Nitrosamine Risk Assessments

1. The most direct approach is to provide us with an analytical determination (report) on the level of nitrosamines found in their API.  This will allow us to compare with the current (and perhaps changing) acceptable level and author a position paper
2. In lieu of 1), we can consider the chemical functionality in the API and the details of the synthetic procedures followed to generate the API.  This is covered in more detail below.
3. Functionality in the API.  If the API contains a tetrazole ring as found in some sartans, or is pioglitazone, ranitidine, nizatidine, and metformin or any other APIs where nitrosamines have been detected previously, analytical testing will probably be the only approach accepted by regulators.

Evaluation of the synthesis of the API (Taken from EMA/189634/2019 Information on nitrosamines for marketing authorisation holders 

1. Nitrosamine impurities can form during API processing under certain processing conditions and in the presence of some types of raw materials, starting materials, and intermediates. They may not be fully purged in subsequent steps of the API manufacturing process.
2. The use of sodium nitrite (NaNO2), or other nitrites, in the presence of secondary or tertiary amines is a potential cause of nitrosamine formation.

Secondary amines can be present in reagents and solvents as impurities or degradants. They may also be part of reagents, solvents, APIs, their degradants, and precursor structures. For example, amide solvents can degrade to secondary amines which are known sources of nitrosamines (such as N,N-dimethylformamide [DMF], N-methylpyrrolidone [NMP], or N,N-dimethylacetamide [DMA]).

Tertiary amines include common bases which have already been observed to allow nitrosamine formation (i.e. triethylamine, diisopropylethylamine [Hunig’s base=DIPEA]). However, other less common bases are sometimes used in manufacturing processes, for example N-methylmorpholine (NMM), tributylamine (TBA) and many others which would lead to formation of different nitrosamines. Tertiary amines are also common functional groups in many APIs and their precursors.

Secondary and tertiary amines could also be present as impurities in or degradants of quarternary ammonium salts such as tetrabutylammonium bromide (TBAB) or even in primary amines such as monoethylamine.

This list of sources is not exhaustive as many other amine reagents, catalysts or solvents can be used to mediate a range of synthetic transformations. Other reagents containing amine functionality should be considered for the potential risk of nitrosamine formation.

In most confirmed cases of nitrosamine contamination of APIs to date, the nitrite source and amine have been used in the same step. However, other cases have been identified where sodium nitrite used as a reagent in one step has been carried over into subsequent steps, despite extensive purification operations, and then reacted with an amine to generate a nitrosamine impurity. Since carry-over from one step to the next cannot be completely ruled out, all processes that use sodium nitrite (or other sources of nitrite) should be considered at risk of generating nitrosamine impurities if amines (see examples above) are present in any step of the synthesis.

1. Nitrosamines may also be present in APIs following the use of contaminated raw materials in the manufacturing process. Recycled solvents, reagents and catalysts, may pose a risk for nitrosamine formation due to the presence of amines in the waste streams sent for recovery and the subsequent quenching of these materials with nitrous acid to destroy residual azide, without adequate control of nitrosamine formation or adequate purification.

Examples of recycled materials observed to be contaminated with nitrosamines include orthoxylene and tributyltin chloride (used as a source of tributyltin azide). It has also been suggested that N,N- dimethylformamide (DMF) could be contaminated in this way. Nitrosamines may be entrained if they have similar boiling points or solubility properties to recovered materials depending on how recovery and subsequent purification takes place (e.g. aqueous washes or distillation).

1. It is also known that the recovery of materials (e.g. solvents, reagents and catalysts) is often outsourced to third parties. In some cases, the third party recovery facilities do not receive enough specific information on the content of the materials they are processing and rely on routine recovery processes carried out in non-dedicated equipment. This can potentially lead to cross- contamination of solvents, reagents and catalysts from various sources or processes if equipment is not adequately cleaned between customers, or if precautions to avoid nitrosamine formation are not in place.
2. Another source of nitrosamines may be contaminated starting materials, including intermediates supplied by vendors that use processing methods or raw materials causing formation of nitrosamines. For example, nitrites are known impurities in raw materials, including reagents, solvents, and excipients used in finished products.

Contamination from vendor-sourced raw and starting materials poses particular challenges because a producer of an API whose manufacturing process is not capable of forming a nitrosamine compound may not be aware of the risk of such impurities being present.

What we would want from clients is then:

1. Chemical structure of the API (CAS is sufficient)
2. Detailed synthetic route to the API including:
   • All starting materials
   • All identified intermediates
   • All solvents
   • All reagents
   • Information on the purity of all materials used in the synthesis
   • COAs for starting materials
   • COAs for solvents
   • COAs for all reagents

COAs for all starting materials or all solvents may not be accessible (whomever made the API for the client may not have them) in which case we will need to add a qualification to the analysis that “we assume all materials used are free of nitrosamines as part of this analysis as COA’s were not available.”

• Assurance that solvents or reagents used in the synthesis of the API are not recycled or if they are recycled, see "recovery of materials" above.