The validation report - content, structure and design tips

Written by Dr. Janet Thode Posted in Method validation

Having already written a blog article about the method validation plan and its contents some time ago and also created corresponding templates, today we’d like to address the question of what the method validation report (to be prepared after execution of the validation experiments) deals with, how it could be structured, and, above all, what makes a good report.

 

First of all, why is method validation necessary?

Method validation is performed to prove that the analytical method in question is suitable for its intended purpose and provides reliable results. Therefore, it concerns analytical methods that are used, for example, in a pharmaceutical quality control laboratory or by a contract manufacturing organization to test the manufactured batches of drug substance or drug product for compliance with their specifications, e.g., prior to their release or during stability studies.

 

The content and structure of a method validation report

It should be noted in advance that it makes sense to write an analytical method validation report in English, as it is part of the marketing authorization application - at least as far as the pharmaceutical sector is concerned.

The following contents and in particular the information on the structure of a method validation report are based on my personal perception and the experience gained during various customer projects. There’s a wide variety of design options and orders that can be used depending on personal taste and internal requirements.

1. Introduction (alternatively: "summary" or "overview")

This chapter addresses the purpose of the document and references the underlying method validation plan as well as the test instruction / method SOP, if it is already available as separate document. A short sentence on the purpose of the method (ID, purity, content, potency ± for which samples / process intermediates ± release / stability) can follow. The validation parameters investigated during validation are also listed. During a co-validation, it is also advisable to name the sites involved at this point.

It can also be useful, e.g., in form of a table, to include the rough key data of the method validation (start and end, if necessary, analysts involved by name abbreviation, project number if applicable, number of the method SOP and the method validation plan (if not previously mentioned) and potentially test material(s) used). Furthermore, sentences on the training status of the analysts and the qualification / calibration status of the equipment used can be added.

At the end, a clear statement can be made as to whether the validation was successful or not.

2. Overview of the validation results

For particularly curious readers, it is advisable to present a tabular overview of the results obtained for the respective validation parameters, their associated acceptance criteria, and their evaluation (pass / fail) in absolute short form at this point. Furthermore, this table could also be supplemented with cross-references to the following chapters of the individual validation parameters and, if necessary, the corresponding raw data references.

3. Test materials, reagents, equipment 

At this point, there could be a chapter or sub-chapters on the test materials, reagents and equipment used. You can do this, but you don't have to (but more on this later).

However, if you want to include these (sub)chapters here, you could tabulate the test materials with their LIMS ID (or description), composition, storage conditions and concentration (if relevant), the reagents and materials with their suppliers, article numbers (if necessary), lot numbers, purity grades (if relevant) and expiry dates, and the equipment used with manufacturer, model (if applicable), reference to internal equipment number and calibration date (if applicable).

Depending on the existence and level of detail of a method SOP, however, a short reference to the method SOP could also be sufficient for the equipment, and for the reagents, it might be mentioned that the details can be taken from the raw data.

If different process intermediates or drug substance and drug product differing only in their concentration are to be tested with the same analytical method in the future, a statement can also be made with appropriate justification that the validation is applicable to both, even if, for example, only drug substance was examined during this validation.

4. Results of the validation

In this chapter, the corresponding results are presented as clearly as possible - organized according to the validation parameters examined – while applying good scientific documentation practice (labeled tables and figures with legends should be a matter of course!!!).

At the beginning of each validation parameter-specific subchapter, a short introductory sentence on how this parameter was examined makes it easier for the reader to understand the subsequent results. For this short introductory sentence, you could, for example, look at how the evaluation of the respective parameter was described in the validation plan and summarize that description in a concise manner.

Tables containing the results, possibly the mean values and other calculated statistical parameters, the acceptance criteria, and an evaluation as well as a reference to the corresponding raw data (sheets / files; if applicable) are suitable for presenting the results obtained.

Finally, an evaluation of the criteria of the system suitability tests performed during validation can follow, if necessary. Do they still fit, or can / should they be tightened?

5. Discussion / conclusion (optional)

A brief summary of the results can be provided here and, in particular, potential peculiarities can be discussed, e.g., if not all parameters did pass. It is conceivable, for example, that in the linearity experiments the highest dilution (lowest concentration) of a process intermediate did not meet the acceptance criterion and therefore the range for this test material must start with the next concentration which passed or if certain robustness experiments have shown that the method is susceptible to this condition.

If not already done elsewhere, this chapter can also end with a clear statement that the method validation has been successfully completed (if necessary, with restrictions, as explained above) and that the analysis method can be used for its intended purpose.

6. Observations / deviations

If deviations from the method validation plan or from the described method performance or its documentation occurred during the validation, all these deviations can be described here, their influence and / or risks can be assessed, and possible consequences can be inferred. If a detailed description is not required here due to internal specifications, a reference to the number(s) of the deviation(s) in the corresponding documentation system may be sufficient.

7. References

The title says it all 😉 All applicable documents and other relevant literature are listed here. This can include the method SOP, the method validation plan, previous method qualification reports, a superordinate overall validation project plan, internal SOPs on archiving, good documentation practice or handling of deviations as well as the ICH Q2(R1) or relevant pharmacopoeia chapters.

8. Overview of executed experiments (optional)

This section provides a clear overview of the experiments carried out. For example, the experiments can be listed chronologically or assigned to the validation parameters in tabular form. It should be possible to see immediately which experiment was performed when (date), why (validation parameters, repetition if necessary), with what (samples used), where it can be verified (reference to raw data sheet / computer file), by whom (analyst à abbreviation or number; if applicable), with which equipment (if necessary) and whether it was valid or not. An additional column for comments (e.g., for invalid experiments, reference to the deviation chapter or explanation) could also be useful.

9. "Other chapters" (optional)

The following points represent possible additional chapters for a method validation report that have not yet been mentioned but could also make sense:

  • Responsibilities, e.g., for contract research laboratories (CRO) or laboratories of contract manufacturing organizations (CMO)... 
  • Reaction principle of the validated method so that the reader understands how the method works (in my opinion, this should already be included in the method SOP) 
  • "Material and method", if there is no separate method SOP, the exact execution of the method is described here (preferably as an appendix) 
  • Formulas used for calculations 
  • List of abbreviations, e.g., right at the beginning or (preferably) at the end 
  • Appendices, if applicable   

 

And what makes it a good report?

Now that we know what should or could be included in a method validation report regarding its content, the question arises as to what makes a good report. This is also a very subjective question.

Clarity is my top priority. For this reason, I personally would always list all information that interferes with the direct flow of reading as appendices. For example, I don't want to start with a page-long method description (as there’s no separate method SOP yet) but get straight to the results. So why shouldn’t we list the method description as an appendix? The situation is similar with the chapter(s) "Test materials, reagents, equipment": For me, a single (small!) chapter on the test materials prior to the results is still ok, but material and equipment overviews can preferably be part of the appendix, because as an impatient reader I don't want to scroll over tables (or worse: loveless blocks) of the reagents used accompanied by their lot numbers... The same applies to the results: in the actual main chapter, a brief outline with illustrations and, if necessary, short (!) tables for each parameter and a statement as to whether the acceptance criteria were fulfilled would be enough for me. I’d like to see the detailed tables with calculations in the appendix. On the other hand, you might argue that you’d always have to jump to the end to check the individual contents...

You may have already noticed from the description above that in this context, I generally advise using descriptive text passages sparely and always prefer tables to present facts clearly. [And if you're now wondering why this article isn't structured this way, please note that this is a blog article and not a method validation report – which I write differently! 😉].

Furthermore, in my opinion, it is advisable to highlight the relevant results (e.g., the mean value, if this is compared with the acceptance criterion) in bold. This catches the eye and makes it easier for the reader to grasp its relevance.

In terms of content, the report must be comprehensible on its own. In my opinion, it’s therefore not possible to present only the results without any further explanation of how they were generated while only referring to the validation plan. The short introductory sentence at the beginning of each chapter for each validation parameter is therefore not unimportant. Nevertheless, the report shouldn’t also be unnecessarily bloated. I don't need gap fillers such as a "List of tables and figures" or an overloaded appendix with scans of the CoA of the standard or pipette tip specifications... Already seen…

Phrasing must be clear, unambiguous, and precise. For example, in case of robustness experiments with the same incubation period (e.g., 24 h) but different temperatures (e.g., RT and 2-8°C), both temperatures should be listed in the table of results next to the incubation time for the purpose of clear assignment...

I also emphasize consistent wording, e.g., a reference standard shouldn’t be introduced at the top with "RS" only to reappear elsewhere as "STD" - please use "RS" consistently! It also goes without saying that all abbreviations used should of course be explained in a list of abbreviations...

Finally, I’d like to say that I’m a friend of utmost transparency and traceability. I therefore consider it a matter of course to also list minor deviations (or "observations"), even if some people may regard this as trivia. From my point of view, it increases the authorities' confidence in the work carried out if such observations are also briefly described and evaluated, rather than being swept under the carpet...