Valsartan / Sartan-containing drugs: Pharmaceutical companies to review manufacturing processes to avoid occurrence of nitrosamine-containing impurities

Measures at EU level

Pharmaceutical companies manufacturing sartan-containing blood pressure medicines (also known as angiotensin II receptor blockers) will have to review their production processes to ensure that nitrosamine-containing impurities are avoided in the future. Pharmaceutical companies will be given a transition period to make any necessary changes. During this phase, temporary strict limits on these impurities will initially apply. After this period, companies will have to demonstrate that their sartan-containing medicines no longer contain any quantifiable levels of these impurities before they can be used in the EU.

These recommendations follow a risk assessment process conducted by the European Medicines Agency (EMA) on impurities of some sartans with N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA), which have been classified as probable human carcinogens (substances that could cause cancer). However, for the vast majority of all sartan-containing drugs, these impurities were not detectable or were present at very low levels.

In the risk assessment process, an estimate was made for the highest, possible cancer risk. This estimate showed that if 100,000 patients took NDMA-contaminated valsartan from Zhejiang Huahai (manufacturing site where the highest levels of impurities were found) every day for 6 years at the highest dose, 22 additional cancer cases could occur over the lifetime of these 100,000 patients. The presence of NDEA in these drugs could also result in 8 additional cancer cases in 100,000 patients if they had taken the drug at the highest daily dose for 4 years.^[1]

The estimates were extrapolated from animal studies and, compared to the normal lifetime risk of developing cancer in the EU (one case per two people), are considered very low.

How impurities occurred in sartans

Prior to June 2018, NDMA and NDEA were not among those impurities identified in sartans and therefore could not be detected by routine testing.

It is now known that these impurities can form during the manufacture of those sartans with a specific ring structure, known as a tetrazole ring, under certain conditions and when certain solvents, reagents, and other starting materials are used. In addition, it is possible that impurities were already present in some sartans because manufacturers accidentally used contaminated equipment or reagents in the manufacturing process.

Pharmaceutical companies must now take steps to avoid the presence of these impurities and subject their drugs to rigorous controls.

Controls during and after the transition period

While the goal is to no longer have quantifiable levels of nitrosamine impurities in sartans, interim limits for NDMA and NDEA have been established for the transition period in accordance with current international guidelines.^[2]

Medicinal products containing either impurities above these limits or medicinal products containing both nitrosamines at the same time, regardless of the amount, will no longer be marketable in the EU in the future.

The limits are based on maximum daily doses derived from animal studies: 96.0 nanograms for NDMA and 26.5 nanograms for NDEA. Dividing this amount by the maximum daily dose for each active ingredient yields the parts per million (ppm) limit (see Table 1).

The transition period of two years will allow pharmaceutical companies to make the necessary changes in their manufacturing processes and implement testing procedures capable of detecting minute amounts of these impurities.

After this transition period, pharmaceutical entrepreneurs will then have to rule out the presence of even lower levels of NDEA or NDMA in their drugs (< 0.03 ppm).

Investigation continues

EMA and national authorities will continue investigations into the presence of nitrosamine-containing impurities in medicines, including other impurities such as N-nitrosoethylisopropylamine (EIPNA), N-nitrosodiisopropylamine (DIPNA) and N-nitroso-N-methylamino-butyric acid (NMBA).

Competent authorities in the EU will also draw the appropriate actions from the reviews to improve the way impurities are identified and handled in medicines.

The EMA's recommendations on NDMA and NDEA impurities will be forwarded to the European Commission for a legally binding decision. An assessment report with further details of this review will be published on the EMA website shortly.

Situation in Austria

In Austria, a number of proprietary medicinal products containing the following active sartan ingredients are approved:

• Candesartan

• Irbesartan

• Losartan

• Olmesartan

• Valsartan

A detailed list of the products approved in Austria can be found by entering the active ingredient on this page or in the Pharmaceutical Specialties Register:

https://aspregister.basg.gv.at

Recommendations of the BASG

Recommendations for users:

• Nitrosamines are potent carcinogens in animals and are considered probable carcinogens in humans.

• These contaminants can form during the manufacture of sartans containing a tetrazole ring when certain reaction conditions are present or when contaminated materials are used.

• For NDMA, the key step is the use of dimethylamine (DMA) in the synthesis, which forms the impurity in the presence of nitrites, usually under acidic conditions. A similar synthesis step - using diethylamine (DEA) - leads to the formation of NDEA.

• Strict control procedures have been put in place to ensure that drugs containing sartan are sufficiently safe.

• Manufacturers must now review their manufacturing processes to prevent the formation of nitrosamines.

• If further recalls or other actions are needed, national authorities will inform you of what action to take.

Recommendations for patients:

• There is a very small risk that nitrosamine-containing impurities at the levels that were present in some sartan-containing drugs may cause cancer in humans.
• Since the impurities were first identified in some sartan-containing medicines, regulatory authorities in the EU have been working to ensure the best possible protection of patient health. Following the tests, some affected medicines were recalled from pharmacies and are no longer used in the EU.

• The EMA is now taking further measures to prevent such impurities from being present in batches of sartan-containing medicines in the future.

• Strict control procedures ensure that medicines containing sartan are sufficiently safe.

• Patients taking medicines containing valsartan should not stop taking the medicine without consulting their doctor.

• If you have any questions about your current medicine or a medicine you have taken in the past, contact your doctor, pharmacist.

More about the medicines

The risk assessment procedure applies to the sartan-containing drugs candesartan, irbesartan, losartan, olmesartan, and valsartan (also known as angiotensin II receptor antagonists or sartan class).

Some sartan-containing drugs have a specific ring structure (tetrazole ring), the synthesis of which could potentially lead to the formation of nitrosamine impurities. Other drugs in the same class that do not have this ring, such as azilsartan, eprosartan, and telmisartan, are not affected by this risk and were not included in the review.

These drugs are used to treat patients with hypertension and patients with certain heart or kidney diseases. They work by blocking the action of angiotensin II, a hormone that constricts blood vessels and increases blood pressure.

More about the procedure

The review of medicinal products containing the active substance valsartan was initiated by the European Commission on July 5, 2018, under Article 31 of Directive 2001/83/EC. On September 20, 2018, the review was expanded to include medicines containing candesartan, irbesartan, losartan, and olmesartan. Update April 2019:

The review was conducted by the EMA Committee for Medicinal Products for Human Use (CHMP), which is responsible for issues related to medicinal products for human use and subsequently issued the opinion. The CHMP opinion was forwarded to the European Commission, which issued a final legally binding decision as of 02/04/2019, applicable in all EU Member States.

Commission implementing decision

http://ec.europa.eu/health/documents/community-register/html/ho26820.htm

Press releases of the CMDh

https://www.hma.eu/249.html

Further information

European Medicines Agency press release (01/02/2019) https://www.ema.europa.eu/en/medicines/human/referrals/angiotensin-ii-receptor-antagonists-sartans-containing-tetrazole-group BASG warning and safety information (05/07/2018): https://www.basg.gv.at/news-center/news/news-detail/article/rueckruf-von-arzneimitteln-mit-wirkstoff-valsartan-vom-chinesischen-hersteller-zhejiang-huahai-pharma/ BASG safety information update (03/08/2018): https: //www.basg.gv.at/news-center/news/news-detail/article/ueberpruefung-der-valsartan-medikamente-update-1255/ BASG safety information, NDEA (23/11/2018): https: //www.basg.gv.at/news-center/news/news-detail/article/produktionsbedingte-verunreinigung-mit-n-nitrosodiethylamin-ndea-im-wirkstoff-valsartan-des-herste/

Inquiries (regulatory)

E-mail: nat@basg.gv.at

Queries(technical) Dr. Christoph Baumgärtel, Tel: 050555/36004 Email: christoph.baumgaertel@ages.at Queries (for media) Communications Management, Tel: 050555/25000 Email: presse-basg@basg.gv.at

^[1] The durations of 6 and 4 years refer to the time NDMA and NDEA were presumably present in valsartan from Zhejiang Huahai.

^[2] International Council for Harmonisation of Technical Requirements of Pharmaceuticals for Human Use (ICH) Guidance: M7(R1).

Further inquiry note

nat@basg.gv.at