Evaluating Risk-Based Specifications for Pharmaceuticals - Pharmaceutical Technology

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Evaluating Risk-Based Specifications for Pharmaceuticals
The author discusses the purpose of analysis and testing and the implications for specifications and their underlying statistical distribution.

Pharmaceutical Technology
Volume 37, Issue 7, pp. 54-60

Risk-based approach to shelf-life estimation
While a risk-based approach is not currently used in product- or material-release specifications, it is accepted as the standard within ICH Q1E on evaluation of stability data for establishing or confirming a registered shelf life (27):

Regression analysis is considered an appropriate approach to evaluating the stability data for a quantitative attribute and establishing a retest period or shelf life.

An appropriate approach to retest period or shelf life estimation is to analyze a quantitative attribute (e.g., assay, degradation products) by determining the earliest time at which the 95% confidence limit for the mean intersects the proposed acceptance criterion.

For an attribute known to decrease with time, the lower one-sided 95% confidence limit should be compared to the acceptance criterion.

Figure 12: Illustration of product shelf-life confirmation based upon a confidence Interval equivalent to a stringent specification requirement.
The ICH Q1E approach is illustrated in Figure 12. The example is taken for a product with a registered shelf life of 24 months. The regression line is derived from long-term product stability data of the API expressed as the percentage of labeled claim with respect to time generated under the appropriate storage condition. As the API degrades with time, calculation of the lower 95% confidence interval is appropriate and is shown as the blue dashed line. This confidence interval intersects the registered regulatory end of life limit at a time beyond 24 months, thereby confirming the shelf life. This use of this confidence interval approach is equivalent to the guard-band proposal for a stringent specification requirement shown in Figure 11.

Figure 13: The proposed guard-band principle and analytical process capability. G is guard band. U is uncertainty of measurement. RV is reportable value.
The adoption of an ISO risk-based specification approach to the control of drug substances and drug products using the guard-band principle and the clinical relevance of the specification is proposed. This approach is summarized in Figure 13. Suppose that the reportable value and its measurement uncertainty are taken from Figure 8 and combined with the four illustrative examples with respect to a specification limit.

From a compliance perspective, options Figure 13 (a) and Figure 13 (d) present no difficulty of interpretation as they are demonstrably OOS and in specification respectively. Figure 13 (b) and Figure 13 (c), however, are more difficult to interpret in a conventional approach whereas this interpretation is easier using the proposed approach. For a clinically relevant specification, example Figure 13(b) would be OOS, but only OOE for a nonclinically relevant specification. Figure 12(c) is OOE for a clinically relevant specification but in specification for a nonclinically relevant specification.

The argument has been made that fixed-limit specifications for pharmaceuticals (i.e., the voice of the customer or regulator) are fundamentally incompatible with the voice of the process. This has been recognized for many years in industries other than the pharmaceutical industry. An internationally recognized ISO standard is available and a proposal to apply it to risk-based specifications pharmaceutical products and processes using the guard-band principle is presented.

The author wishes to thank Dr. R.D. McDowall, principal McDowall Consulting, and R.M. Bonner, chairman of the European Compliance Academy, for helpful discussions during the development of this article.

Christopher Burgess is managing director of Burgess Analytical Consultancy Limited, member of the European Qualified Person Association Advisory Board, member of the USP Council of Experts 2010 to 2015, chairman of the ECA Analytical Quality Control Group, member of the ECA Executive Committee, and a visiting professor, University of Strathclyde's School of Pharmacy and Biomedical Sciences, tel: +44 1833 637 446;


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