(T1130-09-59) Controlling Nitrite Pathways in Drug Manufacturing to Prevent Nitrosamine Impurities: An Active Packaging-Based Approach

Purpose: Nitrite contamination in pharmaceutical excipients and active pharmaceutical ingredients (APIs) has become a significant concern due to its role in the formation of N-nitrosamines compounds, which are classified as probable human carcinogens by the International Agency for Research on Cancer (IARC).¹ These impurities can form when nitrites react with secondary or tertiary amines present in drug formulations, especially under acidic or high-temperature conditions. Notable cases include the detection of N-nitrosamines in widely used medications, leading to global recalls and heightened regulatory scrutiny.² Nitrites can originate from raw materials or manufacturing processes such as spray drying used in excipient production.² Their presence, even in trace amounts, can initiate nitrosation reactions during storage, posing long-term health risks including mutagenicity and carcinogenicity. This leaves a silent threat unaddressed in many drug products. To address this, active packaging solutions incorporating N-Sorb material science technology have been developed as a non-invasive mitigation strategy. These packaging solutions are able to actively scavenge nitrosating agents from the packaging headspace to inhibit nitrosamine formation.

Methods: Different raw active materials (A: oxygen scavenger, B: antioxidant, E: ionic compound, F: Alkaline buffer) that can mitigate nitrosating agents with different mechanisms of action were engineered for inclusion into a polymer matrix (Activ-Polymer™ technology) to form N-Sorb films, which mitigates N-nitrosamine formation by scavenging or neutralizing nitrosating agents. Figure 1 illustrates Activ-Polymer technology, which employs active materials as fillers in composite materials to improve their physical and/or adsorption/absorption properties. Nitrites are major reactive impurities found in Microcrystalline Cellulose (MCC). MCC placebo tablets (66 wt.% of MCC, 33 wt.% of lactose, 1% wt.% of magnesium stearate) were put in contact with N-Sorb film (1 x 2 inches) in aluminum foil bags (2 x 3 inches). These foil bags were then sealed and maintained in an oven at 25°C. Control samples consisted of MCC tablets alone (without N-Sorb film) in aluminum foil bags. Samples were then tested via Greiss reaction on HPLC-UV/VIS, LOQ = 0.1 ppm at different times to determine the remaining nitrite content in the MCC tablets (see Figure 2). Ranitidine capsules were produced in house (41.73 wt.% of MCC, 41.72 wt.% of monohydrate lactose, 10 wt.% of ranitidine hydrochloride, 5 wt.% of sodium starch glycolate, 1% wt.% of magnesium stearate, 0.5 wt.% of silicon dioxide, 0.05 wt. % of sodium nitrite). Each capsule was then placed in a blister cavity. The blister pack was immediately sealed with the lidding foil containing the heat staked N-Sorb film. Control samples consisted of ranitidine capsules placed alone (without N-Sorb film) in blister packs. The blister packs were then placed in a climatic chamber at 40°C and 75% RH. Samples were then analyzed by LC-QTOF, LOQ=0.25 ppm at different times to determine the NDMA concentration in the capsules (see Figure 3).

Results: At 25°C, all three versions of N-Sorb mitigation films exposed to MCC tablets in sealed foil bags during 26 weeks of aging period reduced the average levels of nitrite present in the samples compared to the controls (see Figure 2). After 1 week of aging at 25°C in the oven, the samples containing the MCC tablets that were exposed to N-Sorb B during aging resulted in the lowest level of nitrite concentration remaining in the sample (about 53% nitrite reduction). After 26 weeks of exposure, MCC tablets in contact with N-Sorb B showed the lowest nitrite content (0.297±0.012 ppm) with a 78% nitrite reduction in comparison to MCC control samples. Figure 3 shows that N-Sorb B and F films hindered NDMA growth after 6 months. N-Sorb B showed the best results with a lower generation of NDMA with a 22% reduction in comparison to the control. The same trend was observed at 30°C and 65% RH (result not shown here).

Conclusion: These innovations represent a proactive step toward ensuring pharmaceutical safety and compliance with evolving regulatory standards from agencies such as the FDA and EMA. This technology has the potential to effectively mitigate nitrosamine risk without the need for reformulation, delivering an expedient solution for meeting regulatory guidelines.

References: 1- Li K, et al. Estimated Cancer Risks Associated with Nitrosamine Contamination in Commonly Used Medications. IJERPH. 2021, 18(18):9465.
2- Schlingemann J, et al. The Landscape of Potential Small and Drug Substance Related Nitrosamines in Pharmaceuticals. J. of Pharma. Sciences. 2023, 112(5):P1287-1304.

Figure 1. Representations of Activ-Polymer™ N-Sorb film preparation process by extrusion (left); High-resolution scanning electron microscopy image coupled with EDX analyses of an N-Sorb film (right).

Figure 2. Evolution of nitrite concentration in MCC tablets at 25°C as a function of time in the absence or the presence of N-Sorb films.

Figure 3. NDMA concentration in the capsules over time (up to 6 months).