Food, Healthcare Institutions, Life Sciences, Regulatory Focus News Letter

Investigation of Listeria monocytogenes

Welcome to FWQRC Regulatory focus news LetterHere we are going to review on the Outbreak Investigation of Listeria monocytogenes Linked to Hard-Boiled Eggs, December 2019FDA, CDC, and state and local partners are currently investigating a multistate outbreak of Listeria monocytogenes infections linked to foods that contain hard-boiled eggs. On December 20, 2019, Almark Foods recalled and suspended production of hard-boiled and peeled eggs in pails due to the potential for contamination with Listeria monocytogenes. These hard-boiledand peeled eggs were sold in pails under the following names: Rainbow Select Hard-cooked Eggs, Rainbow Select Hard-cooked Eggs in Vinegar, Nic’s Salad Hard-boiled Eggs, Almark Hard-cooked Eggs, and Sutherland Select Hard-cooked Eggs. A full list of recalled products is included below.RecommendationFood processors, restaurants, and retailers should not sell or serve any of the recalled hard-boiled and peeled eggs in pails from Almark Foods. These products were not sold directly to consumers.Additionally, FDA recommends that food processors, restaurants and retailers who have received Almark Foods bulk, fresh hard-boiled eggs, use extra vigilance in cleaning and sanitizing any surfaces that may have come in contact with these products, to reduce the risk of cross-contamination.Background:As of December 17, 2019, a total of seven people infected with the outbreak strain of Listeria monocytogenes have been reported from five states. In interviews, ill people answered questions about the foods they ate and other exposures in the month before they became ill. Of the five people for whom information was available, four reported eating products containing eggs. Three of these people reported eating hard-boiled eggs in deli salads purchased from grocery stores and in salads eaten at restaurants. Illnesses started on dates ranging from April 10, 2017 to November 12, 2019.Additionally, based on whole-genome sequencing, the Listeria monocytogenes found in environmental samples collected at the firm’s processing facility during an FDA inspection conducted in February 2019 is a genetic match to the outbreak strain. FDA is conducting additional inspections and sampling. Almark Foods has been cooperating with the ongoing investigation and announced a voluntary recall of hard-boiled and peeled eggs in pails on December 20, 2019.This outbreak strain was found during environmental sampling in 2017 of one other food facility. That facility is not currently handling food and ceased operation in 2018.Thank you for viewing FWQRC blogs….

Regulatory Focus News Letter, Your Partner

National Drug Code(NDC)

Hi, Welcome to FWQRC Regulatory focus News Letter….

Here we are going to review the historic step taken by Trump Administration to lower U.S. prescription drug prices

Proposed rule could allow certain prescription drugs to be imported from Canada; draft guidance explains how manufacturers could import drugs, biological products originally intended for sale in another country

Today, President Trump, along with the U.S. Department of Health and Human Services and the U.S. Food and Drug Administration, issued a notice of proposed rulemaking (NPRM) that, if finalized, would allow for the importation of certain prescription drugs from Canada. In addition, the Administration is announcing the availability of a new draft guidance for industry that describes procedures drug manufacturers can follow to facilitate importation of prescription drugs, including biological products, that are FDA-approved, manufactured abroad, authorized for sale in any foreign country, and originally intended for sale in that foreign country.
The NPRM issued today is the first step in implementing a provision of federal law that would allow for the importation of certain prescription drugs from Canada under specific conditions that ensure the importation poses no additional risk to the public’s health and safety while achieving a significant reduction in the cost of covered products to the American consumer. The draft guidance issued today describes procedures for a drug manufacturer to submit documentation that demonstrates that the product offered for import from any foreign country is, in fact, an FDA-approved drug product, including that it is manufactured in accordance with the FDA-approved application.

“Today’s announcement outlines two pathways for the safe importation of certain prescription drugs to help provide safe, effective, more affordable drugs to American patients,” said Health and Human Services Secretary Alex Azar. “These are historic actions by HHS and the FDA, and they represent the bold nature of President Trump’s agenda for lowering drug costs. The President has recognized the opportunity to lower costs for American patients through safe importation, and we at HHS and FDA are delivering on that possibility through a safe, commonsense approach.”

The NPRM would allow states and certain other non-federal government entities to submit importation program proposals to the FDA for review and authorization. An importation program could be co-sponsored by a pharmacist, a wholesaler, or another state or non-federal governmental entity. Referred to as Section 804 Importation Programs, these programs would be authorized by the FDA to manage the importation of certain prescription drugs that are approved in Canada and also meet the conditions in an FDA-approved drug application. Eligible prescription drugs would have to be relabeled with the required U.S. labeling prior to importation and undergo testing for authenticity, degradation, and to ensure that the drugs meet established specifications and standards. Notably, these programs would also have to demonstrate significant cost reductions to the American consumer.

“The FDA continues to assess and act on multiple opportunities to promote competition that can, in turn, help reduce drug prices and improve access to medicines for Americans,” said Assistant Secretary for Health Brett Giroir. “The proposed rule and draft guidance include procedures intended to protect the public’s health and safety. We look forward to receiving public comment on these draft policies, and we will take timely comments into account as we work to finalize the rule and guidance. Our ultimate goal is to provide a robust program that clearly lays out procedures to import drugs that could provide lower prices while also maintaining the high quality Americans expect.”

Of note, the draft guidance describes procedures drug manufacturers could follow to obtain an additional National Drug Code (NDC) for certain FDA-approved prescription drugs, including biological products, that were originally manufactured, and intended to be marketed, in a foreign country. The use of an additional NDC would allow greater flexibility for drug companies to offer these products at a lower price than what their current distribution contracts require.

The draft guidance also recommends that the drug manufacturer include a statement on the product’s label and in the prescribing information to assist pharmacists to accurately identify, dispense and bill for these products. Prescription drugs, including biological products, imported under the pathway described in the draft guidance could be available to patients in a variety of settings, including hospitals, health care providers’ offices, or licensed U.S. pharmacies, and would include the FDA-approved labeling (including prescribing information).

Comments on the NPRM are being accepted for 75 days after publication in the Federal Register and comments on the draft guidance are being accepted for 60 days after publication in the Federal Register

Thank you for viewing FWQRC newsletters……..

GMP, Life Sciences, Regulatory Focus News Letter, Rules

FDA Finalizes Rule to Go From Paper to Electronic Devices Submissions

Hi, Welcome to FWQRC Regulatory Focus News Letter.

Here we are going to discuss about the finalised rule for the submission process.

As part of an effort to improve the US Food and Drug Administration’s (FDA) medical device submission process, the agency on Friday issued a final rule to remove the requirements for multiple paper copy submissions and replace them with a single electronic submission.

The agency said the rule, proposed in September 2018 and will take effect in 30 days, is in response to an executive order from the Trump Administration in 2017 made famous as the “one-in, two-out” order. FDA’s rule is meant to improve the device premarket submission program and create a more efficient submission system.

“The requirement for a single submission in electronic format applies to all submission types that fall within the provisions listed in section 745A(b) of the FD&C Act; under this final rule, FDA is only amending those regulations that specifically mention paper and/or multiple copies of such regulatory submissions and are not consistent with this final rule,” FDA said.

The agency responded to four comments on the proposal but did not update the rulemaking. The agency noted that the final rule will produce cost savings for firms without imposing any additional regulatory burdens for submissions or affect the agency’s ability to review submissions.

“Firms will incur minimal administrative costs to read and understand the rule. We expect the economic impact of this regulation to be a total net costs savings yielding positive net benefits,” FDA said.

The agency also noted that submissions in electronic format can include those created and submitted on CD, DVD or flash drive and mailed to FDA.

For premarket approval applications (PMAs), the final rule changes one section to take out a section requiring an applicant to submit three copies of any updated safety and effectiveness report for pending applications.

FDA also previously required that PMAs be submitted in six copies, each bound in one or more numbered volumes, but that language has been removed with this final rule.

In another section, FDA removes the requirement that a PMA applicant has to provide copies of information that it believes to be trade secret or confidential commercial or financial information in the PMA.

FDA in September also published a draft guidance with “both binding and nonbinding provisions”

Please contact FWQRC for electronic submissions. (+91 8072483812)

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.

FWQRC, GMP, Life Sciences, Pharma

NDMA-Genotoxic Impurity

Hello Readers!!!

Today’s discussion is about the hottest topic in the pharmaceutical industry, where many industries producing the Ranitidine and Valsartan drugs recalled the batches from the MARKET due to the presence of this impurity in the drug above the acceptance criteria.

First of all, What is NMDA and NDEA impurity?
N-Nitrosodimethylamine (NDMA), also known as dimethylnitrosamine (DMN) and N-nitrosodiethylamine, the member N-nitrosoamine class is a semi-volatile organic chemical, produced as a byproduct in chemical synthesis or as a whole.

A bit more about NDMA & NDEA impurities.





Numerous studies were conducted in vitro in bacterial and mammalian cells, there has been overwhelming evidence that NDMA is not only a mutagenic but also clastogenic. The NDMA impurity increased the frequencies of gene mutations, chromosomal damage, sister chromatid exchange, and unscheduled DNA synthesis in a wide variety of cell types including human and rodent cells.

The evidence of genetic effects has also been observed in in vivo studies. Clastogenic effects (e.g., micronuclei, sister chromatid exchange, chromosomal aberrations) in, bone marrow cells, spleen cells and peripheral blood lymphocytes, as well as in oesophageal, kidney cells have been observed in rodents (rats, mice, or hamsters) administered NDMA either orally or by intraperitoneal injection.
Evidence of genotoxicity (e.g., chromosomal aberrations, micronuclei, gene mutation,DNA strand breaks) has also been observed in the offspring of hamsters and mice.

How does it reacts with the human body?
NDMA is metabolized by CYP2E1 enzyme in the liver, which hydroxylates one methyl group. The resulting hydroxymethyl nitrosamine is unstable and decomposes to formaldehyde, which is also used to quantify the metabolic rate and methane-diazonium-ion, which methylates DNA and protein or reacts with water to methanol. The electrophilic intermediates produced by metabolic activation of nitrosamines, react rapidly with cellular nucleophiles and target for carcinogens during tumor initiation.

WhatsApp Image 2019-10-28 at 21.12.11

The discussion about the NDMA impurities has been conversed previously.


  • World Health Organization Guidelines for Drinking-Water Quality, 3rd edition including 1st and 2nd addenda, 2008.

The topic is not only limited to Ranitidine and Valsartan drugs but it is applicable to all the drugs. All the drug substances should be assessed for the NDMA impurity and necessary controls should be taken.

Lets not wait for the regulatory authorities to take action upon the manufacturers. It is the Pharmaceutical manufacturers responsibility to deliver the right drugs to ensure the patient safety…


Genotoxic Impurities

Hi Everyone…

Good evening

Today we are going to discuss on the Genotoxic Impurities and its assessments.

The toxicological assessment of genotoxic impurities and the determination of acceptable limits for such impurities in active substances is a difficult issue.

The data set usually available for genotoxic impurities is quite variable and is the main factor that dictates the process used for the assessment of acceptable limits.

In the absence of data usually needed for the application of one of the established risk assessment methods, i.e. data from carcinogenicity long-term studies or data providing evidence for a threshold mechanism of genotoxicity, implementation of a generally applicable approach as defined by the Threshold of Toxicological Concern (TTC) is proposed.

A TTC value of 1.5 µg/day intake of a genotoxic impurity is considered to be associated with an acceptable risk (excess cancer risk of <1 in 100,000 over a lifetime) for most pharmaceuticals.

From this threshold value, a permitted level in the active substance can be calculated based on the expected daily dose. Higher limits may be justified under certain conditions such as short-term exposure periods.

For determination of acceptable levels of exposure to genotoxic carcinogens considerations of possible mechanisms of action and of the dose-response relationship are important components. Based on the above considerations genotoxic impurities may be distinguished into the following two classes:

  • Genotoxic compounds with sufficient (experimental) evidence for a threshold-related mechanism

This approach calculates a “Permitted Daily Exposure” (PDE), which is derived from the NOEL, or the lowest- observed effect level (LOEL) in the most relevant (animal) study using “uncertainty factors” (UF).

  • Genotoxic  compounds  without  sufficient   (experimental)  evidence  for   a   threshold-related mechanism

The assessment of acceptability of genotoxic impurities for which no threshold mechanisms are identified   should   include   both   pharmaceutical   and   toxicological   evaluations.   In   general, pharmaceutical measurements should be  guided by  a  policy of  controlling levels to  “as  low as reasonably practicable” (ALARP principle), where avoiding is not possible.  Levels considered being consistent with the ALARP principle following pharmaceutical assessment should be assessed for acceptability from a toxicological point of view.

A TTC value higher than 1.5 µg/day may be acceptable under certain conditions, e.g. short-term exposure, for treatment of a life-threatening condition, when life expectancy is less than 5 years, or where the impurity is a known substance and human exposure will be much greater from other sources (e.g. food). Genotoxic impurities that are also significant metabolites may be assessed based on the acceptability of the metabolites.

The concentration limits in ppm of genotoxic impurity in drug substance derived from the TTC can be calculated based on the expected daily dose to the patient using equation (1).

(1) Concentration limit (ppm) = TTC [µg/day]/dose (g/day]

The TTC concept should not be applied to carcinogens where adequate toxicity data (long-term studies) are available and allow for a compound-specific risk assessment.


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