Genotoxic Impurities in Pharmaceutical Products

What is an impurity?

Impurity is anything which restricts the effectiveness of something. Impurities can occur in natural way or added during the process. There are certain impurities which can be destructive in nature i.e.; they may alter the normal working of materials. For instance the ash and debris from the iron ore may get into the actual metal and make it brittle. Therefore these are substances with no positive impact and rather happen to be harmful if not eliminated.

Pharmaceutical impurities

Similarly in the making of pharmaceutical products there are some impurities which have no role in therapeutic outcome rather bring along potential adverse effects. Therefore there is a need to control these kinds of impurities in order to make the pharmaceutical products safe and rational for human use.

Sources of pharmaceutical impurities and their types

There are many sources of impurities in the process of drug manufacturing which include initial materials, reagents, catalysts, solvents, contaminants and few others. Basically the impurities in the medicinal products are classified into two broad categories namely organic impurities and the inorganic ones.

Genotoxic impurities and their carcinogenic effect

In recent years a third category of impurities came into light known as genotoxic impurities, which can potentially cause damage at the genetic level as the name itself indicates. The synthesis of medicinal products requires certain reactive compounds which possess the capacity to alter the DNA and cause mutations which in turn lead to carcinogenicity or simply cancer. These materials are so potent that they can cause extreme damage reportedly at lowest levels.

Examples of genotoxic impurities and their mechanism of action

There are many substances with genotoxic properties like halogens, heavy metals etc. For example a metal called chromium is used in production of gelatin capsules and many other multimineral supplements, this chromium has a transition property which causes a change in the DNA sequence of the target cell thereby causing damage to the DNA which leads to carcinogenic outcomes.

A herbal plant called the COMFREY, which is used for healing wounds and preventing scars exhibited genotoxic effects. The oils obtained from the comfrey plant contained pyrrolizidine alkaloids (PA) which were found to be mutagenic and thus caused cancer. These genotoxins induced varied medical disorders namely the comfrey-induced toxicity along with mutagenesis in the liver cells.

How to determine or test the genotoxic impurities

The increased concern by different researchers gave birth to the question that how can we determine the level of genotoxins. Thus a method was proposed called the genotoxic testing to counter this global issue. In this testing different organisms were exposed to genotoxins and the resultant mutagenic effect was observed.

There are many techniques used in the genotoxic testing. The most widely used are

  • Bacterial reverse mutation assay or Ames assay.
  • In vitro toxicology testing
  • In vivo toxicology testing
  • Comet assays

Regulations and guidelines to limit the genotoxic impurities in pharmaceutical products

At this point there is a need that these genotoxic impurities should be avoided, and if not possible, at the least controlled to the safe level. Many organizations from industry and many regulatory authorities have come up with guidelines with special emphasis on genotoxic impurities.

PhRMA initiative by Muller et al.

The first and foremost approach was made by the Pharmaceutical research and manufacturing association (PhRMA) which came up with some important concepts like

  • Five impurity classification.
  • Staged impurity threshold for short term exposure.

The five impurity classification had the genotoxic impurities classified into 5 classes

Class 1 included impurities with known genotoxicity and carcinogenicity as well.

Class 2 impurities were known to be genotoxic but their carcinogenicity was not confirmed.

Class 3 consisted of impurities with chemical structure unrelated to that of the active drug and  had unknown genotoxic property.

Class 4  impurities had similar structure with the active drug.

Class 5 included impurities with no structural relationship and neither genotoxic potential.

The European medicines agency’s concern

Similarly the European medicines agency / EMA also drafted guidelines in recognition for genotoxic impurities. Thus in the year 2006 The European medicines agency established a committee for medicinal products for human use (CHMP) which drafted guidelines on the limits of genotoxic impurities. The proposed guidelines stated that

  • genotoxins are considered unsafe at any level
  • The limit of genotoxins with known toxicity must to be calculated by determining the (PDE) permitted daily exposure.
  • The limit for genotoxins of unknown toxicity must be determined based on the (TTC)threshold of toxicological concern which is around 1ug/day.

The FDA steps for minimal risk

The FDA in the year 2008 drafted a guideline for the pharmaceutical industry named “genotoxic and carcinogenic impurities in drug substances and products”, these guidelines were similar to those of EMA.

  • Step1 was to change in the process of synthesis or purification for minimal formation and maximal removal of impurities
  • Step 2 set a maximum daily exposure of impurity at 1.5ug per day
  • Step3 advised for advanced characterization of genotoxic and carcinogenic properties.

The ICH initiative

The international conference for harmonization (ICH) had previously come up with guidelines on impurities in medicinal products namely

  • ICH Q3A guideline which dealt with impurities in new drug substances with threshold for reporting, identification.
  • ICH Q3B was a guideline equivalent for impurities in new drugs.
  • ICH Q3C controlled the residual solvent limits used.

A recent advancement in the above guidelines is the ICH Q3D which deals with the limits for heavy metal impurities. 

Philosophical words

We humans want everything to be pure and effective, thus we put on several filters in any selection criteria. Starting from our childhood goodies to selecting a college for graduation, majority of our aspects in life demand purity and effectiveness. When there is need for purity, there also lays responsibility to identify the impurities and implementation of required measures to eliminate them. Hope we all eliminate our impurities by setting up filters of hard work, honesty, empathy and many more.

Abbreviations should be read as

DNA as deoxyribose nucleic acid

PA as pyrrolizidine alkaloids

PhRMA as Pharmaceutical research and manufacturing association

EMA as European medicines agency

CHMP as committee for medicinal products or human use

PDE as permitted daily exposure

TTC as threshold of toxicological concern

FDA as food and drug administration

ICH as international conference for harmonisation.


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