International Regulatory Collaboration on the Analysis of Nitrosamines in Metformin-Containing Medicines
Recalls of some batches of metformin have occurred due to the detection of N -nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each...
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| Veröffentlicht in: | The AAPS journal Jg. 24; H. 3; S. 56 |
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21.04.2022
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| Abstract | Recalls of some batches of metformin have occurred due to the detection of
N
-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches.
Graphical abstract |
|---|---|
| AbstractList | Recalls of some batches of metformin have occurred due to the detection of
N
-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches.
Graphical abstract Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches. Graphical abstract Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches. Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches.Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches. Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng per day. Prior to the recalls, an international regulatory laboratory network had been monitoring drugs for nitrosamine impurities with each laboratory independently developing and validating multiple analytical procedures to detect and measure nitrosamines in metformin drugs used in their jurisdictions. Here, we provide an overview of the analysis of metformin active pharmaceutical ingredients (APIs) and drug products with 1090 samples (875 finished dosage forms (FDFs) and 215 API samples) tested beginning in November of 2019 through July of 2020. Samples were obtained internationally by a variety of approaches, including purchased, received from firms via information requests or selected by regional regulatory authorities (either at wholesalers or during GMP inspections). Only one nitrosamine (NDMA) was detected and was only present in some batches of metformin products. For API samples, 213 out of 215 lots tested had no measurable level of NDMA. For FDF samples tested, the number of batches with NDMA above the AI amount for patient safety was 17.8% (156/875). Based on these data, although the presence of NDMA was of concern, 82.2% of the samples of metformin drug products tested met quality and safety standards for patients. Regulatory agencies continue to collaborate extensively and work with marketing authorization holders to understand root causes of nitrosamine formation and agree on corrective actions to mitigate the presence of NDMA in future metformin batches. |
| ArticleNumber | 56 |
| Audience | Academic |
| Author | Bream, Robert Zmysłowski, Adam Wollein, Uwe Schmaler-Ripcke, Jeannette Keire, David A. Keizers, Peter Wierer, Michael George, Mark Morin, Justin Poh, Jalene Burchardt, Annette Conti, Massimiliano |
| Author_xml | – sequence: 1 givenname: David A. surname: Keire fullname: Keire, David A. email: David.Keire@fda.hhs.gov organization: Office of Testing and Research, Office of Pharmaceutical Quality, Food and Drug Administration – sequence: 2 givenname: Robert surname: Bream fullname: Bream, Robert organization: European Medicines Agency – sequence: 3 givenname: Uwe surname: Wollein fullname: Wollein, Uwe organization: Bayerisches Landesamt Für Gesundheit Und Lebensmittelsicherheit, LGL – sequence: 4 givenname: Jeannette surname: Schmaler-Ripcke fullname: Schmaler-Ripcke, Jeannette organization: Chemisches und Veterinäruntersuchungsamt Karlsruhe, CVUA Karlsruhe – sequence: 5 givenname: Annette surname: Burchardt fullname: Burchardt, Annette organization: Institute for Pharmaceutical and Applied Analytics - InphA GmbH – sequence: 6 givenname: Massimiliano surname: Conti fullname: Conti, Massimiliano organization: Schweizerisches Heilmittelinstitut (Biol. & Pharm.), OMCL Swissmedic – sequence: 7 givenname: Adam surname: Zmysłowski fullname: Zmysłowski, Adam organization: National Medicines Institute, NIL – sequence: 8 givenname: Peter surname: Keizers fullname: Keizers, Peter organization: Centre for Health Protection, National Institute for Public Health and the Environment (RIVM) – sequence: 9 givenname: Justin surname: Morin fullname: Morin, Justin organization: Health Canada – sequence: 10 givenname: Jalene surname: Poh fullname: Poh, Jalene organization: Health Sciences Authority – sequence: 11 givenname: Mark surname: George fullname: George, Mark organization: TGA Laboratories – sequence: 12 givenname: Michael surname: Wierer fullname: Wierer, Michael organization: European Directorate for the Quality of Medicines & HealthCare |
| BackLink | https://www.ncbi.nlm.nih.gov/pubmed/35449372$$D View this record in MEDLINE/PubMed |
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| Cites_doi | 10.1016/0015-6264(79)90115-9 10.1056/NEJMp1901657 10.1016/j.jpba.2018.11.010 10.1038/239165b0 10.1080/02652030701278354 10.1111/j.1749-6632.1982.tb31232.x 10.1016/j.xphs.2021.08.010 10.1016/j.pcl.2017.08.010 10.1016/j.foodchem.2012.07.002 10.1208/s12249-011-9677-z 10.1186/1758-5996-5-6 10.1208/s12248-020-00473-w 10.1208/s12249-019-1376-1 10.1080/15287394.2018.1460782 10.1016/0015-6264(81)90455-7 10.1016/j.chemosphere.2018.07.098 10.1097/CRD.0000000000000323 10.5487/TR.2015.31.3.279 10.1016/j.jpba.2022.114677 10.1101/2020.05.22.20110635 10.1016/j.ejps.2021.106026 10.1016/j.jpba.2020.113877 10.3390/molecules25225304 |
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| Keywords | metformin drug supply nitrosamines NDMA International regulatory laboratories |
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-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng... Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng... Recalls of some batches of metformin have occurred due to the detection of N-nitrosodimethylamine (NDMA) in amounts above the acceptable intake (AI) of 96 ng... |
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| SubjectTerms | Biochemistry Biomedical and Life Sciences Biomedicine Biotechnology Diabetes therapy Dimethylnitrosamine - analysis Humans Independent regulatory commissions Metformin Metformin - analysis Nitrosamines - analysis Nitrosoamines Pharmacology/Toxicology Pharmacy Research Article Type 2 diabetes Valsartan |
| Title | International Regulatory Collaboration on the Analysis of Nitrosamines in Metformin-Containing Medicines |
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