Risk Based Method Validation

[gtma]

I would appreciate your thoughts on what does risk based method validation means to you? Is it the same as phase appropriate validation? Could you provide some examples of how or where it may be used?

[krickos]

A very intresting topic this one.

I would not make a solid = between clinical phase appropiate validation and a "quality risk managed validation"(QRM Validations).
In my opinion you can use similar tools I guess but the criticality of a parameter could/would change depending on clinical phase and current knowledge.


As to "where it may be used", our pharma world is unfourtunatly not always uniform in interpretations of guidelines. For instance I have not so far heard of any sucess in filing alternative/flexible analytical procedures in Japan.
While FDA sometimes have seemed almost irritated at industry for not using/embracing Quality by design principles and similar faster.

To begin somewhere ICH Q9 do talk about QRM validations:
II.6 Quality Risk Management as Part of Production
Validation
To identify the scope and extent of verification, qualification and validation activities (e.g., analytical methods, processes, equipment and cleaning methods;
To determine the extent for follow-up activities (e.g., sampling, monitoring and re-validation);
To distinguish between critical and non-critical process steps to facilitate design of a validation study.

There is also some related in the more drug substance specific ICH Q7 guide:
Methods should be validated to include consideration of characteristics included within the ICH guidelines on validation of analytical methods. The degree of analytical validation performed should reflect the purpose of the analysis and the stage of the API production process.

So for drug substance in process controls like LC/GC conversion analysis would be a suiteble example where you could do a QRM.

Robustness is another area, a matrix/Design of experiments is mentioned in ICH Q2.
Some more simple examples, you would not consider any significant studies of sample stability if you are following for example a hydrogenation reacion as sample typically would degrade/becom non-representative quite fast.
If you revalidate an older procedure and know that the drug substance including all knowm synthetic and degradation products are lipophilic,non water soluble, no pka in 2-12 etc, would you consider study pH in mobilephase as critical as the impact from ACN/Methanol?

Going back a bit.
Ideally for me it does not stop with identifying what is more or less critical in a validation, I hope in the future that "ranges" where you can operate without regulatory approval will be more accepted in analytical procedures, just like manufacture processes have ranges supported by QbD/QRMs/design of experiments data.
This was the initial driver for QRMs/QbD etcetera authorities/patients/costumers gets a better understood product and quality while industry gets more room to operate in order to drive improvments with less regulatory changes.

[gtma]

Thanks krickos. As you alluded to, I have seen a risk based method validation approach used more often for drug substances (DS) than for drug products (DP). There are a number of examples where I think a risk based approach can also be used for DP. For example, do you really need to do accuracy/linearity for all related impurities, especially if they have similar properties e.g. extinction coefficient, solubility, elution, etc? Can a related impurity/degradant that has similar properties to the API be used as a surrogate for unknowns in terms of demonstrating accuracy/linearity? If the DS method is also used for the DP, are there opportunities to do minimum DP validation? Is wavelength robustness ever critical for Assay methods especially if you have selected the UV max for the method? More importantly, are your decisions driven by good scientific data and rationale?

[krickos]

Intresting as said but not easy.

There are a number of examples where I think a risk based approach can also be used for DP. For example, do you really need to do accuracy/linearity for all related impurities, especially if they have similar properties e.g. extinction coefficient, solubility, elution, etc?
In my experiance it tends to be easier with DS as the chance of very similar synthetic impurities would be more likely. But of course it could happen in DS aswell. The other issue is the sample matrix, in DS and not uncommonly intermediates you have 99-100% pure material or Close to it. In DP you would have to consider impact of excipients and more or less complex sample preparations.
As an example I once had an aldehyde that needed revalidation (GC-FID), 4-5 position isomers (different positions of methyl/ehyl groups), -H, -OH and -Cl isomers as well (-COOH impurity had OK individual procedure so excluded apart from specificity and some robustness). After verifying specificity and response factors for all I had acess to, I picked 2 of the isomers and the --H, -OH and -Cl for accuracy/linearity/repeatability.
Responsefactor/extinction coefficient only in a DP would be more risky, larger molecules can be very similar but behave differently in sample prep.


Can a related impurity/degradant that has similar properties to the API be used as a surrogate for unknowns in terms of demonstrating accuracy/linearity?
I would say yes here, if degradation Products in DP is extremly different from the DS and the synthetic impurites, you could use the DS or closely related synthetic impurity to verify linearity/accuracy/precision for any unknown (OK to assume same response).

If the DS method is also used for the DP, are there opportunities to do minimum DP validation?
Some I would say. You would have to look at placebo and special diluent media with regard to specificity including DP specific degradation Products. Would also be difficult to argue exclusion of accuracy/repeatability/intermediate precision due to different sample matrix/sample prep.
Likewise with sample stability, but standard/SST stability might be drawn from DS.
Some Robustness depending on placebo impact and linearity are more likely to be possible to draw from DS.
QL/DL may be impacted of placebo noise.
Minimum range/report limit differ between DS and DP and is dose depending.

Is wavelength robustness ever critical for Assay methods especially if you have selected the UV max for the method?
A scan showing that a +/-2nm variation would not have a significant impact, should be enough to exclude it.

More importantly, are your decisions driven by good scientific data and rationale?
As inclined above, this is important. Good pyuscial propery data on DS may help DP decisions, still placebo impact may cause difficulties.
A capsule with pure DS/noncomplex mix which is emptied for assay/content uniformity/degradation Products is one thing, compared to dissolution testing or more complex tablets compositions.

So I would say, it is more challanging with DP in general, but this does not exlude the possibillity to design a validation that in the end supports a degree of freedom to change analytical parameters during the DP lifecycle.

[aceto_81]

Intresting as said but not easy.

Is wavelength robustness ever critical for Assay methods especially if you have selected the UV max for the method?
A scan showing that a +/-2nm variation would not have a significant impact, should be enough to exclude it.

Just curious: how do you decide what is significant?
For example, my assay method has an absorbonce of about 0.85 @ 254nm.
0.84 @253nm = critical or not?

Ace

[gtma]

what constitute significant depends on what variable you're willing to accept. For example, a variability of 0.05% for impurities below 0.25% may be considered acceptable with +/-2nm change. Consider translating the response to actual assay result before making a decision on what's significant.