Regulatory guidance documents are written by committees, resulting in statements that are both exact and generic. Meeting
regulatory requirements involves not only interpreting these documents correctly but also addressing their omissions. This
article provides practical guidance on issues that are not thoroughly covered by current guidance documents regarding validation
of analytical methods for biopharmaceuticals.
Four of the existing regulatory guidance documents on methods validation state, "Methods validation is the process of demonstrating
that analytical procedures are suitable for their intended use."1–4 We have all read, and likely used, this phrase many times when summarizing method-validation results. According to Muire-Sluis,
development scientists often point out that "validated methods may not be valid."5 The question therefore arises, what exactly makes a validated method valid? According to the Center for Biological Evaluation
and Research (CBER), "the acceptability of analytical data corresponds directly to the criteria used to validate the method."4
Table 1. Validation characteristics per ICH Q2(R1) and relevant product specifications
We can generate evidence for the validity of analytical data in the formal method-validation program where all critical parameters
are extensively tested under a detailed protocol that includes scientifically justified and logical step-by-step experimental
approaches. All planned data sets must fall within pre-established protocol acceptance criteria limits. These criteria should
be derived from and justified in relation to historical data and product specifications. Once evidence for all critical elements
is provided, the validated method will become the official, licensed procedure for that particular product and process step,
and it will then support production and product release. The relationship between "valid" or "suitable and validated" is often
overlooked, but there is a high price when "validated" test systems are simply inappropriate.
Incentives to replace existing licensed test procedures may come from regulatory agencies, or they could be motivated by potential
cost savings, ease of use (automation), and the opportunity to generate more accurate and reliable results.
The International Conference on Harmonization (ICH)'s Q2(R1),1 should be used for basic guidance. However, following just these guidelines will not necessarily produce a "valid" method
and may not provide sufficient evidence that this method is suitable for product release. The intent of USP 30 <1225> is
to provide guidance only on validation requirements for test methods for inclusion into USP with the expectation that validated
USP methods still require verification from users.6–7 The US Food and Drug Administration (FDA) and European Medicines Agency (EMEA) provide guidance on some of the scientific
issues that are not covered by Q2(R1).
Process Map. A process map showing the recommended steps for the selection, development, validation, and potential transfer of analytical
methods, illustrating all proposed functional responsibilities was developed. Frequently, larger companies have separate functional
units for method development, validation, and testing. The process flow in Figure 1 describes an ideal sequence of steps for
better analytical method validation (AMV).
The rigorous standards suggested here are ideal but they are not necessarily required or followed during method development.
Methods can be developed without strict adherence to good manufacturing practices (GMP) regulations if adequate documentation
systems are used.