Valsartan recall: global regulatory overview and future challenges

Valsartan is an orally active antihypertensive drug developed in the 1990s and is a selective angiotensin II receptor blocker (ARB)¹ which relaxes the blood vessels and thus reduces blood pressure; it is also used for treating patients with congestive heart failure and postmyocardial infarction.² There are eight other ARBs that patients may be switched to if they discontinue their valsartan therapy.³ Valsartan was patented by Novartis Pharmaceuticals in 1996 on the US market under the name Diovan. The patent was taken off in the USA in 2012, when valsartan was distributed as a generic.⁴ Valsartan alone and in combination with other drugs is sold by 30 companies in the US market.⁵

On 5 July 2018 the European Medicines Agency (EMA) reviewed medicines containing valsartan following detection of an impurity, N-nitrosodimethylamine (NDMA), a probable human carcinogen, in medicines from Zhejiang Huahai Pharmaceutical Co Ltd, Linhai, China. Since the batches manufactured from this valsartan-active substance have been administered to many patients, the EMA’s review focused on investigating the levels of NDMA in the products and the potential impact on patients who have been taking them. The agency further issued advisory notices on their website for patients not to stop taking their medicine.⁶

NDMA is an organic chemical that forms in both industrial and natural processes, and has been used to make liquid rocket fuel, softeners, and lubricants. NDMA has been studied in animals and found to increase the occurrence of cancer. The US Environmental Protection Agency found an association between NDMA and liver toxicity, which could lead to liver cancer: NDMA exposure may be associated with bladder, renal, pancreatic, intestinal, colon, and stomach cancers.⁷

Immediately following the EMA’s review, 24 countries, Germany, Norway, Finland, Sweden, Hungary, The Netherlands, Austria, Ireland, Bulgaria, Italy, Spain, Portugal, Belgium, France, Poland, Croatia, Lithuania, Greece, Canada, Bosnia and Herzegovina, Bahrain, and Malta, recalled approximately 2300 batches of valsartan products,⁸ while Hong Kong recalled 5 products of 2 companies⁹ and Canada recalled drug products of 5 companies.¹⁰ The Drug Regulatory Authority of Pakistan on 12 July recalled valsartan-containing drugs of nine manufacturers becoming the first developing country to announce separately the recall as a precautionary measure to protect patient health.¹¹ The US Food and Drug Administration (FDA) on 13 July announced the voluntary recall of five valsartan-containing products.¹²

The EMA, FDA, and World Health Organization issued updates on 17 and 18 July declaring that NDMA was not detected by routine tests and that some changes in the manufacturing process introduced by Zhejiang Huahai in 2012 were believed to have produced this impurity as a side product and that this impurity poses an unnecessary risk to patients, therefore, they should use medicines made with drug substances from other sources or consider other available treatment options.^13–15 Immediately after these updates India and South Africa also recalled different valsartan products supplied by Zhejiang Huahai.^16,17

The EMA update on 2 August revealed that the average level of NDMA detected was 60 parts per million which could result in one extra case of cancer for every 5000 patients taking the affected medicines at the highest dose (320 mg) every day for 7 years.¹⁸

A declaration from Hetero Labs Limited - Unit IX, India was made public on 18 July for the voluntary recall of their manufactured valsartan batches due to a possible NDMA impurity in valsartan manufactured at their plant.¹⁹ Novartis Pharmaceuticals, the innovator of valsartan products, initiated a dear doctor letter summarizing the initiation of the review and recall of various valsartan-containing medicines by the EMA, which did not include their products since these do not contain the NDMA impurity. The letter described how Zhejiang Huahai follows a specific route of synthesis using N,N-dimethylformamide, which could lead to the formation of NDMA as an impurity.²⁰ In continuation to this, the EMA on 10 August stated that low levels of NDMA had also been detected in the valsartan-active substance manufactured by a second company, Zhejiang Tianyu, Taizhou, China.²¹ This declaration from both firms and EMA’s latest review raised further questions on the safety of valsartan manufactured by various other manufacturers. On 22 August, the FDA released a gas chromatography-mass spectrometry (GC/MS) headspace method for the detection and quantification of NDMA in valsartan active pharmaceutical ingredient (API) and finished drug products.²²

On 13 September, the EMA reported that another impurity, N-nitrosodiethylamine (NDEA), had been identified in valsartan manufactured by Zhejiang Huahai.²³ On 28 September, the FDA placed Zhejiang Huahai on import alert following a detailed inspection of the site and stopped all of its APIs from legally entering the USA.²⁴ The FDA further posted laboratory analysis results of NDMA levels in recalled valsartan products on 5 October where FDA scientists estimated that if 8000 people took the highest dose of valsartan (320 mg) containing NDMA from the recalled batches daily for 4 years, there may be one additional case of cancer over the lifetimes of the 8000 people.²⁵ On 11 October the FDA published a new analytical method for the quantification of both NDMA and NDEA using the GC/MS technique,²⁶ and further on 16 October 2018, published an alternate method utilizing a GC/MS direct injection technique.²⁷ The FDA on 27 November updated two lists of valsartan products under recall and those not under recall.^28,29

In the world of regulatory sciences, such incidents are common and observed by many drug substance manufacturers during routine and stress testing and even after marketing of the product during real-time stability and postmarketing analysis. Such incidents have been greatly reduced after the implementation of the Common Technical Document for the registration of pharmaceutical drugs by various regulatory bodies since this document contains detailed information on a drug substance including its manufacturing process, controls, critical steps, and intermediates in its module-3.³⁰ Any change in manufacturing process, material, or intermediates, control of critical steps impurities, specification, and analytical procedure is to be informed to marketing authorization holders, who are legally bound to inform the same to their concerned regulatory body.³¹ This regulatory gap was evident in this case since the manufacturers of the API did not inform existing marketing authorization holders regarding the change in the manufacturing process and hence the problem could not be identified in the early stages. National regulatory bodies should take immediate steps to ensure the provision of correct information to healthcare providers and the general public, which in this case seemed to be missing in various countries.