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Updated on February 16, 2026

Unichem Pharmaceuticals (USA), Inc. initiated a recall of Bisoprolol fumarate and Hydrochlorothiazide tablets in the US in January 2026 due to the presence of N-nitroso-bisoprolol, a nitrosamine impurity exceeding acceptable limits. The affected product, a 2.5 mg/6.25 mg combination tablet used to treat hypertension, was manufactured by Unichem Laboratories Ltd in Goa, India.

First reported Recall for NDSRI, N-nitroso-bisoprolol

This is the first reported recall of a bisoprolol fumarate product for nitrosamine drug substance-related impurity (NDSRI), N-nitroso-bisoprolol. As per the USFDA predicted CPCA (Carcinogenic Potency Categorization Approach), the impurity N-nitroso-bisoprolol has a maximum acceptable daily intake of 1,500 ng/day and is classified as Potency Category 4.

Why Bisoprolol is Vulnerable to Nitrosamine Formation

The bisoprolol fumarate molecule contains a secondary amine functional group that is susceptible to forming NDSRI impurities when exposed to nitrosating agents. This nitrosation can occur during API synthesis or during drug product manufacturing and storage, particularly in the presence of nitrosating groups from excipients or other sources.

Synthesis Pathway of Bisoprolol

The typical synthetic route for bisoprolol does not involve nitrosating agents. The standard pathway involves three key steps:

  1. Etherification: A phenol derivative (4-hydroxybenzyl alcohol) is reacted with 2-isopropoxyethanol to form an ether intermediate, 4-[(2-isopropoxyethoxy)methyl]phenol
  2. Epoxidation: The ether intermediate is reacted with epichlorohydrin to get the intermediate 2-[[4-(2-isopropoxyethoxy)methyl]phenoxymethyl]oxirane
  3. Aminolysis: The epoxide ring is opened using isopropylamine to produce bisoprolol free base, which is then reacted with fumaric acid to yield bisoprolol fumarate

Given the synthesis pathway, the source of the NDSRI, N-nitroso-bisoprolol is more likely to be post-synthesis rather than from API manufacturing.

Role of Excipients in Nitrosamine Formation

Common pharmaceutical excipients can be a significant cause of nitrosamine formation in drug products having actives with amine functional groups. Excipients such as Microcrystalline cellulose (MCC) and Crospovidone can contain trace amounts of nitrites. Under acidic conditions or elevated temperatures during manufacturing or storage, these nitrites can undergo nitrosation reactions with the secondary amine group in bisoprolol to form N-nitroso-bisoprolol. Nitrites from fillers like MCC can be particularly problematic because these excipients typically constitute a large percentage of the tablet’s weight, potentially providing a substantial reservoir of nitrosating species.

Risk Assessment & Mitigation strategies:

With increasingly stringent regulatory requirements to control nitrosamines in pharmaceutical products, NDSRI risk assessment and control have become critical elements of drug product quality systems. Proactive risk assessment and implementation of appropriate control strategies are essential for ensuring product quality and patient safety particularly for drugs containing secondary amine functional groups.

  • Nitrosamine risk assessment covering APIs, excipients, process water, and packaging materials
  • Regular testing of finished products for NDSRI impurities as per risk assessment
  • Testing and control of input materials for nitrosamines, nitrites, amines as per risk assessment outcome
  • Selecting low-nitrite grades of excipients in products having a nitrosamine impurity risk
  • Stability studies to monitor nitrosamines and NDSRIs over the shelf life of drug product, materials
  • Ensuring appropriate storage conditions to minimize nitrosamine formation
  • Incorporating nitrite scavengers or antioxidants in formulations
  • Controlling pH and temperature during manufacturing to minimize exposure to nitrosating conditions

Systematic nitrosamine risk assessment of APIs, excipients, process water, packaging materials and the drug product for nitrosamine risk is a key element of the nitrosamine risk mitigation strategy. (refer Qvents Nitrosamine Risk Assessment Tools and templates for Nitrosamine Risk Assessment and Supplier Evaluation). Reference databases like the Lhasa Nitrite Database helps to select excipient sources with low nitrosating potential / lower nitrite levels.

References:
  1. USFDA Enforcement Report – Unichem Recall of Bisoprolol fumarate and Hydrochlorothiazide tablets (January 2026)
  2. Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities: USFDA Guidance document
  3. Risk of Nitrosamines, NDSRIs, Nitrosamine Vulnerable Actives – How Lhasa’s Nitrite Excipient Database Can Help
  4. Nitrosamine Impurities in Pharmaceutical Products: Templates for Risk Assessment and Supplier Evaluation (Qvents)
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