of haloanisole taints,
elimination of other sources of halophenols, and adequate environmental control and ventilation in warehouses and during transportation.
Toxicological and safety studies conducted on TBA demonstrated no mutagenicity or systemic toxicology in rodents when dosed
for up to 28 days at levels a billion-fold higher than potential human exposure from the recalled product. TBA dosing produced
no diarrhea or any macroscopic or microscopic pathological effects along the GI tract in rat toxicity studies. Although nausea
was reported by consumers sensing the musty, moldy odor, adverse event analysis by multiple recalling companies have not established
a causal relationship between TBA and gastrointestinal events. Therefore, reactions of disgust to TBA taints appear to be
a sensory and/or behavioral response and not toxicological and, therefore, is a patient compliance risk rather than a patient
safety risk.
Based on the high margin of safety demonstrated in toxicity studies, there is no meaningful analytical threshold that can
be based on toxicity. It is therefore necessary for individual companies to consider how the odor is being perceived by their
customers and the likelihood that perception to the odor could impact patient therapy (i.e., the concern is that the musty,
moldy odor from these taints could increase the likelihood that patients will not take their medication). Finally, it is up
to the pharmaceutical and consumer product manufacturer to understand their pallet supplier(s), classify them appropriately,
and work with the supplier's controls on pallet manufacturing. Companies should implement internal pallet controls to minimize
risks from TBA (TCA) tainting accordingly as noted in the PDA Technical Report.
This paper was contributed by the Parenteral Drug Association (PDA) TBA Task Force Members.
The content of this article, including the figures and tables, was adapted from PDA Technical Report No. 55, available at
http://store.pda.org/ProductCatalog/Product.aspx?ID=1549.
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