­FDA Guidelines on Genotoxic Impurities

Since the FDA issued the ICH M7 (R1) guideline in March of 2018, expectations around the assessment and control of DNA reactive impurities (Genotoxic impurities, GTIs) in clinical development have become explicit. J-STAR works with our clients to implement risk-based clinical development chemistry strategies, which are both phase-appropriate and cost-efficient to prioritize analytical efforts on those impurities with the highest likelihood of being present in the drug substance or product.

Genotoxic impurities (GTIs) can be generated from the use of reactive chemicals, reagents, solvents, catalysts, and other processing aids, side reactions during the synthesis, or even degradants, and have the potential to adversely react with human DNA.

As such, a detailed understanding of the chemical process, coupled with a GTI risk-based control strategy, is an important component of a drug development strategy. If possible, consideration should be given to obviating the use and creation of genotoxic impurities. While this is not always possible, the development of a GTI control strategy is indicated if GTIs are introduced or created during the synthesis of the API.

J-Star’s Criterion for GTI Issues in the Synthetic Route

J-Star’s analytical team is well-versed in partnering with clients to understand and address relevant GTI concerns within a synthetic route. Based on a client’s risk-based assessment of the effort needed to support GTI-related work in a phase appropriate fashion, J-Star is positioned to support any outcome. Attributes that are part of this decision-making process include, but are not limited to, the:

  1. nature of the program and therapeutic area
  2. projected human dose
  3. stage of the program’s development within the asset maturation lifecycle
  4. nature of the GTI
  5. chemical step in which the GTI compounds are used or have the potential to form
  6. in silico predictions and/or AMES testing results
  7. ability to detect the GTI
  8. ability to purge the GTI


Route Modulation and Risk-Based Analysis

J-Star Process chemists have the ability to modulate the synthetic route or chemical reagents used so that GTIs are obviated. In some cases, this may not be possible - while in other cases this approach may not be warranted due to the phase of the program, budgetary considerations or outcome of a risked-based analysis – all of which are performed by the client.

GTI Monitoring and Purging

If the decision is made to focus on monitoring and purging a GTI (or GTIs), the ability to detect the compound of interest becomes the paramount objective. This work may require analytical methods that have the ability to detect GTIs to < 10 ppm.

J-Star has significant experience in this area. J-Star Analytical and Quality Control Chemists routinely develop quantitative methods using LCMS or GCMS, but other techniques may be considered. Subsequent to method development and optimization, J-Star will validate the method to support release testing of a cGMP API.

Quantitative GTI Method Development and Validation

The Analytical Development / Quality Control group at J-Star can perform quantitative GTI method development and validation work to support analyses in both drug substance (DS) and drug product (DP) samples.