DMF section 3.2.S.3 - Characterization

Section 3.2.S.3 is divided in two parts, first, the elucidation of structure, and then one of the most important parts of the DMF, the impurities chapter.
In the elucidation of structure, the manufacturer will present results of analyses which confirm the identity and structure of that API, such as an infrared spectrum, UV spectrum, NMR, mass spectrum and elemental analysis.
Here we will also see a discussion about isomerism, in case this is applicable to the API, and another property which is very important, the polymorphism.
The API can be amorphous or a crystal, and there may be different crystals for the same API, which we call different polymorphic forms. Different polymorphic forms will have different X-ray diffraction spectra, and in some cases they may exhibit differences in solubility, and even stability - this is why this is an important property which has the potential to impact the performance of the drug product.
In case different polymorphic forms have been described in the literature, the manufacturer needs to discuss the different forms and prove which one is produced, showing also if it's stable and does not convert into another form throughout its shelf life.
After that, the impurities section starts.
Impurities are divided into organic, inorganic, and residual solvents.
Organic impurities have their control described in ICH Q3A, and another guideline which is applicable to them is ICH M7, the guideline for control of mutagenic impurities.
Potential organic impurities include any organic compound that may be present, which is not the API itself, and they can either arise from the process or from degradation.
In case a pharmacopoeial monograph is available for that API, the impurities described in the monograph also need to be discussed, to understand which ones are indeed potential impurities for that route of synthesis, and if controlling all those impurities is applicable.
And for each one of these impurities, a mutagenicity prediction must be presented within the DMF. Those which are potentially mutagenic (classes 1, 2 or 3) need to have their limits defined based on ICH M7, while class 4 and 5 impurities are considered non mutagenic and controlled based on ICH Q3A. To know more about ICH M7, there is a specific video about this topic here in the channel.
Although it's important to discuss all impurities from the route, many of them won't be carried over to the final API, so all these impurities, mutagenic or not, need to have their control explained in the DMF, in line with the strategies described in ICH Q11. Can its elimination be justified through a purge factor calculation? Is there any in-process control or in isolated intermediates? Or is it controlled in the API specification?
It's also important to note that in case any impurity has a limit higher than the qualification threshold described in ICH Q3A, it will be necessary to qualify this impurity, demonstrating that this higher limit does not represent any toxicity concern.
Here we will also see the nitrosamines risk assessment, and you will also find more specific videos about this topic here in the channel.
For residual solvents, the guideline which defines their acceptable limit is ICH Q3C, which also divides them into classes.
Class 2 solvents used in the final stages will usually need to be controlled in the API specification, but those used in initial stages may have their control exempted in case batch analysis results demonstrate their levels are below 10% of the acceptable limit.
Class 3 solvents can be controlled through the non-specific test loss on drying, in case this is part of the API specification with a limit of 0.5%.
In case any class 1 solvent may be present as a contaminant of the solvents used, it should also be controlled or have its absence justified.
Finally, the inorganic impurities from the process need to be described, as well as their control.
The guideline that should to be followed is ICH Q3D, which proposes limits for elemental impurities.
A risk assessment should be performed as explained within the guideline, and once again there is a classification for these impurities, which will determine if they need to be considered even if they are not intentionally added, depending on the route of exposure as well. In case batch analysis results show levels below 30% of the acceptable limit, there is no need to routinely control these elemental impurities.
Other inorganic elements of low toxicity such as sodium, potassium, chlorine, can be controlled through non specific methods such as residue on ignition or sulphated ash.
The impurities chapter is a DMF section which very frequently shows gaps and a very common theme within regulatory deficiency letters. The safety of the API depends on an adequate control of its impurities, and that's why it's so important for this chapter to be very complete, well explained and in line with international guidelines.
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