The European Medicines Agency (EMA) has issued a question-and-answer document to provide guidance on risk evaluation and mitigation of nitrosamines impurities in APIs and finished products with new requirements coming into play in 2021. What do pharma companies, CDMOs/CMOs, and other suppliers need to know?

Nitrosamines impurities continue to be an issue

The issue of nitrosamine impurities in certain active pharmaceutical ingredients (APIs) first emerged in 2018 with both the European Medicines Agency (EMA) and the US Food and Drug Administration (FDA) initiating investigations of nitrosamine impurities in certain “sartan”-containing APIs, used in anti-hypertensive and cardiovascular drugs, such as valsartan candesartan, irbesartan, losartan, and olmesartan. They later broadened those investigations into prescription and over-the-counter forms of ranitidine, a H2 (histamine-2) blocker used to decrease the amount of acid created by the stomach as well as into metformin, a diabetes drug. These investigations led to certain product recalls as well.

Nitrosamines are classified as probable human carcinogens based on animal studies. They are present in some foods and water supplies and are not expected to cause harm when ingested at very low levels. Although several nitrosamine impurities were found in APIs, one nitrosamine, N-nitrosodimethylamine (NDMA), in particular was often cited.

Most recently, in June (June 2020), the EMA finalized a review to provide guidance to marketing authorization holders (MAHs) on how to avoid the presence of nitrosamine impurities in human medicines. EMA’s Committee for Medicinal Products for Human Use (CHMP) also asked all MAHs to review all chemical and biological human medicines for the possible presence of nitrosamines and test products at risk. The call for review was extended to include biological active substances. Review of chemically synthetized active substances has been ongoing since September 2019. Of particular importance in evaluating biologic-based APIs are to evaluate: (1) biologicals containing chemically synthesized fragments, where risk factors similar to chemically synthesized active substances are present; (2) biologicals using processes where nitrosating reagents are deliberately added; and (3) biologicals packaged in certain primary packaging material, such as blister packs containing nitrocellulose.

New risk-evaluation and risk-mitigation requirements

Earlier this month (August 2020), the EMA issued a questions-and-answers (Q&A) document on risk-assessment and risk-mitigation measures required of MAHs with respect to nitrosamines impurities. The measures require MAHs to: (1) design their manufacturing processes and controls to prevent if possible or mitigate as much as possible the presence of N-nitrosamines in their APIs and finished products; (2) assess the risk of the presence of nitrosamine impurities in their APIs and finished products and introduce any resultant changes as needed (e.g. changes to manufacturing processes); and (3) ensure that active substances and excipients used in finished products are manufactured in compliance with GMP.

As specified by the Q&A document, the review required of MAHs consists of three steps: (1) Step 1—MAHs to perform a risk evaluation to identify if APIs and/or finished products could be at risk of presence of nitrosamines impurities; (2) Step 2—If a risk is identified, the MAH must perform confirmatory tests and the results must be reported as soon as possible; and (3) Step 3—If the presence of nitrosamines is confirmed, MAHs should implement effective risk-mitigating measures through submission of variation to their marketing authorization.

The Q&A document specifies that for products containing chemically synthesized APIs, Step 1 (risk evaluation) should be concluded and reported at the latest by March 31, 2021. For products containing biological APIs, Step 1 (risk evaluation) should be concluded and reported at the latest by July 1, 2021.

If a risk is identified, confirmatory testing (Step 2) and submission of changes to the marketing authorization (Step 3) are required. For products containing chemically synthesized APIs, confirmatory testing activities at Step 2 and submission of any changes required to marketing authorizations are required to be finalized at the latest by September 26, 2022. For products containing biological APIs, Steps 2 and 3 are required to be finalized at the latest by July 2023.

When conducting the risk evaluation and risk assessment, the Q&A document specifies that MAHs should use a risk-based approach to prioritize products for evaluations and confirmatory testing. MAHs may consider factors such as the maximum daily dose taken for the concerned medicinal product, duration of treatment, therapeutic indication, and the number of patients treated. For example, medicinal products with higher daily dose and those for chronic use may take priority.

Impact on pharma companies, CDMOs/CMOs and other suppliers

These measures for risk evaluation and risk mitigation of nitrosamine impurities impact the full bio/pharmaceutical manufacturing value chain—from raw materials to APIs to finished products to packaging as all these areas are potential sources for nitrosamines impurities. In the Q&A document, the EMA specifies 11 currently identified sources of nitrosamine impurities as listed below.

1. Use of sodium nitrite (NaNO₂), or other nitrosating agents, in the presence of secondary or tertiary amines within the same or different steps of the manufacturing process;

2. Use of sodium nitrite (NaNO₂), or other nitrosating agents, in combination with reagents, solvents (e.g. dimethylformamide, dimethylacetamide and N-methyl-2-pyrrolidone) and catalysts, which are susceptible to degradation to secondary or tertiary amines, within the same or different process steps;

3. Use of contaminated raw materials in the API manufacturing process (e.g. solvents, reagents and catalysts);

4. Use of contaminated recovered or recycled materials (e.g. solvents, reagents and catalysts), including recovery outsourced to third parties who are not aware of the content of the materials they are processing and recovery processes carried out in non-dedicated equipment;

5. Use of contaminated starting materials and intermediates supplied by vendors who use processes or raw materials which may contain residual nitrosamines or nitrosating agents;

7. Cross-contamination due to different processes being run successively on the same manufacturing line;

8. Carry-over of impurities between process steps due to operator-related errors or insufficiently detailed batch records such as inadequate phase separations during work-up procedures;

9. Degradation processes of starting materials, intermediates and active substances, including those induced by inherent reactivity (e.g. presence of nitro, oxime, or other functionality) or by the presence of an exogenous nitrosating agent. This could potentially occur also during finished product formulation or storage and could be influenced by crystal structure, crystal habit and storage conditions (temperature, humidity etc.);

10. Use of certain packaging materials. Nitrosamine contamination has been observed in finished products stored in blister packs with lidding foil-containing nitrocellulose. Nitrosamines have been shown to form from nitrocellulose degradation products and low molecular weight amines present either in printing ink or in the finished product during the blister heat-sealing process and the transfer to the product within the blister; and

11. Reaction of nitrosatable nitrogen functionality in APIs or their impurities with nitrosating agents present in components of the finished product during formulation or storage.

Requirements for pharma companies, CDMOs/CMOs, and other suppliers

The Q&A document specifies that MAHs/applicants in collaboration with API and finished product manufacturers and their raw material suppliers are required to perform risk evaluations using quality risk-management principles as outlined in ICH guidelines (International Conference of Harmonizationof Technical Requirements for Pharmaceuticals for Human Use  Q9, Quality Risk Management). The principles described in the ICH M7 guideline, Assessment and Control of DNA Reactive (Mutagenic) Impurities in Pharmaceuticals to Limit Potential Carcinogenic Risk, and in the CHMP’s assessment report apply.

In line with their control strategy, once Step 1 (risk evaluation) and Step 2 (confirmatory tests) are completed, MAHs together with API and finished product manufacturers are expected to maintain the quality of their product throughout its lifecycle and to review the outcome of the risk evaluation and testing as and when new information (e.g. on potential root causes for nitrosamine formation or contamination) becomes available. Appropriate timelines for conducting the risk evaluation and testing for the newly identified risks should be implemented depending on the level and impact of the risk identified, according to the EMA’s Q&A document.

Manufacturers of active substances and finished products and their raw material suppliers are required to provide MAHs/applicants with all information necessary for a comprehensive risk evaluation, according to the Q&A document. If the risk of nitrosamine impurity formation was assessed during the development phase of the API/finished product manufacturing processes, the information from this assessment can be used to support the risk evaluation. MAHs/applicants and manufacturers should consider as part of the risk evaluation all potential sources of contamination or formation of nitrosamine, notably the root causes identified by the EMA.

The Q&A document specifies that MAHs/applicants and manufacturers for products containing biological APIs should consider the following aspects that may increase the risks of nitrosamine presence in their products: (1) biologicals containing chemically synthesized fragments, where risk factors similar to chemically synthesized active substances are present; (2) biologicals using processes where nitrosating reagents are deliberately added; and (3) biologicals packaged in certain primary packaging material, such as blister packs containing nitrocellulose

For the purpose of confirmatory testing, testing should be carried out on the finished product. Testing of the API or its intermediates is also recommended if the risk evaluation indicates that the API or its intermediates are a potential source of nitrosamine impurities in the finished product. In such cases, the results of API or intermediate testing may be used to support root cause investigations and the development of a justified control strategy for nitrosamine impurities.

The Q&A document specifies that MAHs should implement a control strategy regarding N-nitrosamines, which should include current and prospective measures to minimize the risk of generation of contamination with nitrosamines (e.g. change of manufacturing process, change of raw material quality, introduction of appropriate specifications and development of appropriate methods, and measures on the premise and equipment such as cleaning procedures and environmental monitoring). MAHs should control nitrosamine levels in line with ICH guidelines and any future changes that may impact on the risk (e.g. change of supplier, change of manufacturing process and change of packaging).

In addition, the Q&A document specifie that MAHs/applicants and API manufacturers should work together and take precautionary measures to mitigate the risk of presence of nitrosamines during the manufacture and storage of all medicinal products containing chemically synthesized APIs. The Q&A document further specifies that MAHs/applicants must ensure that appropriate and robust risk evaluations are carried out by the relevant manufacturing parties, including API manufacturers.  

Other regulatory agencies

In all, the EMA says that regulatory authorities in the EU have been cooperating with international partners in the US, Canada, Japan, Singapore, Switzerland, Australia and other countries to mitigate the presence of nitrosamines in medicinal products and to align requirements.