Impurities found in certain angiotensin II receptor blocker (ARB) products, also known as sartans

Table of Contents

Overview

In the summer of 2018, several valsartan products were recalled in Canada and worldwide because of the impurity, N-nitrosodimethylamine (NDMA), found in the active ingredient manufactured by Zhejiang Huahai Pharmaceuticals in China.

Since that time, NDMA and other similar impurities, N-nitrosodiethylamine (NDEA), N-Nitrosodiisopropylamine (NDIPA) and N-Nitrosomethyl-n-butylamine (NMBA), have been found in valsartan or other drugs in the same class as valsartan (referred to as angiotensin II receptor blockers or ARBs) made by several different manufacturers in different countries and has prompted additional recalls in Canada and worldwide.

ARBs are used to treat patients with high blood pressure to help prevent heart attacks and stroke. NDEA, NDMA, NDIPA and NMBA are nitrosamines that are classified as probable or potential human carcinogens, which means that long-term exposure could increase the risk of cancer. Since the risk of cancer is with long-term exposure, there is no immediate health risk associated with the use of ARBs containing these impurities.

Health Canada recognizes the stress caused by this issue to Canadians who rely on these important medications. The Department has been working with companies and international regulatory partners to determine the root cause of the issue and to verify that appropriate actions are taken to prevent it from happening again.

Health Canada continues to hold manufacturers responsible for the safety and effectiveness of drugs sold on the Canadian market and has taken several actions to mitigate the risk to Canadians, including:

  • Requested, confirmed and monitored the effectiveness of recalls due to this issue. A list of recalled products is provided below and will be updated as needed.
  • Communicated the recalls, NDMA risk estimates, and Health Canada actions to Canadians on several occasions.
  • Contacted all market authorization holders of all ARBs of concern in Canada and assessed the manufacturing processes they use to make products sold in Canada.
  • Determined that the Chuannan site of Zhejiang Huahai Pharmaceuticals and Hetero Laboratories Limited, Unit 1 are Non-Compliant with Good Manufacturing Practices requirements. This means that no products can be imported from those sites, unless they are considered medically necessary. Tested samples of ARBs on the Canadian market. Test results are provided below and will be updated as additional test results become available.
  • Requested market authorization holders of ARBs of concern test all products currently on the market and any new products not yet released for NDEA and NDMA. Companies were also requested to consider using manufacturing practices that avoid the generation and presence of all nitrosamine impurities. This added safeguard will provide greater assurance of the safety of ARBs in Canada.

Health Canada continues to work closely with international regulatory partners, including the US Food and Drug Administration and the European Medicines Agency, to share information and coordinate efforts on inspections, risk assessments and public communications. We will continue to take action and update Canadians should any new risks be identified for products on the Canadian market.

Recalls

Health Canada is publishing a complete list of angiotensin II receptor blocker (ARB) products recalled in Canada due to the presence of or the potential for nitrosamine impurities. This list will be updated if new products are recalled. Products not on this list have not been recalled in Canada due to this issue. It should be noted that recalls taking place in other countries may not impact Canadian products.

Patients taking recalled medications should:

  • Continue taking your medication unless you have been advised to stop by your health care provider.
  • Contact your health care provider to discuss treatment options if you have been using an affected product.
  • Ask your pharmacist if you are unsure whether you are taking a recalled product.
  • Contact your health care provider if you have taken a recalled product and you have concerns about your health.
List of recalled products:
Product name/Active Pharmaceutical Ingredient DIN Strength Lot # Date Recalled API Manufacturer
PRO DOC LIMITEE - IRBESARTAN 02365200 150 mg 604292 March 11, 2019 TEVA API India Ltd.
PRO DOC LIMITEE - IRBESARTAN 02365219 300 mg 601795 March 11, 2019 TEVA API India Ltd.
APO-LOSARTAN 02379058 25 mg NL1453 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN 02379058 25 mg NL1452 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN 02353504 50 mg NK1254 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN 02353504 50 mg NK1253 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN 02353512 100 mg NL1461 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN 02353512 100 mg NG2092 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN 02353512 100 mg NH5932 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN 02353512 100 mg NH5933 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN 02353512 100 mg NL1460 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN 02353512 100 mg NH5934 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371235 50/12.5 mg NL1441 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371235 50/12.5 mg NZ8848 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371235 50/12.5 mg NL1445 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371235 50/12.5 mg NZ8849 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371235 50/12.5 mg NZ8860 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371243 100/12.5 mg NG2087 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371243 100/12.5 mg NL1421 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371243 100/12.5 mg NG2086 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371243 100/12.5 mg NL1422 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371251 100/25 mg NL1429 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371251 100/25 mg NZ8846 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371251 100/25 mg NZ8847 March 8, 2019 Hereto Laboratories Limited Unit 1
APO-LOSARTAN/HCTZ 02371251 100/25 mg NZ8845 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309750 25 mg 498294 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309750 25 mg 605342 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309750 25 mg 611944 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309769 50 mg 498285 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309769 50 mg 600047 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309769 50 mg 600091 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309769 50 mg 603894 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309769 50 mg 612025 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309769 50 mg 612031 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309769 50 mg 612679 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309769 50 mg 616743 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309777 100 mg 498864 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309777 100 mg 602668 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309777 100 mg 603816 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309777 100 mg 605298 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309777 100 mg 605300 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309777 100 mg 613935 March 8, 2019 Hereto Laboratories Limited Unit 1
PMS-LOSARTAN 02309777 100 mg 613936 March 8, 2019 Hereto Laboratories Limited Unit 1
LOSARTAN (PRO DOC LIMITEE) 02394367 25 mg 498292 March 8, 2019 Hereto Laboratories Limited Unit 1
LOSARTAN (PRO DOC LIMITEE) 02394367 25 mg 605344 March 8, 2019 Hereto Laboratories Limited Unit 1
LOSARTAN (PRO DOC LIMITEE) 02394375 50 mg 498779 March 8, 2019 Hereto Laboratories Limited Unit 1
LOSARTAN (PRO DOC LIMITEE) 02394375 50 mg 600046 March 8, 2019 Hereto Laboratories Limited Unit 1
LOSARTAN (PRO DOC LIMITEE) 02394375 50 mg 603903 March 8, 2019 Hereto Laboratories Limited Unit 1
LOSARTAN (PRO DOC LIMITEE) 02394375 50 mg 498284 March 8, 2019 Hereto Laboratories Limited Unit 1
LOSARTAN (PRO DOC LIMITEE) 02394375 50 mg 603895 March 8, 2019 Hereto Laboratories Limited Unit 1
LOSARTAN (PRO DOC LIMITEE) 02394383 100 mg 499008 March 8, 2019 Hereto Laboratories Limited Unit 1
LOSARTAN (PRO DOC LIMITEE) 02394383 100 mg 605299 March 8, 2019 Hereto Laboratories Limited Unit 1
LOSARTAN (PRO DOC LIMITEE) 02394383 100 mg 605297 March 8, 2019 Hereto Laboratories Limited Unit 1
TEVA-LOSARTAN/HCTZ 02358263 50/12.5 mg 35344801A March 6, 2019 Hereto Laboratories Limited Unit 1
TEVA-LOSARTAN/HCTZ 02358263 50/12.5mg 35349397A March 6, 2019 Hereto Laboratories Limited Unit 1
MYLAN-VALSARTAN 02383527 40 mg All lots November 28, 2018 Mylan Laboratories Limited
MYLAN-VALSARTAN 02383535 80 mg All lots November 28, 2018 Mylan Laboratories Limited
MYLAN-VALSARTAN 02383543 160 mg All lots November 28, 2018 Mylan Laboratories Limited
MYLAN-VALSARTAN 02383551 320 mg All lots November 28, 2018 Mylan Laboratories Limited
TEVA-VALSARTAN/HCTZ TABLETS 02356996 80/12.5 mg 35211136A August 17, 2018 Zhejiang Huahai Pharmaceuticals
TEVA-VALSARTAN/HCTZ TABLETS 02357003 160/12.5 mg 35211335A August 17, 2018 Zhejiang Huahai Pharmaceuticals
TEVA-VALSARTAN/HCTZ TABLETS 02357003 160/12.5 mg 35211844R August 17, 2018 Zhejiang Huahai Pharmaceuticals
TEVA-VALSARTAN/HCTZ TABLETS 02357011 160/25 mg 35210937R August 17, 2018 Zhejiang Huahai Pharmaceuticals
TEVA-VALSARTAN/HCTZ TABLETS 02357011 160/25 mg 35210938R August 17, 2018 Zhejiang Huahai Pharmaceuticals
TEVA-VALSARTAN/HCTZ TABLETS 02357011 160/25 mg 35210939R August 17, 2018 Zhejiang Huahai Pharmaceuticals
TEVA-VALSARTAN/HCTZ TABLETS 02357011 160/25 mg 35210940R August 17, 2018 Zhejiang Huahai Pharmaceuticals
TEVA-VALSARTAN/HCTZ TABLETS 02357038 320/12.5 mg 35211546R August 17, 2018 Zhejiang Huahai Pharmaceuticals
ACT-VALSARTAN 40MG FC TABLETS 02337487 40 mg K47338 July 9, 2018 Zhejiang Huahai Pharmaceuticals
ACT-VALSARTAN 80MG FC TABLETS 02337495 80 mg K45370 July 9, 2018 Zhejiang Huahai Pharmaceuticals
ACT-VALSARTAN 80MG FC TABLETS 02337495 80 mg K47652 July 9, 2018 Zhejiang Huahai Pharmaceuticals
ACT-VALSARTAN 80MG FC TABLETS 02337495 80 mg K47653 July 9, 2018 Zhejiang Huahai Pharmaceuticals
ACT-VALSARTAN 80MG FC TABLETS 02337495 80mg K47654 July 9, 2018 Zhejiang Huahai Pharmaceuticals
ACT-VALSARTAN 160MG FC TABLETS 02337509 160 mg K39691 July 9, 2018 Zhejiang Huahai Pharmaceuticals
ACT-VALSARTAN 160MG FC TABLETS 02337509 160 mg K44167 July 9, 2018 Zhejiang Huahai Pharmaceuticals
ACT-VALSARTAN 160MG FC TABLETS 02337509 160 mg K47657 July 9, 2018 Zhejiang Huahai Pharmaceuticals
ACT-VALSARTAN 160MG FC TABLETS 02337509 160 mg K47658 July 9, 2018 Zhejiang Huahai Pharmaceuticals
ACT-VALSARTAN 320MG FC TABLETS 02337517 320 mg K44166 July 9, 2018 Zhejiang Huahai Pharmaceuticals
ACT-VALSARTAN 320MG FC TABLETS 02337517 320 mg K45371 July 9, 2018 Zhejiang Huahai Pharmaceuticals
PRO DOC LIMITEE VALSARTAN 40 MG 02367726 40 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
PRO DOC LIMITEE VALSARTAN 80 MG 02367734 80 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
PRO DOC LIMITEE VALSARTAN 160 MG 02367742 160 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
PRO DOC LIMITEE VALSARTAN 320 MG 02367750 320 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SANDOZ VALSARTAN 40 MG 02356740 40 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SANDOZ VALSARTAN 80 MG 02356759 80 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SANDOZ VALSARTAN 160 MG 02356767 160 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SANDOZ VALSARTAN 320 MG 02356775 320 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SANIS VALSARTAN 40 MG 02366940 40 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SANIS VALSARTAN 80 MG 02366959 80 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SANIS VALSARTAN 160 MG 02366967 160 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SANIS VALSARTAN 320 MG 02366975 320 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SIVEM PHARMACEUTICAL ULC VALSARTAN 40 MG 02384523 40 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SIVEM PHARMACEUTICAL ULC VALSARTAN 80 MG 02384531 80 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SIVEM PHARMACEUTICAL ULC VALSARTAN 160 MG 02384558 160 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
SIVEM PHARMACEUTICAL ULC VALSARTAN 320 MG 02384566 320 mg All lots July 9, 2018 Zhejiang Huahai Pharmaceuticals
TEVA-VALSARTAN/HCTZ TABLETS PP 30s 02357046 320/25 mg 35212731R July 9, 2018 Zhejiang Huahai Pharmaceuticals

Test Results

Health Canada has tested samples of ARBs on the Canadian market for NDMA and NDEA and the results are posted below. Health Canada will continue to assess new developments to determine whether additional testing is necessary.

The results indicate the NDMA or NDEA levels detected, whether they exceed acceptable limits, based on a lifetime exposure, and whether the product was recalled.

Health Canada's testing results:
Market Authorization Holder (Company) Name Product Name DIN Strength
(mg)
Lot Number API Manufacturer Expiry Date NDMA Result
ng / tablet
NDEA Result
ng / tablet
NDMA Limit
(96 ng/day) Exceeded?Footnote *
NDEA Limit
(26.5 ng/day) Exceeded?Footnote *
Recalled in Canada Date Added
Accel Pharma Inc. ACCEL-CANDESARTAN 02463784 32 1805003937 Alembic Pharmaceuticals Limited (API Division - II) 2020-02-29 Not Detected Not Detected No No No December 20, 2018
Actavis Pharma Company ACT VALSARTAN 02337517 320 K44166 Zhejiang Huahai Pharmaceutical Co., Ltd. 2018-07-31 15242.72 12.78 Yes No Yes December 20, 2018
ACT VALSARTAN 02337517 320 K45371 Zhejiang Huahai Pharmaceutical Co., Ltd. 2018-10-31 10770.86 186.67 Yes Yes Yes December 20, 2018
ACT- OLMESARTAN 02442205 40 F83746 Zhejiang Huahai Pharmaceutical Co., Ltd. 2020-03-31 Not Detected Not Detected No No No December 20, 2018
Angita Pharma Inc. AG-IRBESARTAN 02474417 300 IE317017AR Jubilant Generics Limited 2019-10-31 Not Detected Not Detected No No No December 20, 2018
Apotex Inc. APO-OLMESARTAN/HCTZ 02453614 40/12.5 NF7704 Apotex Pharmachem India Pvt. Ltd. 2019-02-28 Not Detected Not Detected No No No December 20, 2018
APO-OLMESARTAN/HCTZ 02453614 40/12.5 NN7635 Signa S.A. de C.V. 2019-12-31 Not Detected Not Detected No No No December 20, 2018
APO-LOSARTAN/HCTZ 02371235 50/12.5 NL1445 Hetero Labs Limited 2019-08-31 Not Detected Not Detected No No No December 20, 2018
APO-LOSARTAN 02353512 100 NL1461 Hetero Labs Limited 2019-08-31 Not Detected Not Detected No No No December 20, 2018
AstraZeneca Inc. ATACAND - CANDESARTAN 02311658 32 KL0275 Takeda Pharmaceutical Company Limited 2021-04-30 Not Detected Not Detected No No No December 20, 2018
Auro Pharma Inc. AURO-CANDESARTAN HCT 02421046 32/12.5 WKSA18004-A Aurobindo Pharma Limited & Chromo Laboratories Limited 2020-07-29 Not Detected Not Detected No No No December 20, 2018
AURO-OLMESARTAN 02443872 40 WOSB18004-A Aurobindo Pharma Unit-I 2020-01-12 Not Detected Not Detected No No No December 20, 2018
AURO-LOSARTAN 02403358 100 WB1018003-A Aurobindo Pharma Unit-I 2021-03-15 Not Detected Not Detected No No No December 20, 2018
AURO-VALSARTAN 02414201 40 VWSA17003-A Aurobindo Pharma Limited, Unit-XI 2019-10-31 Not Detected 1.41 No No No January 16, 2019
AURO-VALSARTAN 02414201 40 VWSA18007-A Aurobindo Pharma Limited, Unit-XI 2020-08-24 Not Detected 1.07 No No No January 16, 2019
AURO-VALSARTAN 02414201 40 VWSA18003-A Aurobindo Pharma Limited, Unit-XI 2020-08-23 Not Detected 1.04 No No No January 16, 2019
AURO-VALSARTAN 02414228 80 VWSB17010-A Aurobindo Pharma Limited, Unit-XI 2019-07-31 Not Detected Not Detected No No No January 16, 2019
AURO-VALSARTAN 02414228 80 VWSB17011-A Aurobindo Pharma Limited, Unit-XI 2019-07-31 Not Detected Not Detected No No No January 16, 2019
AURO-VALSARTAN 02414236 160 VWSC17001-A Aurobindo Pharma Limited, Unit-XI 2018-12-31 Not Detected < 3.20 No No No January 16, 2019
AURO-VALSARTAN 02414236 160 VWSC17005-A Aurobindo Pharma Limited, Unit-XI 2019-05-31 Not Detected < 3.20 No No No January 16, 2019
AURO-VALSARTAN 02414236 160 VWSC18002-A Aurobindo Pharma Limited, Unit-XI 2020-01-19 Not Detected 4.58 No No No January 16, 2019
AURO-VALSARTAN 02414236 160 VWSC18001-A Aurobindo Pharma Limited, Unit-XI 2020-01-19 < 6.40 4.39 No No No January 16, 2019
AURO-VALSARTAN 02414236 160 VWSC18016-A Aurobindo Pharma Limited, Unit-XI 2020-08-24 Not Detected 4.7 No No No January 16, 2019
AURO-VALSARTAN 02414244 320 VWSD17001-B Aurobindo Pharma Limited, Unit-XI 2019-05-31 Not Detected Not Detected No No No January 16, 2019
AURO-VALSARTAN 02414244 320 VWSD18005-A Aurobindo Pharma Limited, Unit-XI 2020-08-25 Not Detected 12.14 No No No January 16, 2019
AURO-VALSARTAN 02414244 320 VWSD18001-A Aurobindo Pharma Limited, Unit-XI 2020-04-15 Not Detected 8.56 No No No January 16, 2019
AURO-VALSARTAN 02414244 320 VWSD18001-A Aurobindo Pharma Limited 2020-04-15 Not Detected 8.61 No No No December 20, 2018
AURO-VALSARTAN HCT 02408112 80/12.5 HHSA18001-A Aurobindo Pharma Limited, Unit-XI 2021-08-02 Not Detected 1.88 No No No January 16, 2019
Jamp Pharma Corp JAMP-OLMESARTAN 02461668 40 MC218002A Glenmark Pharmaceuticals Limited 2020-04-30 Not Detected Not Detected No No No December 20, 2018
JAMP-LOSARTAN-HCTZ 02408252 100/25 LY218001A Jubilant Generics Limited 2019-06-30 Not Detected Not Detected No No No December 20, 2018
JAMP-IRBESARTAN 02418215 300 IE318005A Jubilant Generics Limited 2020-03-31 Not Detected Not Detected No No No December 20, 2018
Merck Canada Inc. OLMETEC - OLMESARTAN 02318679 40 N021852 Daiichi Sankyo Chemical Pharma Co., Ltd. Hiratsuka Plant 2020-04-30 Not Detected Not Detected No No No December 20, 2018
Mint Pharmaceuticals Inc. MINT-LOSARTAN/HCTZ DS 02389673 100/25 1805009844 Alembic Pharmaceuticals Limited (API Division - II) 2021-07-31 Not Detected Not Detected No No No December 20, 2018
Mylan Pharmaceuticals ULC MYLAN-VALSARTAN 02383527 40 3048813 Mylan Laboratories Limited, Unit 8, in Hyderabad, India 2017-11-30 < 1.60 8.32 No Yes Yes January 16, 2019
MYLAN-VALSARTAN 02383535 80 3056368 Mylan Laboratories Limited, Unit 8, in Hyderabad, India 2019-06-30 < 3.20 22.43 No Yes Yes January 16, 2019
MYLAN-VALSARTAN 02383543 160 3056371 Mylan Laboratories Limited, Unit 8, in Hyderabad, India 2019-06-30 Not Detected 62.76 No Yes Yes January 16, 2019
MYLAN-VALSARTAN 02383551 320 3048815 Mylan Laboratories Limited, Unit 8, in Hyderabad, India 2017-11-30 Not Detected 132.77 No Yes Yes January 16, 2019
Novartis Pharmaceuticals Canada Inc. DIOVAN 02289504 320 BEK32 Novartis Pharma Schweizerhalle 2021-07-31 Not Detected Not Detected No No No December 20, 2018
Pharmascience Inc. PMS-CANDESARTAN HCTZ 02391295 16 615170 Zhejiang Huahai Pharmaceutical Co., Ltd. 2020-04-30 Not Detected Not Detected No No No December 20, 2018
PMS-LOSARTAN 02309777 100 613936 Hetero Labs Limited 2021-03-31 Not Detected 10.41 No No No December 20, 2018
PMS-LOSARTAN-HCTZ 02392232 100/12.5 0803847 Dr. Reddy's Laboratories Limited 2020-06-30 Not Detected Not Detected No No No December 20, 2018
PMS-IRBESARTAN 02317087 300 615908 Zhejiang Tianyu Pharmaceutical Co., Ltd. 2021-03-31 Not Detected Not Detected No No No December 20, 2018
PMS-IRBESARTAN-HCTZ 02328526 300/12.5 606524 Zhejiang Tianyu Pharmaceutical Co., Ltd., 2018-11-30 Not Detected Not Detected No No No December 20, 2018
PMS-IRBESARTAN-HCTZ 02328526 300/12.5 611016 USV Private Limited 2019-11-30 Not Detected Not Detected No No No December 20, 2018
Ranbaxy Pharmaceuticals Canada Inc. RAN-VALSARTAN 02363119 160 2884804 Sun Pharmaceutical Industries Limited 2019-05-31 Not Detected Not Detected No No No December 20, 2018
Sandoz Canada Inc. SANDOZ CANDESARTAN 02417340 32 JC3223 Zhejiang Huahai Pharmaceutical Co., Ltd. 2020-06-30 Not Detected Not Detected No No No December 20, 2018
SANDOZ CANDESARTAN PLUS 02420732 32 HY8217 Zhejiang Tianyu Pharmaceutical Co., Ltd. 2020-04-30 Not Detected Not Detected No No No December 20, 2018
SANDOZ OLMESARTAN 02443422 40 HX2039 Zhejiang Huahai Pharmaceutical Co., Ltd. 2020-02-28 Not Detected Not Detected No No No December 20, 2018
SANDOZ LOSARTAN 02313359 100 JD6746 Zhejiang Huahai Pharmaceutical Co., Ltd. 2020-04-30 Not Detected Not Detected No No No December 20, 2018
SANDOZ VALSARTAN 02356775 320 HW4965 Zhejiang Huahai Pharmaceutical Co., Ltd. 2020-12-31 2703.76 Not Detected Yes No Yes December 20, 2018
SANDOZ IRBESARTAN 02328496 300 HX4282 Zhejiang Huahai Pharmaceutical Co., Ltd. 2020-01-31 Not Detected Not Detected No No No December 20, 2018
SANDOZ IRBESARTAN 02328496 300 JD1818 Zhejiang Tianyu Pharmaceutical Co., Ltd. 2020-05-31 Not Detected Not Detected No No No December 20, 2018
Sanis Health Inc. IRBESARTAN 02372398 300 35213058A TEVA API INDIA PVT. LTD. 2019-12-31 Not Detected Not Detected No No No December 20, 2018
Sanofi-Aventis Canada Inc. AVAPRO - IRBESARTAN 02237925 300 KC001 CHINOIN Pharmaceutical and Chemical Works Private Co. Ltd. 2020-01-31 Not Detected Not Detected No No No December 20, 2018
Septa Pharmaceuticals Inc. SEPTA-LOSARTAN 02424983 100 LR318004A Jubilant Generics Limited 2020-03-31 Not Detected Not Detected No No No December 20, 2018
Sivem Pharmaceuticals Inc. LOSARTAN HCT 02388987 100/25 QX1018005-B Zhejiang Tianyu Pharmaceutical Co., Ltd. 2021-06-08 Not Detected Not Detected No No No December 20, 2018
IRBESARTAN 02385309 300 HX7687 Zhejiang Huahai Pharmaceutical Co., Ltd. 2019-12-31 Not Detected Not Detected No No No December 20, 2018
IRBESARTAN HCT 02385325 300/12.5 HY7380 Zhejiang Huahai Pharmaceutical Co., Ltd. 2020-11-30 Not Detected Not Detected No No No December 20, 2018
Teva Canada Limited TEVA-CANDESARTAN 02366339 32 2537058 Pliva Croatia Ltd. 2020-05-31 Not Detected Not Detected No No No December 20, 2018
TEVA-LOSARTAN 02357976 100 2070318 Teva API India Private Ltd 2021-03-31 Not Detected Not Detected No No No December 20, 2018
TEVA-LOSARTAN/HCTZ 02358263 50/12.5 35349397A Hetero Labs Limited 2020-09-30 Not Detected 10.3 No No No December 20, 2018
TEVA-IRBESARTAN 02316412 300 35213086A TEVA API INDIA LTD 2019-12-31 Not Detected Not Detected No No No December 20, 2018
TEVA-VALSARTAN 02356686 320 35211729R Jubilant Generics Limited 2019-03-31 Not Detected Not Detected No No No December 20, 2018
TEVA-VALSARTAN/HCTZ 02357038 320/12.5 35212732 Zhejiang Huahai Pharmaceutical Co., Ltd. 2019-10-31 14538.35 Not Detected This lot was never distributed No No December 20, 2018
TEVA-VALSARTAN/HCTZ 02357038 320/12.5 35211546R Zhejiang Huahai Pharmaceutical Co., Ltd. 2019-01-31 258.19 1770.87 Yes Yes Yes December 20, 2018
TEVA-VALSARTAN/HCTZ 02357046 320/25 35212731R Zhejiang Huahai Pharmaceutical Co., Ltd. 2019-11-30 13367.64 Not Detected Yes No Yes December 20, 2018
Table Footnote 1

These values are based on a drug's maximum daily dose as reflected in the drug label

Return to footnote * referrer

Test Method

Health Canada is providing a method that has been developed to detect and quantify the nitrosamine impurities N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in angiotensin II receptor blockers (ARBs).

Determination of N-Nitrosodimethylamine (NDMA) and N-Nitrosodiethylamine (NDEA) by GC-MS-MS (Direct Injection) in Sartan Finished Products and Drug Substances

1. Principle and Scope

The present method has been developed to detect and quantify the nitrosamine impurities N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA) in Valsartan, Irbesartan and Losartan finished products. The method is performed by gas chromatography-tandem mass spectrometry (GC-MS-MS) using direct injection.

The method can also be used to detect and quantify NDMA and NDEA in candesartan and olmesartan finished products, and in sartan drug substances (e.g. valsartan, irbesartan, losartan, candesartan, and olmesartan). However, if interferences are observed, further validation may be required.

2. Safety

Laboratory safety precautions are followed to ensure a safe and healthy work environment, including the use of personal protective equipment (including but not limited to a lab coat, protective eyewear, and nitrile or butyl rubber gloves) and appropriate laboratory engineering controls (e.g. containment ventilation equipment).

The chemicals used in this method are hazardous. Analysts should carefully read the Material Safety Data Sheet (MSDS) for each chemical. Due to the toxic nature of nitrosamines, it is recommended that diluted reference standard solutions be purchased in order to reduce the extent of potential exposure.

3. Reagents and Reference Standards

  • Methanol, HPLC grade (CAS #: 67-56-1)
  • NDMA: N-Nitrosodimethylamine solution (5000 μg/mL in methanol; CAS #: 62-75-9)
  • NDEA: N-Nitrosodiethylamine solution, (100 μg/mL in methanol; CAS #: 55-18-5)
  • NDMA-d6 solution: N-nitrosodimethylamine-d6 (1000 μg/mL in methanol; CAS #: 17829-05-9)

4. Instrument/Equipment

  • Agilent GC 7890A with MSMS 7000 with EI source or equivalent
  • Agilent DB-624 25 m x 0.32 μm 1.8 μm or equivalent
  • 2 mL amber screw-cap GC vials with caps (PTFE/Silicone)
  • 20 x 125 mm screw cap round bottom glass tubes with caps
  • Automatic pipettes, various volumes
  • Top-loading balance suitable for ± 0.01 g and Analytical balance suitable for ± 0.0001 g readability
  • Volumetric Flasks (class A), various volumes
  • Pasteur pipettes and pipette bulbs
  • Spatula
  • 15 mL amber glass vials with caps
  • 40 mL amber glass vials with caps
  • Vortex mixer, single and multi-tube
  • Vial racks and storage racks
  • Kimwipes
  • Mortar and pestle
  • Ultrasonic water bath
  • Centrifuge, Beckmann-Coulter Allegra X-15R or equivalent

5. Preparation of Solutions

Standard solutions
Reference Standard Stock solutions (as purchased)
  • NDMA standard solution in Methanol (5000 ppm)
  • NDEA standard solution in Methanol (100 ppm)
Internal Reference Standard Stock Solution (as purchased)
  • NDMA-d6 standard solution in Methanol (1000 ppm)
Diluted standard solutions
NDMA standard solution (200 ppm):
Transfer 800 μl of NDMA reference solution (5000 ppm) into a 20 mL volumetric flask, dilute to volume with methanol.
Diluted standard solution (NDMA: 40 ppm, NDEA: 20 ppm):
Transfer 800 μl of NDMA standard solution (200 ppm) and 800 μl of NDEA reference solution (100 ppm) into a 4 mL volumetric flask, dilute to volume with methanol.
Internal standard solution-1 (20 ppm):
Transfer 500 μl of NDMA-d6 standard solution (1000 ppm) into a 25 mL volumetric flask, dilute to volume with methanol.
Internal standard solution-2 (0.2 ppm):
Transfer 5 ml of NDMA-d6 standard solution (20 ppm) into a 500 mL volumetric flask, dilute to volume with methanol.
Calibration solutions
STD-12:
Transfer 500 μl of Diluted standard solution (NDMA: 40 ppm, NDEA: 20 ppm) and 50 μl of Internal standard solution-1 (20 ppm) into a 5 mL volumetric flask, dilute to volume with methanol. Mix well.
STD-7:
Transfer 1000 μl of STD-12 into a 20 mL volumetric flask, dilute to volume with Internal standard solution-2 (0.2 ppm). Mix well. This solution will be used for the system suitability test and system drift check.
STD-11:
1:1 dilution of STD-12 with Internal standard solution-2.
STD-10:
1:1 dilution of STD-11 with Internal standard solution-2.
STD-9:
1:1 dilution of STD-10 with Internal standard solution-2.
STD-8:
3:2 dilution of STD-9 with Internal standard solution-2.
STD-6:
1:1 dilution of STD-7 with Internal standard solution-2.
STD-5:
1:1 dilution of STD-6 with Internal standard solution-2.
STD-4:
2:3 dilution of STD-5 with Internal standard solution-2.
STD-3:
1:1 dilution of STD-4 with Internal standard solution-2.
STD-2:
1:1 dilution of STD-3 with Internal standard solution-2.
STD-1:
2:3 dilution of STD-2 with Internal standard solution-2.
Concentration of calibration solutions:
Description NDMA concentration (µg/mL) NDEA concentration (µg/mL) NDMA-d6 concentration (µg/mL)
STD-1 0.002 0.001 0.2
STD-2 0.005 0.0025 0.2
STD-3 0.01 0.005 0.2
STD-4 0.02 0.01 0.2
STD-5 0.05 0.025 0.2
STD-6 0.1 0.05 0.2
STD-7 0.2 0.1 0.2
STD-8 0.3 0.15 0.2
STD-9 0.5 0.25 0.2
STD-10 1 0.5 0.2
STD-11 2 1 0.2
STD-12 4 2 0.2

For NDMA, STD-1 to STD-6 are used as working range from 0.002 - 0.1 µg/mL, STD-6 to STD-12 are used as working range from 0.1 - 4.0 µg/mL.

For NDEA, STD-1 to STD-5 are used as working range from 0.001 - 0.025 µg/mL, STD-5 to STD-11 are used as working range from 0.025 - 1.0 µg/mL.

The working ranges of NDMA and NDEA can be adjusted as needed.

Sample Preparation
For finished product:

Weigh NLT 20 tablets and calculate average tablet weight. Carefully grind NLT 20 tablets into fine powder using a mortar and pestle.

Prepare triplicate samples for each product. Accurately weigh an amount equivalent to 250 mg of drug substance of the homogenized sample powder into a screw cap round bottom glass tube.

Using an automatic pipette, add 5 mL of NDMA-d6 internal standard solution-2 to each sample tube. Tightly cap the tubes, sonicate for 5 min, and then vortex the rack of tubes on the multi-tube vortex mixer at 2000 rpm for five minutes. Centrifuge the tubes for at least five minutes at 1500 rpm. Carefully remove the tubes from the centrifuge. Use a Pasteur pipette to transfer an aliquot from each tube to a 2 mL GC vial and cap.

Note: Method accuracy was assessed by recovery studies. Valsartan, Irbesartan, and Losartan finished products were spiked with reference standard solution in the following way:

For samples with NDMA above 0.3 ppm and/or NDEA above 0.08 ppm:
Spike sample solution with the reference standard solution at concentration level close to sample concentration and calculate recovery.
For samples with NDMA below 0.3 ppm and/or NDEA below 0.08 ppm:
Spike sample solution with STD-3 (1:1) to get solution containing 0.05 ppm of NDMA and 0.025 ppm of NDEA. Check S/N and calculate the LOD and LOQ.
For drug substance:

Prepare triplicate samples for each substance. Accurately weigh 250 mg of the homogenized sample powder into a screw cap round bottom glass tube.

Continue as per the instructions above for finished product. Spiking to determine method accuracy is recommended.

6. Instrument Operating Parameters:

Suggested GC parameters:

Injector Settings:
Injector Mode:
Pulsed Splitless
Injector temperature:
240 °C
Flow rate:
1.8 mL/min
Septum Purge Flow:
3 mL/min
Purge Flow:
50 mL/min after 0.75 minutes
Injection volume:
2.0 µL
Oven Program:

Initial Temp: 60°C

Hold: 2 min

Ramp # Rate (°C /min) Final Temp (°C) Hold Time (min)
1 5 130 0
2 40 240 5
Total Run Time: 24 min

Suggested MS settings

MS Transfer Line (Aux. Temp):
250 °C
Ion Source:
EI
Source Temperature:
250 °C
Solvent Delay:
6 min
Stop time:
15 min
Quench gas:
Helium at 2.25 mL/min
Collision gas:
Nitrogen at 1.5 mL/min
MS-MS parameters:
Analyte Retention time (min) Segment Retention time window (min) Precursor ion (m/z) Product ion (m/z) CE
(V)
Resolution Dwell (ms)
NDMA-d6 (ISTD) 7.8 1 7.5-8.1 80 50 5 wide/wide 100
NDMA 7.8 1 7.5-8.1 74 42 15 wide/wide 100
74 44 4 100
NDEA 12.7 2 12.4-13.0 102 44 12 wide/wide 150
102 85 2 150

7. System Suitability

The coefficient of determination (R2) for each calibration curve is NLT 0.995.
The signal-to-noise of the STD-1 (NDMA = 0.002 µg/mL; NDEA = 0.001 µg/mL) solution should be NLT 10.

8. Calculation

Construct calibration curves for NDMA and NDEA by plotting the ratio of response factor (NDMA or NDEA peak area divided by internal standard peak area) against standard concentration (µg/mL). Using the slopes and intercepts of the calibration curves, determine the content of NDMA and NDEA in each sample using the following equations.

For finished product:

The results, in ppm relative to the declared amount of sartan drug substance in the product, are given by:

Equation 1
Equation 1

Where,

y =
Ratio of Peak Area of NDMA or NDEA to Peak Area of NDMA-d6
b =
intercept of the linear curve
m =
slope of the linear curve
Wtspl =
sample weight (g)
AVGwt =
average tablet weight (g)
LC =
label claim of sample (g)
V =
5 mL (volume)
Equation 1 - Text Description

Parts per million equals y minus b over m, which is the difference between the ratio of the peak area of the impurity to peak area of internal standard minus the intercept of the linear curve over the slope of the linear curve. This value is multiplied by average tablet weight, then multiplied by the volume, divided by the sample weight and then divided by the label claim of the sample.

For drug substance:

The results, in ppm relative to the drug substance being tested, are given by:

Equation 2
Equation 2

Where,

y =
Ratio of Peak Area of NDMA or NDEA to Peak Area of NDMA-d6
b =
intercept of the linear curve
m =
slope of the linear curve
Wtspl =
sample weight (g)
V =
5 mL (volume)
Equation 2 - Text Description

Parts per million equals y minus b over m, which is the difference between the ratio of the peak area of the impurity to peak area of internal standard minus the intercept of the linear curve over the slope of the linear curve. This value is multiplied by the volume and then divided by the weight of the sample.

9. LOD and LOQ results

LOD/LOQ can be calculated using the S/N of the spiked sample solution (spiked with STD-3 at 1:1).

Theoretical LOD/LOQ:

If no spiked results are available, the theoretical LODs and LOQs can be calculated by using the S/N of STD-1 (NDMA: 0.002 µg/mL; NDEA 0.001 µg/mL).

For reference, the theoretical LOD/LOQ results at Health Canada are as follows:

Table: S/N of NDMA and NDEA of STD-1.
  NDMA NDEA
Drug substance conc. µg/mL µg/mL S/N LOD (calc.) ppm LOQ (calc.) ppm µg/mL S/N LOD (calc.) ppm LOQ (calc.) ppm
50 0.002 74 0.002 0.0054 0.001 55 0.002 0.0073

10. Sample Chromatograms

Figure 1: Chromatogram of sample with NDMA and NDEA detected.
Figure 1
Figure 1 - Text Description

The figure shows chromatograms of a sample showing typical peaks for NDMA and NDEA. The chromatograms are arranged in four rows.

  • The first row shows the Total Ion Current chromatogram from 6.0 to 15.0 minutes. There is a large peak at 8.5 minutes (labelled "matrix") and smaller peaks at 7.7 minutes (NDMA, NDMA-d6) and 12.6 minutes (NDEA).
  • The second row shows a Multiple Reaction Monitoring chromatogram (m/z 80.0 → 50.0) with a single peak at 7.735 minutes for the NDMA-d6 internal standard.
  • The third row shows two Multiple Reaction Monitoring chromatograms (m/z 74.0 → 44.0 and m/z 74.0 → 42.0) each with a single peak at 7.787 minutes for NDMA.
  • The fourth row shows two Multiple Reaction Monitoring chromatograms (m/z 102.0 → 85.0 and m/z 102.0 → 44.0) each with a single peak at 12.561 minutes for NDEA.
Figure 2: Chromatogram of STD-1.
Figure 2
Figure 2 - Text Description

The figure shows chromatograms of the STD-1 standard solution. The chromatograms are arranged in four rows.

  • The first row shows the Total Ion Current chromatogram from 6.0 to 15.0 minutes. There is a large peak at 7.7 minutes (NDMA, NDMA-d6) and a small peak at 8.5 minutes (labelled "matrix").
  • The second row shows a Multiple Reaction Monitoring chromatogram (m/z 80.0 → 50.0) with a single peak at 7.715 minutes for the NDMA-d6 internal standard.
  • The third row shows two Multiple Reaction Monitoring chromatograms (m/z 74.0 → 44.0 and m/z 74.0 → 42.0) each with a single peak at 7.767 minutes for NDMA.
  • The fourth row shows two Multiple Reaction Monitoring chromatograms (m/z 102.0 → 85.0 and m/z 102.0 → 44.0) each with a single peak at 12.515 minutes for NDEA.

The United States Food and Drug Administration (FDA) and the European Directorate for the Quality of Medicines (EDQM) have also published methods to detect NDMA and NDEA:

Health Canada Communications

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