Following new information received recently about the presence of nitrosamine impurities in a drug substance covered by a certificate of suitability (CEP), the EDQM has taken immediate action and suspended
- CEP R1-CEP 2009-247-Rev 02/losartan potassium, form I, held by HETERO LABS, Limited, due to the detection of low levels of N-nitroso-N-methylamino butyric acid (NMBA) and N-nitroso-diethylamine (NDEA)
until appropriate corrective actions will have been implemented by the company. This is part of the on-going review of the CEP applications and exchange of information with international partners for valsartan and other sartan blood pressure substances (ARBs - Angiotensin II receptor blockers).
The EDQM is currently in the final stage of the review of CEP applications for sartan substances, and is assessing the latest responses from the affected companies. As a result of the review, a number of CEPs have been revised or, where applicable, letters of confirmation sent to the holders. For NDMA and NDEA impurities, tentative limits, set in line with current international standards and in collaboration with international partners, have been used as a basis for assessment. They are described in the table below. The EDQM has also been investigating other impurities such as N-nitrosoethylisopropylamine (EIPNA), N-nitrosodiisopropylamine (DIPNA) and N-nitroso-N-methylamino butyric acid (NMBA). For sartan substances containing either impurity above the tentative limits, the respective CEPs have been suspended, waiting for corrective actions.
Temporary limits for NDMA and NDEA impurities:
|Active substance (max daily dose)||Maximum daily intake (ng)||Limit (ppm)||Maximum daily intake (ng)||Limit (ppm)|
|Candesartan (32 mg)||96.0||3.000||26.5||0.820|
|Irbesartan (300 mg)||96.0||0.320||26.5||0.088|
|Losartan (150 mg)||96.0||0.640||26.5||0.177|
|Olmesartan (40 mg)||96.0||2.400||26.5||0.663|
|Valsartan (320 mg)||96.0||0.300||26.5||0.082|
The EDQM will align with the recommendation of the CHMP that companies that make sartan substances are being required to review their manufacturing processes so that they do not produce nitrosamine impurities. Manufacturers of these substances will have a transition period to make the necessary changes to their manufacturing processes and to put in place testing regimes able to detect the smallest amounts of these impurities during which the strict temporary limits listed above will apply. After this transition period, companies will have to demonstrate that their sartan substances have no quantifiable levels of these impurities (less than 0.03 ppm). The CEP applications will have to be revised accordingly via the relevant revision process. The EDQM will contact individually the CEP holders with instructions in the near future.
Nitrosamine impurities can be formed due to the synthetic process used to manufacture valsartan and other ARB substances or they may be introduced into the active substance when recovered materials which are contaminated with these impurities are used in a manufacturing process. Holders of CEPs are reminded that they should immediately inform EDQM of any contamination found in valsartan and other ARBs manufactured and supplied using a CEP.
Nitrosamine compounds are classified as a probable human carcinogens (substances that may cause cancer).
While patients should limit exposure to nitrosamine impurities, some of these impurities exist in other ingested products, such as some charcoal grilled food items. It is important to minimise the risk to patients of ingesting these impurities in the medicines they take whilst also ensuring that there are medicines available to be taken for potentially life threatening conditions. For this reason, anyone concerned about these impurities in a medicine they are taking should discuss this with their healthcare professionals (pharmacists, doctors etc.) before deciding to stop taking their medicine. In addition, the vast majority of these ARB medicines do not contain these impurities.