By David Ulrich, Jorgelina González and Edgar Deomano
This is the first in a series of four articles meant to further the conversation and cooperative efforts between the pharmaceutical industry and wood packaging suppliers.
In 2010, Abbott Laboratory invited the National Wooden Pallet and Container Association (NWPCA) on site for a workshop to understand, from the NWPCA perspective, the issue of 2,4,6 tribromoanisole (TBA) and 2,4,6 trichloroanisole (TCA) taints. Our question was whether the numerous pharmaceutical and over-the-counter (OTC) products that were being recalled was truly a wood pallet issue (i.e. inherent to wood pallets) or was it more of a supply chain pallet management issue (i.e. would appropriate controls mitigate this issue). The goal of these initial discussions was to determine the root cause of the taints.
This series of articles will focus on the following:
- This first installment will give background on the recalls and what TBA or TCA are, where do they come from and why initially were wood pallets accused of being the culprit of the taints and therefore the recalls. It will also give a non-pharmaceutical history of these taints related to the food and beverage industry, based off of the Australian Food and Grocery Council report “Organohalogen Taints in Foods”.
- The second article will focus heavily on controls needed at the mill and the pallet manufacturing site to eliminate the risk of taints in their products. It will also focus on cleaning and how pallet manufacturers can be proactive in mitigating the risk of these taints in their supply chain and manufacturing process, and how the pallet industry can partner with the pharmaceutical industry to educate them on wood pallets.
- The third article will focus on controls needed by the pharmaceutical manufacturers and recommendations that the “pallet management controls” (which will be discussed in this installment) be integrated into their Good Distribution Practices (GDP) and part of their Supply Chain Integrity (SCI) plan.
- The fourth, and final, article will give an overview of a computer based training (CBT) program that will be published by the NWPCA for use by both pallet manufacturers and pharmaceutical manufacturers that will educate on the issue of taints and controls needed by both pallet manufacturer and pharmaceutical supply chain personnel.
Understanding the pallet manufacturing process and not allowing TCP or TBP to be used on wood for pallets is a first step toward controlling these taints in the pharmaceutical supply chain.
Starting in 2009 and continuing into 2011, the pharmaceutical industry began receiving complaints from customers about “musty/moldy odor products.” In the pharmaceutical industry, complaints are categorized into the three distinct categories: 1) Quality Assurance (QA) complaints, e.g. a tablet is cracked); 2) medical complaints/adverse events (AE), e.g. consumer developed a rash at the injection site; and 3) service complaint, e.g. wholesaler states they received shipment day late.
Initial complaints came in on a branded OTC product in the United States and Puerto Rico, but soon included more than a dozen products, both OTC and prescription (Rx), and spread to Canada and western Europe. Initially these were classified as medical complaints because some of the complaints resulted in patients vomiting and a few going to the hospital. During the development of this issue, Ministry of Health (MoH) departments started to get involved, initially the U.S. Food and Drug Administration (FDA), then other country’s MoH.
So What Caused the Odor?
The complaint samples were returned to the manufacturers and tested for mold contamination, which makes sense due to the product’s odor, but no mold was found. This then lead the investigation to the packaging process where the “taint” (odor) was found. Basically, wood used for pallets was treated with a fungicide called 2,4,6 tribromophenol (TBP), or 2,4,6 trichlorophenol (TCP) both of which are used commonly in hot, humid regions – like Brazil and Southeast Asia – to impede the growth of mold on the newly cut wood. Neither TBP nor TCP are registered in the United States by the Environmental Protection Agency (EPA) or the U.S. Department of Agriculture (USDA).
Since this “taint” issue spread throughout many companies and multiple products, a multi-pharmaceutical group under the Parenteral Drug Association (PDA) was formed to collectively work on the root cause analysis (RCA) of this issue. With this initial investigation pointing to wood pallets, many pharmaceutical companies looked into switching their entire supply chain from wood to plastic, or possibly even stainless steel, pallets. They quickly realized this was not a near-term feasible option. Controls were then investigated with wood pallet manufacturers (to be discussed in the next article of this series) AND the pharmaceutical supply chain (article #3). But the first questions to be asked were: what is TBP/TCP and is this a new issue?
What are “taints”?
By far the best educational document available on this issue was published by the Australia Food and Grocery Council. The report chronicles five decades of taints due to TCA and TBA in the food and beverage supply chain. Their musty odor has caused complaints and recalls on food and beverages (see Table 1) for decades. They are ubiquitous in nature (e.g. naturally occurring in potable water system). TBA and TCA (the anisoles) are converted via biomethylation of TBP and TCP (parent phenol compound), respectively. TBP and TCP are phenol-based compounds commonly used as fungicide in some countries (see Figure 1).
| Figure 1. Conversion of fungicide into taints
> 2, 4, 6, tribromophenol (TBP) and 2, 4, 6 trichlorophenol (TCP) are common fungicides used in hot/humid climates to control mold growth on freshly cut wood
> Through biomethlylation (a naturally occurring process and ubiquitous in nature) the phenol is converted to an anisole resulting in 2,4,6, tribromoanisole (TBA) and 2,4,6, tricholoranisole (TCA)
> The anisole have a low odor threshold and smell musty moldy
The Australian Food and Grocery Council published “Organohalogen Taints in Foods” which documented taints detected in food, beverages (e.g. canned beer), water, etc. from the 1960s to 2010 (see Table 1). A number of sources were found to be the root cause of taints including fiberboard and wood floors of shipping containers. The very low odor threshold of various organohalogens was also included in the report. After digesting this informative report, it confirmed that the taint problem is not a pallet issue but more of a pallet management and supply chain issue.
|Table 1. List of organohalogen taints in food and beverages
||Probable Cause of Taints
|Eggs and broilers
||Chicken cage litter containing chlorophenol-treated wood shavings
||Engel et al, 1966; Curtis et al, 1974
||Corrugate and wooden pallets treated with a chlorine-based spray with fungal biomenthylation to form TCA
||Tinsdale and Whitfield, 1989
||Chlorophenols and chloroanisoles absorbed from packaging materials
||Whitfield et al, 1985
||TCA from wooden pallets contaminated with TCP
||Maaerse et al, 1985
|Australian sparking wine
||Champagne corks shipped in polyethylene bags inside corrugate cartons tainted with TCA from a shipping container with TCP-treated wooden floor
||Simpson & Lee, 1990
||Tainting of coffee shipments due to TCA/TBA contamination
||Spadone et al, 1990
||Corking of wine due to TCA/TBA contamination
||Buser et al, 1982; Chatonnet et al, 2004
||TCA derived from packaging materials contaminated HDPE bottle tainted tablets
Ramstad and Walker, 1992
||TCA absorbed into the internal lacquer of the cans during transportation in a shipping container
||Lambert et al, 1993
||TBA tainting of potable water
||Malleret and Bruchet, 2002
||TCA tainting of Japanese rice wine
||Miki et al, 2005
||High density polyethylene resin used to make milk containers contaminated by helophenols during shipment
||Chemical tainting due to TBA derived from shipping containers
||Andrewes et al, 2010
is Moisture an issue?
ISPM 15, which prescribes treating pallets to control quarantine pests from freely moving around the world via wood pallets, prescribes two methods for treating wood: 1) methyl bromide (MB) fumigation, which is very effective but no longer allowed in many countries; and 2) heat treatment, which is also very effective and economical but can increase surface moisture, hence possibly encouraging mold to grow (moisture control and mold control will be addressed in articles #2 and #3).
Initially, the pharmaceutical industry thought heat treatment was an answer to control taints. However, as our industry learned more about heat treating vs. kiln drying, the industry eventually realized it is not intended for mold control but for control of invasive species. We have also learned that heat treatment can actually induce mold growth if not done properly. But this standard was developed for control of quarantine pests – not mold control – so logically a country (e.g. Brazil) that wants to control mold would actively use a fungicide, hence the use of the phenol based TBP and TCP.
Here is the problem: these very effective fungicides are used on wood for pallets and if the pallets are not properly stored (i.e. pallet management program) by either the pallet manufacturer or the supply chain that uses them, the phenol can convert to the anisole which once again smells like mold as it has an extremely low odor threshold.
Obviously, understanding the pallet manufacturing process and not allowing TCP or TBP to be used on wood for pallets is a first step towards controlling these taints in the pharmaceutical supply chain. However, that is not the only corrective action/preventive action (CAPA). Proper storage of pallets, away from weather elements with adequate ventilation, is just as important (more in articles #2 & #3).
The ubiquitous nature of anisoles (and what about bleach)
Let’s say you have a shipping container used to transport pineapples or bananas or any “organic” product, and naturally some juice is leaked onto the container floor. If the transport container has wood runners and the container is washed out with bleach (an acceptable procedure) BUT the bleach is allowed to sit and soak into the wood, this can naturally produce anisole (note bleach is hypochloric acid [HOCl]). These containers that are washed with bleach (but not rinsed), are the cause of a great many of the taints found in food products.
The following recommendations will be discussed in greater detail in articles #2 and #3 however are the initial recommended corrective actions/best practices/standard operating procedures (SOP) for effective pallet management include:
- Pharmaceutical manufacturers need to know their pallet supplier and make them part of their supplier program and an approved vendor (with agreed upon specifications).
- Make pallet management part of an audit program for third party manufactures (TPMs) including packaging supplier and commodity, e.g. plastic bottles.
- Specification of handling instructions, e.g. – “Don’t apply any halogenated fungicides on wood pallets.”
- ISPM 15 compliance is necessary but does not mitigate taints AND the pharmaceutical company needs to know what method the pallet manufacturer uses.
- Pallets should be inspected for “household cleanliness”.
- Pallets should be stored high and dry.
The intent of this article was to review the background on the pharmaceutical recalls due to taints caused by TBA/TCA, and the history of taints in the food and beverage supply chain. We also wanted to introduce the “initial CAPA” and the next steps for the “real CAPA”, which is a comprehensive pallet management program for pharmaceutical manufacturers that includes the pallet manufacturer as part of their supplier quality assurance (SQA) program. The end game is that pallet management is an integral part of the pharmaceutical manufacturers GDP program. There is more to come in articles 2, 3, and 4 – plus a CBT program on pallet manufacturing and management.
(Article published in PalletCentral Magazine, June, 2012)
David Ulrich holds the title of QA director Pharma Supply Chain at Abbott Laboratory. Jorgelina González is the Technical Lead at Paleteras Unidas & Caribe Recycling. Edgar Deomano is former Technical Director at NWPCA.