Placebo Intereference

Discussions about HPLC, CE, TLC, SFC, and other "liquid phase" separation techniques.

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Hi,
One of my drug product is having lambda max 205 nm, for related substances method, I have selected 210 nm wavelength. But there are multiple peaks in the sample due to Placebo.
My queries are as follows on related substances method,
1. Is it acceptable to have multiple peaks in drug product due to placebo?
2. Once the product transfer to plant, are they (QC) need to inject placebo every time?
3. If yes to point no.2, does the Placebo also need to be kept for stability along with drug product batches?
4. Does the change in batch of excipients, will also trigger for new placebo with respective material?
5. Does the one time injection of placebo at the time of method transfer will suffice throughout the stability studies?

Note: All the placebo peaks are well separated from known or unknown peaks.

Thanks and Regards

Ravin
Please note that I am a chromatographer not a regulatory affairs specialist, so take these as my opinion, not any official policy. That said, these are the sort of questions that should be addressed in your company's SOPs. If they are not, then the SOPs need to be updated,

OK:

1. Is it acceptable to have multiple peaks in drug product due to placebo?
Of course, that's why you check the placebo! The problem with a low wavelength like 210 nm is that almost everything has at least some absorbance down there.

2. Once the product transfer to plant, are they (QC) need to inject placebo every time?
3. If yes to point no.2, does the Placebo also need to be kept for stability along with drug product batches?

I would say "yes" to both questions. IF you see "new" peaks, you need to know if they come from the API or the placebo.

4. Does the change in batch of excipients, will also trigger for new placebo with respective material?
Yes, for the same reason cited above.

5. Does the one time injection of placebo at the time of method transfer will suffice throughout the stability studies?
No. Again, if you see "new" peaks, you need to establish whether they come from the API or the placebo.
-- Tom Jupille
LC Resources / Separation Science Associates
tjupille@lcresources.com
+ 1 (925) 297-5374
Hi,

I am a quality person in pharmaceutical and able to answer your question. There is no official SOP or guidance documents available on placebo interference but as per my experience and knowledge I am giving my opinion:

1. Is it acceptable to have multiple peaks in drug product due to placebo?

Yes, multiple peaks in drug products due to placebo may be eluted but shall be separated from peaks of interest.

2. Once the product transfer to plant, are they (QC) need to inject placebo every time?

Yes, As placebo made from combination of excipients used in product which are generally polymers and giving variable response in chromatography hence suggest to inject placebo during commercial and stability study. Sometimes placebo peaks are not matching due to change in lot of excipients or during self life then batch specific placebo should be prepared and confirm the peaks due to placebo in sample injections.

3. If yes to point no.2, does the Placebo also need to be kept for stability along with drug product batches?
Yes
4. Does the change in batch of excipients, will also trigger for new placebo with respective material?
Yes
5. Does the one time injection of placebo at the time of method transfer will suffice throughout the stability studies?
No , then you will find difficulty during integration of peak of interest.

Note: All the placebo peaks are well separated from known or unknown peaks.

Thanks and Regards

Ravin[/quote]
I agree with everything except point 2. As long as you have demonstrated during your method validation that the excipients are well separated (baseline separation) from the API and its related substances (RS) then QC does not have to inject a placebo every time. Blank mobile phase is OK.

However, if there an OOS for the assay or a RS evaluation of the placebo should occur as part of the investigation.

In addition a change in the supplier or grade may change the extraction procedure which would mandate a mini-validation.
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