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API Manufacture: Identifying & Controlling Genotoxic Impurities

Since API manufacturing plays a critical role during clinical development and after approval of a drug, familiarity with genotoxic impurities is an important issue for pharmaceutical firms considering outsourced API manufacturing. Understanding how an API producer – or your own firm’s manufacturing and QA people – identify and resolve genotoxic impurities is critical knowledge for virtually all pharmaceutical execs.

Genotoxic Impurities in Small Molecule Development Programs – A Real Risk
Awareness of the potential for genotoxic impurities (GTIs) during the manufacture of APIs has led to strategies for managing the risks of contamination. We recently took part in hosting a webinar (thanks to everyone who attended) on API Development: Risk Evaluation and Control of Genotoxic Impurities in which we explored the risks of genotoxic impurities in small-molecule API development, today’s regulatory landscape and various approaches to managing GTIs.

If you are not directly involved in the identification and minimization of GTIs, it’s still an important issue. The presence of genotoxic impurities is indicative of contamination and lack of control over the manufacturing process – and, yes, sometimes GTIs are unavoidable. More importantly, they present a potentially serious risk to human health.

The Types and Risks of Genotoxic Impurities
There are three types of genotoxic impurities: mutagens, clastogens and carcinogens. These impurities can also be more than one type; for example, a mutagen can change DNA which leads to cancer – making it a carcinogen as well.

Here’s a short description of types of genotoxic impurities and how they can negatively impact human health:

  • Mutagen
    Mutagens are agents that change a person’s genetic material, typically the DNA. THE RISK: this leads to above-normal levels of mutations, which can cause cancer. Mutagens can cause gene defects as well as changes to the structure & function of proteins in the body, leading to a wide range of diseases and conditions.
  • Clastogen
    Clastogens can cause sections of chromosomes to be added, deleted or rearranged by breaking the chromosome. THE RISK: cells that aren’t killed during this process can become cancerous. They have also been reported to have an effect on fetal development. As with mutagens, clastogens can be lethal or cause serious disease.
  • Carcinogen
    Carcinogens are cancer-causing agents that damage the genome or disrupt cellular processes.

Preventing Genotoxic Impurities
The identification of genotoxic impurities requires a strong, focused analytical chemistry program. Analytical development scientists, in particular, should possess an in-depth understanding of degradation chemistry. Analytical chemists should work closely with the teams developing or manufacturing the API to identify, eliminate or minimize impurities.

Here are two common questions we encounter regarding the risks of GTIs during API manufacture:

  1. Can genotoxic impurities be avoided?
    The fact of the matter is GTIs often are avoidable. It might something as simple as a reagent change, altering the synthetic route, or a purification route change to minimize the formation of the impurity. But not all genotoxic impurities can be completely eliminated.
  2. Impurities are sometimes unavoidable. What can we do to minimize the risk?
    Inevitably, there will be genotoxic impurities that can only be controlled – not eliminated – and the focus shifts towards maximizing the removal of the relevant impurity to comply with the practical impurity limits currently being established by various regulatory bodies. There are steps firms can take to control genotoxic impurities during manufacture, including: adjusting environmental controls, altering purge strategies, using preservatives and others.

During the manufacture of an API – especially at clinical development levels – genotoxic impurities present a very real risk of product contamination. Does your API manufacturing partner have strong analytical development scientists focused on the hazards posed by genotoxic impurities?


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