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

Public and private specifications
The pharmacopoeias, as the guardians of public standards for pharmaceutical materials and products, have long been the bastions of the rigid specification approach, which has been reinforced by the assignment of a value for a primary reference standard without consideration of its uncertainty. There was a deliberate distancing of the pharmacopoeial reference standards from the activities of the ISO Reference Standards Committee. The introduction to ISO Guide 35:2006 states (7):

Pharmacopoeial standards and substances are established and distributed by pharmacopoeial authorities following the general principles of this Guide. It should be noted, however, that a different approach is used by the pharmacopoeial authorities to give the user the information provided by certificates of analysis and expiration dates. Also, the uncertainty of their assigned values is not stated since it is negligible in relation to the defined limits of the method-specific assays of the pharmacopoeias for which they are used.

This position, however, changed dramatically in November 2011 when the United States Pharmacopeial Convention was granted accreditation (8) to ISO Guide 34 (9) and started specifying measurement uncertainty of assigned values for its chemical reference standards. The European Directorate for the Quality of Medicines & Healthcare, which is responsible for the provision of reference standards for the European Pharmacopeia (10), announced that it, too, is moving toward ISO Guide 34 accreditation, which will probably be accomplished in the next two years. From a statistical perspective, this means that in the future, the assigned value of the primary reference standard is no longer a point value but a confidence interval that contains the true value. Therefore, fixed-limit specifications will no longer be scientifically justified on the basis that the primary standard itself has measurement uncertainty.

The cGMPs are quite explicit on the requirement for scientific soundness of specifications as 21 CFR 211.160(b) states:

Laboratory controls shall include the establishment of scientifically sound and appropriate specifications, standards, sampling plans, and test procedures designed to assure that components, drug product containers, closures, in-process materials, labeling, and drug products conform to appropriate standards of identity, strength, quality, and purity.

It is essential to consider analytical procedures as processes to quantify sources of variation and their effect on the uncertainty of an analytical result or reportable value. It is illogical to assign any fixed limits without taking these factors into account.

Figure 1: Generic process flow. (ALL FIGURES ARE COURTESY OF THE AUTHOR)
The nature of testing and measuring processes
The basics of process understanding is well understood. A generic process flow is shown in Figure 1. This model is widely applicable to synthetic API production, drug-product manufacture as well as analysis and testing methods and procedures. This generic model has been adapted by Burgess and McDowall for analytical procedures (see Figure 2) (11). The intent of the analytical testing of a pharmaceutical substance or product is to be able, based upon the testing of a sample, to predict the properties of the population (i.e., batch) from which it was taken and to assign an unbiased best estimate of the property being determined as predefined in the procedure. This unbiased best estimate of the property being determined as predefined in the procedure is called the reportable value or reportable result, which is compared with the registered specification. This approach is the traditional method of determining if a product meets specification.

Figure 2: The analytical "factory," the process of turning samples into data and information (Ref. 11).
This approach, however, is flawed because of the inherent variabilities of the measurement/analysis process, which includes the variability of the reference standard. Any analytical or testing result is subject to the influences of the manufacturing process, the appropriateness of the sampling scheme to ensure representivity, and the test method or procedure. It is important to quantify the capability of the test method or procedure to make an informed decision regarding the analytical outcome with respect to a specification. The capability of the manufacturing and sampling processes should be known.


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