The discovery of Nitrosamine Drug Substance-Related Impurities (NDSRIs) in pharmaceuticals has sent ripples through the industry, prompting stringent regulatory actions and a reevaluation of manufacturing processes. These impurities, tied directly to the chemical structure of active pharmaceutical ingredients (APIs), pose a unique challenge due to their potential carcinogenicity. Guided by frameworks like USP <1469> and the European Medicines Agency (EMA), the pharmaceutical sector is tackling NDSRIs with advanced analytics, risk assessments, and mitigation strategies. This article dives deep into the chemistry of NDSRIs, their sources, regulatory controls, and real-world examples involving drugs like valsartan, ranitidine, metformin, losartan, and nizatidine.
Common NDSRIs include:
NDSRIs form through a nitrosation reaction, where a nitrosating agent (e.g., nitrous acid, NO⁺) reacts with a secondary or tertiary amine in the API. The general reaction is:
R₂NH + NO⁺ → R₂N-NO + H⁺ (Secondary amine forming a stable nitrosamine)
Secondary Amines: These are highly reactive, forming stable nitrosamines like NDMA or NDEA. For example, ranitidine’s dimethylamino group can react with nitrites to form NDMA.
Tertiary Amines: These may degrade into secondary amines under certain conditions (e.g., heat, acidic pH), indirectly forming nitrosamines. For instance, an API intermediate containing triethylamine may break down to diethylamine, leading to NDEA.
Conditions favoring nitrosation include low pH (3–5), the presence of nitrites/nitrates, and mild temperatures, as noted in USP <1469>.
NDSRIs are classified as probable or possible human carcinogens by the International Agency for Research on Cancer (IARC), based on animal studies linking them to liver, kidney, and stomach cancers. Their concerns include:
NDSRIs originate from API-related factors, as detailed in USP <1469> and EMA guidelines:
| Source | Description | Example |
|---|---|---|
| API Structure | APIs with secondary/tertiary amines (e.g., piperidine, morpholine) react with nitrosating agents. | Ranitidine’s dimethylamino group forms NDMA. |
| Degradation Products | API degradation during storage or processing releases amines that form NDSRIs. | Nizatidine degrades to NDMA under heat. |
| Manufacturing | Nitrite-containing reagents or contaminated intermediates introduce nitrosating agents. | Valsartan synthesis using contaminated solvents. |
| Packaging | Nitrocellulose-based coatings or rubber stoppers release nitrosating compounds. | Metformin’s NDMA linked to packaging leachables. |
NDSRIs have been detected in several widely used drugs, leading to recalls and reformulations. Below are detailed case studies:
Issue: In 2018, NDMA and NDEA were detected in valsartan batches due to a change in synthesis using a solvent (dimethylformamide, DMF) contaminated with dimethylamine.
The API’s tetrazole ring formation involved sodium nitrite, enabling nitrosation.
Impact: Global recalls were issued, affecting millions of patients. The EMA estimated NDMA levels in some batches exceeded 0.3 ppm, above the acceptable limit.
Action: Manufacturers revised synthesis processes, eliminating nitrite-containing reagents.
Issue: Ranitidine’s API contains a dimethylamino group, which can self-degrade to form NDMA, especially under heat or acidic conditions. Levels as high as 0.5 ppm were detected.
Impact: The FDA and EMA recalled ranitidine in 2019–2020, citing unacceptable NDMA levels.
Action: Many manufacturers discontinued ranitidine, replacing it with alternatives like famotidine.
Issue: NDMA was found in metformin due to nitrite contamination in excipients and packaging leachables. Levels were typically low (e.g., 0.02–0.05 ppm) but concerning for chronic use.
Impact: Limited recalls occurred, with the EMA requiring enhanced testing.
Action: Manufacturers implemented stricter excipient screening and packaging controls.
Issue: NMBA was detected in losartan due to a byproduct of butyric acid derivatives in synthesis. Levels reached 0.9 ppm in some batches.
Impact: Recalls were issued in 2019, as NMBA exceeded the EMA’s interim limit of 0.96 ppm.
Action: Process optimization eliminated the problematic intermediate.
Issue: Similar to ranitidine, nizatidine’s API contains a secondary amine, leading to NDMA formation during storage, particularly under high humidity.
Impact: Recalls were issued in 2020 after NDMA levels exceeded 0.3 ppm.
Action: Stability studies were enhanced, and storage conditions were tightened.
Regulatory bodies provide robust frameworks to manage NDSRIs, ensuring patient safety.
USP General Chapter <1469> outlines a comprehensive approach to nitrosamine control, including NDSRIs:
The EMA’s “Questions and Answers on Nitrosamine Impurities” mandates a three-step process:
The EMA sets AI limits, such as 96 ng/day for NDMA and 26.5 ng/day for NDEA, with case-by-case limits for novel NDSRIs.
Calculating acceptable NDSRI levels involves the Acceptable Intake (AI) and Maximum Daily Dose (MDD), as per USP <1469> and EMA:
Acceptable Concentration (ng/g) = AI (ng/day) ÷ MDD (g/day)
Example Calculations:
For multiple NDSRIs, the EMA’s “Sum of Ratios” approach (per ICH M7) ensures combined risk is acceptable:
Sum of (Ci / AIi) ≤ 1, where Ci is the concentration of NDSRI i, and AIi is its acceptable intake.
Detecting NDSRIs requires high-sensitivity methods, as outlined in USP <1469>:
Example Workflow:
Both USP <1469> and EMA recommend proactive mitigation strategies:
For the industry, NDSRIs have driven significant changes:
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