At the moment, only analytical method validation is well regulated. Detailed information on analytical method validation can
be found in ICH Q7A, ICH Q2, some FDA guidelines, US and EU compendia as well as technical guides issued by nonprofit groups
such as the Parenteral Drug Association (PDA) (1). Other well-regulated aspects of drug development are linked to dossier
submission requirements for clinical trials and although the specific requirements with respect to analytical methods are
not well described, these documents have an impact on analytical method lifecycle. These documents include:
- Investigational new drug (IND) submission for Phase I and for Phase II/III in the US (2, 3)
- Investigational medicinal product dossier (IMPD) submission for clinical trials in Europe (4, 5)
- FDA/EMA's guidelines on process validation (6, 7)
- ICH M4Q on common technical document (CTD) module 3—quality section
- ICH Q5C on stability testing
- ICH Q6 on test procedures and acceptance criteria
- ICH Q8–11 on pharmaceutical development, risk management, and quality systems.
In Europe, the EMA guidelines on IMPD submissions state that "...for Phase I clinical trials, the suitability of the analytical
methods used should be confirmed. The acceptance limits (e.g., acceptance limits for the determination of the content of impurities,
where relevant) and the parameters (e.g., specificity, linearity, range, accuracy, precision, quantification, and detection
limit, as appropriate) for performing validation of the analytical methods should be presented in a tabulated form." (4, 5)
The analytical methods should be validated before Phase III studies, although it may be not appropriate to engage resources
in formal ICH validation for Phase II submission with respect to the limited level of knowledge on product and process. Likewise,
in the US, appropriate validation data should be provided for the analytical procedures for Phase II/III, although it must
be confirmed for Phase I that the method is scientifically sound, suitable, and reliable for its intended purpose (2, 3).
Interestingly, both EMA and FDA guidance documents describe the requirement that the method, scientific intent, and performance
be assessed at an early stage when the project is transferred from process development to GMP production. Moreover, these
guidelines set the pace for initiating exploratory "prevalidation" work for setting ICH-compliant acceptance criteria used
in validation. In other words, there should be something done at early clinical stage to confirm that the method is scientifically
sound and of reliable method performance before formal ICH validation is done later in clinical stage.
PREPARING ANALYTICAL METHOD VALIDATION
Prevalidation, also known as qualification, ranging from initial performance assessment to method refinement and robustness
assessment has to be smartly staged in the course of the project (8). Qualification, while not an official term employed in
analytics-related regulatory guidelines, is often encountered as the equivalent term referring to analytical activities starting
after the development of the method and ending with the assessment of method validation readiness (see Table II). Unfortunately, there is little information available in guidelines about regulatory expectations regarding qualification
compared with validation. It is then part of the project sponsor's duty to establish its rationale for the analytical method
lifecycle during clinical development.
Table II: Analytical method qualification factsheet.
Different types of analytical lifecycle activities can occur before formal method validation. These activities typically include
the development of the analytical method per se, an initial performance assessment strongly encouraged for Phase I, robustness assessment as part of ICH Q2 prerequisites,
and probably some method refinements in terms of improvement (e.g., for better performance) and optimization (e.g., for higher
throughput). The scientific rationale of the method comes during development as a function of the target product profile,
critical quality attributes, process outline, target method performance, prior knowledge, and scientific expertise.