Potential impurities are the substance which are formed during the reaction or already present in the form of starting materials, by products or intermediate products. Potential Impurities have no therapeutic value and are potentially harmful. Therefore, they need to be controlled. Potential impurities may be arising due to: • Residue of the starting material • Residue of the intermediate • Impurities in the starting material • Reagents • Solvents • Catalysts • Reaction by-products • Degradation products • Excipient-API interactions • Drug substance/product manufacturing process • Container closer interactions

1. Potential Impurities in Drug Substances & Drug Products
Potential impurities are the substance which are formed during the reaction or already present in
the form of starting materials, by products or intermediate products. Potential Impurities have no
therapeutic value and are potentially harmful. Therefore, they need to be controlled.
Potential impurities may be arising due to:
 Residue of the starting material
 Residue of the intermediate
 Impurities in the starting material
 Reagents
 Solvents
 Catalysts
 Reaction by-products
 Degradation products
 Excipient-API interactions
 Drug substance/product manufacturing process
 Container closer interactions
As per ICH Q3A defines potential impurities as those “that theoretically can arise during
manufacture, or storage.” Understanding how the potential degradation products form via specific
degradation pathways or mechanisms. This provides a basis for minimizing or eliminating
degradation e.g. through processing conditions, formulation, storage condition or packing.
Based on the knowledge about the manufacturing process, intrinsic characteristics of the API,
official monographs, forced degradation studies and, possibly, literature references, the API
manufacturer should determine which are the potential impurities.
Genotoxins must be considered carefully due to their toxicity at even very low levels. If you are
looking for an impurity using a test method that cannot detect the impurity then method is not
capable to detect the low levels of impurities. Hence it is important that analytical methods
demonstrated specificity and appropriate LOD/LOQs levels, especially for genotoxins. Analytical
detection and quantification are often challenging and requires sophisticated methods and/ or
derivatisation.

2. Potential degradation impurities in drug substances:
Normally, degradants are chemical collapse compounds of the drug substance formed during
storage. In rare cases, degradants are formed when the drug substance chemically interacts with
other compounds or contaminants. In addition, degradants may also be formed by physical
degradation, e.g. aggregates of proteinaceous material, dimers, trimers, and so forth, of synthetic
compounds, polymorphs of synthetic compounds.
Potential degradation impurities in drug products:
Drug products contain both drug substance and excipients. The resultant biological, chemical
and physical properties of the drug product are directly dependent on the excipients chosen, their
concentration and interactions with the drug substance. Excipients are sub-divided into various
functional classifications, depending on the role that they are intended to play in the resultant
formulation, e.g. fillers, disintegrants, binders, lubricants, colour, flavours and glidants. Also, the
impact of manufacturing process, conditions, packaging and storage of finished dosage forms.
There is a tendency to skip the step-in discussion and just adopt pharmacopeial specifications if a
monograph exists. Hence there is need to find out what are the expected potential impurities?
What is the additional literature-based impurities? What are the other reported impurities?
Consequently, for any drug registration, one of the principal requirements is to specify both
identified and unidentified impurities in drug substance/drug product as per ICH guidelines
Q3A(R), Q3B(R) and Q3C. Characterization of impurities is required, particularly when they are
present at a level higher than the identification threshold to control their levels in the final API or
drug product.