Validating Analytical Methods for Biopharmaceuticals, Part 1: Development and Optimization

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.

Figure 1: Process Map of Analytical Method Development and Validation

Four of the key 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. However, 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 CBER, "the acceptability of analytical data corresponds directly to the criteria used to validate the method."⁴

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 Harmonisation (ICH)'s Q2A and Q2B^1,2 and the United States Pharmacopoeia's USP 27 <1225>⁶ 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. FDA provides guidance on some of the scientific issues that are not covered by Q2A and Q2B or USP 27.^3,4,6

Process Map. A process map showing the recommended steps for the selection, development, validation, and potential transfer of analytical methods, illustrating all 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 GMP regulations if adequate documentation systems are used.

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