Potential toxic chemicals and carcinogens in treatment drugs are one of the biggest problems to plague
Active Pharmaceutical Ingredient (API) manufacturing. Because of this, one of the most important tasks of
any manufacturer is to identify impurities before they impact the quality, efficacy and safety of drugs, as well
as cause costly project delays.
Analyzing the levels of impurities and the physical, structural and behavioral attributes of these impurities in APIs helps to identify the potential cause of variations in the finished product during drug development and
formulation. It’s also useful in spotting potential problems when evaluating new suppliers, changing or
adding manufacturing sites, or scaling up production. Properly identifying impurities before making
potentially critical manufacturing decisions will more often than not save time and money further down the
line and help prevent API waste or prevent failure during clinical trials.
Impurities are chemical substances inside a confined amount of a sample which differ from the chemical
composition of the material or compound of interest. Impurities are either naturally occurring or formed
during the synthesis of a chemical compound. It is virtually impossible to have a molecular substance that is
100 percent pure and free of impurities. The goal for most manufacturers is to exceed the 99 percent range.
Impurities in raw materials
Since raw materials most often have some level of impurity, it’s important to properly vet suppliers to ensure
the highest levels of quality. Many manufacturers perform tests, in advance, on various raw materials to
determine this before they are purchased or before manufacturing begins. Samples can also be used to
perform the quality tests.
Impurities in Process Manufacturing
Another place where impurities can come from is in the process itself. Any impurities in the drug substance
will then be introduced into the drug product.
The origin of the compound may also determine which guidelines to follow in the final evaluation of the drug
impurity. Relevant guidelines include ICH Q3A (Impurities in New Drug Substances), ICH Q3B (Impurities in
New Drug Products), ICH Q3C (Impurities: Guideline for Residual Solvents), and ICH M7 (Assessment and
control of DNA reactive impurities in pharmaceuticals to limit potential carcinogenic risk).
According to ICH guidelines, if there are impurities in the range of .15 or higher, or compounds that are less
than 98 percent pure, the impurities have to be identified and evaluated for potential toxicity.
If the presence of a compound – at the detected concentrations – would pose an unacceptable risk to the
patient, or if it would seriously compromise the quality or efficacy of the drug product, it is clear that
necessary steps should be taken to reduce, or eliminate the presence of this impurity
In a lot of cases, however, the presence of the compound may not pose any safety, quality or efficacy issues
for the drug product. In that case, proper documentation of the impurity (its identity, concentration,
toxicological evaluation and quality impact) may be sufficient.
Identifying and eliminating as many impurities as possible is key to safe and successful product
commercialization. Properly vetting suppliers and conducting testing throughout process manufacturing can
identify impurity levels before they result in the loss of costly raw materials and the need to duplicate key