Chromatography Forum

Please read carefully about my original description:
you just supposed that DS is made by us.
In reality, there are many cases companies outsource both API and excipients and formulate them together using some special techs.
You cannot guarantee the supplier of API/excipicents does not change the synthetic route;
Besides, the method can be validated on early phases (so it can be transferred), not necessary to be at final formulation.

Why do you think the USP method can not be transferred? ok, officially, it is called method verification. Can you answer my former question about how to verify a USP method in your own lab?

- If the supplier of the API changes the synthetic route or if the supplier of the final product changes the API source they MUST inform you. THEN it's time to do a risk analysis and based on this analysis consider further actions, possibly revalidating analytical methods.
- There's NOTHING you can do in advance to circumvent this. Do you want to consider every possible synthetic route of the API during method validation? And yes - it's the VALIDATION where this should be considered, not the transfer.
- "the method can be validated on early phases (so it can be transferred), not necessary to be at final formulation". Validation on early phases? You might consider doing some pre-validation work, but, as said above, once you change the product, the method is not valid anymore. You MUST revalidate in this case.
- There's certainly a difference between transferring a method and implementing a USP method in your lab: there's no transfer partner in the latter case so why would you call it a transfer? In this case on an early stage of development I'd certainly verify specificity and precision at least, possibly accuracy and linearity - it all depends on the complexity of the method and the product. Once you gain some experience with the method, you usually can make some educated guess where to look at further. When the development stage is finished, I would be tempted to do a full validation of the method - although it's a USP procedure. This is a case where you should remember what validation is all about - to prove (to yourself) the method's valid and it will work in your lab! It's not (at least in the first place) about satisfying regulatory authorities.

I am "just shocked" that no two interpret the regulations, guidelines, etc., the same! Lovely world of USP, cGMP.

I especially chuckle right now the USP section on "Volumetric Titrants". For sodium hydroxide, USP has one standardize the 1 N sodium hydroxide by titrating v. primary standard KHP that's been dried. Then one dilutes that 1 N solution to the desired strength, I would've written to standardize the titrant concentration that's actually going to be utilized. Also:
(1) no guidance on if the standardization should be performed in duplicate or triplicate (etc.)
(2) USP uses the term "standardize frequently". What the $$^&*%#^&# does that mean? I beleive only NaOH and KOH solutions include that term.
(3) no guidance whether the KHP would need to be dried each time it's used or could it be dried and stored in a desiccator

OK, so what do we do here, getting back to the original question?
For test method transfer, each location assays blind low, target, high samples, each in full triplicate, and QA compares the results. Think "Intermediate Precision", would not always expect two labs to have as tight of results as just one lab.

For USP Monograph tests, for example assay of citric acid, straightforward titration with standardized base to phenolphthalein endpoint: would degreed chemists really need to verify results v. C of A results? Would degreed chemists need to be verified as to be able to qualify a balance v. high-low weights, weigh sample, open a fresh bottle of certified titrant, ability to add a magnetic stirrer and water, and use of a buret?

If I'm considered qualified to develop, validate, write procedures, protocols, and validation reports - who makes this call? Is it my experience, my Phi Beta Kappa, my publications? I don't remember kneeling before the Queen and having her tap my shoulders with a sword.

I think we have been in agreement with comparative testing, I suggested possibly performing some non-method transfer parameters only as re-assurance the method works, again dependent on the method owner. But since the customer is the owner of the method-I doubt they would want to pay for a complete re-validation as a method transfer.

It is a mix of good science (comparative testing between labs) and good business (re-validation of method to avoid any potential issues). The most conservative approach is to completely re-validate, it has less risk but is more costly. However it can also bring up a new set of issues if the validation parameters do not match, additional work and probably a dis-satisfied customer, unless of course they agreed to it to a complete re-validation.

Method verification protocol requirements will depend entirely on the type and complexity of the method being transferred and if there is a transferring laboratory to compare results with.

An easy example would be read an anlytical method, understand the content and sign to that effect. This would be the case for simple ID testing or appearance testing of tablets.

More challenging methods may require some on site validation activities and possibly lab to lab sample result comparison for known samples.

More complex stability indicating methods or those with complex set up requirements may also require a visit to the other lab to see the method in action. Or an experienced scientist to visit your laboratory to demonstrate the method set up and operation prior to transfer/verification activities.

Either way the lab sending the method should advise during a face to face meeting what is expected in the protocol, explaining any areas of concern to focus on.

If there is no transferring lab, the verifying lab will need to take a more risk managed approach ensuring that the method is adaquately shown to be fit for its intended purpose.

I have never done a verification of an USP method but have a few recommendations you may want to consider. I would recommend you use a risk base approach (sound scientific judgement). Assuming this is a combined assay/impurity method:

1. Specificity: evaluate stability (e.g. expired) and/or forced degradation samples
2. Linearity: limited spiked placebo e.g. 50, 80, 100, 120, 150% for API using n=1 instead of n=3 replicate.....using single stock std. For linearity for impurities, use scientific judgement to evaluate 1-2 impurities only, n=1 replicate. For example, impurity with significant RRF, early or late eluting compds, and/or critical pairs, etc
3. Data from 2. above use for Accuracy......Neat Std vs Placebo Spike.
4. Intermediate Precision (IP) using actual samples, 2 analysts, n=6 each.
5. LOD and LOQ......evaluate like if they are part of the system suitability i.e. n=1 injection. Your two IP runs will give you a good idea if you've achieved acceptable LOD/LOQ.
6. Sample Prep Robustness....for IP above, prep. n=3 at one extreme and n=3 at the other extreme in terms of extraction efficiency and potential solution degradation. If the data at the two extreme are equivalent, combined the n=6 results for IP.
7. Chrom Robustness....if the impurity profile is similar to that of the USP's method, there is no need to conduct this study. But it's wise to do so to understand your design space for the chrom parameters. Perhaps, 1-3 critical parameters will do e.g. change organic (similar to changing flow rate), pH (for acid/base compds).

It seems like a lot but it's basically a mini-validation. I'm assuming your formulation is likely different than the competitor and the impurity profile is slightly different also.

Your comments are appreciated.

I have never done a verification of an USP method but have a few recommendations you may want to consider. I would recommend you use a risk base approach (sound scientific judgement). Assuming this is a combined assay/impurity method..........

I expect that we would not do anything so involved to verify a USP method.

I agree with you if you have demonstrated that your formulation is the same as the registered product method i.e. excipients used and related substance profile.