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Warning letters, 483s, Recalls, Import Alerts, Audit observations
Warning letters, 483s, Recalls, Import Alerts, Audit observations
Glenmark Pharmaceuticals is recalling several lots of the cardiovascular drug Carvedilol in US due to the presence of the NDSRI impurity N-Nitroso Carvedilol above the acceptable intake (AI) limit. This is the first incidence of a recall of Carvedilol for an NDSRI impurity. The impurity N-Nitroso Carvedilol has a limit of 400 ng/day as per the FDA’s CDER Nitrosamine Impurity Acceptable Intake Limits. It is a Category 3 NDSRI based on the Predicted Carcinogenic Potency Categorization (CPCP) approach.
Carvedilol is indicated for the treatment of heart failure, hypertension, and heart attack. Carvedilol by SmithKline Beecham (later GSK) was initially approved in the US in 1995 and now has several approved generics, including those from Mylan, Teva, Aurobindo, Lupin, and Dr. Reddy’s, among others.
NDSRIs (Nitrosamine Drug Substance Related Impurities) are a class of impurities identified as cohorts of concern due to their potential carcinogenicity. NDSRI impurities are formed by drug molecules having an amine functional group (typically secondary amines) in the presence of nitrite impurities. NDSRIs may be formed during the manufacture of the API, the manufacture and/or packaging of the formulation product, or during storage. In drug products, NDSRIs may be formed due to the presence of nitrite impurities in excipients. Nitrous acid (HNO2) can be formed due to nitrites present in excipients, which reacts with the amine functional groups in the active moiety to form specific NDSRIs. The USFDA and EMA have published guidelines for controlling and reducing the risk of NDSRIs in drug products.
NDSRI Impurity N-Nitroso Carvedilol in Carvedilol
The general route of synthesis for Carvedilol involves the condensation of Hydroxy Carbazole with Epichlorohydrin in the presence of a base like Sodium Hydroxide. The resulting Epoxypropoxycarbazole is further reacted with Methoxyphenoxyethanamine to get Carvedilol. As can be seen, there are no nitrosating groups involved in the route of synthesis of Carvedilol. Hence, it is very unlikely that N-Nitroso Carvedilol is an impurity carried over from the API
However, many drug products with vulnerable active ingredients with secondary amine functional groups can form Nitrosamine impurities due to nitrosating agents from excipients or other process ingredients. Excipients like Lactose Monohydrate and Crospovidone used in drug formulations can contribute to nitrite impurities. An IPEC report, The Role of Excipients in Determining N-Nitrosamine Risks for Drug Products, cites that nitrites were measured in samples of excipients like microcrystalline cellulose (MCC), lactose, pregelatinised starch, povidone, crospovidone, sodium starch glycolate (SSG), sodium croscarmellose, stearic acid, hydroxypropyl cellulose (HPC), and silicon dioxide, from 0.9 ppm to a high of up to 286 ppm. Another report by Lhasa points out that nitrite levels can vary batch-to-batch and manufacturer-to-manufacturer. Hence, it is critical to have a robust supplier qualification program and control strategy for excipients, especially for APIs vulnerable to NDSRI formation.
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