Incurred Sample Reanalysis

QPS has been performing Incurred Sample Reanalysis (ISR) for selected sponsors since 2003. In 2008, we implemented a company-wide SOP ISR testing for all sponsors for both small molecules and biologics. Reanalyzing randomly-selected study samples for all PK drug quantitation studies is an additional quality metrics. We collect and measure our ISR data as part of a company-wide training program of continuous improvements.

 

ISR pass/fail rates and observations are continuously documented and updated on a quarterly basis. The ISR pass rate for both chromatographic methods and ligand-binding assays (LBA) for the past 25 months since the implementation of the ISR program are shown in the following figures.

Some of these studies are short term safety studies, while others are long term clinical studies. The ratio of preclinical/nonclinical to clinical studies is lower for biologics as compared to small molecule drugs. Therefore the number of studies using LBA assays (53 studies) vs. chromatography assays (155 studies) is reflected in the ratio.

 

Table 1 represents an overview of the percentage ISR pass rate against the total number of samples and the total number of studies for the past 25 months since ISR was implemented company-wide.

 

Each bar in Figures 2 and 3 represents a single study using either chromatographic or LBA method. The percent deviation from the original data for each ISR sample is grouped together in the three distinct bands within each study. Figures 2 and 3 provide a clear visual metric of how many samples pass ISR and how accurate the ISR data are.

 

In Table 2, each bar represents one chromatographic study, and the percent deviation from the original data for each ISR sample is grouped together in the three distinct bands within each study. Table 2 provides a clear visual metric of how many samples pass ISR and how accurate the ISR data are.

 

Figure 2. Stack Plot of % Deviation from Original Value for Chromatographic Assays (1/21/2009 – 1/19/2010)

 

  • Study 1: This is an activity assay that was used for PK purposes.
  • Study 7, Study 23, Study 27: ISR test passed the acceptance criteria when the previous SOP was in effect. For consistency in comparing all ISR data, the current SOP was used to plot the ISR statistic.
  • Study 29: ISR marginally failed per client ISR SOP. Further investigation did not reveal any conclusive root cause. It was observed that small volume pipetting was frequently employed in this study.
  • Study 30, Study 75: ISR test passed the acceptance criteria when the previous SOP was in effect. For consistency in comparing all ISR data, the current SOP was used to plot the ISR statistic.
  • Study 35: Matrix effect in the study sample was attributed to the failed ISR per further investigation. The matrix effect was minimized by performing a 10-fold dilution with the blank matrix used for standards and QCs. The effectiveness of the dilution to minimize the matrix effect was supported by the successful ISR test after investigation.
  • Study 36, Study 40, Study 99: Matrix effect and instability in the study sample were attributed to the failed ISR per further investigation. The data for this compound were used for information only as this is a minor and insignificant metabolite as per client.
  • Study 55: The failed ISR was determined to be caused by the instability in the study samples because of an additional F/T cycle. ISR was repeated and passed the acceptance criteria when there is no F/T cycle difference between the original assay and ISR assay.
  • Study 95: No assignable cause for the failed ISR per further investigation. There was insufficient support to question the reliability of the original data and reject the original data based on the ISR test result alone. The original data was thus reported as is with the ISR results and a statement indicating potential impact to the study.
  • Study 124: The failed ISR was determined to be an assay limitation due to the nature of study samples. A slight modification to the LC method was needed to reduce on-column matrix accumulation. Another ISR was performed using the modified method, and the ISR passed.

 

Figure 3. Stack Plot of % Deviation from Original Value for Ligand Binding Assays (1/21/2009 – 1/19/2010)

 

  • Study 1: This is an activity assay that was used for PK purposes.
  • Study 7, Study 23, Study 27: ISR test passed the acceptance criteria when the previous SOP was in effect. For consistency in comparing all ISR data, the current SOP was used to plot the ISR statistic.
  • Study 29: ISR marginally failed per client ISR SOP. Further investigation did not reveal any conclusive root cause. It was observed that small volume pipetting was frequently employed in this study.