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David Blok

Posted on August 23, 2019

Residual solvents and Elemental impurities

Residual solvents and elemental impurities are two pharmaceuticals guidelines that went into effect relatively recently. The current revision of the residual solvents guideline was taken into effect as of June 2017, and the current revision of the elemental impurities guideline as of January 2018. In this article we'll try and explain them to you in a shortened version without using too much technical terms.


Residual solvents

During the production of pharmaceuticals (APIs) certain solvents can be used in the production- or purification process. There are dozens of different solvents but as for an example, commonly used solvents are ethanol and acetone.

Solvents can be used to get a greater yield out of the raw material, to ensure a certain purity, or to achieve characteristics such as the crystallized form of a raw material.

However, it is possible that not all of these solvents are completely removed during the manufacturing process. If they are not properly removed, these solvents can jeopardize the quality or even the safety of a drug product.

As this could form a risk to the end user, certain guidelines were set up to ensure safe use of solvents. They're called the ICH Q3D and USP <467> guidelines, and classify solvents in three different classes based on (amongst other things): their toxicity, carcinogenicity and how dangerous they are to the environment,

In short, they are:
Class 1 solvents: Solvents not to be used.
Class 2 solvents: Solvents only to be used within set limits.
Class 3 solvents: Solvents with a low toxic potential, no set limits.
 
Contrary to lots of pharmaceutical guidelines, these ICH and USP guidelines are actually harmonized.
The only difference though is that the ICH Q3C guideline applies to new drug products only, and the USP guideline is also required for pre-existing drug products.

 

Elemental Impurities

Cd, Hg, Mo, Ni and Pb.

Perhaps you know what these letters mean by heart, perhaps you recognize them from your science class back when you were at school, or maybe you have no idea at all what they stand for.

Either way, they are relevant in the pharmaceutical industry, as they are a couple of the 24 elements that are listed in the "elemental impurities" guidelines: ICH Q3D and USP <232> & <233>.

Elemental impurities are traces of metals that can be present in drug products. Metals can be added intentionally during the production process to act as a catalyst, but they can also be released due to the production process, which can't always be avoided.

If the amount of these traces is too high it could have negative effects such as toxicity and/or lessened effectiveness of the drug, amongst other things.

To prevent this from happening and to have control over elemental impurities, guidelines with certain limits were set up for 24 different elements.

The guideline divides the elements in different classes and also provides analytical procedures on how you should measure these impurities. The toxicity limits of these elements is defined as maximum PDE (permitted daily exposure), and the different classes the elements are placed in have different ranges of PDE. Class number 1 has the elements with the lowest PDE, and thus contains the most dangerous elements.

 

The 24 elements that are defined in the guideline

Class 1:
As - Arsenic
Cd - Cadmium
Hg - Mercury (hydrargyrum)
Pb - Lead (plumbum)

Class 2A:
Co - Cobalt
Ni - Nickel
V - Vanadium

Class 2B:
Ag - Silver (argentum)
Au - Gold (aurum)
Ir - Iridium
Os - Osmium
Pd - Palladium
Pt - Platinum
Rh - Rhodium
Ru - Ruthenium
Se - Selenium
Tl - Thallium

Class 3:
Ba - Barium
Cr - Chromium
Cu - Copper
Li - Lithium
Mo - Molybdenum
Sb - Antimony (stibium)
Sn - Tin (stannum)


References
We hope this blog has thaught you something about these guidelines. If you would like more in-depth information about these guidelines, head on over to the ICH website for their Q3C guideline or the Q3D one.

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