Journal of Pharmaceutical and Biomedical Analysis
Harmonization of strategies for the validation of quantitative analytical procedures: A SFSTP proposal—part I
Introduction
The present paper is the first part of a summary report resulting from a new Société Française des Sciences et Techniques Pharmaceutiques (SFSTP) Commission on the harmonization of approaches for the validation of quantitative analytical procedures. The whole report has been published in the French journal of the SFSTP [1]. The different sectors aimed by this commission report are: (1) the corporation's contractors of services; (2) the regulatory bodies; (3) the official quality laboratories; and (4) the industries of various sectors, namely chemistry, pharmacy, bio-pharmacy, food processing, environment, cosmetology, etc. The main references of the SFSTP commission report are: (1) regulatory bodies documents [2], [3], [4], [5], [6], [7], [8], [9], [10], [11]; (2) ICH documents (Q2A and Q2B) [5], [6]; (3) FDA documents (guidance for industry) [5], [6], [10], [11]; (4) ISO documents [12], [13], [14], [15], [16] especially 5725 (AFNOR X06-041) document [13] and ISO 17025 document [14]; and (5) Commission Decision 2002/657/EEC (SANCO) [17].
As can be seen in the bibliography, the validation of the assay procedures is a vast subject that interests the scientific and regulatory worlds since many years [1], [2], [3], [4], [5], [6], [7], [8], [9], [10], [11], [12], [13], [14], [15], [16], [17], [18], [19], [20], [21], [22], [23], [24], [25], [26], [27], [28], [29], [30], [31], [32], [33], [34], [35], [36], [37], [38], [39], [40], [41], [42], [43], [44], [45]. Among these documents, the following documents were also used to support the present guide: (1) SFSTP ‘92 guide [20], SFSTP ‘97 guide [21], [22] and publications related to the Conference of Washington (1990) [11], [18], [19], [21], [22].
The different regulations concerning to the good practices (GLP, GMP, GCP, and others) as well as the normative or regulatory documents (ISO, ICH, EMEA, and FDA) suggest that all procedures have to comply with acceptance criteria. This request imposes, therefore, that these procedures must be validated. There are several documents defining the validation criteria to be tested, but they do not propose experimental approaches and limit themselves, most often, to the general concepts. It is why the members o the SFSTP have contributed to the elaboration of consensus validation guides to help the pharmaceutical industry to validate their analytical procedures (pharmaceutical specialties) [20] and bio-pharmaceutical procedures (procedures implied in pharmacokinetics and bioequivalence studies) [21], respectively.
Today, one can say that these two guides have significantly contributed to make progress the validation of the analytical procedures. Nevertheless, the first guide (SFSTP ‘92) [20] has been considered to be too exclusively dedicated to the pharmaceutical specialties and has showed weaknesses regarding the objective of the validation. For example, the analyst could be penalized when its method was too precise. In addition, he was confronted to a lot of statistical tests generally complicating his decision rather than helping him. This paradoxical situation comes from the confusion between the diagnosis rules and decision rules. Same confusion could be observed in the second validation guide (SFSTP ‘97) [21] devoted to bio-analytical procedures. However, the first bases of accuracy profile was proposed in the second guide. This concept could be extended to other activity sectors such as environment or food analysis but that document was only dedicated to biopharmaceutical analysis [22], [44].
For these different reasons, the goal of the new SFSTP document [1] is mainly to reconcile the objectives of the validation with those of the analytical procedure. It also aims to provide a simple decision tool based on the total error (bias + standard deviation) of the procedure. This approach allows to considerably minimize the risk to accept a procedure that would not be sufficiently accurate or, to the opposite, to reject a procedure that would be capable. Concurrently to these general concepts, the others objectives of the new SFSTP guide are to propose a consensus on the norms usually recognized, while widely incorporating the ISO terminology, and to insist on the validation of the analytical procedure in the same way as it will be used in routine. It also presents experimental strategies for the validation of quantitative procedures, regardless of the industrial sector, to optimally use experiments performed, to extract a maximum of information from the results and to minimize in routine the risks to re-analyze samples. Since it is impossible to synthesize this important work in a single document, the present paper is limited to general concepts and the experimental strategies will be presented in a second paper [46].
Section snippets
Objectives of an analytical procedure
In order to specify the objectives of the validation, it is necessary to go back to the nature itself of an analytical method. Is its objective to demonstrate that the response varies linearly as a function of the concentration, that the bias and the precision are less than x% or rather to quantify as accurately as possible each unknown quantity? These interrogations seem to be the questions of interest. The objective of a “good” analytical procedure is to be able to quantify as accurately as
Objective of the validation
Knowing that the characteristics of “true bias” and of “true precision” are parameters that will always remain unknown but that will be estimated by the measurements obtained in validation phase, what is the objective of validation?
Under these conditions, it seems reasonable to claim that the objective of validation is to give to the laboratories as well as to regulatory bodies “guarantees” that every single measure that will be later performed in routine analysis will be “close enough” to the
Decision rules
The examination of the current situation with respect to the decision rules used in the validation phase [20], [21] shows that the most of them are based on the use of the null hypothesis as follows.with the bias = x − μT, the relative bias = (x − μT/μT) × 100 and the recovery = (x/μT) × 100.
On this basis, a procedure is wrongly declared adequate when the 95% confidence interval of the average bias includes the value of 0 (0% and 100% in the case of
Conclusion
The lack of generalisation between the different validation protocols has conducted several analysts, resulting from different companies but also from previous SFSTP commissions on the validation (1992 and 1997) [20], [21], to elaborate a harmonized approach. Moreover, if the first guides widely contributed to progress the analytical validations, they present, however, weaknesses regarding the conclusions of the tests carried out and thus the decisions to be made on the validity of the
Acknowledgment
The authors wish to thank the members of the SFSTP office for the organization of the meetings.
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