As Recalls Multiply, EU Agency Studies How To Rid Chinese Firm’s Valsartan API Of Probable Carcinogen

European authorities are examining how a manufacturing process change six years ago may have introduced a probable carcinogen into Zhejiang Huahai’s valsartan API that was only recently detected. They hope to learn how the firm could reduce or eliminate the impurity.

A probe underway in the EU could uncover how a blood pressure medicine’s active pharmaceutical ingredient has been contaminated by a probable carcinogen for as long as six years, with lessons not only for the API supplier in China, but also perhaps for others who supply that API or who use similar manufacturing processes, and for their customers.

As customers of Zhejiang Huahai Pharmaceuticals Co. Ltd., Linhai, China, recall tablets made with its valsartan API from markets in the US, the EU and around the world, European authorities are examining how the impurity was generated during the firm’s API manufacturing process and how that process could be improved. There is some concern that other firms’ API plants also could be using similar manufacturing processes.

The initial focus of the European review is on a manufacturing change at Zhejiang Huahai’s API plant that may have introduced the impurity in 2012.

The European review, which extends to all valsartan marketed in Europe regardless of API source, could lead to suspension or revocation of firms’ authorization to market products in the EU that contain the angiotensin II receptor agonist, used in treating high blood pressure, heart failure and post-heart attack left ventricular dysfunction.

The European Commission initiated the review on July 5 and referred it to the European Medicines Agency under Article 31 of Directive 2001/83/EC, the legislation governing EU regulation of medicinal products. (Also see "EU Regulators Recall Valsartan Products Produced In China" - Pink Sheet, 6 Jul, 2018.)

EMA in turn asked its Committee for Medicinal Products for Human Use, or CHMP, to conduct the review and on July 17 published an account of what happened at Zhejiang Huahai and lists of questions the committee drew up July 16 for valsartan API suppliers and marketing authorization holders.

What Happened

The commission said EU authorities were notified June 22 that Zhejiang Huahai had detected the impurity, N-nitrosodimethylamine, or NDMA, in its valsartan API.

The commission noted that the World Health Organization’s International Agency for Research on Cancer classifies NDMA, a yellow, oily liquid also known as dimethylnitrosamine, as a probable human carcinogen.

The commission said Italy’s supervisory authority, AIFA, requested a copy of Zhejiang Huahai’s initial report on a root cause investigation into the discovery of NDMA in valsartan API.

The report said NDMA forms at a certain step in the manufacturing process in amounts that depend on reaction conditions.

EMA said July 17 that NDMA formation likely resulted from changes in the manufacturing process in 2012, and the unexpected impurity was never detected by routine testing.

EMA’s CHMP further explained that the impurity “appears to be generated during the formation of the tetrazole ring by reaction of dimethylamine (which may be present as an impurity or degradant in the solvent dimethylformamide (DMF) and sodium nitrite under acidic conditions (where nitrous acid is formed).”

CHMP added that “other N-nitrosamines could be generated with other solvents or under other specific reaction conditions where other amines are present.”

When Zhejiang Huahai tested a small, random selection of API batches, it detected NDMA levels ranging from 3.4 ppm to 120 ppm, averaging 66.5 ppm.

“According to the principles of ICH M7, these levels raise concerns,” the commission said, referring to the International Council on Harmonization’s guidance on controlling mutagenic impurities to limit potential carcinogen risk.

What’s Next

The commission requested EMA to therefore evaluate the impurity levels and reaction conditions, potential risks and appropriate risk minimization measures for patients who have been exposed, and the suitability of the manufacturing process.

EMA’s assessment of the manufacturing process should address “the reason for the presence of NDMA in the active substance, the suitability of the in-process controls, the analytical methods used and the specifications of the active substance and finished product.”

Additionally, because other valsartan API firms may use similar manufacturing processes that could generate NDMA, the commission told EMA “all valsartan-containing medical products would need to be considered as part of this review.”

Furthermore, the commission said it’s possible the NDMA issue might be relevant to other APIs, something it said EMA should consider as appropriate.

EMA’s CHMP is scheduled to deliver its opinion by Sept. 20.

The commission gave EMA a Dec. 31 deadline for saying whether it believes marketing authorizations should be maintained, varied, suspended or revoked.

Recalls Underway

Recalls of drug products that contain Zhejiang Huahai’s valsartan API are underway around the world.

In the US, there are several recalls of valsartan drug products:

• Teva Pharmaceutical Industries Ltd. began recalling products under the Major Pharmaceuticals label on July 13;
• Zhejiang Huahai’s Prinston Pharmaceuticals Inc. unit, doing business as Solco Healthcare LLC, began recalls on July 17; and
• Teva Pharmaceuticals USA began recalling Actavis-labeled products on July 17.

Meanwhile, Asuka Pharmaceutical Co. Ltd. on July 5 began recalling valsartan tablets from the Japanese market, and Teva, Sandoz and four other firms on July 9 began recalling them from the Canadian market.

EMA said the EU’s national authorities also have launched recalls of the medicine. Affected firms include Stada and Orifarm in Denmark and Accord Healthcare in the UK and Ireland.

EU marketing authorization holders of valsartan and valsartan combinations with other drug products include Novartis Europharm Ltd. and Mylan S.A.S.

A number of firms hold certificates of suitability for use of their valsartan API in the EU, which suggests they could become alternative suppliers there and perhaps elsewhere: Hetero Labs Ltd., Hyderabad, India; Zhejiang Tianyu Pharmaceutical Co. Ltd., Taizhou, China; Teva Pharmaceutical Industries Ltd., Petah Tikva, Israel; Macleods Pharmaceuticals Ltd., Mumbai, India; Second Pharma Co. Ltd., Shangyu City, China; Alembic Pharmaceuticals Ltd., Vadodara, India; Lupin Ltd., Mumbai, India; Sun Pharmaceutical Industries Ltd., Mumbai, India; Novartis Pharma, Basel, Switzerland; Divi’s Laboratories Ltd., Hyderabad, India; Harman Finochem Ltd., Mumbai, India; Aurobindo Pharma Ltd., Hyderabad, India; KRKA d.d., Novo Mesto, Slovenia; Signa S.A. DE C.V., Toluca, Mexico; Dr. Reddy’s Laboratories Ltd., Hyderabad, India; Zhejiang Changming Pharmaceutical Co. Ltd., Tiantai, China; IPCA Laboratories Ltd., Mumbai, India; Mylan Laboratories Ltd., Hyderabad, India; and Jubilant Generics Ltd., Nanjangud, India.

Zhejiang Huahai’s CEP has been suspended, as has that of Zhejiang Hisun Pharmaceutical Co. Ltd., Taizhou City, China.

From the editors of the Gold Sheet