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Nitrosamine impurities in medicines

Information for sponsors and manufacturers

Current information on nitrosamine and other N-nitroso-structure impurities. 

Last updated

At the Therapeutic Goods Administration (TGA), we are working closely with other international regulators and medicine sponsors to investigate and address nitrosamine impurities in medicines.

This page includes relevant information for all medicine sponsors and manufacturers, including those seeking to register new products. Sponsors should also be familiar with the significant amount of information published on nitrosamines from international regulators including the European Medicines Agency (EMA), US Food and Drug Administration (FDA) and Health Canada.

Read our January 2023 alert Nitrosamine impurities in medicines - Information for sponsors and manufacturers.

TGA Actions

We continue to collaborate with our international regulatory partners to investigate the issue of nitrosamine impurities in medicine products. This includes sharing information, determining the actions which may be required and coordinating efforts on inspections, risk assessments and communications. We recognise the benefits of international alignment of the approach to this issue where possible. We will share information with industry should a new risk be identified, and take appropriate regulatory actions including overseeing the implementation of improved manufacturing and testing processes to ensure the safety and quality of medicines in Australia.

Long-term exposure over a period of years to nitrosamines that exceed certain levels can increase the risk of developing cancer. Given this, the aim is to eliminate or minimise the levels of nitrosamines present in affected medicines, as their presence is generally considered unacceptable from both quality and safety perspectives. We have set acceptable intake (AI) limits for many nitrosamine impurities to ensure medicines remain both safe and of high quality. The limits are used to determine if regulatory actions are required for affected products.

A range of regulatory responses can be used to manage this issue, including medicine recalls, suspending medicines, placing conditions on a product's registration and/or actions related to product manufacture. When considering the appropriate regulatory response, we also consider the impact on medicine availability.

Recall actions are available by searching our Recall actions database. Safety advisories are published on our Safety alerts page. Medicine shortages are published on our Medicine shortage reports database

Updated information will be published on this issue as it becomes available.

Sponsor and manufacturer responsibilities

Australian medicine sponsors are responsible for the quality, safety and efficacy of their medicines, including the active ingredients, excipients and other raw materials used in the manufacturing of finished products. After registration, there are ongoing requirements for sponsors to monitor the quality, safety and efficacy of their products, as well as to inform us if they become aware of any issues. This includes monitoring for emerging global issues and for global regulatory actions that may be relevant to Australia.

Sponsors should be aware of the global issue relating to nitrosamine impurities in medicines. Sponsors are required to inform us in writing as soon as they become aware of information that indicates that the quality, safety or efficacy of their goods is unacceptable. This includes both sponsors and manufacturers of medicines and biologicals informing us if they become aware that their medicine is affected by a nitrosamine impurity exceeding the appropriate AI limit. Sponsors should consult our recalls procedures if a recall may be warranted. Sponsors should report any overseas regulatory actions related to nitrosamine contamination of their medicines to us as a significant safety issue (SSI) to Signal Investigation Coordinator within the required timeframe and to TGA Nitrosamines.

Sponsors are also required to ensure that their active ingredients and finished products have been manufactured in accordance with Good Manufacturing Practice (GMP), detailed in the Sponsor responsibilities related to GMP clearance and certification. These responsibilities include the requirement to inform the TGA of information on GMP compliance signals.

We expect that sponsors are familiar with the known and plausible causes of nitrosamine impurities in their products. To meet their regulatory obligations, sponsors should be taking active steps to determine whether their medicines are at risk of containing nitrosamine impurities. Sponsors should ensure that they, and their finished product manufacturers, have access to relevant information from the active pharmaceutical ingredient (API) manufacturer(s) regarding potential formation and presence of nitrosamine impurities, as well as the potential for cross-contamination.

Background to investigations of nitrosamines in medicines

N-nitrosodimethylamine (NDMA), and subsequently other nitrosamines, were first identified in July 2018 in blood pressure medicines known as 'sartan' medicines which were manufactured using an active ingredient sourced from an overseas manufacturer. Later, other sartan medicines from that manufacturer and also from other manufacturers, were found to be affected by nitrosamine impurities.

Several medicines have since been found to have unacceptable levels of the nitrosamine impurities both in Australia and overseas. Medicines affected by nitrosamine impurities in Australia include:

Origin of nitrosamine impurities

Investigations conducted by international regulatory authorities into the presence of nitrosamine impurities have identified a number of confirmed and/or possible sources of contamination. Currently identified or plausible root causes can include synthetic conditions, potential carry-over/contamination with nitrosating agents (including nitrites) and amines/amides, contaminated recycled materials, packaging and degradation. The currently identified root causes for the presence of nitrosamines are available in the EMA's Questions and answers document.

International regulatory authorities are continuing to test for sources of nitrosamine impurities. Information is regularly published by the EMA and other regulatory authorities. The EMA's finalised review under Article 5(3) of Regulation (EC) No 726/2004 provides guidance on how to mitigate the risk of nitrosamine impurities in medicines.

Investigating potential for nitrosamine impurities

The scope of investigations into the potential presence of nitrosamine impurities is very broad. Sponsors are expected to monitor for signals and respond appropriately. This includes prioritising APIs that have been reported overseas as being affected. Sponsors should consider the following factors when prioritising their medicines for consideration:

  • duration of use
  • maximum daily dose
  • indication
  • size of population using the medicine, and
  • any other factors relevant to the medicine.

Given the nature of the safety concerns for nitrosamines, priority should generally be given to products with a chronic duration of use and a high daily dose. This approach is consistent with that suggested by other international regulators, including the EMA.

Sponsors must ensure that they have adequate oversight of the manufacturing process for their APIs and finished products to identify any potential sources of risk.

If a sponsor identifies that a known, plausible, or potential cause of nitrosamine impurities is present for their medicine(s), they should undertake further investigation. It is recommended that sponsors obtain a formal risk assessment from manufacturers to assist in assessing the risk of nitrosamine impurities being present in their medicine. If the risk assessment identifies a risk of nitrosamine impurities in the medicines, the sponsor should undertake testing to determine whether the safety and quality of the medicine remains acceptable and meets the standards set by the TGA. This approach should be used for all existing and new finished products.

We may, including as part of new registration or variation applications, ask sponsors to provide information such as a risk assessment and/or testing results to demonstrate that the sponsor's medicines meet the expected standards for safety and quality. See the Therapeutic Goods Act 1989 and Nitrosamine risk assessment in Category 1 prescription medicine registration applications for further information. 

As detailed below, if a nitrosamine risk is identified for a new or existing medicine, sponsors are expected to conduct confirmatory testing for the nitrosamine in their products and provide results to demonstrate that their medicines comply with the expected limits throughout the entire product shelf life. The limits are applicable for all routes of administration.

Additionally, if a nitrosamine is identified in an existing medicine product, sponsors are expected to take active steps and put in place corrective and preventative actions (CAPAs) to mitigate the risk of formation to below the expected limits, as outlined in EMA's Questions and answers document.

Acceptable intake nitrosamine limits

We determine the appropriate acceptable limit for a medicine using the AI for the nitrosamine impurity and the maximum daily dose. Our approach in setting AI limits for nitrosamines is to align where possible with international regulators.

AI limits can be established using several approaches:

A. If N-nitrosamines are identified with sufficient substance specific animal carcinogenicity data, the TD50 should be calculated and used to derive a substance specific limit for lifetime exposure as recommended in ICH M7 guideline

B. If N-nitrosamines are identified without sufficient substance specific data to derive a substance specific limit for lifetime exposure as described in option A:

  1. The Carcinogenic Potency Categorization Approach (CPCA) for N-nitrosamines should be used to establish the AI, unless other robust data are available that would override this AI.
  2. A negative result in an GLP-compliant enhanced Ames test (EAT) allows control of the N-nitrosamine at 1.5 µg/day. For substances testing positive, the AI should be established using options 1 or 3.
  3. If a surrogate nitrosamine is available with sufficiently robust carcinogenicity data, the TD50 from the surrogate substance can serve as a point of departure for derivation of AI by SAR and read across.
  4. A negative result in a relevant well-conducted in vivo mutagenicity study can allow control of the N-nitrosamine as a non-mutagenic impurity, i.e., according to Q3A/B limits, irrespective of the limit calculated through option 1, 2 or 3. For substances testing positive, the AI should be established using options 1 or 3.

These approaches have been published by the EMA and other international medicines regulators.

  • Established AI limits form some nitrosamine impurities are listed at:

Established acceptable intake for nitrosamines in medicines

  • Established AI limits for some other N-nitroso-structures. N-Nitroso-structures include N nitrosoguanidines, N nitroso-indoles and N nitrosoureas are listed separately at:

Established acceptable intake for other nitroso-structures in medicines

These limits apply for all routes of administration.

Note: The CPCA process used to establish nitrosamine AI limits cannot be used to establish AI limits for other N-nitroso-structures.

The AI in ng/day is used in combination with the Maximum Daily Dose (MDD) to calculate the limit in ppm. For an individual medicine, the limits in ppm should be calculated based on the MDD as included in the Product Information (PI). In the absence of a PI, a clinical justification for the maximum dose used should be provided.

Sponsors should contact us  via TGA Nitrosamines regarding the acceptability of their proposal to apply a limit for a nitrosamine impurity. Further advice for nitrosamines without published AI limits, is available in the following:

The presence of a nitrosamine impurity above the acceptable limit indicates that the safety and quality of the medicine may be unacceptable. Our regulatory actions will be considered on a case-by-case basis, particularly for critical medicines.

Currently, nitrosamine impurities are considered to be absent if below the limit of quantitation (LOQ). The LOQ of the selected analytical method should be sufficient to confirm the presence of the nitrosamine at or below the AI at the maximum daily dose (MDD) of the medicine.

Testing for nitrosamine impurities

Testing for nitrosamines should be undertaken using a validated test method. Methods have been developed and published by some international regulatory agencies, including the US FDA and the European Official Medicine Control Laboratories (OMCL). Some links published by international regulators and others are below in our useful resources.

If testing confirms the presence of a nitrosamine, a sponsor must take steps to ensure their product does not contain nitrosamines at levels that exceed the acceptable limits. Sponsors should submit the appropriate variation application seeking our approval and detailing modifications to their manufacturing process and specifications to address the risk.

Informing the TGA of nitrosamine impurities and associated actions

If a sponsor detects a nitrosamine in their medicine at a level exceeding the AI limit, the sponsor should report this issue to TGA recalls, TGA Nitrosamines and as a significant safety issue (SSI) to Signal Investigation Coordinator. The Pharmacovigilance responsibilities for medicine sponsors are available via our website.

If a nitrosamine is detected at a level below the AI, the sponsor should thoroughly investigate the root cause. Sponsors should continue to monitor nitrosamine levels to ensure that the levels will not exceed the acceptable limits throughout the product shelf life. Sponsors should retain records of the investigation and any corrective and preventative actions (CAPAs) taken to monitor and address nitrosamine levels within their GMP Quality Management System. These records may be reviewed during GMP inspections.

Sponsors should consider whether changes to the manufacturing process and/or controls applied to the API are required to mitigate the formation of nitrosamine impurities. For example, sponsors may include the revision of the synthetic process, raw material or drug substance/product specifications and/or in-process controls or storage conditions to ensure the quality and safety of their medicine is acceptable and that the AI is not exceeded.

Sponsors intending to change the manufacturing process and/or controls to address this issue should make a variation request under section 9D(3) of the Therapeutic Goods Act 1989 (i.e. 'Category 3' request). The notification system cannot be used for this purpose and change code ASNT cannot be used in relation to these types of impurities. Sponsors should refer to the Minor variations guidance for prescription medicines and OTC medicine changes guidance documents for information on the types of changes that require prior approval and on how to submit a variation request.

Sponsors can submit a Category 3 request to justify a nitrosamine limit based on an enhanced Ames test and/or the Carcinogenic Potency Categorization Approach. However, for any other variation requiring evaluation of toxicity data, including an in vivo mutagenicity study, the request should be made via the Category 1 pathway. A justification for a proposed nitrosamine limit or the lack of control of a nitrosamine impurity is equally expected in new registration submissions.

See our requirements for sponsors regarding nitrosamine risk assessments in prescription medicine registration submissions. We are not requesting that sponsors provide risk assessments for the potential for nitrosamine impurities to the TGA where they do not identify a concern in existing medicine products. However, this information should be available if requested by us.

Further information

Useful resources

There is a significant amount of information published on the presence of nitrosamine impurities in medicines. The links below provide additional information. This is not an exhaustive list, given the dynamic nature of this issue. Sponsors should make all reasonable efforts to seek further information relevant to their products.

Relevant ICH guidelines:

Root causes, risk assessment and nitrosamine impurities information

Testing methods

Published validated testing methods that may be used for the development and validation of analytical methods for medicines are below. This list is not exhaustive. Appropriately sensitive analytical methods for determination of the specific nitrosamines in medicinal products should be developed and validated accordingly before testing.

 

Related links

Sartan blood pressure medicines
N-nitroso compounds in 'sartan' blood pressure medicines
Metformin
Ranitidine
Varenicline
Rifampicin
Sitagliptin
Quinapril blood pressure medicines
Safety advisory: Fluoxetine
Safety advisory: Duloxetine
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