Nitrosamine Impurities – Concern of the Time

The term nitrosamine describes a class of compounds having the chemical structure of a nitroso group bonded to an amine (R1N(-R2)-N=O), Due to their potent genotoxic effects found in several animals, FDA published interim acceptable limits for these impurities following the discovery of nitrosamine contaminants in ARBs, and several other medications

These compounds are formed by nitrosating reaction between amines (secondary, tertiary, or quaternary amines) and nitrous acid (nitrite salts under acidic conditions)

General Root Causes for the Presence of Nitrosamine Impurities in APIs are

Formation of nitrosamines is possible in the presence of secondary, tertiary, or quaternary amines and nitrite salts under acidic reaction conditions

What are the currently identified root causes for presence of nitrosamines for all products?

• Use of sodium nitrite (NaNO2), or other nitrosating agents.
• Use of contaminated raw materials in the API manufacturing process (e.g. solvents, reagents and catalysts).
• Use of recovered materials (e.g. solvents, reagents and catalysts).
• Use of contaminated starting materials and intermediates by nitrosamine.
• Cross-contaminations due to different processes run on the same line.
• Degradation processes of starting materials, intermediates and drug substances. This could potentially occur also during finished product formulation or storage.
• Use of certain packaging materials.

New Testing Requirements

It is imperative that manufacturers understand the possible source of nitrosamine formation in their manufacturing process and add proper controls to reduce the possibility of formation of these carcinogenic impurities.

The pharmaceutical industry needs to look beyond the obvious and understand that the quality of the reagents and solvents, even those used relatively upstream in the manufacturing process, are critical for assuring the quality of the final drug  substance.

Since September 2019, all EU Marketing Authorization Holders (MAH) of medicines for human use are facing a new requirement to review their drug products for the possible presence of nitrosamines. The European Medicines Agency (EMA) has sent a notice, to marketing authorization holders to review their human medicinal drug products containing chemically synthesized APIs on the potential risk of containing nitrosamines impurities before April 2020, including:

• Step 1: Risk Evaluation
MAHs should perform risk evaluation of their medicinal products containing chemically synthesized APIs.

• Step 2: Confirmatory Testing
Confirmatory testing should be carried out using appropriately validated and sensitive methods in MAHs should inform the Competent Authorities immediately if tests confirm the presence of a nitrosamine impurity irrespective of the amount detected.

• Step 3: Changes to the Marketing Authorization
MAHs should apply for a variation in a timely manner to introduce any required changes, such as an amendment of the manufacturing process or changes to product specifications.

FDA recommendations that API Manufacturers take the following actions:

• API manufacturers should optimize the design of the manufacturing process for APIs during route of synthesis (ROS) development to minimize or prevent the formation of nitrosamine impurities.
• Avoiding reaction conditions that may produce nitrosamines whenever possible; when not possible, demonstrating that the process is adequately controlled and is capable of consistently reducing nitrosamine impurities through appropriate and robust fate and purge studies.

•  Using bases other than secondary, tertiary, or quaternary amines (when possible) if ROS conditions may form nitrosamines.

•  Using caution when the ROS involves the use of amide solvents (e.g., N,N- dimethylformamide, N,N-dimethylacetamide, and N-methylpyrrolidone).

• Replacing nitrites with other quenching agents for azide decomposition processes.

•  Optimizing and consistently controlling the sequences of reactions, processes, and reaction conditions (such as pH, temperature, and reaction time).

•  Designing a manufacturing process that facilitates the purge of nitrosamine impurities in the subsequent processing steps.

• API manufacturers should consider removing quenching steps (when there is a risk of nitrosamine formation, e.g., using nitrous acid to decompose residual azide) from the main reaction mixture to reduce the risk of nitrosamine formation.

• FDA recommends the manufacturers should to audit their supply chains and monitor them for any at-risk raw materials, starting materials, and intermediates.

• To avoid cross-contamination when recovered materials such as solvents, reagents, and catalysts are used in the manufacturing process, recovered material should be used only in the same step or in an earlier step (if there is sufficient purification) of the same process from which it was collected. The recovered materials should meet appropriate standards before reuse.

• API manufacturers should be aware that potable water used in API manufacture may contain low levels of nitrite and even nitrosamines from environmental contamination.
• If a nitrosamine is introduced to the API through exogenous sources that can be avoided, manufacturers should eliminate the source of contamination
• API batches may be reprocessed or reworked to control the level of nitrosamine impurities as provided in ICH Q7 for amending and controlling such operations. If a batch is found to contain nitrosamine and is reprocessed or reworked in any way, these operations should be conducted under oversight of the quality unit.

In order to support the nitrosamine testing of drug substances and products to ensure safe release of medicines, ISP Standards is continuing to develop our nitrosamine portfolio, including new nitrosamine single- solutions to allow for safer handling, storage and shipping. Check our protfolio – Product page opens