👋🏻 Fantastic Regulatory Update Europe, US, LATAM

I came across this fantastic summary of Nitrosamines Impurities update considering scenarios in Europe, USA, and LATAMN -Full credit to folks from Vita Pharma Consulting


In 2018, nitrosamine impurities, including N-nitrosodimethylamine (NDMA), were found in several blood pressure medicinal products, known as sartans (angiotensin receptor blockers – ARBs). This led to some product recalls and a regulatory review, which set new strict manufacturing requirements for these medicinal products.

Subsequently, a nitrosamine impurity was detected in batches of ranitidine, a medicinal product used to treat heartburn and stomach ulcers, and the Committee for Medicinal Products for Human Use (CHMP) in the European Medicines Agency (EMA) initiated a review.

Internationally, the repercussions related to nitrosamines generated recalls and other preventive measures and, following these movements from internationally recognized agencies such as EMA and FDA, several agencies in Latin America have also published their actions related to nitrosamine impurities. Many of these publications were based entirely on international actions, but some were local actions prepared by these same authorities.

The fact is that the nitrosamine issue is causing concerns for all links of the pharmaceutical supply chain.

Nitrosamines are chemical compounds classified as probable human carcinogens based on animal studies.

Since then, several actions have been taken by regulatory agencies around the world and it is very important that everyone be aware of publications on the subject in order to take preventive and effective actions.

This publication aims to compile internationally published data on this topic. In order to facilitate the visualization, below we list the publications separated according to the agencies / regions responsible.

Europe:

EMA has been posting guidelines to marketing authorization holders (MAHs) on its website on how to avoid the presence of nitrosamine impurities in medicinal products for human use.

There are also step-by-step guidelines with response models for cases in which the risk is or is not identified, as well as a constantly updated questions and answers (Q&A) document. It’s worth checking it out (Nitrosamine impurities | European Medicines Agency).

In November 2019, an important publication was brought in a new chapter in the Q&A document (https://bit.ly/3ro7yPo), describing the causes currently identified for nitrosamine contamination. These are summarized below:

  • Use of sodium nitrite (NaNO2), or other nitrosating agents, in the presence of secondary, tertiary amines or quaternary ammonium salts, within the same or other synthesis steps (if carry-over may occur).
  • Use of sodium nitrite (NaNO2), or other nitrosating agents, in combination with reagents, solvents and catalysts, from which secondary or tertiary amines are generated by degradation reactions within the same or another synthesis step (where carry-over may occur)
  • Contaminated raw materials (solvents, reagents, catalysts) in the API production process.
  • Recovered materials (solvents, reagents, catalysts), especially when reprocessed by third parties, using non-dedicated equipment.
  • Contaminated starting materials and intermediates from suppliers whose manufacturing processes or starting materials may allow the formation of nitrosamine.
  • Cross-contamination between different manufacturing processes on the same production line that is not clearly allocated and operator related errors.
  • Degradation processes of starting materials, intermediates and APIs, including those induced by inherent reactivity in combination with carry-over of sodium nitrite or other nitrosating agents. This can also occur during the formulation or storage of the finished product.
  • Primary packaging materials, such as blisters in which the nitrocellulose cover film reacts with amines in the paint primer, generating nitrosamines, which would be transferred to the product during the packaging process.

On December 6, 2019, EMA has confirmed that small amounts of NDMA were found in a small number of metformin-containing medicines outside the European Union (EU). There were no data indicating that EU medicines were affected. EMA and the European national competent authorities have been working closely to test EU medicines. EMA will provide updates as soon as possible.

The European agency has advised patients in EU to continue taking metformin as the risks of not treating diabetes far outweigh any possible effects of the low NDMA levels observed in the tests. (updated 16th December, 2019)

In August 2020, EMA published the update of the document Questions and Answers concerning Nitrosamines. It is important to note that the Questions and Answers refer to the Scientific Opinion Report prepared by the Committee for Medicinal Products for Human Use (CHMP) updated in June 2020. This report gathers all the available scientific knowledge about N-nitrosamines impurities in medicines humans containing chemically synthesized active pharmaceutical ingredients and their impact on the safe use of medication, and there are 90 pages of content related to nitrosamines. (updated 14th August)

In early February 2022, EMA issued a new version of its Q&A document (initially published in November 2019, available via the link: https://bit.ly/3gPXCKc). In this new revision, a new nitrosamine to be tested was included, N-nitrosodipropylamine (NDPA), with a threshold of 26.5ppm, and more clarity was given regarding the risk assessment of multiple nitrosamines in APIs. (Updated on 15th February 2022).

In March 2022, EMA published an update to the Q&A on the control of nitrosamines in drug products (Rev.8). Below is a summary of the updates present in the Q&A:

  • What are the currently identified risk factors for the presence of nitrosamines?
  • How should confirmatory testing be conducted by MAHs and manufacturers?
  • When should a test for nitrosamines be included in the MA dossier?

Link: https://bit.ly/3ro7yPo. (updated on May 9, 2022).

Check out some other publications related to the subject in the region below:

  • Complete review of all CEPs and CEP requests for preparations containing ARBs: https://bit.ly/2Ou8Fu2
  • Valsartan recall: https://bit.ly/35mXSbTCooperation with Official Medical Control Laboratories (OMCLs) about adequate analytical methods for the detection of nitrosamine contaminants (Update on detection of nitrosamines in valsartan and validated testing method - European Directorate for the Quality of Medicines & HealthCare)
  • Publications of analytical methods for nitrosamines detection:
  • Updates on the review of CEP requests for ARBs and the currently available detection methods for nitrosamines in ARBs: Update on the review of CEP applications for sartans and the availability of test methods for nitrosamines - European Directorate for the Quality of Medicines & HealthCare
  • Update on the analysis of CEP requests for ARBs and CEPs requests: Update on the review of CEP applications for sartans and the availability of test methods for nitrosamines - European Directorate for the Quality of Medicines & HealthCare
  • Companies to review the manufacturing processes of ARBs to avoid the presence of nitrosamine impurities: https://bit.ly/2qZ0sFX
  • Update on EMA work to avoid impurities in ARBs medicinal products: https://bit.ly/2KxogHX
  • Publication on the pharmacopoeial monographs review of 5 ARBs (valsartan, candesartan, irbesartan, losartan and olmesartan): Control of nitrosamine impurities in sartans: revision of five Ph. Eur. monographs - European Directorate for the Quality of Medicines & HealthCare
  • Further update on the review and withdrawal of the ARBs CEPs: https://bit.ly/2Qw2atg
  • Press releases for nitrosamine impurities:
  • Review of ranitidine medicinal products after the detection of NDMA: Ranitidine-containing medicinal products | European Medicines Agency
  • Communication regarding metformin-containing medicines: EMA update on metformin diabetes medicines | European Medicines Agency (updated 16th December)
  • EMA extends the deadline for drug manufacturers to carry out the risk assessment (step 1) to identify their products with a risk of N-nitrosamine formation or cross-contamination. Due to the challenges encountered in meeting the original deadline and the impact of the existing severe restrictions to combat the COVID-19 pandemic, the deadline was revised and extended to October 1, 2020. (updated 27th March)
  • EMA reviews the Notice and extends the need for evaluation of nitrosamine impurities to biological active substances. To allow marketing authorization holders enough time to implement the Article 5(3) opinion, the European Medicines Regulatory Network agreed new deadlines, which will be (link: https://bit.ly/3gUPu9C):
    • Phase 1:
      • March 31th, 2021: Chemical Medicines;
      • July 1st, 2021: Biological Medicines.
  • In June and July 2021, EMA published an update to the Q&A document. The document was published as 4th revision, and the new version has the following changes:
    • Question 3: Clarifications on Step 2 – Confirmatory testing, including the presentation of results and respective deadlines. It is important to mention that confirmatory testing must be performed if a potential risk of contamination by nitrosamines is detected in the Step 1 – Risk Assessment.
    • Question 10: Inclusion of the acceptance limit for N-nitrosomorpholine, NMOR4 (59-89-2) impurity at 127 ng/day. Link: https://bit.ly/3ro7yPo (updated on 22nd July, 2021)
    • The template documents related to Step 2 – Confirmatory Tests were also updated. Link:Nitrosamine impurities | European Medicines Agency (updated on 22nd July, 2021)
  • In September 2021, The CHMP has performed an assessment of the presence of a nitrosamine impurity, N-nitroso-varenicline, in the product containing the API varenicline. In conclusion, it was recommended that the Drug Product manufacturer submit a variation in order to ensure that the control of this impurity complies with the acceptable intake limits for nitrosamines, according to the Guideline ICH M7 (link: Meeting highlights from the Committee for Medicinal Products for Human Use (CHMP) 13-16 September 2021 | European Medicines Agency). As a precaution, the Drug Product manufacturer also proceed to the voluntary recall of several batches and stopped its distribution in the European Union, since June 2021. Links: Champix (varenicline) - lots to be recalled due to presence of impurity N-nitroso-varenicline above the Pfizer acceptable daily intake limit | European Medicines Agency and https://bit.ly/3oB3bB9. (updated on 6th October 2021)
  • Additionally, the CHMP updated the Q&A to include the limit for N-nitrous-varenicline impurity. Link: https://bit.ly/3ro7yPo. (updated on 6th October 2021)
  • In April 2022, CMDh also published a Notification to Drug Product MAHs calling for a review of the manufacturing process for all products containing biological or chemically synthesized actives to identify and, if necessary, propose actions to mitigate the risk of the presence of nitrosamines impurities. The European medicines regulatory network encourages marketing authorization holders to submit the outcome of step 1 before the deadlines if they complete the risk evaluation or identify a risk in their products. Link: Heads of Medicines Agencies: Nitrosamine impurities. (updated on May 9, 2022)
  • In May, June, and July 2022, there were some updates to the Q&A document regarding the presence of nitrosamine impurities in human medicines, published by EMA and CMDh. Check out the updates below:
    • Inclusion of a new question to provide clarification on what regulatory steps should be performed to dealing with scenario A cases, i.e. in cases of identification of one or more N-nitrosamines exceeding the AI (acceptable intake) in the finished product, or in case the sum of all detected N-nitrosamines exceeds the 1 in 100,000-lifetime risk.
      • Update question 10 to include limits for the following impurities:
      • N-nitrosomethylphenidate;
      • N-nitrosopiperidine;
      • N-nitrosorasagilene;
      • 7-Nitroso-3-(trifluoromethyl)-5,6,7,8-tetrahydro[1,2,4]triazolo-[4,3-a]pyrazine;
      • N-nitroso-1,2,3,6-tetrahydropyridine;
      • N-nitrosonortriptyline;
      • N-methyl-N-nitrosophenethylamine.
    • Update of question 5 to provide clarification to MAH on the Authority’s expectation that they continue to revisit the risk assessments when new information becomes available, particularly for APIs-nitrosamine risk.
    • Update of question 10 to include the newly adopted limit for the impurity N-nitrosodabigatran, to indicate the APIs where related nitrosamines have been identified, and to provide clarification on how to set limits for products containing API in salt, hydrate, or solvate forms.
    • Update of question 14 to reference the new risk assessment template for use in MA submissions.
    • Update of question 3 to provide clarification on the Step 1 amendment submission and Step 3 deadline extension.
  • In October and December 2022, there were updates to the EMA Q&A document on the control of Nitrosamines in Drug Products. Please find below the summary of the main updates:
    • Update of question 10 to include impurities N- nitrosoduloxetine, N-nitrosofluoxetine, N-nitrosoparoxetine, N-nitrosodiphenylamine, N-nitroso-mefenamic acid, N-nitrosopyrrolidine and N-nitroso diethanolamine.
    • Inclusion of question 21 on the approach to control the presence of nitrosamine while the AI (Acceptable Intake) is being established.
    • Inclusion of question 22 on the approach to control the presence of N-nitrosamine exceeding the AI while CAPAs are being implemented.
    • Update of question 20 to consider the possibility of using a temporary AI (t-AI) while the formal AI is established or an interim limit based on the LTL (Less than life) approach during CAPA implementation for purposes of market actions.
    • Updated of question 21 to increase clarification regarding the application of t-AI, which should not be used as a target for the development of validated analytical methods to quantify new nitrosamines, as the limits adopted by CHMP may be lower than the t-AI.

Access the updated document through the link: https://bit.ly/3ro7yPo.(updated on February 1st, 2023).

Additionally, in July 2022, EMA and CMDh have extended the deadline for submission of synthetic drug product change applications (Step 3) to include the control of nitrosamines in the quality control from September 26, 2022, to October 1, 2023, as indicated in the Q&A document. (updated on August 08, 2022). Check out the complete information on the authorities’ websites:

United States of America:

There are ongoing updates in the Food and Drug Administration (FDA) website on recalls, as well as publications on methods to provide regulators and industry with an option to detect impurities (NDMA). Updates regarding ARBs and ranitidine hydrochloride can be found respectively at: FDA Updates and Press Announcements on Angiotensin II Receptor Blocker (ARB) Recalls (Valsartan, Losartan, and Irbesartan) | FDA and FDA Updates and Press Announcements on NDMA in Zantac (ranitidine) | FDA.

In addition, on November 20, 2019, news was published about an update to the United States Pharmacopeia (USP), with a proposed update on the chapter on elastomers used in packages for injectable medicinal products. The update would also include elastomers in packages for inhalable medicinal products, and would add testing and acceptance criteria for N-nitrosamines. The inclusion of nitrosamine testing is due to the fact that nitrosamines are reaction products between specific organic precursor molecules, secondary amines, and a “nitrosating agent”. In the compounding of rubber, secondary amines are likely formed from vulcanization accelerators. The full proposal can be found in through the link: Nitrosamines in Elastomers? - ECA Academy.

In early April 2020, the FDA issued a warning requesting the withdrawal from the market of all medicinal products containing ranitidine. Based on this warning, the agencies in Honduras and Panama took the same action, requesting the withdrawal of medicines containing ranitidine from their respective markets (updated 28th April)

Also in August 2020, the FDA published a note informing about the presence of nitrosamine impurities in two antibiotics used to treat tuberculosis. In order to avoid shortages, the FDA will maintain production authorization for some manufacturers of these drugs, even with the detection of impurities above the defined limits, until they manage to reduce or eliminate impurities, while studying, together with manufacturers, on the source of these impurities.

The identified impurities and their respective intake limits are:

  • Rifampin: impurity 1-methyl-4-nitrosopiperazine (MNP) – Limit: 0.16ppm.
  • Rifapentin: impurity 1-cyclopentyl-4-nitrosopiperazine (CPNP) – Limit: 0.1ppm. (updated 31th August)

In September 2020, the FDA published another guidance for industry, entitled “Control of N-Nitrosamine Impurities in Human Drugs”. This guidance recommends steps manufacturers of active pharmaceutical ingredients and drug products should take to detect and prevent objectionable levels of nitrosamine impurities in pharmaceutical products. The guidance also describes conditions that may introduce nitrosamine impurities. (updated 2nd September) In February, FDA published the new version of this Guidance. This version extends the time period for preparing initial risk assessments to March 31, 2021 (i.e., within 7 months of publication of the original guidance). (updated 1st March 2021)

Check out some other publications related to the subject in the country below:

FDA informs that it is aware that some diabetes medicines containing metformin in other countries have been reported to have low levels of NDMA. Based on the available information, NDMA levels observed outside the US are within the naturally occurring range of some foods and water. While some non-US regulatory agencies may be recalling some metformin medicines, there are no metformin recalls that currently affect the US market: Statement from Janet Woodcock, M.D., director of FDA’s Center for Drug Evaluation and Research, on impurities found in diabetes drugs outside the U.S. | FDA (updated 16th December)

Brazil:

In Brazil, the repercussions related to nitrosamines not only generated recalls and other preventive measures but also gave rise to the publication of Resolution RDC 283/2019, which regulates investigation, control, and elimination of potentially carcinogenic nitrosamines in ARBs

On November 18, 2019, ANVISA published another preventive measure in the Federal Official Gazette, due to the presence of the NDMA impurity for the active pharmaceutical ingredient (API) ranitidine hydrochloride.

On January 14, ANVISA issued an official letter to the regulated sector (Letter# 3/2020/SEI/GIMED/GGFIS/DIRE4/ANVISA) establishing the 6-month deadline for all drug registration holders containing chemically synthesized active substances to review the synthesis routes for the presence of nitrosamines and test their products for this risk.

ANVISA emphasizes that reviews should be comprehensive and consider the entire manufacturing process for Drug Substance and the Drug Product and recommends the principles outlined in Guideline ICH M7 (R1) for determining acceptable intake.

In cases where nitrosamines are detected in any of their medications, registration holders should notify ANVISA immediately in accordance with RDC 55/2005 procedures (updated 17th January).

On March 12, 2020, ANVISA published the Resolution – RE N° 702 of 2020, which includes the adoption of the preventive measure for all importin’s companies, distributors, fractionators of pharmacies that suspend the commercialization, distribution, or use of ranitidine hydrochloride until they are subjected to quality control on available stocks that indicate that the NDMA is at levels below 2.13 ppm.

Only batches that have obtained results below this limit and can be released using periodic statistics that guarantee that the raw material is kept within the acceptable limit (updated 13th March, 2020).

In September 2020, ANVISA launched in Brazil the Program for Monitoring Nitrosamines in Medicines. Initially, the focus of the program is on drugs that belong to the class known as “sartans”. The nitrosamine monitoring program aims to protect public health and guarantee the quality, efficacy and safety of medicines for human use. The program will start on September 30th, 2020 which the first analysis of the program involving the active ingredient losartan is scheduled.

The participants involved in this project are:

  1. Management of Public Health Laboratories – GELAS / DIRE4.

  2. General Management of Medicines and Biological Products – GGMED / DIRE2.

  3. Management of inspection and surveillance of Medicines and Pharmaceutical Ingredients – GIMED / GGFIS / DIRE4.

  4. National Institute for Quality Control in Health – INCQS / Fiocruz.

The program steps are:

  • Phase 1: voluntary sending of losartan and valsartan samples to INQS, which will perform laboratory analyzes for the identification and quantification of nitrosamines. Before sending, the companies must fill out a form with the product data. Access the link of the form for voluntary participation in the program: Microsoft Forms
  • Phase 2: carrying out the analyzes of losartan, valsartan and other products according to the schedule, in a total of nine active ingredients until June 2021.

The following activities will be conducted in this program:

  • Validation of analytical methodology.
  • Analysis of samples for identification and quantification of nitrosamines;
  • Establishment of the monograph at Brazilian Pharmacopoeia (FB).

Access the Program for Monitoring Nitrosamines in Medicines in Brazil launched by ANVISA here. (updated 29th September, 2020)

On January 11, 2021, ANVISA published in Brazilian Official Gazette, the Public Notice N° 1, of January 7, 2021, calling on pharmaceutical companies to provide information on the presence of N-nitrosodimethylamine (NDMA) impurity in drug products batches containing metformin hydrochloride as active pharmaceutical ingredient (API).

This Public Notice applies to API manufacturers, distributors and fractionators, as well as Marketing Authorization holders of Drug Products containing the API metformin hydrochloride, alone or in association. This Notice does not apply for distributors and fractionators of API which are exclusively distributed to the pharmaceutical industry.

The companies in the scope of the Notice must present an assessment on the presence of the impurity NDMA, considering the following aspects:

I. observe the acceptable daily intake limit for the impurity NDMA which is 96ng/day or 0.038ppm, considering the maximum daily intake of 2.550mg recommended by the reference Drug Product package leaflet for the forms of immediate and prolonged release of metformin hydrochloride alone. Considering the maximum daily dose of 2,000mg metformin hydrochloride. (updated 12th February, 2021)

II. perform the NDMA quantification tests on the API and finished product containing metformin hydrochloride, alone or in association, which are on regular market and with valid batches.

a) for APIs, at least 3 different batches should be used, considering the oldest company retention samples, for each API manufacturer, synthesis route and packaging material configuration.

b) for drug products, at least 3 different batches should be used, considering the oldest company retention samples, for each API manufacturer, strength, dosage form, type of release, and primary packaging. In case of multiple strengths which formulations are qualitatively equal, proportional, manufactured in the same site and with the same manufacturing process, the company can perform the quantification tests only for the highest strengths.

III. adopt validated methodology for such tests in accordance with RDC 166 of 24 July 2017, or Q2 ICH guideline.

IV. if the presence of NDMA is detected in any of the analyzed batches, the company should: present risk analysis to identify the probable root causes of the contamination, including, at least, the API synthesis route, potential for cross-contamination and reuse of solvents, interaction with excipients and with primary packaging material; extend the analyses to all batches that are within shelf life; and justify the control strategy that will be used by the company to ensure that the NDMA limit remains below the acceptable limit based on the strategies described in Chapter 8 of the Guideline ICH M7 – ASSESSMENT AND CONTROL OF DNA REACTIVE (MUTAGENIC) IMPURITIES IN PHARMACEUTICALS TO LIMIT POTENTIAL CARCINOGENIC RISK.

Note: The Drug Product Marketing Authorization Holders may present the quantification in the API and/or finished product performed by the foreign manufacturer of the imported drug product, provided they refer to batches of API and/or finished product made available to Brazil. The analyses must be performed in accordance with the criteria described in this Notice.

The companies should submit the data and results through ANVISA’s system, by using the following subject codes:

  • API manufacturers, distributors and fractionators: 70751 – Avaliação de Nitrosaminas em IFA – (fabricante de IFA, importadoras, distribuidoras e fracionadoras) (“Evaluation of Nitrosamines in API – (API manufacturer, importers, distributors and fractionators”)
  • Drug Product Marketing Authorization Holder: 70752 – Avaliação de Nitrosaminas em Medicamento – (Detentor do registro) (“Evaluation of Nitrosamines in Drug Product (Marketing Authorization Holder”).
  • Drug Product Marketing Authorization Holder which are not marketing the products in the moment and which do not have batches within shelf life in the market: 70752 – Avaliação de Nitrosaminas em Medicamento – (Detentor do registro) (“Evaluation of Nitrosamines in Drug Product (Marketing Authorization Holder”). NOTE: In this case, in order to return to marketing, the company is prevented from launching the product until the documentation requested in this Notice is submitted to ANVISA.

The deadline for sending this information: 90 (ninety) days, from the publication of this Notice (11th January, 2021 – 11th April, 2021).

Access the Notice through the link: https://bit.ly/3qnuQmZ (updated 28th January, 2021)

On April 22nd, 2021, ANVISA published RDC Nº 494, from April 15, 2021, which amends the RDC Nº 283/2019, which provides for investigation, control, and elimination of potentially carcinogenic nitrosamines in angiotensin II receptor antagonists.

According to this regulation, the presence of nitrosamines in API of the drug products that belong to the class of angiotensin II receptor antagonists (called “sartans”) will not be acceptable after December 31st, 2021. Also, an absence is considered when the result of analysis is below the detection limit of the method, that being not more than 0.03ppm.

Check the RDC 283/2019 in full through the following link: https://bit.ly/3ewF2VL (updated 28th April, 2021)

On June 2, 2021, the following regulations were published in the Brazilian Official Gazette:

  • RDC No. 500, of May 27, 2021, which amends art. 10 of RDC 283/2019; and
  • Public Consultation No. 1,050, of May 31, 2021.

According to RDC 500/2021, in cases where the elimination of nitrosamine impurities, present in angiotensin-II-receptor antagonists (sartans), demands a variation that requires tests/proofs in the drug product, this application must be submitted until December 31rst, 2021.

Regarding CP 1.050/2021, the draft text brings a proposal for a resolution that provides for the risk assessment and control of potentially carcinogenic nitrosamines in drug products for human use. With this, the evaluation and control of nitrosamines will be extended to other classes of drugs, not just angiotensin II receptor antagonists.

Additionally, the “Guideline for conducting nitrosamine analyses” will be published, which will propose the establishment of the main steps, procedures, and deadlines for the assessment of this impurity in finished drug products, and respective APIs. The objective of the regulation and the guideline is that companies gradually implement the control of nitrosamines in products, according to their risk classification.

Deadline for Contributions: June 9, 2021 to July 9, 2021.

Access the full draft through the link: https://bit.ly/34TyagC (updated 7th June, 2021)

On July 6, 2021, ANVISA published the first version of the Guideline No. 50/2021, which provides for the Control of Nitrosamines in Active Pharmaceutical Ingredients and Drug Products.

The document presents recommendations for control of nitrosamines in all chemically synthesized Active Pharmaceutical Ingredients (APIs) and drug products for human use that contain them, as well as biological products, if applicable. In addition, it clarifies the responsibilities of companies in the control step of these impurities, presents strategies for calculating limits, and addresses other concepts related to them.

The recommendations presented in the Guideline also apply to Marketing Authorization variations that may result in the formation of nitrosamines, such as changes related to the API, the composition and packaging material of the drug product, but not limited exclusively to these.

The Guideline entered into force on the date of its publication (July 6, 2021) and it is also open to contributions for the period from July 13, 2021 to September 13, 2021.

Access the Guideline No. 50/2021 (Version 1) through the link: https://bit.ly/3xusjvd (updated 9th July, 2021)

On December 29, 2021, Resolution RDC 593/2021 was published, which amends RDC 283/2019, of May 2019, on the investigation, control and elimination of potentially carcinogenic nitrosamines in angiotensin II receptor antagonists (ARB). In this amendment, RDC 494/2021 is revoked, which considered the absence of nitrosamines as the result of analysis below the detection limit, not being greater than 0.03ppm. In the new wording, the limits for the presence of nitrosamines are defined as those described in the annex to RDC 283/2019 and, in cases where there is contamination by more than one impurity, the limits must ensure that the risk is negligible.

RDC 593/2021 and RDC 283/2019 consolidated with the updates can be accessed, respectively, through the links: https://bit.ly/34OHExg and https://bit.ly/33mKKrE. (Updated on February 23, 2022)

On March 9th, 2022, ANVISA published a release containing a summary of the actions performed by the Authority to control these impurities in medicines. A panel with the results of the nitrosamine monitoring program, launched in 2020, was also made available. Access it by the link: Anvisa adota medidas para garantir a segurança de medicamentos do tipo "sartanas" utilizados no Brasil — Agência Nacional de Vigilância Sanitária - Anvisa (updated on March 16, 2022)

After a long period of discussion between ANVISA and the pharmaceutical industries, on May 4th, 2022, the Resolution (“Resolução”) – RDC nº 677 of April 28th, 2022, which provides for the risk assessment and control of potentially carcinogenic nitrosamines in active pharmaceutical ingredients and drug products for human use. This rule provides for the compliance with the requirements in stages, according to the risk attributed to each product and will replace the rule RDC Nº 238, of May 17th, 2019 (currently in force).

ANVISA also published the version 2 of Guideline 50/2021, which provides for the Control of Nitrosamines in Active Pharmaceutical Ingredients and Drug Products. This document contains recommendations on the responsibility of companies and presents strategies for calculating limits, among other requirements.

Both are applicable to new drug products marketing authorization, as well as variations that may result in nitrosamines formation, such as changes related to the API, the composition and package of drug product, but not restricted exclusively to these.

Guideline 50/2021 (version 2) is already in force, and RDC 677/2022 will come into force on June 1st, 2022.

Health Canada/Canada:

  • The Canadian agency is aware that some metformin products available outside Canada contain a nitrosamine impurity, NDMA, above the acceptable limit. Health Canada is currently unaware of any metformin products in Canada that contain NDMA above acceptable levels. The Department has asked companies to test their products with metformin and is collecting samples from companies to conduct their own tests. The orientation is that patients should not stop taking metformin without discussing options with their doctor: https://bit.ly/2YHfHAc (updated 16th December)

ISP/Chile:

Digemid/Peru:

CECMED/Cuba:

ANMAT/Argentina:

COFEPRIS/Mexico:

INVIMA/Colombia:

ARCSA/Ecuador:

  • Updates and history of all actions related to valsartan: https://bit.ly/2qwGVgf
  • Recall alerts for ranitidine:
  • Resolution ARCSA-DE-009-2019-SPMV, with guidelines for the manufacture and marketing of drugs containing angiotensin II receptor antagonists:
  • Submission of API information until December 1st, 2019. Term extended until June 1st, 2020 by Resolution ARCSA-DE-014-2019-JRC (link: https://bit.ly/3gRqQsr).
  • Defines allowable limits for nitrosamine contaminants.
  • Submission of post-registration change to comply with the limits, if the impurities are above the determined.
  • The transition period was two years, until July 4, 2021. Link: https://bit.ly/3kHqAx9. (updated on 3rd September, 2021)

Minsa/Costa Rica:

DNFD/Panama:

DNM/El Salvador:

ARSA/Honduras:

8 Likes

That’s really a very good summary. I think folks in middle east and ASIA can follow the same steps to form a complete picture.

1 Like

Great summary, I am wondering what Japan is doing? Do not hear too much about them even from clients who have submissions in Japan.

Hi, @ASrinivasan,
PMDA published a Q&A for “Self-inspection on Risks of Contamination with Nitrosamines in Drug” in Dec. 2022. I added the Q&A translated by google translation. The deadline for step 1 is the end of April. 2023 and pharmaceutical companies in Japan now work hard to meet the deadline. And lots of us consider that suppliers in Japan are not cooperative in sharing information in some cases.

The Q&A of self-inspection(google translation).pdf (233.2 KB)

Responses by PMDA.pdf (158.4 KB)

2 Likes

Thanks a lot, the translation will be very helpful.

2 Likes

I heard the second Q&A was also under preparation, but I’m not sure when it will be published.

Please keep us updated when you hear about it.

1 Like

@Yosukemino is there a checklist that companies are using to collect the information from the ingredients suppliers? Have PMDA express desire to work in such checklist? I know that they leverage can be significant when it comes to collect information. Thanks for sharing all the updates…

Dear, @Naiffer_Host

I am sorry for my delayed response. Some companies use existing checklists like IPECs, and others use their original or improved ones in Japan.

PMDA asks manufacturers involved in the manufacture of drug substances or drug products, or their packaging, and suppliers of excipients, reagents, container closure systems, etc. to cooperate with this self-inspection by evaluating the risk of contamination with nitrosamines and providing information to the MAHs as much as possible in the notification. However, cooperation does not work well.

PMDA may be considering optimistically that pharmaceutical companies in Japan can finish the risk assessment in the same way as Europe, the USA, and other countries have done. But recent NDSRIs’ cases make us pessimistic. I believe cooperation, like sharing information, among companies is necessary to overcome difficulties now.