validation finished products

[scio2]

Hi there, can anyone clarify if synthetic impurities are used in the validation procedure when validating a finished product method. I thought only degradation impurities were utilised in the validation procedure

Can anyone clarify if this is correct
Scio

[tom jupille]

My interpretation has always been "if there's a possibility that it's in there, then it must be included". Starting materials, intermediates, and synthesis by-products could all be in there!

[scio2]

Thanks Tom

I thought that since synthetic impurities are controlled in the API then when we get to the finished product, we dont need to monitor them as such, but we do need to check that the method separates them from the api, potential degradants and excipients.

So, we would do specificity and then when we finish the validation and finalise the method use the synthetic impurities in the peak id solution.

Any thoughts?

Scio

[tom jupille]

I try not to think (it hurts my head!).

Seriously, I agree with that approach.

[scio2]

Thanks Tom

[HW Mueller]

Now I have a headache, just swallowed a pill and now think again there might have been all kinds of impurities in it which some agency failed to specifically require to check. . . .
Also, all those terms cause problems upstairs. A validation is a quality control? So the API (headache term) is to be controled? So if the synthetic people say it is "pure" than it is not controled? If the people who prepare the final pill say its OK, it is not controled?

[Bruce Hamilton]

Hans,

You haven't got a headache.

If you had known the gory details of Pharmaceutical quality systems and the abbreviations, then you would have a perpetual headache.

Basically, the Active Pharmaceutical Ingredient ( API ) is tested by the manufacturer for impurities ( eg related substances and process impurities such as residual catalysts, solvents ), and efficacy. These tests, or a subset, are repeated for each batch of product manufactured.

The stability of the unformulated API is also tested under various conditions to ensure it doesn't degrade before use. All of that information is provided to regulators in Drug Master Files for prior approval before it can be commercially marketed.

Note that any change to the approved process will require a major reinvestigation of the effects on product quality.

Typical cost for new API approval = about three times the annual proposed total bonus payments to AIG staff.

The formulator is required to repeat most tests on each batch of their own products to show that they haven't added toxins, encouraged API degradation, or affected efficacy.

If the API and formulation are in compendial protocols ( eg Pharmacopeia, Codex, or Formulary ) then some of the testing may be foregone, but then the manufacturer has to show compliance with all the compendial requirements.

The compendial and regulator requirements often use ICH Q-series guidelines for the whole process, and terms like verification and validation are defined in their documents, available at the ICH www site.

However, in many countries, it's only health foods ( eg "organic" ) that escape most form of chemical quality control.

Hope the above doesn't cause a headache...

Please keep having fun,

Bruce hamilton

[pkenny]

This is from ICH Q3B(R2) - Impurities in New Drug Products

"Generally, impurities present in the new drug substance need not be monitored or specified in the new drug product unless they are also degradation products (see ICH Q6A guideline on specifications)."

and this from Q6A...

"2.10 Impact of Drug Substance on Drug Product Specifications In general, it should not be necessary to test the drug product for quality attributes uniquely associated with the drug substance. Example: it is normally not considered necessary to test the drug product for synthesis impurities which are controlled in the drug substance and are not degradation products."

So it looks like they don't have to be included in the validation other than for specificity.

[HW Mueller]

Does this say that if there was a quality control performed regarding synthesis impurities, etc., you don´t have to repeat that when you do the degradation stuff (" . . .for synthesis products which are controled . . .")?

Bruce, I have trouble, sometimes, distinguishing between paranoia and a headache.

[Alex Buske]

Yes, you are right. If synthesis includes for instance ethylation and in the ethyl reagent is some methyl reagent they would end up with an methylated species as an impurity of the ethylated main product. That is controlled and specified.
Does determination of the methylated impurity in the finished drug product and in stability testing improve patient security and customer satisfaction?
I don't think so.
That would be different with salicylic acid in ASA.

Alex