Nitrosamine impurities in medicines - Information for sponsors and manufacturers

The TGA continues 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. The TGA has 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, the TGA also considers the impact on medicine availability.

Recall actions are available on the TGA System for Australian recall actions database. Safety advisories are published on the TGA website - external site. Medicine shortages are published on the TGA Medicine shortage reports database - external site.

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

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 the TGA 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 the TGA 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 the TGA if they become aware that their medicine is affected by a nitrosamine impurity exceeding the appropriate AI limit. Sponsors should consult the TGA recalls procedures if a recall may be warranted. Sponsors should report any overseas regulatory actions related to nitrosamine contamination of their medicines to the TGA as a significant safety issue (SSI) to Signal Investigation Coordinator within the required timeframe.

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.

The TGA expects 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.

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:

•  'sartan' blood pressure medicines in 2018
• metformin products and ranitidine products in 2019
• varenicline products in 2021
• rifampicin products in 2021
• sitagliptin products and quinapril products in 2022

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 - external site 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 - external site provides guidance on how to mitigate the risk of nitrosamine impurities in medicines.

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.

From time to time the TGA may, including as part of new registration or variation applications, ask sponsors to provide information - external site such as a risk assessment and/or testing results to demonstrate that the sponsor's medicines meet the expected standards for safety and quality.

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:

1. 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 - external site
2. 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) - external site 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) - external site 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 - external site and other international medicines regulators.

Established AI limits form some nitrosamine impurities that the TGA considers acceptable are in Appendix 1. These apply for all routes of administration.

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

• the EMA's Assessment Report Procedure under Article 5(3) of Regulation EC (No) 726/2004 Nitrosamine impurities in human medicinal products (pdf,1.26Mb) - external site
• the EMA's Questions and answers for marketing authorisation holders/applicants on the CHMP Opinion for the Article 5(3) of Regulation (EC) No 726/2004 referral on nitrosamine impurities in human medicinal products (pdf,753kb) - external site and
• the US FDA guidance Control of Nitrosamine Impurities in Human Drugs - external site
• Health Canada's Nitrosamine impurities in Medicines: Guidance - external site

The presence of a nitrosamine impurity above the acceptable limit indicates that the safety and quality of the medicine may be unacceptable. The TGA’s 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 should be at or below a value sufficient to confirm the presence of the nitrosamine at or below the AI for the finished product.

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.

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

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 and as a significant safety issue (SSI) to Signal Investigation Coordinator. The Pharmacovigilance responsibilities for medicine sponsors are available via the TGA 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 the corrective actions 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 the TGA’s requirements for sponsors regarding nitrosamine risk assessments in prescription medicine registration submissions. The TGA is 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 the TGA.

• For notifications of significant safety issues associated with medicine quality issues, email: si.coordinator@health.gov.au
• For notifications of medicine quality defect issues that is likely to warrant a recall, email: recalls@health.gov.au
• For reports of serious adverse reactions associated with medicine quality issues, email: adr.reports@tga.gov.au
• For confirmed medicine quality issues unlikely to warrant a recall, email Nitrosamines@health.gov.au
• For notifications of GMP compliance issues, email: GMPCompliance@health.gov.au

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:

• Quality Risk Management Guideline ICH Q9 - external site
• ICH M7(R1) Assessment and control of DNA reactive (mutagenic) impurities in pharmaceuticals to limit potential carcinogenic risk” (ICH M7 (R1)) - external site

Root causes, risk assessment and nitrosamine impurities information

• Committee for Medicinal Products for Human Use (CHMP) Assessment report Referral under Article 31 of Directive 2001/83/EC angiotensin-II-receptor antagonists (sartans) containing a tetrazole group. 14 February 2019. EMA/217823/2019 (pdf,531kb)* - external site
• The European Medicines Agency (EMA) Nitrosamine Impurities - external site webpage includes information including the EMA Opinion review, EMA Assessment report, EMA Questions and Answers document and EMA's templates for nitrosamine risk assessment.
• US FDA Information about Nitrosamines Impurities in Medications - external site webpage including the FDA guidance for industry.
• Health Canada Nitrosamine impurities in medications: Overview - external site webpage.
• US Pharmacopoeia/National Formulary (USP/NF) Nitrosamine impurities - external site and Nitrosamine impurities general chapter - external site webpages.
• EDQM response nitrosamine contamination - external site and general chapter n-nitrosamines webpages.
• European Pharmacopoeia (Ph. Eur) general chapter n-nitrosamines - external site webpage.

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.

• European Official Medicines Control Laboratories - external site (OMCL)
• FDA test method - external site (Liquid Chromatography-High Resolution Mass Spectrometry (LC-HRMS) method for the Determination of six nitrosamine Impurities in ARB Drugs).
• US FDA test methods for ranitidine and nizatidine - external site and for metformin - external site
• Swissmedic limit test for the determination of Nitrosamines by GC-MS/MS
• Health Sciences Agency (HSA; Singapore) methods for metformin - external site and for ranitidine - external site.
• Health Canada test methods - external site and Angiotensin Receptor Blocker - external site webpages.
• Taiwan FDA methods for testing for N-nitrosamines in medicines - external site webpage.