FWQRC, GMP, Life Sciences, Pharma

Need for a proactive approach-To protect our loved one and also to continue the business without financial drop down.

We have heard the presence of NDMA impurities in Sartans and Ranitidine drugs. Initially it was only sartans, later Ranitidine and what’s next now?

Now let’s extend the concept to OTC drugs that may contain Nitrosamines impurity. Lets us review the sources of Nitrosoamines.

  1. Solvents:

The source for nitroso amines may also be from solvents.

DMF: NDMA can also be formed from Dimethyl formamide as shown below.

DMA is present as an impurity in DMF, a precursor in the industrial DMF process. It may also formed as a degradant during storage of the solvent.


Similar to DMA formation, DEA could be formed by degradation of triethylamine (TEA) or exist as impurity in TEA raw material.

Some common organic solvents (e.g. NMP which could give rise to 4- (methyl)(nitroso)amino)butanoic acid = NMBA) and amine bases (e.g. diisopropylamine = DIPEA which could give rise to N-Nitrosodiisopropylamine (DIPNA) and N-Nitrosoethylisopropylamine (EIPNA)) would present such risks.

  • Reagents Like piperazine, a secondary amine, reacts slowly with NOx in the presence of O2 to form a nitrosamine derivative under conditions similar to those found in industrial amine-based post-combustion CO2 capture processes.

The genotoxic and mutagenic assessment is at most performed for Raw materials, reagents, catalysts etc., But do we really assess the Recycled solvents, reagents and catalysts and this may be chance 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). 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).

Simple checks during the manufacturing process can identify the impurities and avoids the market recall.

  1. Evaluate the solvents, reagents for the structural alert that are similar like nitrosoamines.
  2. Recovered solvents, recovered materials that are outsourced by a third party vendor.
  3. Evaluation of drug product formulation and process.

In-depth analysis during drug development should actually identify all the issues.

Budding and Small-scale industries who cannot identify the sources of the impurity or who cannot have sufficient capacity to analyse the drugs can take the help of qualified labs/ consultancies as a onetime activity.

Best advice is our cost saving should not cost the life of our fellow citizens.

A proactive approach for the high market value molecules to avoid any surprise in the future.

OTC Drugs

  • Drugs that contains Piperazine ring are Ranolazine, Trimetazidine, Amoxapine, Amoxapine, Befuraline, Buspirone, Flesinoxan, Ipsapirone, Nefazodone, Piberaline, Tandospirone, Trazodone, Vilazodone, Zalospirone, Meclozine, Cinnarizine, Hydroxyzine, Cetrizine, Levo citrizine, Niaprazine, Fluphenazine, PERPHENAZINE, Prochlorperazine, THIOTHIXENE, Quipazine, Imatinib, Benzylpiperazine, Buclizine, Ziprasidone,Etc…

Out of the above drugs listed, The OTC drugs are Cetirizine, Hydroxyzine etc are into the consideration of Nitrosoamine impurities and other prescription should also be taken into consideration.

  • One of the article which was published in the year 2001, has concluded that nitrosoamine was detected in the patients urine, who is consuming the long term treatment with Omeprazole, a Proton pump inhibitor.

Omeprazole, with the maximum daily dose of 360 mg/day is prescribed for some patients with Zollinger-Ellison Syndrome for treatment period longer than 5 years.

Since, these OTC drugs are easily available in the market and consumed without doctors prescription, there is a quick need for evaluation and control of   these impurities in the Drug substance as well as drug product.

The above statement is just an example and further evaluation is REQUIRED.

Since the method for the detection of the nitrosamines is available, why delay, start assessing and perform a risk assessment for your drugs.

Assess, Analyse, Announce your results and be responsible for public health, since these are OTC drugs.

Leave a Reply

Fill in your details below or click an icon to log in:

WordPress.com Logo

You are commenting using your WordPress.com account. Log Out /  Change )

Google photo

You are commenting using your Google account. Log Out /  Change )

Twitter picture

You are commenting using your Twitter account. Log Out /  Change )

Facebook photo

You are commenting using your Facebook account. Log Out /  Change )

Connecting to %s