A wave of drug recalls hits Indian pharma firms in US

Indian generic drug manufacturers continue to recall high blood pressure medicines from the US market after the key ingredients used in the drugs were detected with probable cancer causing impurity.

In a latest, Ahmedabad-based Torrent Pharmaceuticals said it is expanding its voluntary recall of hypertension drug Losartan potassium tablets USP to a total of 10 lots due to detection of trace amounts of an unexpected impurity, N-nitrosodiethylamine (NDEA), found in an active pharmaceutical ingredient (API). Earlier in December, it initiated a voluntary recall of 2 lots for similar reason. The API was manufactured by Hetero Labs Ltd.

According to US Food and Drug Administration (FDA), the impurity NDEA, which is a substance that occurs naturally in certain foods, drinking water, air pollution and industrial processes, has been classified as a probable human carcinogen as per International Agency for Research on Cancer (IARC) classification.

The recall is at the consumer level, and Torrent is only recalling lots of Losartan-containing products that contain NDEA above the acceptable daily intake levels released by the FDA. The recall is for products which are above the interim acceptable intake level of 0.27 parts per million.

However, the company has not received any reports of adverse events related to this recall till date, according to a notification on the US FDA website.

Losartan is used to treat hypertension, hypertensive patients with left ventricular hypertrophy and for the treatment of nephropathy in Type 2 diabetic patients.

In August last year, the pharmaceutical company also recalled around 109 lots of Valsartan, and in combination with amlodipine or amlodipine plus hydrochlorothiazide in the US due to detection of trace amounts of another probable human carcinogen, N-nitrosodimethylamine (NDMA), in an API manufactured by Zhejiang Huahai Pharmaceuticals. The medicines are used for controlling high blood pressure

Recently, Hyderabad-based Aurobindo Pharma initiated a similar recall of 80 lots of Valsartan. In October, it pulled off 22 lots of another high blood pressure medicine Irbesartan voluntarily after it was tested positive for NDEA.

Not just Indian generic manufacturers, blood pressure medicines manufactured by multinationals were also found with trace amounts of the two probable human carcinogens.

Teva Pharmaceuticals, Mylan Pharmaceuticals, Sandoz Inc, ScieGen Pharmaceuticals, Inc, Camber Pharmaceuticals, Major Pharmaceuticals and Prinston Pharmaceutical Inc have recalled blood pressure drugs in the US, after the impurity NDEA/NDMA were detected in their key ingredients used to manufacture the finished products. The APIs contained in many of these finished products are manufactured in China and India.

Last month, the US agency in a press statement said that NDMA and NDEA are probable human carcinogens and should not be present in drug products.

"We are currently aware of NDMA and NDEA in certain valsartan, irbesartan and losartan-containing products, and those products and some active pharmaceutical ingredients (API) used to manufacture them have been recalled from the U.S. market. Drug products that contain NDMA or NDEA above the limits in the table below pose an unacceptable risk to patients," the drug regulator said in its statement.

It has also issued a warning letter to Zhejiang Huahai Pharmaceutical (ZHP) in Linhai, Taizhou Zhejiang China regarding the ongoing investigation into probable cancer-causing impurities found in the key ingredients manufactured by the company. FDA's letter outlines several manufacturing violations at ZHP's Chuannan facility, including impurity control, change control and cross contamination from one manufacturing process line to another. Since September, the facility was put under an import alert, which stopped all API manufactured at ZHP's facility and finished products made using its API from legally entering the US.

Taking note of this, drug regulators in the UK, Europe, Japan and Canada have also increased their scrutiny on drugs likely to be contaminated with NDEA or NDMA.

In October last year, the European Directorate for the Quality of Medicines & Healthcare (EDQM) suspended Aurobindo Pharma's CEP (a certificate of compliance with European standards for quality testing), effectively stopping the supply in the EU of medicines containing Irbesartan from the company.

In November, it issued a statement saying that EDQM has suspended Mylan Laboratories Ltd's CEP, effectively prohibiting the use of Valsartan in EU medicines, after some batches of Valsartan made by the company in Hyderabad were found to contain NDEA.

"The presence of impurities in Valsartan medicines and other sartans is thought to be linked to the synthesis of a specific ring structure (tetrazole) which is present in some sartan medicines.

Companies marketing sartan medicines in the EU have been asked to test their products for these impurities. Additional testing is being carried out by EU laboratories," the European Medicines Agency (EMA) said recently," EMA had said in its statement in November.

According to an analyst, who does not wish to be named, this may not immediately have any significant financial impact on the companies recalling drugs in the US, but companies, whose APIs were detected with the impurity, must review their manufacturing practices. He, however, said that the outcome of the impurities is unintentional as it may have caused due to changes made in the manufacturing process of APIs.

Meanwhile, Lupin Pharmaceuticals, Inc. has also initiated voluntary recall 42 lots of Ceftriaxone for Injection, USP, at hospital/ physician level since the products have been found to contain visual grey particulate matter in reconstituted vials.

The US FDA said that improper piercing and use of a needle greater than 21 gauge (larger internal diameter), while reconstituting the vial, can push rubber flecks into the solution. If injected, this product (containing rubber particulate matter from the stopper) could cause vein irritation/phlebitis or pulmonary embolic events that could result in permanent impairment of body function or damage to body structures, such as the lungs and vascular system. In addition, as Ceftriaxone can be administered intramuscularly, the use of the product may result in local muscle inflammation and/or abscesses.

There were no grey flecks seen prior to the reconstitution of the vials and the issue was identified upon standard visual inspection prior to patient administration, the regulator further said.

Ceftriaxone for Injection, USP, is used as a sterile, semi-synthetic, broad-spectrum cephalosporin antibiotic for intravenous or intramuscular administration. It is used to reduce the development of drug-resistant bacteria and maintain the effectiveness of ceftriaxone sodium and other antibacterial drugs.

The recall has been made for 5 lots of 250 mg, 10 lots of 500 mg, 24 lots of 1 g and 3 lots of 2 g.

The company has not received any reports of adverse events related to the recalled lots to date, the FDA said.

BITTER DOSE 

• Torrent Pharma is expanding its voluntary recall of hypertension drug Losartan potassium tablets USP 
   
• Recently, Hyderabad-based Aurobindo Pharma initiated a similar recall of 80 lots of Valsartan