Stage one: method design
The method design stage involves selecting appropriate technologies and developing a method that will meet the ATP requirements.
Appropriate studies are then performed to understand the critical method variables that need to be controlled to ensure the
method is robust and rugged.
Once the ATP has been defined, an appropriate technique and method conditions are selected that will likely meet the requirements
of the ATP as well as business needs. This step can range from developing a new method to making a change to an existing method.
While method development is obviously a very important part of the method lifecycle, it is not necessary to elaborate here
because it has been extensively addressed in the literature.
Based on an assessment of risk (i.e., the method complexity and potential for robustness or ruggedness issues), an exercise
focused on understanding the method (i.e., understanding which key input variables impact the method's performance characteristics)
may be performed. From this a set of operational method controls is identified.Experiments can be undertaken to understand
the functional relationship between method input variables and each of the method performance characteristics. Knowledge accumulated
during method development provides input into a risk assessment. Tools, such as the fishbone diagram and failure mode effects
analysis (FMEA), can be used to determine which variables need studying and which require controls. Robustness experiments
are typically performed on method factors using design of experiments (DoE) to ensure that maximum understanding is gained
from a minimum number of experiments. The output from the DoE should be used to ensure the method has well-designed system-suitability
tests, which can be used to ensure that a method meets ATP requirements (i.e., is operating in the method design space).
When developing an understanding of the method's ruggedness, it is important that variables that the method is likely to encounter
in routine use are considered (e.g., different analysts, reagents, instruments). Tools such as measurement system analysis
(i.e., precision or ruggedness studies) can be useful in providing a structured experimental approach to examining such variables
(11). Precision or ruggedness studies may instead be performed as part of Stage two, particularly if a developer has sufficient
prior knowledge to choose appropriate method conditions and controls.
Method design output.
A set of method conditions and controls that is expected to meet the ATP should be developed and defined. These conditions
should be optimized based on an understanding of their impact on method performance.
Stage two: method qualification
Having determined a set of operational method controls during the design phase, the next step is to qualify that the method
will operate in its routine environment as intended, regardless of whether this is research and development or industrial
quality control. Method qualification involves demonstrating that the defined method, including specified sample and standard
replication levels and calibration approaches, will, under routine operating conditions, produce data that meet the precision
and accuracy requirements defined in the ATP. This may involve performing a number of replicate measurements of the same sample
to confirm that the precision of the method is adequate and to demonstrate that any potential interferences do not introduce
an unacceptable bias by comparing results with a sample of known quality. If the respective experimental results have already
been obtained during Stage one, they only need to be summarized for the final evaluation.
Stage three: continued method verification
The goal of this stage of the method lifecycle is to continually ensure that the method remains in a state of control during
routine use. This includes both continuous method-performance monitoring of the routine application of the method as well
as performance verification following any changes.
Continued method performance monitoring.
This stage should include an ongoing program to collect and analyze data that relate to method performance (e.g., from replication
of samples or standards), by trending system suitability data, assessing precision from stability studies (12), or by trending
data from regular analysis of a reference lot. This activity aligns with the guidance in USP Chapter <1010> on system performance verification (13). Close attention should also be given to any out-of-specification
(OOS) or out-of-trend (OOT) results generated by the method once it is being operated in its routine environment. Ideally,
by using a lifecycle approach to method validation, laboratories should encounter fewer analytically related OOS results,
and if they do, it will be easier to determine or exclude a root cause. Monitoring performance parameters also serves to
control method adjustments (i.e., changes within the method design space).
Method performance verification.
Method performance verification is undertaken to verify that a change in the method that is outside the method design space
has no adverse impact on the method's performance. The activities required to be performed as part of method performance verification
are determined through risk assessment of the impact of the change on the ability of the method to meet the requirements of
the ATP. These activities may range from a review to ensure that the post-change operation of the method continues to meet
the system suitability requirements to performing equivalency studies aimed at demonstrating that the change has not adversely
affected the method's accuracy or precision. (See Appendix 1 for examples of how a risk assessment could be performed.)