In February 2021, the EMA further detailed the procedure to be followed in order to control and limit the concentrations of nitrosamine impurities in medicinal products.
Where scientifically justified and in line with the provisions of Swiss legislation on therapeutic products, Swissmedic aims to harmonise its requirements with those of European authorities.
Relevant EMA documents:
he EU requirements, as updated in February 2021, will also apply in future to Switzerland, with the following clarifications and exceptions (reference is made to the relevant questions in the EU Q&A document, as appropriate):
The EU requirements apply to all new marketing authorisation applications of products containing biotechnological / biological active substances.
Exception: For biological medicinal products already authorised at the time of this publication, Swissmedic only expects in-depth investigations if risk factors arise from the ingredients or as a consequence of the manufacturing conditions.
As communicated on 9 November 2020 on the Swissmedic website (Potential nitrosamine contamination: request to perform a risk evaluation), the EU deadlines apply:
Exception: On completion of step 1, and in contrast with the EU practice, documents do not need to be submitted to Swissmedic if no risks were identified.
On completion of the evaluation of the risk of nitrosamine contamination of authorised medicinal products, the EMA forms (response templates) can be used to record the results of steps 1 and 2.
Exception: If no risk was identified, a "No risk identified template" does not need to be submitted.
Swissmedic adopts the limits defined in the EU for nitrosamine impurities in medicinal products. This also applies to sartans.
Exception: For metformin preparations the conditions imposed by Swissmedic continue to apply until further notice in view of the uncertainty surrounding the causes of NDMA contamination.
An analytical method with sufficient sensitivity must be used for confirmatory testing. The general requirement previously used by Swissmedic calling for a method with a limit of quantification (LOQ) of 30 ppb no longer applies.
As regards the acceptable intake (AI) of specific nitrosamines, the limits stated below apply:
Limits for nitrosamines without corroborated substance-specific toxicological data can be set according to the EU requirements. This can involve either a generic class-specific limit of 18 ng/day or a limit based on an analysis of the structure-activity relationship (SAR).
Until further notice, Swissmedic accepts a negative Ames test conducted according to ICH M7 as proof of the absence of mutagenicity.
Changes to a medicinal product that potentially affect the risk of nitrosamine contamination (e.g. new active substance manufacturer, new DMF, manufacturer using multi-purpose equipment, new grade(s) of starting material(s), modified manufacturing methods, different packaging materials) should be documented in the relevant sections of modules 3.2.S and 3.2.P. The impact of the change, particularly in connection with the submission of a new DMF or significant changes to the manufacturing process, needs to be subjected to a risk evaluation and, if applicable, a risk assessment in combination with confirmatory testing.
All documents that are relevant to the re-evaluation of the nitrosamine risks should be submitted with the variation application. In certain cases, stability tests may also be needed if new risk factors are identified.
As published on the Swissmedic website on 21.04.2020 (Evaluation of potential nitrosamines in connection with new authorisations (swissmedic.ch)) new or ongoing marketing authorisation applications should always be accompanied by a risk evaluation or, if a potential risk is identified, an in depth risk assessment (to be submitted in module 1 with references to the relevant sections of modules 2 and 3). The submitted documentation should include an evaluation of the impact on the benefit/risk profile, a risk mitigation strategy and a test plan for confirmatory analytical tests and test results (“confirmatory testing”). This procedure is in line with the EU requirements.
Potential nitrosamine contamination – harmonised implementation (update)
On 15 November 2019 Swissmedic requested all marketing authorisation holders of human medicinal products with chemically synthesised active substances to check whether their products might be contaminated with nitrosamines. The Agency requested a procedure in three steps, for which the deadlines shown in the table below were defined.
Owing to the COVID-19 crisis, the deadlines were first revised on 3 April 2020. For step 1, the deadline was extended to 1 October 2020. However, according to the results of an industrial survey presented to Swissmedic on 13 October 2020 during a Regulatory Round Table, a large majority of the companies had not managed to complete step 1 by 1 October 2020. Swissmedic is therefore revising the deadlines again (see table). The new deadlines are in line with those issued by the EMA, which has also published a deadline extension
Swissmedic would point out the following deviations from the procedure in the EU:
Swissmedic would also point out that the Swissmedic laboratory will be checking medicines distributed in Switzerland specifically for nitrosamine contamination over the coming months as part of its market monitoring activities.
| Stages | Original deadlines, communication dated 15.11.2019 | Update 1, communication dated 03.04.2020 | New deadlines (update 2) Communication dated 09.11.2020 |
|---|---|---|---|
Step 1
|
to be completed by 15 May 2020 | to be completed by 1 October 2020 | to be completed by 31 March 2021 (chemical medicines) or by 1 July 2021 (biological medicines) |
Step 2 and 3
|
to be completed by 15 November 2021 | to be completed by 1 October 2022 | to be completed by 1 October 2022 (chemical medicines) or by 1 July 2023 (biological medicines) |
On 15 November 2019 Swissmedic requested all marketing authorisation holders of human medicinal products to take precautions to minimise the risk of nitrosamine contamination of medicinal products with synthetic active substance.
Owing to the global COVID-19 crisis, it has become difficult for many authorisation holders to meet these deadlines. Swissmedic is therefore extending deadlines in step with other international authorities, as follows:
| Stages | Previous dates | New dates |
|---|---|---|
Step 1
|
to be completed by 15 May 2020 | to be completed by 1 October 2020 |
Step 2 and 3
|
to be completed by 15 November 2021 | to be completed by 1 October 2022 |
Marketing authorisation holders of human medicinal products asked to conduct their own evaluation of the potential risk of contamination with nitrosamines
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.[1] 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.
| Nitrosamine | Limit (ng/day) |
|---|---|
| NDMA | 96 |
| NMBA | 96 |
| NDEA | 26.5 |
| NDIPA | 26.5 |
| NEIPA | 26.5 |
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.
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.
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).
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.
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:
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).
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.
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.
Potential nitrosamine contamination – harmonised implementation (update)
Swissmedic
Market Monitoring of Medicines
Quality defects
Hallerstrasse 7
3012
Berne
Switzerland
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.
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:
[1] Further information on the subject of contamination of sartans with nitrosamines:
