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Updated on November 15, 2024

In October 2024, Accord Healthcare recalled over 25 lots of Cinacalcet tablets in various strengths (30 mg, 60 mg, and 90 mg) due to levels of the Nitrosamine Drug Substance-Related Impurity (NDSRI), N-nitroso-cinacalcet, exceeding the Acceptable Daily Intake (ADI) limits. These Cinacalcet tablets, manufactured by Intas Pharmaceuticals in India, were found to contain this NDSRI at levels that surpassed regulatory thresholds. According to the U.S. FDA’s Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities, N-nitroso-cinacalcet is categorized as a potency Category 3 impurity, with an ADI of 400 ng/day.

Cinacalcet, a calcimimetic agent, is indicated for treating secondary hyperparathyroidism (HPT) and parathyroid carcinoma. Originally approved by the FDA and EMA in 2004 under an NDA by Amgen, Cinacalcet now has multiple generic versions available in the U.S. market, including products from manufacturers such as Intas (Accord), Aurobindo, Cipla, Lupin, Strides, Sun Pharma, and Alkem.

Nitrosamine Impurity (NDSRI) in Cinacalcet 

Cinacalcet is a secondary amine drug substance with an R-NH group susceptible to generation of N-Nitroso impurity under facilitating conditions in presence of nitrite or nitrate salts and an acidic environment.

In October 2024, Dr. Reddy’s Laboratories also recalled over 300,000 bottles of Cinacalcet tablets across various strengths due to the detection of N-nitroso-cinacalcet.

The synthesis of Cinacalcet generally involves the reaction of a trifluoromethylphenyl derivative with a naphthylethylamine core, typically via:

  1. Reductive Amination: The naphthylethylamine group is coupled with the aldehyde intermediate. The aldehyde and amine form an imine intermediate, which is subsequently reduced to produce a stable secondary amine.
  2. Amide Coupling: The naphthylethylamine reacts with an acid or ester intermediate, wherein the carboxylic acid is first activated (e.g., as an acid chloride) to facilitate coupling.

(Trifluoromethylphenyl derivatives as precursors for Cinacalcet:  – Trifluoromethylphenyl cinnamaldehyde or propionaldehyde, Trifluoromethylphenyl propionic acid,  Trifluoromethylphenyl ester etc.)

These synthetic routes for Cinacalcet typically do not involve nitrites or nitrates, which are the primary sources of nitrosating agents necessary for nitrosamine formation. Therefore, the standard chemical synthesis of Cinacalcet itself does not inherently present a risk for direct formation of N-nitroso-cinacalcet.

However nitrosamine impurities in Cinacalcet could be generated through indirect sources or contaminants, such as:

  1. Nitrites/Nitrates:  From excipients used in the drug product or from starting materials or reagents used in the manufacture of drug substance
  2. Traces of Nitrates/Nitrites in Process Water: Both in the drug product manufacturing and drug substance manufacturing, though generally low risk.
  3. Recovered Solvents with Residual Nitrosating Agents: In the drug substance manufacturing
  4. Cross-Contamination in Shared Equipment: Shared equipment in both drug substance and drug product manufacturing could retain residues from other products containing nitrosating agents or amines.
  5. Degradation Pathways: Nitrosamine impurity could form during extended storage under specific conditions, even if they aren’t produced directly during synthesis. Factors, like high humidity or acidic conditions during storage, could facilitate nitrosation reactions if trace nitrosating agents are present.
 

Potency Category and Acceptable Intake for N-Nitroso-Cinacalcet

The USFDA-CDER recommended  Acceptable Intake (AI) Limits for N-Nitrosocinacalcet is 400ng/ day as per the Predicted Carcinogenic Potency Categorization (PCPC) approach. N-nitroso-cinacalcet has a potency score of 3, based on the structural features surrounding the N-nitroso group. It has three alpha-hydrogens (1,2), providing it with an α-hydrogen score of 3, alongside a deactivating chain of ≥5 consecutive non-hydrogen atoms on both sides of the acyclic N-nitroso group (score +1) and an activating aryl group bonded to the α-carbon (score -1). This results in a total potency score of 3, correlating to an AI of 400 ng/day.

Control Strategy for Nitrosamines and NDSRIs – Risk Analysis and Risk Mitigation

Drug products with Nitrosamine vulnerable actives like Cinacalcet always carry always a risk of Nitrosamine impurities and NDSRIs. A robust risk assessment must be performed for mitigation of the risk of nitrosamines and NDSRIs in drug products as emphasized in USFDA and EMA guidelines.

  • Risk assessment covering all excipients used in drug product manufacture, starting materials, intermediates, catalysts and reagents in drug substance
  • Supplier qualification programme to assess the excipients, starting materials, intermediates etc. for the potential for nitrosamine impurity precursors like nitrosating groups and amines. Onsite vendor audits must be performed where the risk is significant.
  • Recovered Solvents: Assessing the possibility of nitrosating group carryover in recovered solvents, both from the manufacturer’s facility and any third-party facilities involved.
  • Risk from process water need to be assessed, though generally the risk is low when purified water is used in manufacture of drug products.
  • Shared equipment in the manufacture of drug products, drug substance and drug intermediates is another key risk factor to be considered. Other products or intermediates themselves may not have a risk of nitrosamines if facilitating conditions like nitrosating reagents, amines and conducive conditions for formation of nitrosamines are absent. However they could leave residues of nitrites / nitrates in traces in shared equipment which can cause nitrosamines formation in vulnerable molecules like Cinacalcet.
  • Shelf-Life Stability : Even if initial levels are within acceptable limits there is a risk of the NDSRI being formed and exceeding the limits during shelf life, and this risk should be evaluated in the risk assessment.

A robust risk assessment and well defined control strategies is a must to mitigate risk of Nitrosamines and NDSRI impurities in drug products especially for those containing structures vulnerable to nitrosamine formation.

References:

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