Discussion forum for Pharma Quality events, Regulatory Actions
Warning letters, 483s, Recalls, Import Alerts, Audit observations
Warning letters, 483s, Recalls, Import Alerts, Audit observations
Lupin recalled 3 batches of Desloratadine tablets in Dec 2023 for N-Nitroso Desloratadine impurity exceeding acceptable intake (AI) limit. Desloratadine is an antihistamine for treatment of allergies, such as sneezing, itching, and runny nose.
USFDA Enforcement Report – Lupin Desloratadine Recall
Lupin Desloratadine Recall Notice
Nitrosamine impurities has been a concern in different Pharma products ever since June/July 2018, when EMA started reviewing Valsartan medicines and FDA raised concerns about the impurities in distributed lots of Valsartan, over presence of N-nitrosodimethylamine (NDMA) impurity. Valsartan is a drug for treatment of high blood pressure and heart diseases. Nitrosamine impurities in Pharma products are a cause of concern as the Nitrosamine impurities could be carcinogenic and are considered to be members of the “Cohort-of Concern” as per the ICHM7 guideline and has to be controlled in drug products.
N-Nitroso Desloratadine impurity in Desloratadine, cause of the Lupin recall, is an NDSRI (Nitrosamine Drug Substance Related Impurity). NDSRIs are API-derived complex nitrosamines, due to nitrosation of the APIs (or nitrosation of impurities in the API). NDSRIs may be formed during manufacture of the API, manufacture and /or packing of formulation product, during storage of the API or formulation products. USFDA and EMA has published guidelines for controlling and reducing risk of NDSRIs in drug products. As is well known nitrosamine impurities are produced by a nitrosating reaction between amines (secondary, tertiary, or quaternary amines) and nitrous acid (nitrite salts under acidic conditions). One reason for formation of NDSRIs in drug products containing actives with a facilitating structure for formation of nitrosamines (vulnerable amine functional group) is presence of Nitrite impurities in excipients (inactive substances). Nitrous acid (HNO2) can be formed due to nitrites present in excipients which reacts with the amine functional groups in the active structure to form specific NDSRIs.
Desloratadine has a secondary amine functional group which is very vulnerable to formation of nitroso impurity Nitroso Desloratadine
Since 2018, there has been several hundreds of products recalls due to Nitrosamines impurities in US and other markets (sartans, antidiabetic drugs, antihistamines, and antibiotics – for example Valsartan, Ranitidine, Metformin and so on). However no incidents of recall of Desloratadine for Nitrosamine impurities seems to be reported so far. For Nitroso Desloratadine a limit of 400ng/day for acceptable intake (AI) is defined by both USFDA and EMA (USFDA (Updated Information: Recommended Acceptable Intake Limits for Nitrosamine Drug Substance-Related Impurities (NDSRIs)); EMA (Appendix 1: Acceptable intakes established for N-nitrosamines)
This recall of Desloratadine is as an alert for drug manufacturers that drug products with Nitrosamine vulnerable actives carry always a risk of Nitrosamine impurities and NDSRIs. Even if the amount of NDSRIs are below acceptable levels during batch release there is a risk of the NDSRI exceeding the limits during shelf life. For controlling the risk of nitrosamines and NDSRIs a robust risk assessment and control strategy should be implemented as emphasised in the USFDA and EMA guidance’s. The control strategies shall include a supplier qualification programme involving potential nitrite impurities across excipient suppliers and excipient lots. Nitrite scavengers – antioxidants such as ascorbic acid (vitamin C) or alpha-tocopherol are reported to inhibit formation of Nitrosamine related impurities. As formation of Nitrosamines occur under facilitating acidic conditions, excipients (like sodium carbonate) which can modify the microenvironment in a drug product to neutral or basic pH may also inhibit formation of NDSRIs. FDA encourages manufacturer’s to consider these as well as well as other innovative strategies to reduce the formation of NDSRIs to acceptable levels in drug products.
While nitrites in excipients is a major factor of risk for formation of nitrosamines in drug products containing actives with vulnerable amines, there has been limited information on nitrite levels across the wide spectrum of excipients used in Pharma Industry. However, there is a database of nitrite concentrations in common excipients maintained by Lhasa Limited. The platform hold data donated by pharmaceutical company members on nitrite concentrations measured with validated analytical procedures. The database shows there is a substantial differences in nitrite content in batches from different excipient vendors. This imply that selection of sources and batches of excipients with low nitrite levels will help reduce risk of nitrosamine formation where drug products contain vulnerable amines (Reference paper A Nitrite Excipient Database: A Useful Tool to Support N-Nitrosamine Risk Assessments for Drug Products, Ruth Boetze et.al, Journal of Pharmaceutical Sciences; Volume 112, Issue 6, June 2023, Pages 1615-1624). The database shows materials like Magnesium stearate (lubricant), Crospovidone (Disintegrant) typically have higher amount of nitrites (above 2 ppm, but generally less than 10ppm) while excipients like MCC (Microcrystalline cellulose, diluent), Lactose (Diluent), Hypermellose (stabiliser) have lower amount of nitrites in the range of 1-2ppm. However, for solid dosage forms nitrite contribution will be dominated by excipients used in higher proportion (diluents, fillers) than others like glidants and lubricants. Desloratadine tablets contain excipients anhydrous lactose, colloidal silicon dioxide, FD&C Blue#2/Indigo Carmine Aluminium Lake, hydrogenated vegetable oil, hypromellose, microcrystalline cellulose, polyethylene glycol, pregelatinised starch and titanium dioxide (Lupin Product label).
The above reference paper Ruth Boetze et.al also provides a useful formula for estimating conversion of nitrites into nitrosamines and thus Nitrite threshold (amount that may be allowed) for excipients from the Acceptable Intake for specific NDSRIs.
It will be prudent for manufacturers of drug products having actives (and/or impurities) with vulnerable amines, to test and control nitrites in excipients using analytical methods like Ion Chromatography with conductivity detection or Griess method (Liquid chromatography and UV detection) to control risk of formation of nitrosamines. Along with this an efficient supplier qualification and monitoring programme for selection of excipients and sources and further control strategies for altering the microenvironment in formulation product for inhibiting formation of nitrosamine products will help in reducing the overall risk of nitrosamines and NDSRIs in drug products.
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