Since
2018, several drug products, including angiotensin II receptor blockers (ARBs),
ranitidine, nizatidine and metformin, have been found to contain
unacceptable levels of nitrosamines. The presence of nitrosamines has been
confirmed by several regulators, including the US Food and Drug Administration
(FDA) and the European Medicines Agency (EMA), prompting them to recall and withdraw certain batches of these drugs and also
issue safety alerts.
This
week, we speak to Richard Sidwell, Vice President and Chief Scientific Officer,
and Wayne Wiley, Vice President, Regulatory Affairs and Pharmacovigilance, at Recro, on the steps pharmaceutical
companies need to take to assess and mitigate risks from nitrosamine
impurities. Recro is a contract development and manufacturing organization
(CDMO) with expertise in solving complex manufacturing problems. Recro provides
oral solid dosage form development, end-to-end regulatory support, clinical and
commercial manufacturing, and packaging and logistics services to the global
pharmaceutical market.
What are nitrosamines? And how do they harm us?
Richard
Sidwell: Nitrosamines
are a class of compounds having the chemical structure of a nitroso group
bonded to an amine (R2N-N=O where R is usually an alkyl group). Nitrosamines
are recognized as probable human carcinogens, and five of them (NDMA, NDEA,
NMBA, NIPEA, and NMPA) have been detected in active pharmaceutical ingredients
(APIs) or drug products.
The
discovery of nitrosamines in some types of drug products led the FDA and other
international regulators to conduct a detailed analysis of these impurities in
affected APIs and drug products. Nitrosamine impurities have been found in
some drug products, and many batches of these products have been recalled where
unacceptable levels of these impurities had been detected. However, nitrosamine
impurities might exist in other APIs and drug products as well, due to the use
of processes and materials that are conducive to the formation of these organic
compounds.
What
conditions can lead to the presence of nitrosamines?
Richard
Sidwell:
Nitrosamine impurities can form by a nitrosating reaction between amines
(secondary, tertiary, or quaternary amines) and nitrous acid (nitrite salts
under acidic conditions). Both high temperatures and low pH contribute to
nitrosamine formation. In API manufacturing, one must consider all starting
materials, intermediates, reagents, and solvents because residual amounts of
these materials may carry over into subsequent steps. These residual materials
are susceptible to all subsequent processing conditions in the final API steps
and the manufacturing of the drug product. It is important to consider that it’s not just the chemistry between the
intended raw materials that should be assessed but also the possibility of
impurities within each raw material. In some cases, nitrosamine impurities were
traced to impurities present in recycled solvent used in the API manufacturing
process.
Is
there any guidance from health authorities on nitrosamines?
Wayne
Wiley: Yes,
there are numerous guidance documents that have now been published on
detection, control and regulation of nitrosamines. I have listed the more
notable guidance documents below:
FDA – Control of nitrosamine impurities in human drugs
EMEA – Nitrosamine impurities
Health Canada – Nitrosamine impurities in medications: Overview
Each of
these guidance documents provide specific details about acceptable levels,
possible sources of nitrosamine impurities, how they can be formed, possible
ways to mitigate, and recommendations for steps to take and appropriate timings
thereof.
What
can companies do, as a first step, to deal with the potential for nitrosamine
impurities in their commercial products?
Wayne
Wiley: The
FDA guidance recommends performing an immediate risk assessment with respect to
the potential presence or formation of nitrosamines in all FDA-approved
pharmaceutical products. At a high level, this involves assessing all raw
materials for the possible presence of nitrosamine impurities and the presence
of impurities/moieties that could contribute to the formation of nitrosamines
within the finished product either during processing or on stability.
If this
risk assessment indicates the possibility of nitrosamine presence or formation,
the product should be tested to confirm the absence of such impurities. In
light of the regulatory agency recommendations, contract lab nitrosamine
testing capacity has been in high demand.
While
planning, product sponsors should consider the potential for delays in testing
to ensure availability of results within the recommended timelines. If testing
confirms the presence of nitrosamine impurities, further steps to mitigate
become imperative.
The FDA
had recommended completion of the primary risk assessment within seven months
of the original September 2020 guidance publication (i.e., by March 31, 2021).
Confirmatory testing, if required, should begin immediately for products
considered at high risk. Both confirmatory testing and submission of any
required changes in drug applications for mitigation purposes should be
concluded on or before October 1, 2023.
What
does this mean for drug products that are still under development?
Richard
Sidwell:
Development programs should plan to submit nitrosamine assessments as part of
the original filings, whether as a new drug application (NDA), abbreviated new
drug application (ANDA), or a drug master file (DMF).
According
to the guidance, the FDA recommends that applicants conduct both a risk
assessment for nitrosamine impurities and confirmatory testing, if necessary, before
the submission of an original application.
Wayne
Wiley: The
FDA may accept the filing of this information in an amendment during the review
period if it is not available at the time of filing. However, this should be
done quickly so as not to adversely impact the review timeline.
For
products earlier in their development cycle, there is an important opportunity
to avoid potential nitrosamine impurity concerns by careful selection of raw
materials and processing conditions. Early risk assessment during excipient
selection and formulation development can avoid the necessity of testing and
possible complexity of downstream mitigation efforts and could be included in
the original pharmaceutical development report.
Impressions: 3626