TGA update: Nitrosamine impurities acceptable intakes

The TGA has published a web page providing information on the updated TGA acceptable intake (AI) for nitrosamine impurities in medicines. The TGA provides that the update to nitrosamine AI is consistent with recent (15 January 2024) EMA updated information, and is applicable for all routes of administration. The TGA provide that additional updated information on this issue will be published on the TGA website as it becomes available. 

Other than minor editorial amendments, the changes include: 

  • Inclusion of 34 recently internationally determined AI limits for numerous nitrosamine impurities in medicines. 
  • Details of the newly added AIs are available at Appendix A of this alert.  
  • Recently updated AIs are available at Appendix B of this alert. 

Most of the new additions and updates relate to prescription substances. Calcium folinate / Calcium levofolinate is the only new substance added to Appendix A that is a listable complementary medicine ingredient. The acceptable intake is listed as “NMI” which is a “non-mutagenic impurity”. 

As per the TGA website, they use the approach published by the EMA to determine the appropriate acceptable limit for a medicine using the AI for the nitrosamine impurity and the maximum daily dose. AI limits can be established using several approaches. The approaches highlighted below are relevant to those marked “NMI” such as calcium folinate: 

  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 
  1. 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. 
  1. 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. 
  1. 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. 
  1. 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. 

Sponsors and manufacturers are encouraged to review the current TGA established AI for nitrosamine impurities in medicines to ensure that nitrosamine impurities do not exceed the AI limits in the Maximum Daily Dose (MDD) of the medicine.  

Members may contact us at technical@cmaustralia.org.au if they are aware of  complementary medicine raw materials or products with detected nitrosamines, as part of CMA’s industry-level quality monitoring and awareness activities. 

Background 

2021 

  • Following the identification of N-nitrosodimethylamine (NDMA), and subsequently other nitrosamines in blood pressure and other medicines in Novemebr 2021, the TGA in collaboration with other international regulators has been investigating the issue. Although nitrosamines are naturally occurring in foods, the TGA stated that their presence in medicines is not acceptable from a quality and safety perspective and the TGA’s aim is to eliminate or minimise the levels of nitrosamines present in affected medicines. The TGA also published information for all medicine sponsors and manufacturers, including those seeking to register new products.  
  • The TGA set acceptable intake (AI) limits for many nitrosamine impurities to ensure medicines remain both safe and of high quality, and shared their expectation that sponsors should be taking active steps to determine whether their medicines are at risk of containing nitrosamine impurities; and to 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. 

July 2022 

  • The TGA published an updated webpage in relation to nitrosamine impurities, which included detail on sources, limits and quality references and a number of information resources for sponsors, manufacturers and raw material suppliers.  
  • International guidance generally, and the advice provided by the TGA specifically largely appears to be related to registered medicines (i.e., ‘sartan’ blood pressure medicines, metformin products, ranitidine and varenicline) however, the TGA indicated that the information provided in the nitrosamine web page alert is applicable to all medicines, including complementary medicines.  
  • The TGA have previously advised they consider the most likely source of nitrosamines contamination to be via poorly controlled use of recovered solvents, and/or cross contamination. However, other compounds could also present a risk. While the risk of nitrosamine contamination of complementary medicines may be considered to be potentially low, based on ingredients, manufacturing processes, and the typical frequency/duration the medicines are taken, nitrosamine content of complementary medicines cannot be ruled out as a concern.   
  • In particular, CMA became aware that there is potential for nitrosamine contamination in vitamin substances, we also understand that this has been reported to the TGA in accordance with their guidelines. Members may wish to consider reviewing risk assessment profiles for the presence of nitrosamines in raw materials, in case of risk to consumers and/or further TGA investigations. 

CMA’s March 2023 tech alert contains additional background information on nitrosamine impurities and also provides resources and international perspectives from Health Canada and EFSA.  

Resources 

Appendix A: Newly added Established acceptable intake for nitrosamines in medicines (as of 31 January 2024) 

Nitrosamine (CAS number, Abbreviation)  Source2 AI limit (ng/day)1  CPCA Potency category  First published  
1-(2,3-Dichlorophenyl)-4-nitrosopiperazine Aripiprazole 400 31 January 2024 
5-Chloro-4-methyl-2-[(2S)-2-methyl-1-nitrosopyrrolidin-2-yl]-1H-benzimidazole (IDOR-1135-8758) Daridorexant 1500 31 January 2024 
Indapamide impurity A / 
2-Methyl-1-nitroso-2,3-dihydroindole 
Indapamide 1500 31 January 2024 
N-Nitroso desmethyl nintedanib Nintedanib 400 31 January 2024 
N-Nitroso imatinib Imatinib 1500 31 January 2024 
N-Nitroso quetiapine HEEP impurity / 
2-(2-(4-Nitrosopiperazin-1-yl)ethoxy)ethan-1-ol 
Quetiapine 1500  31 January 2024 
N-nitroso ranolazine impurity 1 / 
1-(2-Methoxyphenoxy)-3-(4-nitrosopiperazin-1-yl)propan-2-ol 
Ranolazine 400 31 January 2024 
N-Nitroso-azacyclonol (1038-06-8) Azacyclonol 400 31 January 2024 
N-Nitroso-betaxolol Betaxolol 1500 31 January 2024 
N-Nitroso-calcium folinate Calcium folinate / Calcium levofolinate NMI  31 January 2024 
N-Nitroso-celiprolol Celiprolol 1500 31 January 2024 
N-Nitroso-cinacalcet Cinacalcet 400 31 January 2024 
N-Nitroso-desethyllidocaine Lidocaine / Lignocaine 100 31 January 2024 
N-Nitroso-desmethyl sumatriptan Sumatriptan 18 31 January 2024 
N-Nitroso-desmethyl-azelastine Azelastine 100 31 January 2024 
N-Nitroso-desmethyl-citalopram Citalopram 18 31 January 2024 
N-Nitroso-desmethyl-sildenafil Sildenafil 400 31 January 2024 
N-Nitroso-desmethyl-terbinafine / 
(E)-N-(6,6-Dimethylhept-2-en-4-yn-1-yl)-N-(naphthalen-1-ylmethyl)nitrous amide (NDT / NHNA) 
Terbinafine 18 31 January 2024 
N-Nitroso-desvenlafaxine Desvenlafaxine 18 31 January 2024 
N-Nitroso-dorzolamide Dorzolamide 1500  31 January 2024 
N-Nitroso-esmolol Esmolol 1500 31 January 2024 
N-Nitroso-ethylenediamine-triacetic acid (862542-34-5) Isosorbide mononitrate 1500 31 January 2024 
N-Nitroso-iminodiacetic acid (25081-31-6) Isosorbide mononitrate 1500 31 January 2024 
N-Nitroso-leniolisib Leniolisib 1500 31 January 2024 
N-Nitroso-mirtazapine Mirtazapine 400 31 January 2024 
N-Nitroso-N-methylaniline / 
N-Methyl-N-phenylnitrous amide (614-00-6, NMPA) 
– 100 31 January 2024 
N-nitroso-ribociclib impurity 1 / 
7-Cyclopentyl-N,N-dimethyl-2-((5-(4-nitrosopiperazin-1-yl)pyridine-2-yl)amino)-7H-pyrrolo[2,3-d]pyrimidine-6-carboxamide 
Ribociclib 400 31 January 2024 
N-Nitroso-rivaroxaban amide / 
(S)-5-Chloro-N-(2-hydroxy-3-(nitroso (4-(3-oxomorpholino)phenyl)amino) propyl)thiophene-2-carboxamide 
Rivaroxaban 1500 31 January 2024 
N-Nitroso-rivaroxaban open-ring acid 
(S)-2-(2-((4-(5-((5-Chlorothiophene-2-carboxamido)methyl)-2-oxooxazolidin-3-yl)phenyl)(nitroso)amino)ethoxy) acetic acid 
Rivaroxaban 1500 31 January 2024 
N-Nitroso-terbinafine degradant 
N-[(2E)-6,6-dimethyl-2-hepten-4-yn-1-yl]-N-nitrosomethanamine (NTD / NHMA) 
Terbinafine 18 31 January 2024 
N-Nitroso-terbinafine impurity A 
N-methyl-N-(napthalen-1-ylmethyl)nitrous amide (296760-88-8, NTA / NMNA) 
Terbinafine 18 31 January 2024 
N-Nitroso-tetracaine Tetracaine 400 31 January 2024 
N-Nitroso-uradipil Uradipil 1500 31 January 2024 
N‐Nitroso‐ticagrelor (2476859-55-7) Ticagrelor 1500 31 January 2024 
  1. Acceptable Intake (AI) Limit to be applied to maximum daily dose (MDD) of the drug product. These limits are applicable only if a product contains a single N-nitrosamine. 
  1. Potential presence of nitrosamine impurities with structures derived from drug substances or their related impurities. This does not mean that the impurity will be found in all products or pharmaceutical forms containing the drug substance. Please refer to EMA’s Q&A 4 on the risk factors for the presence of nitrosamines for details. 

Appendix B: Updated acceptable intake for nitrosamines in medicines (as of 31 January 2024) 

Nitrosamine (CAS number, Abbreviation)  Source2 AI limit (ng/day)1  CPCA Potency category  First published  
N-Nitroso-ambroxol Ambroxol 1500  24 August 2023 Updated 31 January 2024 
N-Nitroso-dabigatran etexilate (NDAB) Dabigatran etexilate 1500  5 January 2023 Updated 24 August 2023 and 31 January 2024 
LinkedIn
Facebook
Twitter
Email

RECENT ARTICLES

Vale Stephen Myers

It is with great sadness that we learned of the passing of Emeritus Professor Stephen Myers late last week. Stephen was a giant in the

Read More