Nitrosamine Impurities: API & Pharmaceutical Products
Nitrosamine
Impurities: API & Pharmaceutical Products
The Sartans case substantiates the necessity for the
pharmaceutical industry to improve the standards on application of risks
management tools, particularly regarding post approval activities. The case
also showed some of the potential risks associated with the lack of transparency
between MAHs, API manufacturers, and others over patient safety and the shift
required to increase transparency through revisions of the regulatory framework
whilst ensuring safeguarding of confidential information.
Medicine regulatory authorities were alerted of the presence of
the nitrosamine impurity, N-nitrosodimethylamine (NDMA), in products containing
valsartan in July 2018. Valsartan is an Angiotensin II Receptor Blocker (ARB)
belonging to a class of products commonly referred to as sartans. The medicines
containing valsartan API were immediately recalled, and a regulatory review was
triggered in accordance with Article 31 of Directive 2001/83/EC. Further
nitrosamine impurities were detected in other sartan drugs as well as in
pioglitazone, ranitidine, nizatidine, and metformin products.
The use of the solvent dimethylformamide (DMF) alongside other
reagents was ascertained as the main source of nitrosamine impurities. It is
the concurrent presence of dimethylamine, a degradation product of DMF along
with sodium nitrite in the presence of an acid which generated NDMA.
Other contamination factors included solvent, reagents, and poorly cleaned
manufacturing equipment already contaminated with nitrosamines, leading to
potential cross contamination. The Committee for Medicinal Products for Human
Use (CHMP) immediately set interim limits for NDMA in APIs based on acceptable
intake calculated in accordance with International Council for Harmonization
(ICH) M7. All concerned marketing authorization holders (MAHs) were
subsequently required to make necessary changes to their API manufacturing
process to minimize nitrosamine contamination.
The European network (European Commission, the European
Medicines Agency [EMA], national competent authorities in the European Economic
Area [EEA], and the European Directorate for the Quality of Medicines and
Healthcare [EDQM]) decided that the outcome of the Article 31 review of sartans
must be considered by all MAHs for medicines containing chemically synthesized
active substances (and later on biological products) through an Article 5(3)
procedure to evaluate the risk of nitrosamines being present in their product
and to take appropriate risk mitigation measures.
Root causes of the presence of nitrosamines
Nitrosamines belong to a well-known group of carcinogens
known as N-nitroso compounds because of their reactivity with DNA
metabolizing into potent carcinogen diazonium ions. Nitrosamine formation
lies in the oxidative release of the known nitrosating agents and subsequent
nitrosamine formation by reaction with secondary and tertiary amines or
dealkylated ammonium salts under acidic conditions.
The reagents, solvents, catalysts, and reaction conditions
used during the tetrazole ring formation of sartans are the main causes for
the presence of nitrosamines. Quenching of the starting material azide with
nitrosating agent in the presence of solvent DMF and the sartan product to
ensure fast and complete depletion of explosive hydrazoic acid is favoured for
process safety reasons. This combination of reagents was a key pathway for
nitrosamine formation and was successfully prevented through isolation of the
drug substance before precarious quenching.
Importantly during the Article 31 review, it was noted that sodium
nitrite was seldom identified in the drug substance documentation, or it
was briefly listed as a raw material and omitted from the drug substance
process description. In some cases, sodium nitrite was added in the process
as part of a scale up activity, introduced through variation procedures,
which could be categorized as a minor change providing the scale up is
up to 10-fold and the API specification is unchanged; thus lacking rigorous agency
evaluation leading to potential failure in risk identification.
The review also found that the use of recycled solvents,
reagents, or catalysts from third-party suppliers were further causes of
nitrosamine contamination, as were good manufacturing practice (GMP)
violations that resulted in cross-contamination in multi-purpose facilities
and operator-related issues, such as inadequate phase separations.
Contamination of finished products packaged in nitrocellulose blisters
was also discovered. In this case, elimination of the nitrocellulose primary
packaging through a minor regulatory change to the container closure system
eliminated the risk of nitrosamine formation.
Degradative mechanisms for amine generation and nitrosamine
formation without considering the potential presence of secondary and tertiary
amine impurities in the applied solvents (such as dimethylformamide [DMF] or
N-methylpyrrolidone), reagents (such as trialkyl amines), and catalysts (such
as quaternary ammonium salts) were the predominant focus of the Article 31
root cause analysis as the most plausible cause for the origin of nitrosamines
in sartans. These multiple root causes pose a risk of nitrosamine formation and
should be avoided in manufacturing processes unless proved necessary.
Lessons learnt and recommendations
The efficacy and robustness of the European network guidelines,
developed in conjunction with international partners - CHMP’s Guideline on the
Chemistry of Active Substances, ICH Q11, ICH Q3A (R2), and ICH M7 (R1) - were
challenged during the investigations subsequent to the contamination of
nitrosamines in sartans and other APIs. In light of the Article 31 exercise for
the sartans products, a series of lessons learnt were published on the EMA
website.
The importance of the possible side reactions leading to
formation of nitrosamines as well as the thorough investigations of the potential
interactions between all the materials and degradants necessitates more
detailed information to be present in the regulatory dossiers.
The need for transparent exchange of technical information
through improved quality agreements between the APIs manufacturers, third-party
manufacturers, and MAHs during process development, supplier qualification, but
also subsequently during the lifecycle of the product through better quality
audits. Confidentiality aspects between the MAHs, active substance master
files (ASMFs) holders, and certificate of suitability (CEP) of API substances
can significantly hamper the scientific evaluation required.
The correct class of variations were not always selected due to
lack of clarity in the conditions to be fulfilled. In particular, in case of Type
IA category, an in-depth scientific regulatory assessment may be missed during
evaluation.
Potential revisions to the guidelines for controlling impurities
Publication of detailed information about potential sources of
nitrosamine impurities and other ‘cohort-of-concern’ compounds, as defined in
ICH M7 (R1), for substances containing some structural groups with high
mutagenic or carcinogenic suspected potency.
Addition of stringent requirements to the European general
monograph on substances for pharmaceutical use to mitigate the risks of
nitrosamines.
Strengthening of some of the development studies provisions of
the European guideline on the chemistry of active substances to prevent the
generation of cohort-of-concern compounds and implementation of appropriate
risks mitigation measures. It could include a requirement for the MAHs to
submit a justification for the proposed manufacturing processes and mitigation
measures as part of the regulatory dossier.
Potential amendments to ICH guidelines:
ICH M7 - to elaborate control of impurities requirements,
implement mitigation measures, and establish limits for cohort-of-concern
compounds as well as considering retroactive application of the guideline to
legacy products
ICH Q7 - to limit the use of reagents or recovery processes that
may be a source of cohort-of-concern compounds and clarify mitigation measures
ICH Q9 - to provide benchmark expectations for suitable and
robust risk assessments.
Additional clarifications in GMP guidelines regarding regulatory
expectations for technology transfers, supplier qualification, as well as
qualification and validation of facilities processes for active substance
manufacturing were also part of the group recommendations.
Recent recommendations for industry
In July 2020, the CHMP assessment report of the Article 5(3) on
‘nitrosamines impurities’ was published providing recommendations for industry
regarding the prevention of presence of nitrosamines in human medicines.
Concomitantly, the US Food and Drug Administration (FDA) released a guidance
concerning the control of nitrosamine impurities in human drugs. The CHMP
assessment report and the FDA guidance advise API and drug product
manufacturers to conduct risk assessments of their approved or marketed
products and products with pending applications and take appropriate actions to
reduce or prevent the presence of nitrosamines in their products.
The FDA guidance and the CHMP assessment report recommend the
following acceptable intake (AI) limits for the nitrosamine impurities detailed
in Table 1. They also advise that manufacturers use these AIs when
determining limits for nitrosamine impurities in APIs and drug products. The
overall aim is to limit patient exposure to a total risk of not more than 1 in
100,000 life-time risk.
Table 1. Acceptable intake limits for some specific nitrosamines
in drug products.
API and drug product manufacturers should also take a three-step plan to mitigate nitrosamine impurities in their products:
Assess the risk of nitrosamine impurities in APIs, marketed
products, and products under approved and pending applications, and retain
those in case requested; for licensed products, this step should be completed
by 1 March 2021 for US medicines, by 31 March 2021 for EU chemical medicines
and by 1 July 2021 for EU biological medicines.
Conduct confirmatory testing when there is any risk for the
presence of nitrosamine impurities using suitable analytical procedures as soon
as risks are identified; for licensed products, this step should be completed
by 1 Sept. 2023 for US medicines and confirmatory testing results should be
reported as soon as completed for EU medicines.
Report changes implemented to prevent or reduce nitrosamine
impurities in APIs and drug products to agency; for licensed products, this
step should be completed by 1 Sept. 2023 for US medicines, by 26 Sept. 2022 for
EU chemical medicines and by 1 July 2023 for EU biological medicines.
In October 2020, EMA also requested all MAHs of metformin‑containing
medicines to test their product before release to the market as a preventive
measure to safeguard patients.
For pending applications, both agencies expect industry to
initiate those mitigation steps and would request the applicant’s relevant
risks assessments, and confirmatory test (if required) during assessment.
Reporting changes to regulators
As per FDA guidance, the drug manufacturers must report
changes implemented to prevent or reduce nitrosamine impurities. Those changes
must be directly documented by the impacted manufacturer in the applicant
dossier in case the API is not covered by a DMF or through reference to
relevant DMF amendments. Reprocessing or rework of any batch of API
containing a nitrosamine should be reported in the DMF or application.
Equally, changes to the drug product preventing nitrosamine formation must be notified
through supplement to FDA by the application holder. Holders of pending applications
must update their applications through submission of an amendment.
Likewise, the Co-ordination Group for Mutual Recognition and
Decentralized Procedures - human (CMDh) requests the MAHs to introduce
necessary changes to their API and/or finished products through the timely
submission of appropriate variation(s) in accordance with the guideline on
classification of variations. In case nitrosamine(s) are identified, the
corresponding limit(s) as defined in Table I should be introduced in the finished
product specifications. Relevant amendments pertaining to ASMF or CEP that are
necessary to control nitrosamine impurities in the active substance and/or
finished products should be considered for variation applications.
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