NMDA, a nitrosamine impurity called N-nitrosodimethylamine, classified as only a probable human carcinogen. It is a known environmental contaminant which is also found in water, foods, including meats, dairy products, and vegetables. Since 2018, FDA has been investigating & found NDMA in blood pressure and heart failure medicines, ARBs & had recommended recalls when discovered unacceptable levels of NDMA. FDA has set the acceptable daily intake limit for NDMA at 0.096 micrograms or 0.32 ppm for ranitidine in Nov 2019. FDA has tested numerous ranitidine products and found levels of NDMA similar to levels you would be exposed to if you ate common foods like grilled or smoked meats. Not all ranitidine may have NDMA. This may be a contaminant in manufacturing process which can be controlled. Also proven by FDA that NDMA is not formed after ranitidine has been exposed to acid in the stomach. As per 2018 ICH Guidance M7(R1), if people consume 96nanogram of NDMA daily for 70 years, the probable risk of cancer would be 1 in 100,000 patients. Neither USFDA / EDQM / DCG(I) has called for recall of Ranitidine. They have asked for a voluntary recall only if NDMA found is more than permissible limits

1. NDMA
Getting the clarity
For the use of a registered medical practioner

2. Executive summary
■ NMDA, a nitrosamine impurity called N-nitrosodimethylamine, classified as only a probable
human carcinogen.
■ It is a known environmental contaminant which is also found in water, foods, including meats,
dairy products, and vegetables.
■ In 2018, FDA has been investigating & found NDMA in blood pressure and heart failure
medicines, ARBs & had recommended recalls when discovered unacceptable levels of NDMA.
■ FDA has set the acceptable daily intake limit for NDMA at 0.096 micrograms or 0.32 ppm for
ranitidine in Nov 2019.
■ FDA has tested numerous ranitidine products and found levels of NDMA similar to levels you
would be exposed to if you ate common foods like grilled or smoked meats.
■ Not all ranitidine may have NDMA. This may be a contaminant in manufacturing process which
can be controlled.
■ Also, proven by FDA, that NDMA is not formed after ranitidine has been exposed to acid in the
stomach.
■ As per 2018 ICH Guidance M7(R1), if people consume 96nanogram of NDMA daily for 70 years,
the probable risk of cancer would be 1 in 100,000 patients.
■ Neither USFDA / EDQM / DCG(I) has called for recall of Ranitidine. They have asked for a
voluntary recall only if NDMA found is more than permissible limits.

3. NDMA
EPA Factsheet
■ A Nitroso compound.
■ Can be formed in the body generally if Nitrites converted
to nitrates from food.
NDMA is a semi-volatile
organic chemical that
forms in both industrial and
natural processes. It is
member of N-
nitrosamines.16,17
16. https://www.epa.gov/sites/production/files/2017-10/documents/ndma_fact_sheet_update_9-
15-17_508.pdf. Last accessed on 11th October, 2019.
17. Mitch, W.A., Sharp, J.O, Trussell, R.R., Valentine, R.L., Alvarez-Cohen, L., and D.L. Sedlack.
2003b. “N-Nitrosodimethylamine (NDMA) as a Drinking Water Contaminant: A Review.”
Environmental Engineering Science. Volume 20 (5). Pages 389 to 404.

4. NDMA (N-
Nitrosodimethyla
mine)
■ N-nitrosamines such as NDMA*, are classified as
“probable” carcinogens by IARC and US EPA,
can be easily found in various foods. They are
reaction products between nitrogen oxide and
secondary amines, but can also be generated
during fermentation.15
Park J et al. Distribution of Seven N-Nitrosamines in Food. Toxicol Res. 2015; 31(3): 279–288.

5. NDMA & Indian context
■ In an Indian study the Dietary sources of N-nitrosamines in a high-risk area for
Esophageal cancer--Kashmir, India were studied by Siddiqui MA et al., at IARC.
Samples of foods consumed, were analysed for the presence of volatile N-
nitrosamines
■ Relatively high levels of NDMA, were detected in
– Smoked fish (20 µg/kg NDMA),
– Sun-dried spinach (5.8 µg /kg NDMA),
– Mixed vegetables (10 g /kg NDMA).21
■ NDMA is a drinking water contaminant of concern because of its miscibility with
water, as well as its carcinogenicity and toxicity.22
21. Siddiqi MA et al. Dietary sources of N-nitrosamines in a high-risk area for oesophageal cancer--Kashmir, India. IARC Sci Publ. 1991; 105: 210-3.
22. https://www.epa.gov/sites/production/files/2014-03/documents/ffrrofactsheet_contaminant_ndma_january2014_final.pdf. Last accessed on 11th October, 2019.

6. NDMA: Water & Food
■ The EPA’s Integrated Risk Information
System (IRIS) estimates that a NDMA
concentration of 7×10-4 g/L in drinking
water is associated with a 10-6 cancer
risk.23
■ The World Health Organization (WHO)
(2006) estimates that 0.1 g/L NDMA in
drinking water corresponds to an
upper-bound 10-5 cancer risk.24
■ A recent study of 21 U.S. and Canadian
drinking water treatment plants
reported a range of NDMA levels from
below the minimum reporting level
(MRL) of 6×10-4g/L to 2.4×10-2g/L.25
23. EPA 1993 Integrated Risk Information System (IRIS): NNitrosodimethylamine (CASRN 62-75-
9). US Environmental Protection Agency, Office of Research and Development, URL:
http://www.epa.gov/iris/substance_nmbr=0045. Accessed: 9/26/04.
24. https://www.who.int/water_sanitation_health/dwq/chemicals/ndma_2add_feb2008.pdf.
Last accessed on 14th October, 2019.
25. Valentine, R. L., Zho Chen, J. C., Barrett, S. E., Cordelia Hwang, C., Guo, Y., Wehner, M.,
Fitzsimmons, S., Andrews, S. A., Werker, A. G., Brubacher, C. & Kohut, K. 2006. Factors affecting
the formation of NDMA in water and occurrence. American Water Works Research Foundation,
Denver, CO, pp. 99–138.
■ NDMA can form in food when
secondary amines are exposed to nitrite
during processing or preservation.
Dietary sources of NDMA include
– Beer,
– Fish and fish products,
– Dairy products including cheese,
dried milk and infant formula,
– Meat and cured meats,
– Cereals and vegetables.26
26. Chowdhury S. N-Nitrosodimethylamine (NDMA) in Food and Beverages: A Comparison in Context to Drinking
Water, Human and Ecological Risk Assessment: An International Journal 2014; 20(5): 1291-1312. DOI:
10.1080/10807039.2013.817144.

7. NDMA & Endogenous intake
■ NDMA can form endogenously from the nitrosation of secondary amines, such
as DMA, contained in ingested meat and fish; Nitrosation involves the reaction
of Stomach acid with nitrite and nitrate rich foods as well as nitrate created in
the stomach to form nitroso groups, which are free to react with amines in food
to form NDMA.27
■ Vegetables, primarily spinach, beets, cabbage, broccoli and carrots, are the
predominant dietary source of nitrate, with additional exposures from cured
meats, fish and, to a lesser extent, drinking water.28
27. TRICKER, A.R., PFUNDSTEIN, B., and PREUSSMANN, R. (1994). Nitrosatable secondary amines: Exogenous and endogenous exposure and nitrosation in vivo. In R.N. Leoppky and C.J. Michejda, Eds., Nitrosamines and Related N-Nitroso Compounds:
Chemistry and Biochemistry ; Washington, DC: American Chemical Society, pp. 93–101.
28. Mirvish SS. In vivo formation of N-nitroso compounds: formation from nitrite and nitrogen dioxide and relation to gastric cancer. https://www.researchgate.net/publication/313149918_In_vivo_formation_of_N-
nitroso_compounds_formation_from_nitrite_and_nitrogen_dioxide_and_relation_to_gastric_cancer/stats.

8. NDMA studies - Endogenous
■ The amount of NDMA formed
endogenously appears to depend on
the relative concentrations of nitrate,
nitrite, nitrosatable substances28, pH,
the presence of enhancing or inhibitory
agents or the presence of nitrosating
bacteria29.
■ Several in vivo studies reported
maximum NDMA levels of 1.3 g/day in
the urine after consumption of foods
high in nitrite, nitrate and nitrosatable
substances.30-33
28. Mirvish SS. In vivo formation of N-nitroso compounds: formation from nitrite and nitrogen dioxide and relation to gastric cancer. https://www.researchgate.net/publication/313149918_In_vivo_formation_of_N-
nitroso_compounds_formation_from_nitrite_and_nitrogen_dioxide_and_relation_to_gastric_cancer/stats.
29. Ralt, D. & Tannenbaum, S. R. 1981. The role of bacteria in Nitrosamine formation. In N-Nitroso compounds (ed. R. A. Scanlan & S. R. Tannenbaum) American Chemical Society, Washington, DC, pp. 157–164.
30. Fine, D. H., Ross, R., Rounbehler, D. P., Silvergleid, A. & Song, L. Formation in vivo of volatile N-Nitrosamines in man after ingestion of cooked bacon and spinach. Nature 1977; 265(5596), 753–755.
31. Milligan, J. R., Zucker, P. F., Swann, P. F. & Archer, M. C. Absence of urinary N-Nitrosodimethylamine in fasting humans following alcohol consumption. IARC Sci. Publ. 1987; 84, 297–298.
32. Vermeer, I. T., Pachen, D. M., Dallinga, J. W., Kleinjans, J. C. & van Maanen, J. M. Volatile N-Nitrosamine formation after intake of Nitrate at the ADI level in combination with an amine-rich diet. Environ. Health Perspect. 1998; 106(8), 459–463.
33. Spiegelhalder, B., Eisenbrand, G. & Preussmann, R. 1982 Urinary excretion of N-Nitrosamines in rats and humans. In N-Nitroso Compounds: Occurrence and Biological Effects, IARC Scientific Publications No 41 (ed. H. Bartsch, M. Castegnaro, I. O’Neill & M. Okada)
International Agency for Research on Cancer, Lyon, France, pp. 44–449.
■ It has been reported that the
contents of nitrosamines changes
with respect to
– Cooking methods,
– Temperature, time,
– Moisture of food, or
– Fat composition.
■ People may be consuming Nitroso
derivatives even from their daily
food36
36. Fristachi A and Rice G. Estimation of the total daily
oral intake of NDMA attributable to drinking water.
Journal of Water and Health 2007; 5(3): 341-355.

9. NDMA & ARB
Learning from the ARB episode37

10. ■ NDMA is a “probable” carcinogen for
Humans. It is an animal carcinogen.
Available data suggests that agent is not
likely to cause cancer in humans except at
uncommonly high levels of exposure.
NDMA may be present everywhere
■ NDMA contamination is specific to some
conditions and surely when “heated”
■ NDMA is process driven – If found,
correctable by use of different solvents,
adopting order of steps to avoid formation,
Control measures in raw materials etc.,
The European Directorate for the
Quality of Medicines (EDQM) gave
detailed brief on incidence and
learnings in relation to the Valsartan
episode through a detailed
presentation in Feb’2019 by the
head of certification department Ms.
H Bruguera. The following are the
important learnings and inferences.
EDQM Update on Valsartan incident and lesson learned, Ms H Brugeura-4th Indian
Pharmaceutical forum Feb 2019

11. The European Directorate for the
Quality of Medicines (EDQM) gave
detailed brief on incidence and
learnings in relation to the Valsartan
episode through a detailed
presentation in Feb’2019 by the
head of certification department Ms.
H Bruguera. The following are the
important learnings and inferences.
■ According to EDQM, the following molecules may have
NDMA as an impurity
Active Pharmaceutical Ingredients (API) that may have NDMA impurity
Abacavir Doxylamine
Alfentanil Ergometrine
Aminopyrimidine Erythromycin
Amitriptyline Etomidate
Cefamandole Imipramine
Cefazolin Methapyrilene
Cefmenoxime Metronidazole
Cefonicid Noscapine
Cefoperazone Oxytetracycline
Cefotetan Pregabalin
Cefotiam Promazine
Cefoxitin Propoxyphene
Cefpiramide Sodium Lauryl Sarcosinate
Chloramphenicol Sulbactum
Chlorpromazine Tetracycline
Cliostazol Trimipramine
Dalteparin Vindesine
Diphenhydramine Zanamivir
EDQM Update onValsartan incident andlessonlearned, Ms H Brugeura-4th IndianPharmaceutical forumFeb 2019

12. Ranitidine
■ Ranitidine was commercially introduced in 1981, which had a longer duration
of action and fewer side effects and is now available for use globally in more
than 120 countries.1
■ Ranitidine is a selective, competitive H2RA and inhibits acid secretions
stimulated by Gastrin or Pentagastrin.2
■ These antagonists are used to treat different peptic ulcer conditions and are
also useful in the prevention of stress ulceration and recurrence of gastric
and duodenal ulcers.3
■ This molecule impacted the QOL (Quality of Life) for millions of patients’
worldwide.1
■ Even today, with the advent of newer class of drugs, Ranitidine has stood up to
the expectations of medical fraternity for not only being safe and efficacious,
but also economical and it also features on the World Health Organization's
List of Essential Medicines.4
1. Mills JG et al. The safety of ranitidine in over a decade of use. Aliment Pharmacol Ther 1997; 11: 129-137.
2. Palop D et al. Histamine H2-receptor antagonist action of ebrotidine. Effects on gastric acid secretion, gastrin levels and NSAID-induced gastrotoxicity in the rat. Arzneimittelforschung. 1997; 47(4A): 439-46.
3. https://www.medicines.org.uk/emc/product/6040/smpc. Last assessed on 14th October, 2019.
4. https://www.who.int/medicines/publications/essentialmedicines/EML2015_8-May-15.pdf. Last accessed on 11th October, 2019.

13. Ranitidine
Since 40 years, Ranitidine has been studied in
different clinical settings and numerous studies
have been published, coupled with successful
clinical experiences of healthcare providers and
patients. Safety data on Ranitidine has been
obtained in a wide range of doses from a large
number of varying patient populations.1
Data from following principle sources are
available:
■ World-wide clinical trials & medical
literature
■ Global spontaneous adverse events
database
■ Post marketing surveillance studies
40 years documented safety
Mills JG et al. The safety of ranitidine in over a decade of use. Aliment
Pharmacol Ther 1997; 11: 129-137.

14. Ranitidine – Adverse events?
■ Data from 189 clinical trials conducted on 29,342 patients; evaluated the safety
of Ranitidine at doses ranging from 75 - 1200 mg/day. The treatment duration
of half of these trials was for more than 4 months’ use.
■ Overall, adverse events were reported by 20% of those treated with Ranitidine
and 27% for those receiving placebo. Serious adverse events occurred in ≤1%
study patients with incidence of neoplasm reported to be 0.14% & lung cancer
(0.01%).
■ World-wide spontaneous adverse event database (serious and non-
serious) reported an adverse event reporting rate of <0.01% (102
events/million) patients receiving Ranitidine with most frequent events
encountered were nausea and/or vomiting, diarrhoea and abdominal pain.
■ Carcinoma or carcinoids of the gastrointestinal tract were reported at a
rate of 0.2 events per million patient treated which was unlikely to be causally
associated with Ranitidine treatment.
Mills JG et al. The safety of ranitidine in over a decade of use. Aliment Pharmacol Ther 1997; 11: 129-137.

15. Ranitidine – Adverse events? (PMS)
■ Comparison with the regional cancer registry, data showed no increase in the
development of malignant disease associated with Ranitidine treatment.1
■ The safety of Ranitidine has been documented in four major post-marketing
surveillance (PMS) studies carried out in US, UK & Italy which included
(>69,000 patients).5-7
■ These PMS data reported adverse event in < 1% patient population, with
headache & dizziness being the most common reported events.1
■ Thus, review of data from a large population of controlled clinical trials,
analyses of post-marketing surveillance studies and spontaneously reported
adverse events confirmed the excellent safety profile of Ranitidine.1
Mills JG et al. The safety of ranitidine in over a decade of use. Aliment Pharmacol Ther 1997; 11: 129-137
Imman WHW. History of prescription event monitoring (PEM). Prescription event monitoring news 1983; 1: 1-16.
Eandi M, De Carli GF, Recchia G, et al. Ranitidine : Eight years of post-marketing surveillance. Post Marketing Surveillance 1990; 4: 1-8.
Das AF, Freston JW, Jacobs J, et al. An evaluation of safety in 37252 patients treated with cimetidine or ranitidine. Intern Med 1990; 11: 127-49.

16. O'Connor et al., 1986 and Grant et al.,
1989 concluded that there was no
increase in mutagenic activity of gastric
juice following treatment with Ranitidine
150 mg twice daily for 4 to 20 weeks or
150mg at night for 12 months.8,9
8. O'ConnorRJ, Riley SE,Axon ATR, GarnerRC. Effects of histamine H2-receptor antagonist(H2RA)therapy on mutagenic activity in gastric juice. Abstract. Gut 1986; 27: A608.
9. Grant SM,LangtryRD, Brodgen RN. Ranitidine:an updatedreview of its pharmacodynamic and pharmacokinetic properties and therapeutic use in peptic ulcer disease and other allied diseases. Drugs 1989; 37: 801-870.

17. Del Risco et al. 1984 & Thomas et al. 1987
reported that after 24 hours or following 6 weeks of
treatment with ranitidine 150mg twice daily, there
was no change in the concentration of N-nitroso
compounds, and the values were no different from
controls after 12 months of continuous therapy. Also,
no information about the synthesis of N-nitroso
compounds during treatment with Ranitidine is
available.10,11
10. Del Risco FG, Rolin 0, Farinotti R, Chau NP, Mourot J, et al. Influence de la ranitidine durant une periode de 24 heures sur la teneur en nitrites, nitrates, nitrosamines et sur la flore bacterienne du suc gastrique du sujet sain. Gastroenterologie Clinique et Biologique 1984; 8: 749-753.
11. Thomas JM, Misiewicz JJ, Cook AR, Hill MJ, Smith PLR, et al. Effects of one year's treatment with ranitidine and of troncal vagotomy on gastric contents. Gut 1987; 28: 726-738.

18. 10 years teatment
Vial et al., 1991, in a long
term study showed no
excess risk of gastric
neoplasia during treatment
with Ranitidine for a
continuous treatment
period of more than 10
years.12
12. Vial T et al. Side Effects of Ranitidine. Drug Safety 6 (2): 94-117. 1991.

19. Ranitidine and
Carcinoma
■ Brusselaers N et al., in 2017 and 2018
carried out a population-based cohort
study which confirmed that the risk of
gastric cancer & Esophageal cancer
respectively [adenocarcinoma
(SIR=0.39) & squamous cell carcinoma
(SIR=0.50)] was not increased in the
group receiving H2RA.13,14
■ Ranitidine has shown good safety even in
most of recently published studies from
2015 onwards when compared with newer
class of drugs used to treat similar
conditions.
Recent studies
13. Brusselaers N et al. Maintenance therapy with proton pump inhibitors and risk of gastric cancer: a
nationwide population-based cohort in Sweden. BMJ Open 2017;7:e017739. doi:10.1136/bmjopen-
2017-017739.
14. Brusselaers N et al. Maintenance proton pump inhibition therapy and risk of oesophageal cancer.
Cancer Epidemiology 2018; 53:172–177.

20. RANITIDINE
& NDMA impurity

21. Sept 2019 – THE NDMA STORY SO FAR
The purity of Ranitidine has been
challenged based on citizen petition
filed in Sept 2019 by an online
pharmacy company in USA
USFDA has set NDMA permissible
limits in relation to the angiotensin
receptor blockers (ARBs) and not for
Ranitidine.
USFDA observed the testing method
used by a third-party laboratory, which
generated very high levels of NDMA
from Ranitidine products. Begins its
own testing.
USFDA has published the method for
testing angiotensin II receptor blockers
(ARBs) for nitrosamine impurities.
USFDA has recommended using
a LC-HRMS (Liquid Chromatography
High Resolution Mass Spectrometry)
testing protocol for levels of NDMA in
Ranitidine.
The USFDA also cautioned that to
date, the agency’s early, limited testing
found unacceptable levels of NDMA in
samples of Ranitidine. The agency will
provide more information as it
becomes available.38
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine. Last accessed on 12th October, 2019.

22. USFDA & NDMA
USFDA38
(13th Sept 2019)-
The FDA is not calling for individuals to stop taking Ranitidine at this time; however, patients
taking Rx Ranitidine who wish to discontinue should talk to their Health care professional
about other options.
(2nd Oct 2019)-
Agency observed that the testing method applied by a “third-party laboratory” used higher
temperatures. “The higher temperatures generated very high levels of NDMA from Ranitidine
products because of this test procedure. USFDA published the method used for testing ARBs
for nitrosamine impurities. That method is not suitable for testing Ranitidine because heating
the sample generates NDMA.”
(11th Oct 2019)-
Not all ranitidine medicines marketed in the U.S. are being recalled. FDA does not have
scientific evidence to recommend whether individuals should continue or stop taking
ranitidine medicines at this time. The agency is conducting further tests to determine the risk
to consumers.
https://www.fda.gov/drugs/drug-safety-and-availability/fda-updates-and-press-announcements-ndma-zantac-ranitidine. Last accessed on 12th October, 2019.
USFDA has not asked for recall of Ranitidine

23. MHRA & NDMA
MHRA39
(8th Oct 2019)-
“We are advising that patients should not stop taking their
medication, but should speak to their doctor or pharmacist
if they are concerned and should seek their doctors before
stopping any prescribed medicine.
Currently there is no evidence that medicines containing
nitrosamines have caused any harm to patients, but the
Agency is closely monitoring the situation, and working
with other Regulatory Agencies around world.”
https://www.gov.uk/government/news/zantac-mhra-drug-alert-issued-as-glaxosmithkline-recalls-all-unexpired-stock. Last accessed on 12th October, 2019.
MHRA has not asked for recall of Ranitidine

24. EPA & NDMA
EMA40
(26th Sept 2019)-
European Medicine Agency - EMA’s human medicines
committee (CHMP) is requesting as a matter of
precaution that marketing authorization holders for
human medicines containing chemically synthesized
active substances review their medicines for the
possible presence of nitrosamines and test all
products at risk.
40. https://www.ema.europa.eu/en/news/ema-advises-companies-steps-take-avoid-nitrosamines-human-medicines. Last accessed on12thOctober, 2019.
EMA has not asked for recall of Ranitidine

25. DCG(I)
DCG(I)41
(23rd Sept 2019)-
Informed all state /UT drug controllers to ask all API and
formulation manufactures under their jurisdiction to verify
their products and take appropriate measures to ensure
patient safety
41. DCG(I): Govt of India, Directorate General of Health Services F No 12-03/19-DC (Safety-007) Dated 23-09-2019.
In India DCG(I) has not asked for recall of Ranitidine

26. ICH (M7)42
The calculated daily intake levels would thus be 1.5 µg for
treatment duration of 70 years, 10 µg for 10 years, 100 µg
for 1 year, 1270 µg for 1 month and approximately 38.3 mg
as a single dose, all resulting in the same cumulative
intake and therefore theoretically in the same cancer risk (1
in 100,000).
A guideline from ICH
Harmonised Guideline:
Assessment and Control of
DNA Reactive (Mutagenic)
Impurities in
Pharmaceuticals to Limit
Potential Carcinogenic
Risk, M7 (R1) - (Current
Step 4 version dated 31
March 2017)
ICH(M7)
1 in 1,00,000 patients taking a
impurity drug daily for 70
years may have a risk of
cancer
https://database.ich.org/sites/default/files/M7_R1_Guideline.pdf Last accessed on 12th October,
The International Council for Harmonisation of Technical
Requirements for Pharmaceuticals for Human Use (ICH)

27. RANITIDINE & NDMA
“Only in Nov 2019, FDA has set the acceptable daily
intake limit for NDMA at 0.096 micrograms (0.96
nanogms) or 0.32 ppm for ranitidine”

28. Facts
■ The regulatory authority of India (DCGI / CDSCO) has not asked for any recall
or any ban on the drug Ranitidine or its formulations.
■ International regulatory authority like USFDA has not asked for ban. However,
recently (2nd Nov) asked for voluntary recall of those brand who have NDMA
detected above permissible limit.
■ Recall of finished goods initiated from the market is a voluntary recall by
manufacturers on their own.
■ API vendors got the product analyzed as per international guidelines who
reported NDMA well within permissible limits. Risk analysis report submitted to
regulatory authorities.

29. 1st and 2nd NOV : USFDA – Excerpts / summary
■ The agency has tested numerous ranitidine products on the market over the past few
months, and today we’re releasing a summary of the results we have to date.
■ Through our testing so far, we have found levels of NDMA in ranitidine that are similar
to the levels you would expect to be exposed to if you ate common foods like grilled or
smoked meats.
■ We also conducted tests that simulate what happens to ranitidine after it has been
exposed to acid in the stomach with a normal diet and results of these tests indicate
that NDMA is not formed through this process.
■ Similarly, if ranitidine is exposed to a simulated small intestine environment,
NDMA is not formed.

30. 1st and 2nd NOV : USFDA – Excerpts / summary
■ FDA also developed a simulated gastric fluid (SGF) model to be used with the LC-MS
testing method to estimate the biological significance of in vitro findings.
■ The SGF and simulated intestinal fluid (SIF) models are intended to detect the
formation of NDMA in systems that approximate the stomach and intestinal fluids,
respectively. The results of these tests showed no additional NDMA generated in
the stomach. Although many of these levels of NDMA observed through FDA testing
are much lower than the levels some third-party scientists first claimed
■ FDA has set the acceptable daily intake limit for NDMA at 0.096 micrograms or 0.32
ppm for ranitidine. The calculated acceptable intake for NDMA in drugs is based on
methods described in the 2018 ICH Guidance M7(R1): Assessment and Control of
DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential
Carcinogenic Risk (1:100,000 chance if 100,000 people consume >0.096mg of NDMA
daily for 70 years).

31. 1st and 2nd NOV : USFDA – Excerpts / summary
■ If NDMA levels above the acceptable limits, we are asking companies to voluntarily
recall ranitidine. The FDA is committed to sharing all findings when we have adequate
understanding of the situation and of what actions should be taken. We will continue to
work with drug manufacturers to ensure safe, effective, and high-quality drugs for the
American public.
NUTSHELL: If within permissible limit, needs no recall and its safe.