Risk assessments in method validation

Risk assessments are a good thing and can make life easier in the pharmaceutical environment. Everywhere it is said that this or that has to be or has been defined "risk-based"...

Hmm, all well and good, but where are the potential applications in the validation of analytical methods?

We’d like to make a deep dive into this question in today's blog post.

Risk assessments, or so-called risk analyses, are part of risk management in the pharmaceutical but also medical device environment and have many applications. Their purpose is to filter out from a variety of parameters (e.g., successive steps in a process) those critical factors that pose an increased risk (e.g., to product quality, patient or user safety, but also, for example, to obtaining expected results). There are various useful tools such as e.g. the FMEA.

Of all parameters, that can be validated during method validation, robustness seems to be a good candidate. With the help of a brief risk assessment, we can evaluate the individual steps of the analytical method’s performance and consider the extent to which each of these steps can be regarded as critical or what other influencing factors there are for this method that could come into play. For all those steps / influencing factors that are considered to be potentially critical, it is then determined what, if anything, is to be investigated or whether, for example, documents from the development exist, such as a qualification report, in which this aspect has already been investigated and to which reference can therefore be made.

Let's have a look at how this can be done in practice. For our example, let’s imagine that we want to validate a RP-HPLC method for the quantitative determination of impurities. In the method validation plan’s chapter on robustness, after a definition of robustness, the risk assessment could be presented, for example, in the form of a small table. In doing so, we consider the respective influencing factor (What happens if this or that occurs?) and, if applicable, the action to be performed during our robustness study of the method validation.

Influencing factor and potential consequence	Potential action
Changed flow rate → changed peak area?	Investigation of flow rates of 0.5 & 0.7 mL/min (normal: 0.6 mL)
Changed column temperature → changed peak area?	Investigation of column temperatures of 28 & 32°C (normal: 30°C)
Use of aged mobile phase → changed peak area?	During development, the sample’s peak area was investigated using mobile phase previously stored for 6 weeks (see report xyz).
Time in autosampler before starting the analysis → altered sample stability?	Investigation after 24, 48 and 72 h of sample storage inside the autosampler at 5°C
Multiple sample freeze-thaw cycles → altered sample stability?	Investigation of the sample after 1, 2, 3 freeze-thaw cycles
etc.

We do not need to depict here the aspects of using different column lots, different HPLC equipment, or the performance at different days or by different analysts, as this is usually part of the evaluation of intermediate precision.

For the aspects to be investigated that have resulted from the risk assessment, the acceptance criteria to be met are then defined in the validation plan, e.g. a relative deviation of the result by x% compared to the analysis performed in parallel under normal conditions.

The example of a risk assessment shown here is only intended to serve as a first illustration. There are certainly other possible applications in the field of method validation, so I welcome good suggestions and a lively discussion on how the use of risk assessments in method validations is practiced elsewhere in the big wide pharmaceutical world.