An LOQ question during early phase DP purity mth development

[darasc0211]

All:

I am reposting and hope my title is better this time cause I really want to know.

I am developing a DP method to support first in human IND filing. The fomulation is super low dose (1ug) softgel capsule (capsule contains 1ml formulation) so I had to develop different assay and impurity methods.

For impurity method development, I can see consistent peak area at 0.005ug/ml. I know for supporting phase I, the LOQ is normally targeted to be 0.05-0.1%, but is the 0.05% (or 0.1%) of the drug product label claim or the nominal standard concentration decided in the method? If it's of the label claim, 0.005ug/ml is 0.5% of 1ug, which may be OK for this low dose. but if it's of nominal std, it will be much higher because I'll have to dissolve the capsule in order to prepare the sample.

I am really confused about ICH requirement regarding LOQ and please help.

Thanks in advance.

[krickos]

Hi

If you screen through the recommended data section of ICH Q2 R1 you will note that the recommended data typically is based on the specification (intended or set one) for impurities while assay requirements for example range is based on test solution concentration.

So unless there are a specific early development guideline that states otherwise, 0,05% would mean 0,05% w/w of the active drug substance in the formulation. So in your case it would be 0,05%*1µg/ml= 0,0005µg/ml.

[darasc0211]

Hi, Krickos:

Thanks a lot for your explaination. But I still have the following question and hope to continue our discussion.

Right now my sample concentration can reach as high as 0.35ug/ml, I know my LOQ can only reach 0.005ug/ml (10 times higher than 0.0005ug/ml which is 0.05% of 1ug/ml as you mentioned).

My question is: if I calculate impurities by area%, It will be the area of impurity whose area is larger than LOQ area devided by area of API peak in the sample. This seems to calculate out of the sample concentration though.

Is that relavent to the decision of LOQ? Shall I think of these two things together?

Note: ICH Q3B R2 attachment 1 specifies"Thresholds for degradation products are expressed either as a percentage of the drug substance or as total daily intake (TDI) of the degradation product." does this drug substance mean API in the drug product, or API in the test solution?

Thanks again.

[gtvofigo]

Hello!

First you will need to improve for sensitivity (concentrating the solution or by other method)

According to ICH you must "see" at 0.05% of your current concentration in the solution you are testing. You must ensure if there exist an impurity at that level you could "see" it.

I hope this helps to clarify this topic....
Gustavo

[krickos]

Hi

Well I am too unexperianced when it comes to early development, late development where one is close/at commercial requirements is something else, so will leave whats accepteble others with better experiance of early development. However in you case one should keep in mind that it seems like a very low dosage form (1 µg/capsule), which obviously can cause some challenges in early development from an analytical point of view compared to more traditional dosage forms (mg levels) as such I would in general not rule out that a scientific discussion with involded authorities can be benifical with regard to what LOQ is accepteble.

As for the ICH 3A-B guidelines in general, the limits typically means % of the drug substance or total daily intake (TDI), whichever is the lowest. Again thats once one comes closer into NDA/MAA submissions (commercial).

As a personal note I think the ICH guidelines are generally good but always becomes trickier on the extreme low/high doses where scientific discussions are more worthwhile/needed, not to mention when a risk versus benefit (no other options availeble) situation occur.

[darasc0211]

Hi, gtvofigo and Krickos:

Thanks a lot for your explaination. I agree with a need of a scientific discussion with involded authorities regarding such a low dose.

I was actually requested to tell our client what the LOQ in percentage is I can reach and don't want to mislead my client.

You two seem to have different opinion on wheather the LOQ percentage should be based on my current concentration in the solution you are testing, or based on the dose label claim (1ug/ml).

Can anyone garantee one is a definate answer than the other?

Seeking more inputs...

Thanks a lot........

[krickos]

Well the following text, point number 2 from ICH Q3B is quite clear is it not? Or am I risking my left index finger know?(joke)

Notes on Attachment 1
1 The amount of drug substance administered per day
2 Thresholds for degradation products are expressed either as a percentage of the drug substance or as total daily intake (TDI) of the degradation product. Lower thresholds can be appropriate if the degradation product is unusually toxic.
3 Higher thresholds should be scientifically justified.

For any unfamiliar, thresholds refers to various limits for reporting, identification and qualification of impurities deneping upon maximum daily dose.

Perhaps I also should add that is it usually good to consult some guidelines in parallell, like the ICH Q2, Q3A and/or B and even Q6A depending on what you currently do.

[gtvofigo]

Hi,

I think we must differenciate between Reporting threshold (RT) and limit of quantitation (LOQ).
The RT always is equal or higher to LOQ.
the RT refers to a limit above (>) which a degradation product should be reported.
The LOQ refers to the minimum amount of something that could be quantified by a method.
The total daily intake (TDI) is used for large amount of Drug could be taken by a pacient according to the prospectus of the product.
An example is the 4-aminophenol in product with paracetamol. If the med guide saids TDI 900mg the RT is 0,1%, but if the med guide saids TDI 1500mg the RT is 0,05%. Usually the LOQ for the 4-aminophenol is 0,02% or less...
But always the 0,1% refers to the RT when the maximum daily intake is less than 1gr (this is your case).

well this is my experience, but I love my finger, so I don't want to risk it...
I hope this helps,

Slds,

G

[krickos]

I think Gustavo summed it up very nicely and we can both keep our fingers

As I see it we mean the same thing but approached the question differently.