Chemistry Reference
In-Depth Information
Drug, and Cosmetic Act [1,2], and every USP since has included guidelines on
method validation. More recently, new information has been published, updat-
ing the previous guidelines and providing more detail and harmonization with
International Conference on Harmonization (ICH) guidelines [3,4]. The inclusion
and definition of some terms differ between the FDA, USP, and ICH, but as a
process, harmonization on a global basis has provided much more detail than was
available in the past, and it helps to minimize the differences between global regu-
latory requirements.
Validation is regulated by the FDA and has roots in manufacturing practice
guidelines for the laboratory environment. Two of the most common references to
these practices are cGMP [current Good Manufacturing Practice, e.g., (7, 8)] and
the International Organization on Standardization (ISO) 9000 Global Management
Standards [9] and related ISO documents. The two most important guidelines for
any method validation process are USP Chapter 1225: Validation of Compendial
Methods [2], and the International Conference on Harmonization (ICH) Guideline:
Validation of Analytical Procedures: Text and Methodology Q2 (R1) [6]. Although
the main focus of this chapter is on HPLC, both the USP and ICH guidelines are
generic; that is, they apply to any analytical procedure, technique, or technology
used in a regulated laboratory.
Even though the USP is the sole legal document in the eyes of the FDA, this chap-
ter draws from USP and ICH guidelines for definitions and methodology; and for the
most part, the FDA, USP, and ICH guidelines agree. Where the guidelines disagree,
it is up to the user to decide upon an appropriate interpretation of the guidelines and
a justification. Often, the interpretation and justification are the responsibility of the
user's quality assurance unit and may be aided by review of the latest regulatory
actions (e.g., FDA-issued Form 483 Inspectional Observations, which are available
on the FDA's website). In addition to these guidelines, sometimes a regulatory body
publishes other information that can be useful for interpretation of the guidelines.
One of these is a “reviewer guidance” [10] published by the FDA. Reviewer guid-
ance is intended to help FDA auditors determine what constitutes a good method, so
many users try to adhere to the suggestions in this document to help ensure that their
methods will pass regulatory scrutiny.
4.3 terms And deFInItIons
Method validation sometimes seems to have a vocabulary of its own, with many
terms in common, everyday use in the laboratory, so this chapter begins with a dis-
cussion of these terms and definitions. Several parameters, generally referred to as
analytical performance characteristics, may be investigated during any method vali-
dation protocol. These parameters are listed in Figure 4.1.
Although most of these terms are familiar and are used daily in any regulated
HPLC laboratory, they sometimes mean different things to different people. For
example, ruggedness, which forms a part of any well-designed precision study, is
often confused with robustness, and for this reason the term
ruggedness
is falling out
of use. Hopefully, the following definitions taken directly from the guidelines will
clear up any confusion.
