Verification of compendial methods

 

If analytical methods are used in pharmaceutical QC laboratories, there is the question to which extent methods from pharmacopoeias (for example the European Pharmacopoeia) have to be tested for suitability. Since these methods have already been tested extensively, a validation isn’t necessary anymore. Nevertheless, it must be ensured that the procedure can be used “under the particular conditions according to the relevant monographs, the general chapters and the quality systems” (excerpt from the Aide-mémoire 07123101 of the ZLG) and with the product in scope. This is why this case is called method verification. We want to identify what the regulatory requirements are and how you can determine your personal verification parameters of compendial methods in the following paragraphs.

 

What are the regulatory requirements?

The topic of verification of compendial methods is covered by different guidelines, respectively laws, in a more or less detailed manner. We’ve summed up the respective central statements for you.

21 CFR 211.194 "Laboratory Records":

The American health authority FDA (Food and Drug Administration) touches upon the issue in general only. Paragraph 211.194 of their CFR (Code of Federal Regulation) states that compendial methods can be used, provided that they haven’t been changed. It’s necessary to refer to the source of the respective procedure. Furthermore, the law calls for the verification of any testing method as to their suitability under the given conditions in the laboratory.

WHO guideline "Analytical Method Validation" 2016:

The WHO guideline is a bit more specific. Besides demanding a test for the suitability of the method, it describes that procedures for content determination or detection of impurities must be tested. In addition, the guideline describes how verification is defined generally and when it’s used. It defines verification as a partial validation.

USP <1226> "Verification of Compendial Procedures":

The most detailed information is in the American pharmacopoeia USP (United States Pharmacopoeia) in chapter <1226>. It doesn’t only define when it’s necessary to verify compendial methods, but gives background information for the actual verification process and the necessary activities. It also provides impulses on the question which aspects have to be taken into account during the planning of the verification. In the course of this, it discusses the staff, the necessary materials and the composition of the product to be tested. Furthermore, it describes which standard procedures are exempt from verification.

FDA Guidance for Industry "Analytical Procedures and Methods Validation for Drugs and Biologics" 2015:

These FDA recommendations orient themselves on the USP chapter, but mainly discuss the content of the verification protocol that needs to be created. They define which parameters need to get a look and evaluated in detail. This depends on the method, the preparation to be tested and the conditions in the laboratory. Here, the term “validation” is used as well, which can be partly necessary.

ANVISA Resolution RDC N^o. 166, dated July 24^th, 2017:

The Brazilian authority requires for compendial methods to perform a partial validation, whereby at least the parameters precision, accuracy and specificity have to be evaluated. For quantitative determinations of impurities, the limit of quantification (LOD) must also be taken into account, while for limit tests only specificity and LOD must be evaluated.

 

Selecting the verification parameters

It’s essential to specify the verification parameters needed for verification. Before conducting the method, basic research must be done, and the method to be verified must be examined closely for this. In doing so, it must be examined since when the method has been established, if it still conforms to the newest state-of-the-art technology, how complex it is and which accuracy it promises. From this first analysis, parameters to be tested for can already be derived. These have to be put down in a verification plan subsequently. Type and extent of the parameters depend heavily on the method description’s accuracy and the type of product. The latter might not react because of other components and chemical characteristics. That’s why it’s important to test for detection limits, and for example, also if the API content of the product can be determined correctly. The suitability of certain devices and consumables must be tested for as well. Another important aspect is the accuracy of the analysis method.

Taking the well-known LAL test for endotoxin determination as well as the Karl Fischer titration for water content determination as examples we checked a compendial method verification in practice.

 

Clear documentation – the most important thing

As with most activities in the pharmaceutical industry, documenting the verification is of decisive importance. The verification plan should emphasize the parameters that need to be tested clearly. In doing so, it must be established how they’ve been determined and on which scientific basis. The performance of the verification has to be documented exactly to prove the suitability of the testing method for the laboratory without any doubt.

 

Conclusion

Conducting verification of compendial methods isn’t trivial. Since the respective regulatory requirements are rather unclear, many laboratories are puzzled. That’s why it’s important to think sufficiently about which aspects are the most important for the procedure to be conducted and where problems can occur. A risk analysis in advance can help here. The verification shouldn’t be conducted alone, but in a team. That way, a functioning testing procedure can be established demonstrably. It should also be kept in mind that in the event of a change within the compendial method, the impact of this change on the verification status must be assessed and, if necessary, the method must be re-verified.