What do you consider for method verification protocol

[zheyin]

I am here to see your opinions:
IF you have experience transfering method and doing verification based on the validation protocol and report.
For a validated HPLC method (impurities/assay)
to transfer it to another lab,
what parameters would you consider in the verification protocol?

Just got USP35: Chaper <1224> Transfer of Analytical Procedures
There are several recommended approaches:
1) Comparative Trsting (test the same samples)
2) Covalidation btw 2 labs
3) Revalidation or partial revalidation
4) Transfer waiver

There are two voices in this forum 1) and 3)

I am the 3) side
system suitability, specificity, LOD/LOQ, Linearity, range, accuracy, repeatability, ruggedness (intermediate precision).
Since these parameters depend on instrument/operator.

I’d not do stability/robustness since this is the intrinsic character of the API/ DS/DP and the method.

This covers almost everything in the validation, but with the validation results, it is much easier to do.

[Johnny Rod]

Check out ICH Q2 which gives a table of what is required depending on analysis type i.e. assay, impurities etc. I think you'd do linearity and range, LOD/LOQ if it's for imps, specificity, accuracy and precision, but for a qualified instrument I don't think you need to repeat robustness as this relates to the analysis method not the equipment. You might do a reduced amount of validation though e.g. fewer points for linearity and range as this was proved in the original validation.

[HPLCaddict]

What you're describing is almost a complete validation .

For a method transfer of a validated method honestly I'd rely on comparative analysis of some representative samples in both labs. For an impurity method include a verification of LOQ. System suitability for the method should be proven, of course (I postulate that a decent method includes a decent SST).
You might do more depending on the specific method. If it includes special/complex sample pretreatment, I'd certainly focus on that one instead of stupid re-verification of linearity...

[zheyin]

Thanks for the opinions above.
As you can see.
2 opposite opinions above:
1 says needs linearity
the other says no need to repeat stupid linearity.

ICH guidelines are for validation, not verification.
And the table even does not have robustness.

[zheyin]

Check out ICH Q2 which gives a table of what is required depending on analysis type i.e. assay, impurities etc. I think you'd do linearity and range, LOD/LOQ if it's for imps, specificity, accuracy and precision, but for a qualified instrument I don't think you need to repeat robustness as this relates to the analysis method not the equipment. You might do a reduced amount of validation though e.g. fewer points for linearity and range as this was proved in the original validation.

I'd agree with you that robustness is not needed to repeat.
Given that even for factors such as flow rate/temp variations won't differ from lab to lab as assuming both instruments are qualified.

Besides,
I assume by precision, you meant repeatability.
I am using terms defined in ICH Q2.
Precision covers: repeatability (same operator, same system)
intermediate precision
and reproducibility (inter lab repeatability which does not apply here)

[zheyin]

What you're describing is almost a complete validation .

For a method transfer of a validated method honestly I'd rely on comparative analysis of some representative samples in both labs. For an impurity method include a verification of LOQ. System suitability for the method should be proven, of course (I postulate that a decent method includes a decent SST).
You might do more depending on the specific method. If it includes special/complex sample pretreatment, I'd certainly focus on that one instead of stupid re-verification of linearity...

I can't agree with you much.
LOD? how do you pprove your lab can achieve the same LOD as the 1st one if not included in verification? how do you report your data below LOQ?

Specificity? what is the ground you based on to omit this?

the focus on sample prep you talked about:
this is repeatability (part of): I don't think this applies to only complex/special sample prep.
Even a simple weighing/dissolving will need proof that the 2nd lab is capable of performing it.

[LC_labrat]

For a validated HPLC method (impurities/assay)
to transfer it to another lab,
what parameters would you consider in the verification protocol?

Are you verifying the method or performing a method transfer?

Is this an internal or external verification/transfer? If this is a external company (such as contract lab) transferring the method in-house, I would want to know if an audit has been performed and the data is found to be acceptable?

Internal verification/transfer-I would suggest different critieria if it is within the company. No specificity, linearity, range, robustness, accuracy or LOD. I would perform system suitability, LOQ and ruggedness (with a comparison between labs on the same samples), the typical parameters used for routine testing.

External verification/transfer would be dependent on who "owns" the method. If audit was satisfactory-I would again reduce the verification to perform system suitability, LOD/LOQ, rugedness (with a comparison between labs), I might add linearity, range, and accuracy, but would depend on the qualifications of owner of the method.

What is the point of repeating the entire validation study, it is has already been performed? There will be some lab to lab variation, but a validated method should work with just a few minor modifications if there are instrumentation differences, which would be within the robustness of the method.

[HPLCaddict]

What is the point of repeating the entire validation study, it is has already been performed? There will be some lab to lab variation, but a validated method should work with just a few minor modifications if there are instrumentation differences, which would be within the robustness of the method.

Full ACK. That's what I wanted to say .

LOD? how do you pprove your lab can achieve the same LOD as the 1st one if not included in verification? how do you report your data below LOQ?

Well, usually as "nq". Is there any other serious way to report it?
And, maybe I'm a bit too pragmatic here, but why would you want to verify LOD? I'm talking about impurity methods here - if you've proven that you can achieve the necessary LOQ, do you really need to verify the LOD? An to go a bit further, I'd even say that you do NOT have to prove that you can achieve the same LOQ as the original lab. You have to prove, that the LOQ you achieve is low enough concerning the specifications. I've seen methods to quantify impurities with a reporting threshold of 0,1% and ridiculously low LOQs of something like 0.0005%...?

Even a simple weighing/dissolving will need proof that the 2nd lab is capable of performing it.

Do I also have to prove that they're capable of reading the method's SOP?

Again, maybe I'm too pragmatic, but when transferring an impurity method, I'd verify the LOQ, prove that I can satisfy the (decent!) SST, and do a comparative analysis of, let's say three representative samples. "Representative" is the magic word here. For an impurity method it means, the samples MUST contain decent levels of the impurities to quantify. Let the analysis of these samples be done independendly by two analysts on two HPLCs and you've got a measure on repeatability and robustness. Done! I'd say this approach is MUCH more practical orientated than "artificial" stuff like linearity. I don't say that linearity is unimportant but it has already been proven and if it's a robust method (which it should be if it's validated) I don't really see the need for repeating that stuff.

What it boils down to is - by validation, the original lab has proven that this method works in their lab. If I'm able to get the same results on the same samples as they do, I've proven that it works in my lab (AND that I'm capable of weighing and dissolving). OK, that was very short...

[zheyin]

For a validated HPLC method (impurities/assay)
to transfer it to another lab,
what parameters would you consider in the verification protocol?

Are you verifying the method or performing a method transfer?

Is this an internal or external verification/transfer? If this is a external company (such as contract lab) transferring the method in-house, I would want to know if an audit has been performed and the data is found to be acceptable?

Internal verification/transfer-I would suggest different critieria if it is within the company. No specificity, linearity, range, robustness, accuracy or LOD. I would perform system suitability, LOQ and ruggedness (with a comparison between labs on the same samples), the typical parameters used for routine testing.

External verification/transfer would be dependent on who "owns" the method. If audit was satisfactory-I would again reduce the verification to perform system suitability, LOD/LOQ, rugedness (with a comparison between labs), I might add linearity, range, and accuracy, but would depend on the qualifications of owner of the method.

What is the point of repeating the entire validation study, it is has already been performed? There will be some lab to lab variation, but a validated method should work with just a few minor modifications if there are instrumentation differences, which would be within the robustness of the method.

To answer your questions:
In my lab, it is method transfer from a customer to us.
Customer validated, and we transfer it.
I would not think we audit the customer.

So based on your idea,
for my case,
there should be
system suitability, LOD/LOQ, rugedness (intermediate precision), linearity, range, and accuracy.

The "(with a comparison between labs)" is termed as reproducibility in ICH Q2
This parameter (include or not) depends on if this is 1-way or 2-way transfer, and it is usually only required for official method validation project.

Counting all of the above as you suggested, this is almost a full validation work, isn't it?
I still think repeatability is needed for verification.

[zheyin]

What is the point of repeating the entire validation study, it is has already been performed? There will be some lab to lab variation, but a validated method should work with just a few minor modifications if there are instrumentation differences, which would be within the robustness of the method.

Full ACK. That's what I wanted to say .

LOD? how do you pprove your lab can achieve the same LOD as the 1st one if not included in verification? how do you report your data below LOQ?

Well, usually as "nq". Is there any other serious way to report it?
And, maybe I'm a bit too pragmatic here, but why would you want to verify LOD? I'm talking about impurity methods here - if you've proven that you can achieve the necessary LOQ, do you really need to verify the LOD? An to go a bit further, I'd even say that you do NOT have to prove that you can achieve the same LOQ as the original lab. You have to prove, that the LOQ you achieve is low enough concerning the specifications. I've seen methods to quantify impurities with a reporting threshold of 0,1% and ridiculously low LOQs of something like 0.0005%...?

Even a simple weighing/dissolving will need proof that the 2nd lab is capable of performing it.

Do I also have to prove that they're capable of reading the method's SOP?

Again, maybe I'm too pragmatic, but when transferring an impurity method, I'd verify the LOQ, prove that I can satisfy the (decent!) SST, and do a comparative analysis of, let's say three representative samples. "Representative" is the magic word here. For an impurity method it means, the samples MUST contain decent levels of the impurities to quantify. Let the analysis of these samples be done independendly by two analysts on two HPLCs and you've got a measure on repeatability and robustness. Done! I'd say this approach is MUCH more practical orientated than "artificial" stuff like linearity. I don't say that linearity is unimportant but it has already been proven and if it's a robust method (which it should be if it's validated) I don't really see the need for repeating that stuff.

What it boils down to is - by validation, the original lab has proven that this method works in their lab. If I'm able to get the same results on the same samples as they do, I've proven that it works in my lab (AND that I'm capable of weighing and dissolving). OK, that was very short...

So in your opinion (or practice too)
you just test the same samples and prove you get the same results.
have you ever done this verification and have you ever been audited by FDA on this type of work?

[HPLCaddict]

OK, I'll elaborate a bit more on this topic. Maybe I've been too short-answered .

First of all, no, I've never been auditioned by FDA. Had a lot of audits by both customers and regulatory authorities, though. Don't know how FDA would consider "my approach".

Generally, a method transfer for me begins with a thourough check of the documentation, that is AT LEAST the methods' SOP and the method validation report. Of course it's hard to judge a method just from paper, but often just by looking at the method you can see where problems might arise. Is the sample preparation complex/extraordinary/somehow novel for your lab? Any extraordinary mobile phases? How do example chromatograms look like? Which parameters are checked during SST? ec., etc. ...
It's very handy if you additionally have access to actual batch data, so you can see how the method and the product behave "in practice" - are there any out-of-trend-results visible, re-analysis necessary, etc.

If
- the method looks "reasonable" enough, i.e. it includes nothing extraordinary or strange, example chromatograms "look fine"
- the validation seems comprehensive, so I can expect the method actually IS valid
- the method includes a "decent" SST, i.e. obviously critical parameters are checked with the SST, for example the resolution of a critical peak pair
then I'd invest only minimum effort in the method transfer. I'd conduct comparative analysis of 2-3 representative batches of the product. They should of course contain sufficient levels of impurities so you actually have something to analyze . Let the analysis be done by two analysts on two different HPLCs in your lab, so you get a feeling for intermediate precision. Verify LOQ. Compare results and chromatograms. Done.
For assay or dissolution determinations the work is even less, as you usually don't have to bother with LOQ here (can be interesting for dissolution of modified release products though, where low levels of the analyte actualy can arise).

If I have doubts or certain forebodings regarding the method, I'd invest more work and time, depending on what arises the suspicions. Complex sample preparation or complex eluents? Include more product batches and/or more workers in order to verify robustness and precision. Extraordinary stationary phases? Include at least two different batches of that phase. Huuuge peaks - probably verify linearity to check that you're not saturating the detector. Etc., etc. ...

Again, I don't say that it's wrong to verify linearity, accuracy, etc. during a method transfer. I just think that it's usually too much...

[zheyin]

OK, I'll elaborate a bit more on this topic. Maybe I've been too short-answered .

First of all, no, I've never been auditioned by FDA. Had a lot of audits by both customers and regulatory authorities, though. Don't know how FDA would consider "my approach".

Generally, a method transfer for me begins with a thourough check of the documentation, that is AT LEAST the methods' SOP and the method validation report. Of course it's hard to judge a method just from paper, but often just by looking at the method you can see where problems might arise. Is the sample preparation complex/extraordinary/somehow novel for your lab? Any extraordinary mobile phases? How do example chromatograms look like? Which parameters are checked during SST? ec., etc. ...
It's very handy if you additionally have access to actual batch data, so you can see how the method and the product behave "in practice" - are there any out-of-trend-results visible, re-analysis necessary, etc.

If
- the method looks "reasonable" enough, i.e. it includes nothing extraordinary or strange, example chromatograms "look fine"
- the validation seems comprehensive, so I can expect the method actually IS valid
- the method includes a "decent" SST, i.e. obviously critical parameters are checked with the SST, for example the resolution of a critical peak pair
then I'd invest only minimum effort in the method transfer. I'd conduct comparative analysis of 2-3 representative batches of the product. They should of course contain sufficient levels of impurities so you actually have something to analyze . Let the analysis be done by two analysts on two different HPLCs in your lab, so you get a feeling for intermediate precision. Verify LOQ. Compare results and chromatograms. Done.
For assay or dissolution determinations the work is even less, as you usually don't have to bother with LOQ here (can be interesting for dissolution of modified release products though, where low levels of the analyte actualy can arise).

If I have doubts or certain forebodings regarding the method, I'd invest more work and time, depending on what arises the suspicions. Complex sample preparation or complex eluents? Include more product batches and/or more workers in order to verify robustness and precision. Extraordinary stationary phases? Include at least two different batches of that phase. Huuuge peaks - probably verify linearity to check that you're not saturating the detector. Etc., etc. ...

Again, I don't say that it's wrong to verify linearity, accuracy, etc. during a method transfer. I just think that it's usually too much...

Thanks for your thorough comments.
My thoughts about your approach:
What if the method transfer happens before final formulation is determined?
In the r&d process and no final product batches available for comparison?
Even though your formulation is final, how do you make sure the drug substances, any related excipients your company will use in future production are the same from the original ones? How do you know if the synthetic route is totally the same?
At least, in this case, specificity should be tested.

Have your been in this scenario:
You adopted a compendial method on a very similar drug product decribed in the method.
How do you verify?
My rule is:
do not try to save 3-hour by reducing the transfer protocol and see troubles in the future, and you'll need to waste 300-hr.
I'm not saying doing more work on the transfer can guarantee a better method. But a thorough verification report can shut those picky mouth off by A stack of paper, simply.

[HPLCaddict]

[
Thanks for your thorough comments.
My thoughts about your approach:
What if the method transfer happens before final formulation is determined?
In the r&d process and no final product batches available for comparison?
Even though your formulation is final, how do you make sure the drug substances, any related excipients your company will use in future production are the same from the original ones? How do you know if the synthetic route is totally the same?
At least, in this case, specificity should be tested.

Have your been in this scenario:
You adopted a compendial method on a very similar drug product decribed in the method.
How do you verify?
My rule is:
do not try to save 3-hour by reducing the transfer protocol and see troubles in the future, and you'll need to waste 300-hr.
I'm not saying doing more work on the transfer can guarantee a better method. But a thorough verification report can shut those picky mouth off by A stack of paper, simply.

??? What are we talking about here?
Changed formulation? Changed excipients? Changed synthetic route?
These questions are not related to method TRANSFER. They're related to method VALIDATION. If you change the product, the method is not valid anymore. What stack of paper do you want to create during the TRANSFER (that's what we were talking about, right?) of a method that will keep the method valid, if you change the product afterwards???
Method transfer before the final formulation is determined and no production batches available? In that case you don't even have a validated method! Worrying about the transfer of a non-validated method???
Concerning compendial procedures - this is not a method transfer, either! Of course you have to prove specificity in this case, at the least!

What is this thread about? Method transfer? Method validation? Method implementation?
We can argue for months if we don't talk about the same thing!

[LC_labrat]

I suggest reading the USP, I have included a partial excerpt below. In this case I would have both labs perform repeatability and LOQ as suggested in the Comparative Testing.
USP35–NF30 Page 876
Pharmacopeial Forum: Volume No. 37(1)

1224 TRANSFER OF ANALYTICAL PROCEDURES

INTRODUCTION
Testing to the specification of an ancillary material, intermediate, and/or ingredient and product is critical in establishing the quality of a finished dosage form. The transfer of analytical procedures (TAP), also referred to as method transfer, is the documented process that qualifies a laboratory (the receiving unit) to use an analytical test procedure that originated in another laboratory (the transferring unit), thus ensuring that the receiving unit has the procedural knowledge and ability to perform the transferred analytical procedure as intended.
The purpose of this general information chapter is to summarize the types of transfers that may occur, including the possibility of waiver of any transfer, and to outline the potential components of a transfer protocol. The chapter does not provide statistical methods and does not encompass the transfer of microbiological or biological procedures.


TYPES OF TRANSFERS OF ANALYTICAL PROCEDURES
TAP can be performed and demonstrated by several approaches. The most common is comparative testing performed on homogeneous lots of the target material from standard production batches or samples intentionally prepared for the test (e.g., by spiking relevant accurate amounts of known impurities into samples). Other approaches include covalidation between laboratories, the complete or partial validation of the analytical procedures by the receiving unit, and the transfer waiver, which is an appropriately justified omission of the transfer process. The tests that will be transferred, the extent of the transfer activities, and the implementation strategy should be based on a risk analysis that considers the previous experience and knowledge of the receiving unit, the complexity and specifications of the product, and the procedure.
Comparative Testing
Comparative testing requires the analysis of a predetermined number of samples of the same lot by both the sending and the receiving units. Other approaches may be valid, e.g., if the receiving unit meets a predetermined acceptance criterion for the recovery of an impurity in a spiked product. Such analysis is based on a preapproved transfer protocol that stipulates the details of the procedure, the samples that will be used, and the predetermined acceptance criteria, including acceptable variability. Meeting the predetermined acceptance criteria is necessary to assure that the receiving unit is qualified to run the procedure.


Disclosure: These are my own opinons and do not reflect the opinions of my company.

I have worked in a GMP lab for many years, each one has been audited at some point (internal QA, external consultants, regulatory agencies), but audits are process based and may or may not have included the method transfer process. In one facility the FDA and DEA were camped out for over a month due to an unexpected manufacturing issue -so they weren't concerned with the transferring of methods between labs-but lots of investigational lab work-no 483s were received

[zheyin]

[
Thanks for your thorough comments.
My thoughts about your approach:
What if the method transfer happens before final formulation is determined?
In the r&d process and no final product batches available for comparison?
Even though your formulation is final, how do you make sure the drug substances, any related excipients your company will use in future production are the same from the original ones? How do you know if the synthetic route is totally the same?
At least, in this case, specificity should be tested.

Have your been in this scenario:
You adopted a compendial method on a very similar drug product decribed in the method.
How do you verify?
My rule is:
do not try to save 3-hour by reducing the transfer protocol and see troubles in the future, and you'll need to waste 300-hr.
I'm not saying doing more work on the transfer can guarantee a better method. But a thorough verification report can shut those picky mouth off by A stack of paper, simply.

??? What are we talking about here?
Changed formulation? Changed excipients? Changed synthetic route?
These questions are not related to method TRANSFER. They're related to method VALIDATION. If you change the product, the method is not valid anymore. What stack of paper do you want to create during the TRANSFER (that's what we were talking about, right?) of a method that will keep the method valid, if you change the product afterwards???
Method transfer before the final formulation is determined and no production batches available? In that case you don't even have a validated method! Worrying about the transfer of a non-validated method???
Concerning compendial procedures - this is not a method transfer, either! Of course you have to prove specificity in this case, at the least!

What is this thread about? Method transfer? Method validation? Method implementation?
We can argue for months if we don't talk about the same thing!

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?