Overseas manufacturing of key pharmaceutical ingredient leads to massive generics recalls

The debacle of valsartan recall expanded to include some losartan and irbesartan in 2019  and irbesartan in 2021

(November 25, 2018) Updated 9/20/2019 Torrent Pharmaceuticals losartan potassium; losartan potassium products from Teva 6/12/2019 and Legacy 4/29/2019 and Vivimed 5/6/2019 and MacLeods 6/26/2019 and Lupin 10/15/21

Important: please check this FDA press release for the most up-to-date valsartan, losartan, and irbesartan recalls.
Check this FDA release on irbesartan recalls announced by Lupin in October 2021.

History of the recall:

In early July of 2018, the European Medicines Agency (EMA), Health Canada, and drug agencies in Japan, Taiwan, and Hong Kong began a recall of certain suppliers' versions of valsartan, a popular blood pressure drug.

Chinese manufacturer Zhejiang Huhai had reported to international regulators that trace amounts of a contaminant N-nitrosodimethylamine (NDMA) were detected in its valsartan product. NDMA is known to be a cancer-causing carcinogen in animals and is considered to be a probable carcinogen in humans. NDMA can make its way into products as a result of certain manufacturing processes. For example, it is a byproduct from some fish processing and pesticide manufacturing and is also an organic chemical used in making liquid rocket fuel. While this sounds alarming, the amounts of impurities detected in tests by the EMA and the FDA have been very small and unlikely to have caused harm in patients who have already consumed them.

FDA Response
By mid-July of 2018, the U.S. FDA joined in the recall for valsartan drugs tied to Zhejiang Huhai, the Chinese manufacturing facility. Since then, two other plants, including another in China and one in India, have been linked to the NDMA impurity or a similar contaminant called NDEA (N-nitrosodiethylamine). On November 21, 2018, the FDA updated its recall list to include two other generic blood pressure drugs in the angiotensin II receptor blocker (ARB) treatment category: losartan by Sandoz (one lot due to NDEA) and irbesartan by ScieGen (some lots due to NDEA).

The FDA put Zhejiang Huahai Pharmaceutical Co. on its import alert list as of September 28, 2018, and will not allow drugs manufactured using ingredients produced at that plant to be marketed in the U.S.

What has become apparent to consumers from this debacle is that despite numerous pharmaceutical companies holding regulatory agency approvals to manufacture the same generic drug, in reality there are just a handful of production sites that manufacture and supply the vital ingredients (or "active pharmaceutical ingredients") to the many generic drug companies worldwide. So when NDMA and NDEA contaminated the valsartan production from just three plants located in China and India, it affected the supply available to dozens of generic pharmaceutical companies worldwide and in turn the availability of the treatment for tens of thousands of patients.

While about 40% of registered API manufacturing facilities are located in China or India, the share of total production supply from those facilities is much greater. CNBC reports that about 80% of the APIs in U.S. drugs come from facilities in China and India. The chart below shows the locations by country of U.S. registered API manufacturers:

Chart of API Manufacturers by Country

Inspecting the quality of hundreds of overseas manufacturing facilities is not easy. As of 2018, just 22 FDA staff were present in China. The European Medicines Agency (EMA), similar to the U.S. FDA, conducts 20-40 facility inspections per year. About ten percent of those inspected are found to be non-compliant with good manufacturing practices.

At least three manufacturing facilities are responsible for producing the valsartan ingredient that triggered massive drug recalls so far:

1. Zhejiang Huahai Pharmaceutical Co. Ltd. (China) NDMA contamination
U.S. suppliers
Torrent Pharmaceuticals
Solco Health*
Teva
Solco relabler Remedy Repack
HJ Harkins
NuCare Pharmaceuticals
Torrent relabler Remedy Repack
Teva relabler Actavis
Canadian Suppliers
Sandoz
Teva Canada
ACT
Sanis
Sivem
Pro Doc
2. Hetero Labs
(India) NDEA or NMBA contamination
U.S. suppliers
Camber
Vivimed Life Sciences
Camber resellers
Preferred Pharmaceuticals, Inc.
AvKARE
Bryant Ranch
Northwind Pharmaceuticals
Remedy Repack
Vivimed Life Sciences distributor
Heritage Pharmaceuticals

3.  Mylan Laboratories Limited facility

Mylan's facility in Hyderabad, India, has been plagued with quality problems for a number of years. On November 19, 2018, the EMA announced that in addition to a recall, it has banned all products (not just valsartan) produced at this facility from being sold or distributed in the European Union. Furthermore, other companies marketing valsartan products in the EU have been asked to test their products for the impurities. A Mylan facility (Unit 8) that makes active pharmaceutical ingredients (API) for valsartan in Andhra Pradesh, India received a warning letter from the U.S. FDA in November 2019 for deviating from good manufacturing practices: Letter to Mylan

The EMA plans to work with the pharmaceutical companies to determine how to reduce or eliminate the impurities from future production batches. Unfortunately, authorities do not know how long ago the problem began. Drugwatch.com reports that the contaminants may have been present in the products since 2012 or earlier.  In November 2018, Teva Pharmaceuticals recalled amlodipine/valsartan combination tablets that used product made at the Mylan facility in India. NDEA was detected in those products.

Not all valsartan-containing products have been recalled. The original brand name versions of the drug, Diovan and Diovan HCT by Novartis, are not affected by recalls in any country. However, Novartis' generics company Sandoz recently announced a recall of losartan in the U.S. and Sandoz Canada issued a recall on some of its valsartan products in July 2018.

Below is a list of FDA-identified companies that produce at least some valsartan (or irbesartan, losartan, or related products) that have not been recalled in the U.S. Note that some companies may appear on both recall and non-recall lists, so double check with your pharmacist or the FDA (see link below) to find out if your medication is affected by the recall:

COMPANIES WITH SOME VALSARTAN AND RELATED PRODUCTS THAT ARE
NOT AFFECTED BY THE RECALL AND DO NOT HAVE DETECTED LEVELS OF CONTAMINANT

ACCORD HEALTHCARE INC
ALEMBIC PHARMACEUTICALS INC
ALEMBIC PHARMACEUTICALS LIMITED
AMNEAL PHARMACEUTICALS LLC
APHENA PHARMA SOLUTIONS - TENNESSEE, LLC
A-S MEDICATION SOLUTIONS LLC
ASCEND LABORATORIES, LLC
AVKARE, INC
BRYANT RANCH PREPACK
GLENMARK PHARMACEUTICALS INC., USA
HISUN PHARMACEUTICALS USA, INC
INTAS PHARMACEUTICALS LIMITED
JUBILANT CADISTA PHARMACEUTICALS, INC
MACLEODS PHARMACEUTICALS LIMITED
NORTHWIND PHARMACEUTICALS
NUCARE PHARMACEUTICALS INC
OHM LABORATORIES INC
PROFICIENT RX LP
REMEDYREPACK INC
SCIEGEN PHARMACEUTICALS, INC
SUNSHINE LAKE PHARMA CO., LTD

(Source: FDA's "Assessment of Currently Marketed ARB Drug Products" 5/3/2019)

FDA Takes Steps to Deal with Shortages of Valsartan and Losartan-containing Products

Because hundreds of lots of the drugs have been recalled since last year, valsartan is on the FDA's drug shortage list. Unfortunately, price gouging has occurred. According to industry analysts, Indian company Alembic Pharmaceuticals, one of the few producers not involved in a recall, more than tripled the price of its versions of valsartan. The FDA has taken two specific steps recently to help alleviate the shortfall:

     
  • 1. On Mach 12, 2019, the FDA approved a new generic form of valsartan manufactured by Alkem Laboratories in Mubai, India. It was approved on a priority basis because of the growing drug shortage. The drug is available in 40, 80, 160, and 320 MG oral tablets and will be distributed in the U.S. by Ascend Laboratories, LLC. At least one of Alkem Labs' India plants has had some questionable practices; an FDA inspection of a plant in Baddi in March 2017 had numerous quality inspection issues. However, for this new generic product, the FDA said it has evaluated and been satisfied with Alkem's manufacturing process. In addition, Zydus Cadila received approval for a new generic version of valsartan hydrochlorothiazide (HCT) on March 15. It will be manufactured at a plant in Alamaheda, India.
  • 2. Consumers may not be reassured by this step, but on March 20, 2019, the FDA announced its decision to raise the acceptable limit -- temporarily -- of the minimum amount of contaminant NMBA for losartan from .96 parts per million (PPM) to 9.82 parts per million (PPM) for a six month period only. This is a ten-fold increase in levels of the impurity. "Agency scientists evaluated the risk of exposure at levels up to 9.82 ppm and determined that it presents no meaningful difference in cancer risk over a six-month time frame when compared to a lifetime of exposure of NMBA at .96 ppm." The FDA expects that in six months, the manufacturing issue will be solved and that many companies will be able to manufacture losartan without any impurities. On May 6, 2019, the FDA announced a recall of 19 lots of Vivimed (Heritage is the supplier) losartan potassium products because of NMBA levels of greater than 9.82 parts per million. See "FDA press release" below.

May 3, 2019: FDA Posts Some Lab Results of Contaminant Levels

FDA is posting test results showing NDMA and NDEA levels in recalled valsartan. "The analyses reflect average levels of the impurities present in a single tablet based on the strength of the tested medicines within the lots tested, which are identified in the table." Click here for FDA lab results.

Sources and More Reading:

FDA Press Release, with periodic updates: FDA updates on angiotensin II receptor blocker (ARB) recalls including valsartan, losartan and irbesartan.
-- FDA Import Alert list is a list of companies that have effectively been barred from providing ingredients for drug products in the U.S.: "Detention Without Physical Examination of Drugs From Firms Which Have Not Met Drug GMPs." The list includes Zhejiang Huahai Pharmaceutical Co in China which is associated with some of the valsartan recalls.
--FDA ARB drug recall list. As of September 23, 2019 this list contains 1,159 lot numbers of recalled ARB drugs. The list has not been updated since September 23, 2019. September 20, 2019 was the last announced recall of related products, and it was by Torrent for losartan potassium products.
--FDA ARB drugs that are under review or have been cleared and are not under recall: "Assessment of currently marketed ARB drug products." This list gives the availability status; as of February 27, 2020 there are just 43 drugs that have been tested and are not under recall and 386 products that are still being marketed but are "under review" with a status of "to be determined." No new information has been posted since April 2019.
--FDA Lab Results Showing Levels of Contaminant in valsartan products: FDA lab results posted May 3, 2019.
--Valsartan has been included on the list of drug shortages since 8/18/2018. This FDA page includes companies and valsartan products affected, along with status. Many of them are in recall status.
--Valsartan products recalled and not recalled in Canada by Health Canada plus these updates from March 9, 2019 for Losartan in Canada.
--FDA Questions and Answers regarding ARBs recalls
--EPA (Environmental Protection Agency) technical sheet on NDMA
--List of ARBs including valsartan, losartan, irbesartan, and olmesartan on AskaPatient web site with links to reviews  --A 'one-off opportunity:' Drug company hikes price of blood pressure drugs after competitors' drugs recalled. 1/30/2019: USA Today.
--In June 2019, an independent online pharmacy (Valisure) found another carcinogen, called DMF, in some valsartan products and sent notification to FDA. FDA says the amount is well below allowable levels, but will review the information. Valisure's report indicated that Macleods Pharmaceuticals had the highest levels of DMF among the samples tested. Bloomberg News 
--Information on the related recall for NDMA impurities in heartburn drug ranitidine: https://www.askapatient.com/news/otc-heartburn-stomach-acid-treatments.asp