Referance : https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-human-drugs
The Food and Drug Administration (FDA, Agency, or we) is announcing the availability of a final guidance for industry entitled “Control of Nitrosamine Impurities in Human Drugs.” This guidance recommends steps manufacturers of active pharmaceutical ingredients (APIs) and drug products should take to detect and prevent unacceptable levels of nitrosamine impurities in pharmaceutical products. The guidance describes two general structural classes of nitrosamine impurities: small-molecule nitrosamine impurities (i.e., nitrosamine impurities that do not share structural similarity to the API), and nitrosamine drug substance-related impurities (NDSRIs), which share structural similarity to the API and are generally unique to each API. The guidance discusses the potential root causes of the presence of nitrosamine impurities, detection of nitrosamine impurities, and recommendations for risk assessments, testing, and implementation of controls and other appropriate strategies to prevent or reduce the presence of nitrosamine impurities in APIs and drug products. Recommendations for an alternative bioequivalence approach if manufacturers and applicants decide to reformulate their products to mitigate nitrosamine impurities are also provided in the guidance. This guidance revises the final guidance of the same name issued on February 24, 2021.
To reflect the evolving and highly technical nature of the relevant information, FDA is providing certain updated information in connection with this guidance, at this web page: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits.
Specifically, FDA intends to include on this web page updated information on:
(1) recommended AI limits for certain nitrosamine impurities, based on their predicted carcinogenic potency categorization (CPCA), including certain recommended AI limits for drug products with a hypothetical risk of forming NDSRIs;
(2) recommended AI limits for certain nitrosamine impurities based on compound-specific data from carcinogenicity and mutagenicity data or read-across analysis from a surrogate;
(3) recommended interim AI limits for certain nitrosamine impurities;
(4) recommended implementation timelines;
(5) other emerging scientific and technical issues;
(6) recommended analytical methods for confirmatory testing of certain nitrosamines impurities; and (7) recommended safety testing methods for nitrosamine impurities.
__________________________________________________________________________________________________________
Referance : https://www.intertek.com/pharmaceutical/news/nitrosodimethylamine-ndma-valsartan-drug-substance/
Nitrosamine impurities, classified as a probable human carcinogen, became a focus in July 2018, when the FDA announced a recall of some angiotensin II receptor blocker (ARB) medicines. In 2019, some over-the-counter medicines used to prevent and relieve heartburn such as ranitidine, were also the subject of some recalls with the HSA in Singapore and Swissmedic laboratory (OMCL) also detecting levels of contamination with NDMA in certain metformin preparations, used in the treatment of type 2 diabetes. More recently the FDA has issued an alert following the recall of some nizatidine products in association with suspected low levels of NDMA.
Although nitrosamine impurities have been found in only some drug products, and batches of those products have been recalled when there were unacceptable levels of these impurities, nitrosamine impurities might exist in other APIs and drug products due to use of certain processes and materials that may produce nitrosamine impurities.
Additional impurities including N-nitrosodiethylamine (NDEA), N-nitrosoethylisopropylamine (NIEPA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), and N-nitrosomethyl-4-amino-butyric acid (NMBA) have also been flagged as potential nitrosamine impurities. The FDA has been working closely with industry to ensure products entering the market do not contain these impurities in the future, whilst establishing suitable analytical methods to determine acceptable levels of these nitrosamine impurities and establish interim limits. In September 2019, the EMA began a review under Article 5(3) of Regulation (EC) No 726/2004 to provide guidance to marketing authorisation holders on how to avoid the presence of nitrosamine impurities in human medicines. As part of this review, in early 2020, the CHMP requested that marketing authorisation holders for human medicines conduct a risk evaluation in order to identify products at risk of N-nitrosamine formation or (cross-) contamination.
The FDA has released the following methods for the determination of NDMA impurities in drugs.
GC/MS Headspace Chromatography Mass Spectrometry Approach
The FDA Office of Testing and Research have developed a combined GC/MS headspace method for the simultaneous evaluation of four nitrosamine impurities in ARB drug substance and drug product. These impurities are; N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), and N-nitrosoethylisopropylamine (NEIPA). The method was developed and validated on valsartan drug substance and drug product.
At Intertek we also offer a GC-MS/MS approach which has allowed our experts to achieve excellent LOD and LOQ values. Overall, GC has proved extremely useful for some difficult projects, helping us to present an alternative and successful route to avoiding challenges associated with Liquid Chromatography co-elution of NDMA and DMF, as well as other potential interferences, where present. This flexibility in platform approaches means we can apply sample and nitrosamine-specific, tailored analytical solutions that are highly relevant for your nitrosamine testing needs.
Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Method for the Determination of NDMA in Ranitidine Drug Substance and Solid Dosage Drug Product
This method is a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of NDMA in ranitidine drug substance and drug product. This LC-MS method based on a triple-quad platform may be used as an alternative or confirmatory method for the liquid chromatography high resolution mass spectrometry (LC-HRMS) method. The triple-quad platform is more widely available than the LC-HRMS platform.
Liquid Chromatography High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of NDMA in Ranitidine Drug Substance and Drug Product
The FDA have observed that the method for testing angiotensin II receptor blockers (ARBs) for nitrosamine impurities is not suitable for testing ranitidine because heating the sample generates NDMA. A LC-HRMS method was subsequently developed by the FDA to measure the levels of NDMA in ranitidine drug substance and drug product following ICH Q2(R1), with LOD 10ng/g, lower LOQ 33ng/g and upper LOQ 3333ng/g.
Intertek's Nitrosamine Impurity Analysis Services
Our GMP analytical team are experienced in providing analytical services according to FDA GC-MS, GC-MS/MS, LC-MS/MS and LC-HRMS methods, including performing the required method validations where the data can be used to support regulatory submissions or quality assessment of the API or drug product.
With scientists who are adept at method development and validation of suitable analytical procedures, we regularly help clients overcome the challenges of low detection levels, difficult matrices and identification of unknowns in the course of pharmaceutical impurities analysis. Additionally, we offer highly sensitive and specific method development and validation expertise to assess other carcinogenic or genotoxic impurities in drug products.
In addition to experienced pharmaceutical impurity analysis, we can support with toxicological risk assessments. Our experienced consultants conduct risk assessments to address the impact associated with exposure to residual solvents, process impurities, extractables & leachables, elemental impurities (ICH Q3D) and other substances that may find their way into a given pharmaceutical product.
Referance : https://www.fda.gov/regulatory-information/search-fda-guidance-documents/control-nitrosamine-impurities-human-drugs
The Food and Drug Administration (FDA, Agency, or we) is announcing the availability of a final guidance for industry entitled “Control of Nitrosamine Impurities in Human Drugs.” This guidance recommends steps manufacturers of active pharmaceutical ingredients (APIs) and drug products should take to detect and prevent unacceptable levels of nitrosamine impurities in pharmaceutical products. The guidance describes two general structural classes of nitrosamine impurities: small-molecule nitrosamine impurities (i.e., nitrosamine impurities that do not share structural similarity to the API), and nitrosamine drug substance-related impurities (NDSRIs), which share structural similarity to the API and are generally unique to each API. The guidance discusses the potential root causes of the presence of nitrosamine impurities, detection of nitrosamine impurities, and recommendations for risk assessments, testing, and implementation of controls and other appropriate strategies to prevent or reduce the presence of nitrosamine impurities in APIs and drug products. Recommendations for an alternative bioequivalence approach if manufacturers and applicants decide to reformulate their products to mitigate nitrosamine impurities are also provided in the guidance. This guidance revises the final guidance of the same name issued on February 24, 2021.
To reflect the evolving and highly technical nature of the relevant information, FDA is providing certain updated information in connection with this guidance, at this web page: https://www.fda.gov/regulatory-information/search-fda-guidance-documents/cder-nitrosamine-impurity-acceptable-intake-limits.
Specifically, FDA intends to include on this web page updated information on:
(1) recommended AI limits for certain nitrosamine impurities, based on their predicted carcinogenic potency categorization (CPCA), including certain recommended AI limits for drug products with a hypothetical risk of forming NDSRIs;
(2) recommended AI limits for certain nitrosamine impurities based on compound-specific data from carcinogenicity and mutagenicity data or read-across analysis from a surrogate;
(3) recommended interim AI limits for certain nitrosamine impurities;
(4) recommended implementation timelines;
(5) other emerging scientific and technical issues;
(6) recommended analytical methods for confirmatory testing of certain nitrosamines impurities; and (7) recommended safety testing methods for nitrosamine impurities.
__________________________________________________________________________________________________________
Referance : https://www.intertek.com/pharmaceutical/news/nitrosodimethylamine-ndma-valsartan-drug-substance/
Nitrosamine impurities, classified as a probable human carcinogen, became a focus in July 2018, when the FDA announced a recall of some angiotensin II receptor blocker (ARB) medicines. In 2019, some over-the-counter medicines used to prevent and relieve heartburn such as ranitidine, were also the subject of some recalls with the HSA in Singapore and Swissmedic laboratory (OMCL) also detecting levels of contamination with NDMA in certain metformin preparations, used in the treatment of type 2 diabetes. More recently the FDA has issued an alert following the recall of some nizatidine products in association with suspected low levels of NDMA.
Although nitrosamine impurities have been found in only some drug products, and batches of those products have been recalled when there were unacceptable levels of these impurities, nitrosamine impurities might exist in other APIs and drug products due to use of certain processes and materials that may produce nitrosamine impurities.
Additional impurities including N-nitrosodiethylamine (NDEA), N-nitrosoethylisopropylamine (NIEPA), N-nitrosodiisopropylamine (NDIPA), N-nitrosodibutylamine (NDBA), and N-nitrosomethyl-4-amino-butyric acid (NMBA) have also been flagged as potential nitrosamine impurities. The FDA has been working closely with industry to ensure products entering the market do not contain these impurities in the future, whilst establishing suitable analytical methods to determine acceptable levels of these nitrosamine impurities and establish interim limits. In September 2019, the EMA began a review under Article 5(3) of Regulation (EC) No 726/2004 to provide guidance to marketing authorisation holders on how to avoid the presence of nitrosamine impurities in human medicines. As part of this review, in early 2020, the CHMP requested that marketing authorisation holders for human medicines conduct a risk evaluation in order to identify products at risk of N-nitrosamine formation or (cross-) contamination.
The FDA has released the following methods for the determination of NDMA impurities in drugs.
GC/MS Headspace Chromatography Mass Spectrometry Approach
The FDA Office of Testing and Research have developed a combined GC/MS headspace method for the simultaneous evaluation of four nitrosamine impurities in ARB drug substance and drug product. These impurities are; N-nitrosodimethylamine (NDMA), N-nitrosodiethylamine (NDEA), N-nitrosodiisopropylamine (NDIPA), and N-nitrosoethylisopropylamine (NEIPA). The method was developed and validated on valsartan drug substance and drug product.
At Intertek we also offer a GC-MS/MS approach which has allowed our experts to achieve excellent LOD and LOQ values. Overall, GC has proved extremely useful for some difficult projects, helping us to present an alternative and successful route to avoiding challenges associated with Liquid Chromatography co-elution of NDMA and DMF, as well as other potential interferences, where present. This flexibility in platform approaches means we can apply sample and nitrosamine-specific, tailored analytical solutions that are highly relevant for your nitrosamine testing needs.
Liquid Chromatography-Tandem Mass Spectrometry (LC-MS/MS) Method for the Determination of NDMA in Ranitidine Drug Substance and Solid Dosage Drug Product
This method is a liquid chromatography-tandem mass spectrometry (LC-MS/MS) method for the determination of NDMA in ranitidine drug substance and drug product. This LC-MS method based on a triple-quad platform may be used as an alternative or confirmatory method for the liquid chromatography high resolution mass spectrometry (LC-HRMS) method. The triple-quad platform is more widely available than the LC-HRMS platform.
Liquid Chromatography High Resolution Mass Spectrometry (LC-HRMS) Method for the Determination of NDMA in Ranitidine Drug Substance and Drug Product
The FDA have observed that the method for testing angiotensin II receptor blockers (ARBs) for nitrosamine impurities is not suitable for testing ranitidine because heating the sample generates NDMA. A LC-HRMS method was subsequently developed by the FDA to measure the levels of NDMA in ranitidine drug substance and drug product following ICH Q2(R1), with LOD 10ng/g, lower LOQ 33ng/g and upper LOQ 3333ng/g.
Intertek's Nitrosamine Impurity Analysis Services
Our GMP analytical team are experienced in providing analytical services according to FDA GC-MS, GC-MS/MS, LC-MS/MS and LC-HRMS methods, including performing the required method validations where the data can be used to support regulatory submissions or quality assessment of the API or drug product.
With scientists who are adept at method development and validation of suitable analytical procedures, we regularly help clients overcome the challenges of low detection levels, difficult matrices and identification of unknowns in the course of pharmaceutical impurities analysis. Additionally, we offer highly sensitive and specific method development and validation expertise to assess other carcinogenic or genotoxic impurities in drug products.
In addition to experienced pharmaceutical impurity analysis, we can support with toxicological risk assessments. Our experienced consultants conduct risk assessments to address the impact associated with exposure to residual solvents, process impurities, extractables & leachables, elemental impurities (ICH Q3D) and other substances that may find their way into a given pharmaceutical product.