Calculating the Reportable Result from Retest Data - Pharmaceutical Technology

Latest Issue
PharmTech

Latest Issue
PharmTech Europe

Calculating the Reportable Result from Retest Data
Two methods to evaluate retest data following out-of-specification results.


Pharmaceutical Technology
Volume 37, Issue 2

H15 approach

A more statistically sound approach is to include the OOS result directly using a robust procedure based on the median and deviations from it, because medians are less influenced by outlying values.

The method briefly described here is based on Huber's H15 method (6). This method is more difficult to calculate than the standard confidence interval as it relies on an iterative procedure. However, it is easily accomplished using an Excel spreadsheet without the necessity for macros. The mathematical details are given in Ellison, Barwick, and Duguid Farrant (7) and are not covered here.

This robust statistical procedure has a major advantage in that the calculation includes the outlier as part of the data set and provides values for the robust mean and robust standard deviation. This calculation procedure meets the FDA requirement outlined earlier because active consideration is given to the OOS result. In addition, it calculates the 99% confidence interval rather than the 95% that provides greater assurance of compliance with specification.

Briefly, the algorithm used is as follows:




1. Calculate the initial estimates of the median and robust standard deviation




2. Evaluate all the data points using

This step replaces points outside the range with values at the calculated 99% confidence limits but leaves other values unchanged.

3. Update the estimate for the standard deviation based on the current estimate with a correction factor, β, for the normal distribution.

4. Repeat steps 2 and 3 for the updated data until the values for the robust mean and robust standard deviation no longer change, for example, by 0.1% (i.e., the calculation converges).

5. Calculate the final 99% confidence interval from 2.96 Ŝi/β where i is the cycle at which it converges.


Figure 3: Illustration of the H15 approach for calculating the robust mean and robust standard deviation. LSL is lower specification limit.
It is easier to understand the process graphically (Figure 3) rather than the maths, and this approach is illustrated using the same data set as the original example. The initial OOS result is shown as a red circle and the retest data are shown as green circles (initial data line). The LSL is also marked on the plot. The first iteration moves both the initial OOS result and one retest result to the calculated robust 99% confidence interval shown as blue dots with a red outline. Note that five of the six retest results are unchanged throughout all the iterative calculations. As the iterations proceed, the robust mean and robust standard deviation change until the values converge. In our example, it took 28 iterations to obtain convergence. The biggest change during the iterations is to the robust standard deviation. The final 99% confidence interval is well within the specification and the robust mean value for the reportable result (based on all seven data points) is 96.64.


ADVERTISEMENT

blog comments powered by Disqus
LCGC E-mail Newsletters

Subscribe: Click to learn more about the newsletter
| Weekly
| Monthly
|Monthly
| Weekly

Survey
FDASIA was signed into law two years ago. Where has the most progress been made in implementation?
Reducing drug shortages
Breakthrough designations
Protecting the supply chain
Expedited reviews of drug submissions
More stakeholder involvement
Reducing drug shortages
33%
Breakthrough designations
11%
Protecting the supply chain
39%
Expedited reviews of drug submissions
11%
More stakeholder involvement
6%
View Results
Jim Miller Outsourcing Outlook Jim Miller Health Systems Raise the Bar on Reimbursing New Drugs
Cynthia Challener, PhD Ingredients Insider Cynthia ChallenerThe Mainstreaming of Continuous Flow API Synthesis
Jill Wechsler Regulatory Watch Jill Wechsler Industry Seeks Clearer Standards for Track and Trace
Siegfried Schmitt Ask the Expert Siegfried SchmittData Integrity
Sandoz Wins Biosimilar Filing Race
NIH Translational Research Partnership Yields Promising Therapy
Clusters set to benefit from improved funding climate but IP rights are even more critical
Supplier Audit Program Marks Progress
FDA, Drug Companies Struggle with Compassionate Use Requests
Source: Pharmaceutical Technology,
Click here