Dear Partners,

Necessitated by the unprecedented situation created by Covid-19, several industry events and tradeshows across the world have been postponed or stand cancelled. While we were looking forward to meet you, we at Piramal Pharma Solutions have had to take several precautionary measures to protect both our employees and customers, worldwide.

As we move forward in these extraordinary times, we want to assure you that that we are operational by taking the right safety measures and abundant precautions to ensure that we continue to support you and your patients.

While all of us are working remotely for now, you can schedule a discussion with us and we would be glad to help ensure you meet your pharmaceutical development and supply needs and thereby, your clinical and commercial timelines.

Please feel free to reach out to us at:

Our best wishes to colleagues, friends and family.

Best Regards,
Piramal Pharma Solutions

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The concept of Genotoxic Impurities (GI) and Potential Genotoxic Impurities (PGI) is defined in the ICH M7 (2014) and EMA (2006) guidelines. The focus of these guidelines are on DNA reactive substances – those when present at low levels have a potential to directly cause DNA damage and lead to mutations, thereby potentially causing cancer. For late stage compounds and marketed products, acceptable increased cancer risk is set at a theoretically calculated Threshold of Toxicological concern (TTC) level of 1.5 mg/day.

Genotoxic impurities are classified into two types; Actual and Potential. Actual impurities are formed during i) manufacturing ii) long time storage iii) reaction with primary and secondary packaging iv)degradation and v) stress studies. The actual impurities include those observed in the drug substance above the ICH Q3A reporting thresholds and are required to be identified.

Potential impurities in the drug substance can also include those present in starting materials, reagents, by-products and intermediates in the route of synthesis and impurities formed during long term storage conditions.

As stated in Q3A guideline, these impurities should be identified, based on

Impurities are expected to be identified based on knowledge of chemical reactions and conditions involved. Potential genotoxic impurities should be identified guided by existing genotoxicity data or structural alerts. When a potential impurity contains structural alerts, additional genotoxicity testing typically a bacterial reverse mutation assay should be considered and the approval limit (TTC) defined. Studies using isolated impurities are much more appropriate for this purpose and highly recommended.

It is difficult to define a safe exposure level (zero risk concept) for genotoxic carcinogens without a threshold. Moreover, complete elimination of genotoxic impurities from drug substances is often unachievable. Hence, it becomes necessary to implement  a concept of an acceptable risk level, i.e. an estimate of daily human exposure at and below which there is a negligible risk to human health. To determine the limits, possible mechanism of action and dose-response relationship is considered.

Table: Acceptable intakes of mutagenic impurities

Duration of treatment ≤1 month >1-12 months >1-10 months >10 years to lifetime
Daily intake (mg/day) for individual impurity 120 20 10 1.5
Total daily intake (mg/day) for multiple impurities 120 60 30 5

The concept of Threshold of Toxicological Concern (TTC) was developed to define an acceptable intake for any unstudied chemical that poses a negligible risk of carcinogenicity or other toxic effects. For application of a TTC in the assessment of acceptable limits of mutagenic impurities in drug substances and drug products, a value of 1.5 μg/day can be justified based on the lifetime exposure calculation.

Structure-based assessments are useful for predicting bacterial mutagenicity outcomes based upon the established knowledge. There are a variety of QSAR approaches to conduct this evaluation including a review of the available literature, and/or computational toxicology assessment.

Some structural groups were identified to be of such high potency that intakes even below TTC would theoretically be associated with potential carcinogenic risk. This group of high potency mutagenic carcinogens are referred to as the “cohort of concern”, and comprise of aflatoxin-like-, N-nitroso-, and alkyl-azoxy compounds. These functional groups are either avoided or require strict controls.

Control strategy

What we do at Piramal?

Decision tree for Assessment of Acceptability of Genotoxic impurities


Posted in Newsletters on Aug 02, 2016