Analytical considerations

Due to the complex nature of haloanisole tainting, there are varied analytical targets and methodologies that may be employed to detect haloanisole taints. Regulatory guidelines are available for testing and qualification of impurities, extractables and leachables, and genotoxic compounds. For haloanisoles, these levels are several times higher than the levels at which odorous taints can be detected. Further, because human sensory detection is highly variable, detection thresholds range from low ppt to not being able to detect the odor at all. Taint concentrations typically found in pharmaceutical and consumer healthcare samples range from 1 to 2000 ppt and includes both haloanisoles and halophenols. These concentrations require matrix-specific sampling, preconcentration, and the most sensitive detectors to obtain an analytical response. In addition to the complexity introduced by low concentrations, there is a formulary complexity in that materials have different rates of adsorbing, absorbing, and desorbing halocompounds. The solubility of TBA in solids is significantly related to the polarity of the material and, therefore, the impact on TBA recovery and methodology is also discussed in the technical report.

The PDA Technical Report reviews various analytical methods employed for the detection of haloanisoles and halophenols. Several of these methods include: olfactory detection, closed-loop stripping analysis, solid-phase microextraction, liquid–liquid microextraction, GC, and GC/MS. There is no single analytical method or control strategy recommended but rather a useful "toolkit" of methods is presented in the PDA Technical Report to aid in understanding and supporting a control strategy for mitigation of haloanisoles in pharmaceutical and consumer healthcare products. In general, these analytical methods are more suitable for investigatory testing than for routine monitoring. Attention is drawn to the report of TBA Analytical Methods published in Pharmaceutical Technology in November 2011 by scientists from Microanalytics (a contract analytical services laboratory specializing in aroma and odor issues) (6).

Although not widely used in prescription and over-the-counter products, sensory panels have historically been used for consumer products, including those in the food and wine industries. They have also been used for the monitoring and control of raw material shipping containers. The benefits of applying sensory assessment techniques or odor panels in quality control include timeliness and flexibility (i.e., materials can be assessed before they even leave the truck), the ability to correlate results to the potential for customer perception as part of quality risk management, and the fact that sensory perception can be both targeted and non-specific at the same time. The series of ISO standards and guidance documents related to the food industry, specifically ISO 13299, offer good insight into how sensory assessment and odor panels may be adapted for use in the context of monitoring components and finished goods for targeted compounds (9).

Monitoring moisture content of wood

Reduction of wood moisture content may be used to control fungal growth on pallets. Fungi require free moisture termed water activity greater than 0.7 to grow. Controlling moisture to levels below those necessary to support fungal growth (i.e., 20% or lower in water content) reduced the possibility of biomethylation resulting in the formation of taints.

Simple techniques to verify moisture content include conductivity and loss on drying (LOD). Inexpensive handheld conductivity meters common in the construction industry are available. One such device is the Extech MO210, available through various outlets that sell lumber and other building materials. This device measures the conductivity between two metal prongs inserted into the surface of the wood. The conductance measurement is converted to percent moisture reading through an algorithm to a digital readout.

Marketing surveillance and regulatory considerations

Pharmaceutical companies marketing products in the US are required by regulation to establish a postmarketing safety surveillance/pharmacovigilance program, and to communicate to FDA in accordance with 21 CFR 314.80 for reports of adverse events associated with the use of a drug. Further, GMP regulation 21 CFR 211.198 requires pharmaceutical companies to establish a complaint vigilance program and have written procedures for the investigation of any product quality complaint. Such procedures are required to include provisions for review by the quality control unit, of any complaint involving the possible failure of a drug product to meet any of its specifications and, for such drug products, a determination as to the need for an investigation in accordance with 21 CFR 211.192.

Such procedures shall include provisions for review to determine whether the complaint represents a serious and unexpected adverse drug experience, which is required to be reported to the FDA in accordance with 21 CFR 310.305 and 314.80. Two key components of vigilance programs are safety signaling and adverse product quality complaint trending. Adverse events are evaluated by healthcare professionals, typically physicians running the pharmacovigilance program, and product quality complaints are typically investigated by QA professionals.