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

Calculating the value of U
The evaluation of uncertainty requires consideration of all the possible sources of variability affecting the analytical reportable value. Although a detailed study of this kind may require considerable effort, it is important that the effort expended should not be disproportionate. In practice, a preliminary study will identify the most significant sources of uncertainty, and the value obtained for the combined uncertainty is almost entirely controlled by the major contributions. A good estimate of uncertainty can be made by concentrating effort on the largest contributions.

This measurement uncertainty is arrived at by means of an error budget that enables the calculation of u c, the standard deviation of the procedure and is described in detail in a EURACHEM/CITAC Guide QUAM:2012.P1 document (22). An error budget is used to:

  • Define all the process elements involved
  • Identify all error sources
  • Group error sources as required
  • Estimate, for each error source, individual contributions and convert them to standard deviations
  • Combine these standard deviations to produce an overall estimate of standard deviation
  • Estimate the expanded uncertainty using an appropriate coverage factor.

Uncertainty of measurement is estimated and evaluated according to the Guide to the Expression of Uncertainty in Measurement (GUM) (23) and is consequently expressed as the expanded uncertainty, U, where U = k*u c with a default coverage factor (k) of 2. This coverage factor (k) of 2 corresponds to a probability of 95.45% (Note if k = 1.96, the probability would be 95.0%). The prerequisite for adopting these approaches is that both the manufacturing and measurement processes are shown to be under statistical control and are statistically capable.

Consequences for pharmaceutical specifications
The primary purpose of quality control is to assure quality of the manufactured product by testing of samples in accordance with registered methods and specifications contained in a marketing authorization in the EU or in a new drug application or abbreviated new drug application in the US. Safety and efficacy are assessed and assured during development prior to the granting of such authorization. Impurities, however, are always a safety concern. As D. Jacobson-Kram and T. McGovern of FDA note (24):

While the use of pharmaceuticals is always a balance of risks and benefits, the same is not true for impurities in pharmaceuticals; impurities convey only risk. While impurities should always be reduced to the lowest levels that are reasonably practical, it is acknowledged that impurities cannot be reduced to zero and specifications for impurities need to be established.

A risk-based approach to the specification of physicochemical quality parameters, such as assay and in-process controls, where a small difference in value is highly unlikely to have any adverse effect on the patient, should be different from that for impurities that might have an adverse effect.


Figure 10: A risk-based relaxed specification zone for nonclinical critical specifications. LSL is lower specification limit. USL is upper specification limit. G is guard band. OOS is out of specification.
A guard band, G, is defined as the magnitude of the offset (U) from the specification limit to the acceptance or rejection zone boundary (17). For nonclinical critical specifications, it is reasonable to adopt a risk-based relaxed specification zone that allows for the uncertainty of the method or procedure itself (see Figure 10). In this approach, the author proposes that a reportable value does not become OOS until it exceeds the guard band. It is not expected to occur frequently, so reportable values falling in this guard zone should be treated as out-of-expectation (OOE) results and investigated to assure analytical integrity. Impurities, on the other hand, which are regarded as clinically critical, should be subject to a stringent specification zone (see Figure 11).


Figure 11: A risk-based stringent specification zone for clinically critical specifications for impurities. USL is upper specification limit. G is guard band. OOS is out of specification.
This approach has already been applied to regulated pesticide residue analyses in the EU (25), and the approach is more fully described by Ellison and Williams (26). This document referenced and built on the American Society of Mechanical Engineers' approach from 2001 (17).

A key point for regulatory concern using this approach is the magnitude of U and hence the guard band. The size of the guard band must be strictly controlled and limited to prevent abuse. For example, it has been suggested for physical metrology (17) that the size of the guard band should not exceed one-eighth of the specification range. For analytical methods, the size of the guard band should be based on the measured process capability index C pk and an uncertainty budget.


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