Top Mistakes in Analytical Method Validation and How to Avoid Them

Method validation is an important step carried out during method development to ensure reliability, quality, and consistency of the development method. Properly executed validation processes allow scientists to prove and document the effective performance of the underlying method. The whole procedure helps in the manufacturing of safe biochemical products.

However, many a time, methods are not correctly validated which leads to inconsistent pharmacological results. This situation may cause a delay in the approval of the product or the scientists may have to conduct the whole drug discovery and development again, which might consume a lot of time.

Hence, in this article, we will discuss the common mistakes in analytical method validations and tips to avoid these mistakes.

FDA Requirements

According to the FDA, your method validation data should document the quality, identity, strength, potency, and purity of the drug products and compounds. This method should also be reproducible for future use.

FDA provides several guidelines for method validations which align with ICH guidelines.

The methodology and instrumentation used in method validation should be according to the scope and purpose of the method.

Parameters such as accuracy, precision, linearity, specificity, the limit of detection, range, and the limit of quantitation should be evaluated during validation.

In the early phases of method development, the robustness of the method should be ensured.

Mistakes During Review

There are multiple clear guidelines by FDA, ICH, and many other authorities. However, following these guidelines is harder than anticipated, especially when a shortcut approach is followed for development. This shortcut approach might not take API (Active pharmaceutical ingredient) or NCE (New chemical entity) in consideration.

There are four main categories where mistakes are usually observed:

Using methods that are not validated for critical drug-related decisions.

Inadequate or inconsistent validation of methods which fails to offer clear information.

Method validations that lack proper controls to ensure validation integrity.

Using methods without establishing the causes of interference that can occur during procedures.

Incomplete or inconsistent method validation not only delays the clinical trials but also influences the quality of drug product. The stability of these drug products may be questioned at the time of FDA approvals.

Avoiding these Mistakes

Inconsistent test method validations are often a result of a low understanding of molecule properties. The physio-chemical properties of the underlying compound should be correctly analyzed during method validation.

For example, if a compound is sensitive towards the light, this information should be included in the validation document. It ensures that scientists don’t expose the compound to light or heat.

Below we have explained how you can avoid validation mistakes:

Think about the end-goal and validate methods keeping in mind that the efficiency of the method will be tested at every stage. Further, be prepared for any changes in the method or its validation whenever it is required during any stage of drug development.

Every method should be optimized such as improving sensitivity, specificity, solution stability, etc.

Set reasonable acceptance criteria in the validation protocol to ensure appropriate execution of the experiment.

Thoroughly review all sources of interference during method validation. This is true especially when you are dealing with a complex sample matrix or a sample containing multiple reagents.

Method validation is a necessary step in drug development as sound methods pave the way for successful FDA approval. Since this step helps in designing efficient and safe drug compounds, mistakes in this phase should be avoided.


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Written by Jack Roberts

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