IntroductionAnalysis of drug concentration in biological samples is an integral part of the drugdevelopment process . Concentration data from biological samples is required to study the absorption, distribution and elimination properties of a new chemical entity and to understand its dose-response relationship in both clinical and non-clinical studies. A clear understanding of pharmacokinetic variability becomes increasingly important in later stages of clinical studies, especially for pivotal bioequivalent studies such as those required for changes in formulation. Unlike a manufacturing process, contamination in an analytical laboratory does not directly impact the product. However, contamination leads to reporting biased results that
impacts the validity of the derived decisions and increases regulatory risk.
Laboratory contamination is defined as an unintended and undesirable transfer of analyte or interfering compounds into an analytical sample or sample extract before or during the analytical process. The following is a short list of the characteristics of laboratory contamination.
- Usually observed as a positive bias.
- Blank, placebo or pre-dose (first dose) has detectable analyte(s).
- Results do not fit the trend of the concentration profile.
- May or may not be detected by standards or quality control samples.
- Contaminated animals or subjects.
- Contamination during sampling at the site.
- Contamination during sampling at laboratory.
- Contamination during analysis.
Laboratory contamination during the sample analysis process may be classified into two categories, carryover and cross-contamination. Carryover is the result of transferring an analyte from an earlier sample to later samples, usually due to the sharing of a common
container or transferring device. Carryover is serial in nature and occurs in both sample preparation and the analytical process. Carryover is generally distributed in a narrow zone (Figure 1). The effect of HPLC autosampler carryover may be estimated from the
results of a few samples and that the relative effect of carryover on concentration results may be calculated [6, 7, 8].
Cross-contamination is the transfer of an analyte from a sample to another that is processed with it. Cross-contamination is parallel in nature and may not involve a medium. For a bioanalytical assay, the major sources of cross-contamination are spills, aerosols and drips
during transfer. Because both the occurrence and magnitude are random, cross-contamination is difficult to estimate and manage. The term contamination will be used to describe both carryover and crosscontamination.
Recognize the contamination incidentUnlike accuracy and precision, contamination may not be detectable by the generally accepted QC program, but positive bias in low QC or low standards (more data points exhibit positive bias than negative bias or observation of large positive bias) are clues. A critical review of historical data would give good estimate for contamination potential of a method. If the results justify an investigation, performing experiments to understand the root cause will minimize