Reducing the risks associated with nitrosamines in formulations using excipients manufactured by DFE Pharma

The challenge of nitrosamine in the pharmaceutical industry

Evaluating nitrosamines in pharmaceutical products presents a significant challenge for formulators in the industry. The European Medicines Agency (EMA) reported the recall of drugs containing Valsartan in 2018 due to nitrosamine contamination. Nitrosamines are potential genotoxic agents and some are classified as probable or possible human carcinogens. The acceptable intake limits for some species of nitrosamines often present in pharmaceutical preparations range between 26.5-96 ng/day (EMA, 2022; US FDA, 2021).

Nitrosamine impurities can originate from drug substance manufacturing or form during shelf-life storage. While it is possible to eliminate impurities formed during drug substance manufacture, it is not feasible to do so for those formed in the final drug product. Secondary amines can react with nitrosating agents such as nitrite, leading to the formation of nitrosamines. Thus, the quantity of nitrite collectively present in the dosage form can influence nitrosamine levels, particularly for sensitive APIs.

To address these concerns, regulatory authorities now require Market Authorization Holders (MAHs) to reduce nitrosamine impurities. The U.S. Food and Drug Administration (FDA) and EMA indicate a three-step strategy: risk assessment, testing to confirm identified risks, and reporting changes implemented to prevent and minimize nitrosamine formation (risk mitigation) (EMA, 2022; US FDA, 2021).

During risk assessments, excipients are considered as potential contributors to nitrosamine formation. While the risk of nitrosamine presence in excipients is generally low, many excipients contain traces of nitrites that could lead to nitrosamine formation under specific conditions. Excipient suppliers should provide relevant information to assist MAHs in evaluating the risk of nitrosamine impurities in the final drug product.

Mitigation strategies

Mitigation strategies outlined by the FDA and EMA include formulation design and supplier qualification, with an emphasis on reducing nitrosamine formation.

Formulation design involves re-formulating a product with excipients with lower nitrite content to suppress nitrosamine formation. Incorporating antioxidants like ascorbic acid or alpha-tocopherol, as well as increasing the pH of the micro-environment, are also suggested as strategies to inhibit nitrosamine formation.

Supplier qualification is a recommended strategy outlined in the FDA guidance, which can have minimal impact on the drug product's registration dossier. The rationale behind this approach is rooted in the notable variations in nitrate and nitrite levels among different excipient lots and suppliers (Boetzel et al., 2022). It is common for excipient suppliers to provide nitrite information based solely on risk assessment, while in some cases, nitrite content is measured using less sensitive analytical methods. As a result, distinguishing between suppliers becomes challenging.

Variability of nitrites across excipients

Understanding the variability in nitrite levels across excipients, suppliers, and batches is valuable for MAHs considering reformulation or supplier qualification strategies. Wu et al. (2011) investigated nitrite and nitrate levels in various excipients, finding omnipresent impurities that varied depending on the excipient type and supplier. Minor manufacturing differences, such as processing water, acid titration steps, and drying, were suggested as factors contributing to these impurities. Additionally, the "Nitrites in Excipients" database developed by Lhasa Limited, as shared in Boetzel et al.'s article, revealed significant differences in nitrite levels among excipients and suppliers.

Table 1 presents the median nitrite levels of eight microcrystalline cellulose (MCC) suppliers, as extracted from Boetzel et al., 2022. It is important to note that the number of samples tested differed for each supplier. Readers can refer to the original article for further information. The median nitrite levels can differ significantly among suppliers, with variations of over 16-fold.

Table 1. Median nitrite levels of MCC from different suppliers (Boetzel et al., 2022). ppm = µg/g

For excipients present in a large percentage of the formulation, like fillers, the impact of impurities is relatively higher compared to low-dosed ingredients such as disintegrants, glidants, and lubricants. However, even for low-dosed excipients, specific cases may warrant consideration. For instance, crospovidone, a superdisintegrant, exhibited nitrite levels 9 to 12 times higher than those of fillers like MCC and lactose. Thus, the contribution of nitrites from crospovidone can still be significant despite its lower concentration. Substituting crospovidone with croscarmellose sodium, which has a 15-fold lower mean nitrite value, could be a viable option for formulations containing sensitive APIs (Boetzel et al., 2022).

Nitrite levels in DFE Pharma excipients

DFE Pharma, as a supplier of excipients, has been proactive in addressing the issue of nitrosamine formation. Leveraging the expertise of its parent company, FrieslandCampina, which dealt with nitrosating agents in the food industry, DFE Pharma embarked on supporting MAHs with their nitrosamine risk assessment. They developed a comprehensive questionnaire, encompassing  risk factors such as the excipient's structure, production process, water type, solvent usage, presence of amines, and equipment usage. The results indicated a very low probability of nitrosamine and nitrosating agent presence, which was supported by analytical data demonstrating that nitrosamine, nitrate, and nitrite content were below the detection limits.

Initially, the quantification method employed was not sensitive enough to detect the low levels of nitrites in the excipients. To address this, a more sensitive method, specifically ISO-14673-2: 2004 (E) segmented flow analysis, was identified. Although this method is validated for milk and milk products rather than excipients, it enabled better quantification. Table 2 presents the nitrite and nitrate content in DFE Pharma's excipients.

Table 2. Nitrite levels in DFE Pharma excipients. The ISO-14673-2:2004(E): Segmented flow analysis method was used for the analysis. All value are n=1 (at least)

Typically, the nitrite values in DFE Pharma’s excipients were found to be below the limit of quantification (LOQ) of 0.1 ppm. However, the main limitation of this approach was that most products had levels below the LOQ of the detection method. Consequently, the reported value of <0.1 ppm nitrite represents an overestimated worst-case scenario, and the exact values below the LOQ remain unknown. More precise data will be collected once a more sensitive quantification method becomes available for testing.

Сomparing the obtained data with the findings reported by Boetzel et al., it is evident that DFE Pharma demonstrates low levels of nitrites in MCC, lactose, and superdisintegrants.

Choose DFE Pharma as your go-to-supplier for nitrosamine risk mitigation

DFE Pharma stands out in the market with excipients that have remarkably low levels of nitrites. This achievement reflects their commitment to quality throughout the manufacturing process. When it comes to addressing the challenge of nitrosamines, whether through reformulation or supplier qualification, choosing DFE Pharma provides assurance and peace of mind. Their track record of delivering excipients of high quality and consistency makes them a trusted and reliable option for your needs.

References

1. EMA, 2022. Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products. EMA/409815/2020 Rev.11.
2. US FDA, 2021. Control of Nitrosamine Impurities in Human Drugs: Guidance for Industry. Cent. Drug Eval. Res. Silver Spring, MD, USA.
3. Boetzel, R., Schlingemann, J., Hickert, S., Korn, C., Kocks, G., Luck, B., Blom, G., Harrison, M., François, M., Allain, L., 2022. A Nitrite Excipient Database: A useful Tool to Support N-Nitrosamine Risk Assessments for Drug Products. J. Pharm. Sci.
4. Wu, Y., Levons, J., Narang, A.S., Raghavan, K., Rao, V.M., 2011. Reactive impurities in excipients: profiling, identification and mitigation of drug–excipient incompatibility. Aaps Pharmscitech 12, 1248–1263.

katerina.chuienko@imcd.at
www.imcdgroup.com