The word Nitrosamine impurities are blasted in the pharmaceutical industry from July 2018 after identifying the traces of the toxic nitrosamine genotoxic impurities like N-nitrosodimethylamine (NDMA) & nitrosodiethylamine (NDEA) in the APIs made by china manufacturer Zhejiang Huahai, Zhejiang Tianyu, and Indian manufacturer Hetero lab manufactures generic sartans, the angiotensin inhibitor blockers (ARBs), a generic valsartan distributed by Torrent Pharmaceuticals prescribed to some patients to treat high blood pressure.
During investigation also noticed that
- Nitroso amine impurities are likely to be present in the batches since 2012 when a change of process was made.
- NDMA was unexpected therefore not controlled
- Significant levels found.
- NDMA is a possible carcinogen for Humans.
Even though initially NDMA identified, number of following Nitroso impurities identified as part of further investigation.
NDMA- Nitrosodimethylamine
NDEA- Nitrosodiethylamine
NDBA- Nitrosodibutylamine
NMBA- Nitrosobutyl amino butyric acid
NDIPA- Nitrosodiisopropylamine
NIPEA- Nitrosoisopropyl ethylamine
Origin of NDMA/NDEA:
Regulatory firms identified that Indian Hyderabad based solvent recovery firm Lantech Pharmaceutical processing methods are left open the chances of cross-contamination of solvents that contained the impurities known as NDMA & NDEA and there is a potential to contain nitrosamine impurities through mix-up & cross-contamination for all products manufactured in their facility.
The chemical structure of Angiotensin II receptor blockers (ARBs) contains a tetrazole group. It is apparent that tetrazole ring formations, coupled with certain manufacturing conditions in presence of DMF, produce these types of impurities in drug substance intermediates used in sartans. Other tetrazole ring formations produce APIs like Olmesartan, candesartan, irbesartan, and losartan. The impurity may also roll over to other compounds normally known as “zoles,” such as omeprazole, etc.
Impacted Products:
Valsartan, Losartan, Irbesartan, almost all sartans expect Telmisaratn and ranitidine …etc
Currently identified all root causes for the presence of Nitrosamines:
Currently identified sources of nitrosamine impurities are listed below:
- Use of nitrosating agents like sodium nitrite (NaNO2) in the presence of secondary (2°), tertiary (3°) amines, or quaternary (4°) ammonium salts within the same or different process steps (if carryover can occur).
- Use of nitrosating agents like sodium nitrite (NaNO2), along with catalysts, solvents, and reagents, that are likely to degradation to secondary (2°) or tertiary (3°) amines, within the same or different process steps (if carryover can occur).
- 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), 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.
- Use of contaminated starting materials and intermediates supplied by vendors that use processes or raw materials that may allow nitrosamine formation.
- Cross-contamination due to different processes run on the same line and due to operator-related errors such as inadequate phase separations.
- Degradation of starting materials, intermediates, and drug substances, including those induced by inborn reactivity in combination with carry-over of nitrosating agents like NaNo2 could potentially occur also during finished product formulation or storage.
- MAH observed the use of certain packaging materials (containing nitrocellulose printing primer) with lidding foil that may react with amines present in printing ink to produce nitrosamines which would then transfer to the product under certain packaging process conditions. (e.g. during vaporization & condensation of heat-sealing blistering processes may produce nitrosamines then transfer onto the drug product) .
How to perform risk evaluation for Nitrosamine Impurities:
- MAHs along with API and finished product manufacturers are required to perform risk assessment using ICH Q9 & ICH M7 guideline in relation to toxicology assessment, control strategy and changes to the manufacturing processes for active (API) substances should be applied.
- Nitrosamine impurity formation risk should be assessed from the development phase of the API/ Finished product manufacturing process.
- The risk of nitrosamine formation should be assessed w.r.t API process, reagents, solvents, catalysts, starting materials, intermediates, impurities, and degradants.
- The potential risk of nitrosamine contamination (e.g. from recovered materials such as catalysts, reagents, solvents, equipment, degradation, starting materials, or intermediates) should be assessed.
- Is there any potential of nitrosamine formation during the manufacture of the finished product and/or during storage throughout its shelf life should be assessed.
- A representative number of samples of the relevant starting material, intermediate, API, or finished product should be tested with an appropriately validated analytical method for the evaluation of nitrosamine impurities. The number of batches/samples tested should be scientifically justified.
Limits for nitrosamine Impurities:
For reference, consuming up to 0.096 micrograms or 0.32 parts per million (ppm) of NDMA per day is considered reasonably safe for human ingestion based on lifetime exposure. (which means, if a person consumes 0.32ppm / 0.096mg of NDMA for the entire life of 70 years)
The regulatory requirement from the industry:
- All authorized human medicinal products containing chemically synthesized APIs are to be studied, including over-the-counter (OTC) and generics products. However, in view of a large number of authorized products, MAHs should use a risk-based approach and prioritize their evaluations and confirmatory testing.
- MAHs should prioritize products in order to establish the sequence in which their products are to be evaluated. For the purposes, MAHs may consider factors such as the maximum daily dose is taken, duration of treatment, therapeutic indication, and the number of patients treated. For example, medicinal products with a higher daily dose, and those for chronic use may take priority.
- In order to undertake the analysis of the identified medicinal products at risk, MAHs can also use tools such as Failure Mode Effects Analysis (FMEA) and Failure Mode, Effects, and Criticality Analysis (FMECA) as stated in the ICH Q9 quality guideline on quality risk management.
- If MAHs identify that changes are necessary in their production process and/or product formulation, they should communicate with competent authorities in order to assess the type of variation required and to submit one as needed in a timely manner.
- This risk evaluation must be concluded within six months after the regulatory statement was published.
- The risk evaluation’s documentation must not be submitted, though it is to be made available upon request.
- If a risk of potential contamination has been detected, the marketing authorization holder should go for conformity testing via validated and appropriately sensitive analytical methods.
- If nitrosamine is found, the competent authorities are to be informed immediately, irrespective of the amount detected.
