Marketing authorisation holders of human medicinal products asked to conduct their own evaluation of the potential risk of contamination with nitrosamines
15.11.2019 / 22.11.2019
In June 2018, Swissmedic learned that the nitrosamine N-nitrosodimethylamine (NDMA) had been detected in the valsartan produced by a manufacturer of active pharmaceutical ingredients (APIs). Another nitrosamine, N-nitrosodiethylamine (NDEA), was subsequently detected, and other angiotensin II receptor antagonists (ARA-II, also known as sartans) from various manufacturers were also affected. Various other nitrosamine impurities, such as N-nitrosodiisopropylamine (NDIPA), N-nitrosoethylisopropylamine (NEIPA) and N-nitroso-N-methyl-4-aminobutyric acid (NMBA), have since been discovered in a range of medicinal products containing sartans. Two further impurities recently came to light (N-nitrosomethylphenylamine [NMPA] and an isomer of N-nitrosodibutylamine [NDBA]). All these nitrosamines are considered to be potentially carcinogenic in humans. NDMA and NDEA belong to a group of highly carcinogenic and mutagenic compounds that are classified as probably carcinogenic in humans by the WHO International Agency for Research on Cancer (IARC) and the United States Environmental Protection Agency (EPA). The international regulatory authorities assume that NDIPA, NEIPA and NMBA possess a toxicological profile similar to that for NDMA and NDEA.
Based on their risk profile and their unexpected detection in sartans, globally dedicated measures and efforts have been implemented to tackle the problem of nitrosamine contamination and eliminate affected products from the market.
Swissmedic has taken numerous corrective actions: sent letters to the relevant marketing authorisation holders, ordered the recall of medicinal products, conducted extensive tests on medicinal products in the Swissmedic laboratories, investigated the actual causes, called for risk evaluations, inspected manufacturing sites and banned the use of APIs from non-conforming foreign manufacturing sites.
Swissmedic has ordered medicinal products containing sartans to be checked for nitrosamine impurities by the relevant authorisation holders before distribution in Switzerland set provisional limits for nitrosamine impurities in these medicinal products (see Table 1). Please note that these provisional limits remain valid until 31.12.2020. The target is to achieve nitrosamine-free active substances from 1.1.2021, i.e. the limit of 30ppb will not be exceeded. If a product is contaminated with a nitrosamine that is not listed in Table 1, the authorisation holders concerned must follow the principles outlined in the ICH M7 (R1) recommendations in order to determine the acceptable quantities.
Swissmedic continues to work closely with its international partners that regulate medicinal products in Europe, Japan, Australia, Singapore, Canada and the USA in order to exchange information and coordinate the operations connected with inspections, risk evaluations and informing the public. We will continue to take further measures and inform both industry and the Swiss population when new risks are discovered.
Contamination of other human medicinal products
As far as is known at present, nitrosamine impurities may be present not only in sartans, but also in other active pharmaceutical ingredients (APIs) and medicinal products, depending on the manufacturing process in each case. In other countries, for example, traces of NDMA have been found in pioglitazone hydrochloride from one API manufacturer. As the nitrosamine levels in this case were below the provisional limit for sartans, no market actions were considered necessary. Nevertheless, the marketing authorisation holders of medicinal products containing pioglitazone have been asked to investigate and clarify possible nitrosamine contamination.
NDMA was recently discovered in medicinal products containing ranitidine, and recall procedures have been introduced.
Responsibilities of marketing authorisation holders
Marketing authorisation holders are responsible for the quality, safety and efficacy of their products, including the quality of the APIs, excipients and raw materials used in the manufacture of their finished products. The marketing authorisation holders should therefore ensure (if applicable via compliance with the provisions of their conformity declarations) that they and the manufacturers of finished products have access to relevant information from the API manufacturers concerning the potential presence of nitrosamine impurities and the risks of cross-contamination. The authorisation holders are also reminded of their responsibility to ensure the use of APIs that have been manufactured in accordance with the rules of Good Manufacturing Practice (GMP).
Potential sources of nitrosamine impurities
A series of possible and plausible causes (not exhaustive) of nitrosamine formation and contamination has been identified, and these should be considered in the evaluation of the risk of nitrosamine formation in medicinal products. These are listed in the Annex.
Call for review by the marketing authorisation holders
Based on the knowledge of the findings on nitrosamine contamination of medicinal products with and without sartans, and in view of the growing extent of the problem with nitrosamines, the marketing authorisation holders and the manufacturers of APIs are being asked to take precautionary measures to lower the risk of contamination with nitrosamines for all APIs and medicinal products.
All marketing authorisation holders are urged to work together with the API and human medicinal product manufacturers to check their processes for manufacturing the APIs and medicinal products and evaluate the risks of contamination or cross-contamination with nitrosamine impurities, taking into account their knowledge of the manufacturing processes as well as the potential sources of nitrosamine impurities described in the Annex.
The following steps should be taken:
Step 1: Risk evaluation
The marketing authorisation holders are asked to evaluate the risks of their medicinal products containing chemically synthesised APIs. In this risk evaluation, the authorisation holders and API manufacturers should prioritise their APIs and medicinal products based on quality risk management principles (see ICH guideline Q9). Other factors to be considered as priorities include the maximum daily dose of the medicinal product, the duration of treatment, the administration route, dosage and special patient groups such as pregnant women and children.
The marketing authorisation holder is responsible for the risk evaluation, which should take into account all potential nitrosamine impurities, including those not mentioned in this publication. These risk evaluations should be kept on file by the marketing authorisation holders. While we realise that the quantity of affected products can be considerable for certain authorisation holders, they are nevertheless required to carry out these risk evaluations as quickly as possible, but at the latest within the next six (6) months of the publication of this call (at the latest 15 May 2020).
Step 2: Confirmatory testing
If a risk of nitrosamine formation has been identified or if such compounds have been detected, confirmation testing using validated and sufficiently sensitive methods (LOQ < 30ppb) should be carried out in accordance with the list of priorities produced during the risk evaluation in step 1. Medicinal products identified as high priority should be tested as soon as possible. Confirmatory testing of all APIs and medicinal products that are exposed to a risk of nitrosamine contamination should be concluded, at the latest, within 2 years of this publication (by 15 November 2021), or earlier if necessary, and the required changes to the manufacturing authorisations should be submitted by this deadline (described in step 3). These confirmatory tests should be carried out by a GMP-compliant facility using appropriate analytical methods. Various validated methods for detecting nitrosamines in sartans are published on the websites of Swissmedic and international regulatory authorities. The detection of every nitrosamine impurity must lead to an investigation of the causes, and appropriate corrective and preventive actions should be taken in accordance with GMP. As with any case of an identified problematic risk, companies must follow the standard procedure and inform Swissmedic immediately if nitrosamines are detected in APIs or medicinal products – regardless of the quantities – and submit a risk evaluation.
Step 3: Changes to the authorisation
Marketing authorisation holders must within a reasonable period apply for the necessary variations, e.g. changes to the manufacturing process or specifications for the API or finished product, in accordance with our guidance document "Variations and extensions HMV4".
Swissmedic should be informed immediately if the evaluation findings indicate an immediate risk to public health.
Market Monitoring of Medicines
This request is intended for the marketing authorisation holders of human medicinal products, including over-the-counter medicines. It is not intended for marketing authorisation holders of biological products, radiopharmaceuticals or veterinary medicinal products.
Annex: List of possible causes
List of possible and plausible causes for the formation of nitrosamines and for contamination sources that should be considered in the evaluation of the risk of nitrosamine formation in medicinal products (not exhaustive).
The following checklist can serve as a guide in the risk analysis.
Manufacture of API
Potential causes of the contamination of active pharmaceutical ingredients (API) and/or proprietary medicinal products during the manufacture of API and observations connected with these contamination sources are listed below:
1. Specific reaction conditions in the presence of certain raw materials and starting compounds:
Nitrosamines can occur under suitable reaction conditions in the presence of certain raw materials (including starting compounds and intermediates) and, in the event of inadequate purification and incomplete purging in the subsequent steps of the manufacturing process for an API, can be carried over into the medicinal product as an impurity.
2. Sodium nitrite (NaNO2) or other nitrites in the presence of secondary or tertiary amines:
NaNO2 or other nitrite salts can form nitrosamines in the presence of secondary or tertiary amines under suitable reaction conditions (e.g. pH, temperature). Other conceivable causes for the formation of nitrites in the synthesis process include the reduction of nitrates or nitric acid, chlorination of urea or ammonia, cleavage of organic nitrates and conversion to nitrites under reductive conditions.
Secondary amines can be used as synthesis components, reagents, catalysts or solvents. They can also exist as a constituent of the molecular structure of the API itself or its intermediates or as impurities or degradants in raw materials or can form during the actual process. For example, amide solvents can be degraded to secondary amines. Known sources of secondary amines include N,N-dimethylformamide [DMF], N-methylpyrrolidone [NMP] or N,N-dimethylacetamide [DMA].
Tertiary amines used in synthesis chemistry include common bases, whose involvement in the formation of nitrosamines has already been observed (e.g. triethylamine, diisopropylethylamine [Hünig's base, DIPEA]). However, other less common bases are sometimes used in manufacturing processes, e.g. N-methylmorpholine (NMM) or tributylamine (TBA) and many others that could lead to the formation of various nitrosamines.
Secondary and tertiary amines might also be present as impurities or degradants of quaternary ammonium compounds such as tetrabutylammonium bromide (TBAB) or also in primary amines such as monoethylamine.
This list of possible sources is not exhaustive, since many other reagents with amino groups as well as catalysts or solvents can be used for a wide variety of synthesis steps. Other reagents with functional amino groups should also be considered in the evaluation of the potential risk of nitrosamine formation.
In most confirmed cases of contamination to date, a nitrite and an amine were used in the same manufacturing step. However, other cases have been identified in which the sodium nitrite used in one step appeared in the subsequent synthesis stages despite extensive purification operations and then reacted with an amine to generate the nitrosamine impurities, and vice versa. Since the possibility of carry-over from one step to the next cannot be ruled out, all processes that use NaNO2 or that involve potential nitrite sources must be considered and evaluated in respect of the risk of the formation and subsequent carry-over of nitrosamine impurities if amines (see examples listed above) are present in a synthesis step.
3. Recovered or recycled material:
Contaminated raw materials in the manufacturing process can be a source of nitrosamines. Recovered or recycled material (e.g. solvents, reagents and catalysts) entails a risk of nitrosamine formation if the solvents, reagents or catalysts to be recovered or recycled contain amines and if they are subsequently treated with nitrous acid, e.g. in order to destroy residual azides without adequate control of the processes.
O-xylene and tributyltin chloride (as a source of tributyltin azide) are examples of recycled substances that can be contaminated by nitrosamines. It is also thought that DMF might be contaminated in this way.
4. Recovery by third parties:
The recovery of materials (e.g. solvents, reagents and catalysts) is often entrusted to third parties. Sometimes these external recovery companies do not receive sufficiently specific information about the composition of the materials treated by them, and they use routine treatment processes and generally accepted equipment. This can lead to cross-contamination of the solvents, reagents and catalysts (which originate from various sources and processes) if the equipment is not adequately cleaned between customer orders or if no precautions are taken to prevent nitrosamine formation.
5. Contaminated raw materials, including intermediates:
The presence of nitrosamines may also be caused by contaminated raw materials or intermediates from distributors that use conversion methods or raw materials that can lead to the formation of nitrosamines. For example, nitrites or amines are known to occur as impurities in raw materials, particularly in reagents, solvents or excipients that are also used in finished products.
In such cases, the contamination of raw materials, starting materials and/or intermediates procured from external suppliers then becomes problematic if the manufacturer of an API that exclusively employs processes in which no nitrosamines are formed is not aware that the risk of nitrosamine impurities even exists.
Technological excipients used in large quantities, such as industrial nitrogen (which is often used to clean containers, degas solvents or transfer liquids) and water, should also be considered as potential sources of nitrites or nitrogen oxides.
6. Defective optimisation of the manufacturing processes for an API:
A defective optimisation of the manufacturing processes for an API, i.e. unsuitable or poorly controlled reaction conditions in respect of temperature, pH or the order in which reagents, intermediates or solvents are added, can also lead to the formation of nitrosamine impurities. This may be the case particularly if there is inadequate knowledge of the synthesis pathway or the conditions during the manufacture of the API, thus resulting in the formation of nitrosamine impurities.
Medicinal product manufacture
The potential sources of nitrosamine contamination during the manufacture of a medicinal product and corresponding considerations are as follows:
- The risk of nitrosamine impurity formation during the manufacture and packaging of the medicinal product (such as when certain containers, API or packaging components come into contact with amines or nitrites, e.g. reaction of secondary amines in printing inks with certain nitrocellulose lacquers or coating materials when heated) should be considered in the risk evaluation.
- Processes in which constituents of the medicinal product containing nitrites or amines occur together in solution or in suspension (e.g. during granule manufacture) or are kept at high temperatures (e.g. during drying steps) can be associated with an increased risk of nitrosamine formation.
- Nitrosamines formed during the manufacture of a medicinal product, unlike the situation for API manufacture with multiple synthesis stages thanks to subsequent purification steps, are almost impossible to remove from the medicinal product.
 Further information on the subject of contamination of sartans with nitrosamines: