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Nitrosamine impurities are probable human carcinogens. |
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Nitrosamines (N-Nitrosodimethylamine [NDMA] and
N-Nitrosodiethylamine [NDEA]), impurities containing Nitroso functional
group. |
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NDMA is a common contaminant found in water and foods
including cured and grilled meats, dairy products and vegetables. |
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Everyone is exposed to some level of NDMA on daily basis. |
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FDA and the international scientific community do not
expect it to cause harm when ingested at low levels. |
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The FDA’s acceptable intake limit for NDMA in drug formulations is 96 nanograms per day. |
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Nitrosamine impurities may increase the risk of cancer if
people are exposed to them above acceptable levels and over long periods of
time, but a person taking a drug that contains nitrosamines at-or-below the
acceptable daily intake limits every day for 70 years is not expected to have
an increased risk of cancer. |
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The source of NDMA can be related to the drug’s
manufacturing process or its chemical structure or even the conditions in
which they are stored or packaged. |
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Only limited impurity-specific toxicity data is available
for NDMA and NDEA. |
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Due to their structural similarity, NDIPA, NEIPA, and NMBA
are considered by international regulators to exhibit a toxicological profile
like NDMA and NDEA. |
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Currently
identified sources of nitrosamine impurities are listed below: |
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1. |
Use of sodium nitrite (NaNO2), or other nitrosating agents,
in the presence of secondary, tertiary amines or quaternary ammonium salts
within the same or different process steps (if carry over can occur). |
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2. |
Use of sodium nitrite (NaNO2), or other nitrosating agents,
in combination with reagents, solvents and catalysts, which are susceptible
to degradation to secondary or tertiary amines, within the same or different
process steps (if carry over can occur). |
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3. |
Use of contaminated raw materials in the API manufacturing
process (e.g. solvents, reagents and catalysts). |
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4. |
Use of recovered materials (e.g. solvents, reagents and
catalysts), including recovery outsourced to third parties who are not aware
of the content of the materials they are processing and routine recovery
processes carried out in non-dedicated equipment. |
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5. |
Use of contaminated starting materials and intermediates
supplied by vendors that use processes or raw materials which may allow
nitrosamine formation. |
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6. |
Cross-contaminations due to different processes run on the
same line and due to operator-related errors such as inadequate phase
separations. |
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7. |
Degradation processes of starting materials, intermediates
and drug substances, including those induced by inherent reactivity in
combination with carry-over of sodium nitrite (NaNO2), or other nitrosating
agents. This could potentially occur also during finished product formulation
or storage. |
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8. |
Use of certain packaging materials. |
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Manufacturers are responsible for understanding their
processes, which includes preventing the presence of unacceptable impurities.
Manufacturers are also responsible for developing and using suitable methods
to detect and limit unacceptable impurities, including any new impurities
that may arise when they make changes to their manufacturing processes. |
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