Response factor calculations

[bhaskarac]

Can anybody help me in calculation of response factors in HPLC analysis.If sample is in salt form and impurity is is a base, should I give the correction for the salt(i.e. HCl,Maleate etc..)?
Is this calculation same for both for drug substance and drug product?

Thanks in advance,

Bhaskar

[bhaskarac]

Even ICH guidelines clearly mentioned that Response factor must be calculated with ''drug substance'' only.
Please find the below material from ICH Q3A.
''The study conducted to charectarize the structure of actual impurities present in the new drug substance at or above apperent level of 0.1%(Calculated by using the response factor of drug substance) should be described.

At the same time ICH dfines the Drugsubstance as below.
''The designated therapeutic moiety which has not been registered previously in the region or member state. It may be a complex,simple ester or salt of previously approved drug substance.

So that we are thinking that the correct way of response factor calculation is with respect to It's respective salt only, but not on free base.

Please comment.

Bhaskar

[Daren]

Hello Bhaskarac,

It does not matter if your drug substance is in a salt form. You just have to make sure that you are comparing equimolar samples of drug substance and impurity. What I typically do to determine response factor is make samples at three concentrations bracketing your impurities quant. range (LOQ to whatever). For each concentration try to make your drug and impurity as close as possible in concentration(Molar). Analyze and calculate your impurities response factor across it's quant. range, should be the same for all but sometimes the LOQ conc is off a little. Hope this helps

Daren

[adam]

In my view, the response factors of the active and impurities should be compared on a weight basis, not a molar basis. After all the basic point is to prove that the area-% result can be taken as equivalent to weight-% (or, if it's not equivalent, to figure a correction factor).

[Daren]

Hi Adam,

I agree with you that it could be calculated that way, however by that approach when comparing compounds that have the same on column absorptivity, you would end up introducing a response factor, which by definition of response factor, is not accurate, since both compounds have the same response. It really comes down to how the data is reported. Even thought the drug substance comes as salt it is being analyzed on column as a freebase, just like the impurities. So to be accurate in reporting a response factor, one should compare apples to apples etc.

Daren

[bhaskarac]

Daren & adam,
Thanks for the reply.

But If you want to compare apple with apple, you must do the weight correction (Eventhough u r taking salt you should make correction to get the free base weight)

Am I correct

[Rob Burgess]

We're likely to be doing some detremination of impurity response factors in the near future and I'd be interested in hearing anyone's else's reply on the best way to determine these.

My initial gut feeling would be to do it on a w/w basis to enable a correction factor to be applied; but there seems to be a diiference of opinion here. Any other thoughts on this topic anyone?

[Hemal]

As per request of Rob Burgess & in the interest of forum members following are the conversations had with Mr.Bhaskar regarding the Response factor:

Dear Bhaskar,

You can either way express the response factor. If you are considering the salt form in calculation then you needs to document it as like response factor due to IMP (Impurity base) with respect to XYZ.HCl (or salt) is ABC depending upon your calculation consideration.

Or it can also be transformed in to base as response factor due to Imp (Impurity base) with respect to XYZ (base) for XYZ.HCL salt.

The reporting will depend on the claims of your product and/or standard practice of your laboratory.

I think this will clear your confusion.

Confirm me receipt of this mail.

Regards,
Hemal Bhavsar

Dear Hemal,

Thanks for your response. We are facing the problem where our customer is calculating it as base in his drug product(ie.Almodipine besylate), where as we (API) considering it a besylate salt.

Best regards,
Bhaskar Reddy

Dear Hemal,

Even ICH guidelines clearly mentioned that Response factor must be calculated with ''drug substance'' only.
Please find the below material from ICH Q3A. (Embedded image moved to file: pic25667.jpg)
At the same time ICH dfines the Drugsubstance as below.

(Embedded image moved to file: pic26299.jpg)

So what we say is the response factor must be calculated as amlodipine besylate only, not as Amlodipine base.
Please comment.
Best regards,
Bhaskar Reddy
Dear Bhaskar
It's always preferable to calculate response factor in terms of salt form. Since both in API & Drug product we are using the API salt as reference standard instead of impurity & applying the response factor. So while calculating, the % Impurity in API we get directly as % of Salt form & that is desired as per regulatory requirements.

Confusion mainly arises where the label claim for drug product is in terms of base; as in your case also .

Even if the drug product is claimed as base one should consider the response factor w.r.t. salt since this does't require to consider the molecular weights of base & that of salt in calculation formula. Since consideration of response factor in calculation is use of API salt instead of impurity.

Regards,
Hemal Bhavsar