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

Confidence in analytical data
As previously discussed, the outcome of an analytical procedure is not an exact value but a predicted range at a predetermined level of confidence. The current accepted practice within the pharmaceutical industry is to validate analytical procedures in accordance with ICH Q2(R1), last revised in 1995 (14). This approach also is adopted by the US Pharmacopeia (USP) General Chapter <1225>. In this approach, the conventional analytical chemistry methodology of separating the measure of location (there called accuracy) and the measure of dispersion (there called precision) is adopted. In addition, ICH Q2(R1) describes three different precision levels according to the number of process factor influences. As ICH Q2(R1) focuses on the methodology, it omits the fourth and lowest level, which is system or instrument precision. The hierarchy of the four precision levels in ascending order is system (i.e., instrument) precision, repeatability, intermediate precision, and reproducibility (15). From a quality-control perspective, the most important precision level is intermediate precision as this level represents the day-to-day capability of a given procedure within a particular laboratory.


Figure 7: The relationship between accuracy and precision: (a) conventional analytical chemistry methodology and (b) ISO approach.
The relationship between accuracy and precision in conventional analytical chemistry methodology is illustrated by the target model (see Figure 7[(a]). The definition of accuracy in Validation of Compendial Procedures, USP General Chapter <1225>, and in ICH Q2(R1) corresponds to unbiasedness only. In the International Vocabulary of Metrology (VIM) and ISO documents, accuracy has a different meaning. ISO defined a new term, "trueness," to mean the closeness of agreement between an average value obtained from a large series of measurements and an accepted reference value. In other words, trueness implies a lack of bias. The concept of trueness in ISO leads directly to the idea of measurement uncertainty, which combines the variabilities associated with both accuracy and precision. The ISO approach is illustrated by an adapted target model in Figure 7(b). The United States Pharmacopeial Convention has updated USP General Chapter <1010> on the interpretation of analytical data to include a comparison of the ISO measurement uncertainty (MU) approach with the conventional confidence interval approach.

ISO recognized the incompatibility of the concept of (MU) of the testing or measuring process and fixed-limit specifications, particularly in the engineering and medical-device industries. The result was the publication of a standard (ISO 14253-1:1998) on decision rules for proving conformance or nonconformance with specifications, which took into account measurement uncertainty of the testing/metrology process (16). The current version of ICH Q2(R1) (14) on the validation of analytical methods was developed almost 20 years ago, and the parent guideline was published in 1994. It is long overdue for revision.

ISO approach to conformance with specification
ISO 14253-1 addresses the problem arising when a measurement result falls close to or on a specification limit. In this instance, it is not possible to prove conformance or nonconformance with specification because the measurement result plus or minus the expanded uncertainty of measurement includes the limit itself. The estimated uncertainty of measurement has to be taken into account when providing evidence for conformance or nonconformance with specification. This ISO guide led to the development of more detailed and recent guidance from the American Society of Mechanical Engineers (17, 18) although the basis of this approach has been available in the literature for more than 60 years (19, 20). The overall ISO risk-based approach may be summarized in terms of conformance versus specification zones and a complete statement of a result of measurement of a reportable value. This complete statement of a result of measurement is determined by a full execution of the analytical procedure, including the uncertainty range, 2U.


Figure 8: Pictorial representation of the reportable value (RV) and its measurment uncertainty. U is uncertainty of measurement.
Figure 8 shows that the reportable value (RV) is the best estimate of the true value, but at 95% confidence, this value can fall within the range 2U. Consideration of how to determine U is discussed later in this article. In the ISO approach, the conformance zone(s) is defined as the specification zone reduced by the expanded uncertainty of measurement, U. A recent article on using target measurement uncertainty to determine "fitness for purpose" for analytical procedures discusses the guard-band principle (21).


Figure 9: ISO 14253-1:1998 approach to conformance with specification. LSL is lower specification limit; USL is upper specification limit. U is uncertainty of measurement. OOS is out of specification.
The essential features of the ISO approach are illustrated in Figure 9. Because of U, there are three distinct zones rather than the normal two. The nonconformance zone(s) lies outside the specification zone extended by the expanded uncertainty of measurement, U. These two zones are separated by the uncertainty range equal to 2U. The nonconformance zone(s) are OOS. The variance contributions that define U are only due to the analytical procedure itself and includes the uncertainty in the reference standards and must not include any manufacturing or sampling variances. The uncertainty range surrounds the specification limit(s), where neither conformance nor nonconformance can be proved taking into account the uncertainty of measurement (2U).


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