Comprehensive Nitrosamine Risk Assessment: ProductLife Group's Expertise

Comprehensive Nitrosamine Risk Assessment: ProductLife Group’s Expertise

EU regulators first became aware of nitrosamines in medicines in mid-2018 when nitrosamine impurities, including N-nitroso dimethylamine (NDMA), were detected in blood pressure medicines known as “sartans.” Based on animal studies, nitrosamines are classified as probable human carcinogens.

Regulatory Guidance on Nitrosamines: Essential Insights

The EMA finalized a review under Article 5(3) of Regulation (EC) No 726/2004 in June 2020 to guide marketing authorization holders (MAHs) on how to avoid the presence of nitrosamine impurities in human medicines. The FDA and other health authorities have taken a similar approach. The CHMP asked MAHs to review all chemical and biological human medicines for the possible presence of nitrosamines and test products at risk.

Effective Control Strategies for Mitigating Nitrosamine Impurities

Companies must have appropriate control strategies to prevent or limit the presence of these impurities and, where necessary, improve their manufacturing processes. The authority proposed a three-step approach.

Step 1 Risk Evaluation: The outcome of a risk evaluation to identify active substances and finished products at risk of N-nitrosamine contamination must be reported by 31 March 2021 for chemical medicines and 1 July 2021 for biological medicines.

Step 2 Confirmatory Testing: If a risk was identified in Step 1, confirmatory testing on the products should be performed. The presence of nitrosamines with reference to acceptable levels was required to be reported by 26 September 2022 for chemical medicines and 1 July 2023 for biological medicines.

Step 3 Update of Marketing Authorization: When testing performed in Step 2 confirmed the presence of nitrosamines, the MAH was required to control the limits in the API and/or make any necessary changes to the manufacturing process of the finished product (including packaging) to remove the nitrosamine risk by requesting a variation. The MAH was required to complete the confirmatory testing and submit their variation application by 1 October 2023 for chemical medicines and 1 July 2023 for biological medicines.

Ongoing Lifecycle Management for Nitrosamine Risk Mitigation

The deadlines for the above steps 1 to 3 have passed. However, MAHs have a continuing commitment to mitigate the nitrosamines risk in their products by reviewing the outcome of the risk assessment if new information becomes available which may potentially pose a new risk. This includes:

• Changes in the API or Finished Product manufacturing routes
• Changes in the suppliers of starting materials, intermediates, reagents, or solvents for the manufacture of API
• Changes in the composition of the Finished Product or the suppliers of excipients or raw materials
• Changes to the packaging of the Finished Product
• Publishing of a new Acceptable Intake (AI) by the EMA in Appendix 1 for a potential nitrosamine impurity, with particular reference to the formation of Nitrosamine Drug Substance Related Impurities (NDSRIs)

The EMA has reminded MAHs of their ongoing responsibilities to ensure their medicines’ quality, safety, and efficacy and adhere to the nitrosamines guidance outlined by the EU Network.

Proactive Measures to Mitigate Nitrosamine Risks in Manufacturing

MAHs and manufacturers should work together and take precautionary measures to mitigate the risk of the presence of nitrosamines during the manufacturing and storage of all authorized medicinal products and throughout the lifecycle of the product if any changes are made. This can be achieved by:

• Changing the manufacturing process and/or changing the raw material quality
• Introduction of appropriate specifications and development of appropriate analytical methods
• Introduction of measures at the manufacturing premises and to production equipment, such as cleaning procedures and environmental monitoring

MAHs should update any previous notifications, if necessary, using the response templates and reporting mechanisms previously established in Steps 1 to 3 above.

How ProductLife Group Supports Your Nitrosamine Control Strategies

ProductLife Group (PLG) can provide help to MAHs at several stages of the above procedures, as follows:

Step 1: Thorough Risk Evaluation for Nitrosamine Contamination

Re-evaluation after the introduction of changes with a potential to affect the nitrosamines risk, with particular reference to guidance which has been updated since the original risk assessments were made, and the advancement of scientific and technical knowledge during this period, including the following:

• MAHs should note the risk of formation of nitrosamine impurities (NDSRIs) from active substances (or their related impurities) containing a vulnerable amine. They arise during finished product formulation and/or storage due to the presence of traces of nitrites. This was identified as a risk factor based on understanding gained during the review period. MAHs that did not take into account this risk as part of their original step 1 response for their products containing active substances with vulnerable amines should reconsider their original step 1 risk evaluations with reference to this new information.
• A new approach for setting nitrosamine limits was introduced in July 2023, based on robust scientific knowledge: the Carcinogenic Potency Categorization Approach (CPCA). This approach is based on an assessment of activating or deactivating structural features present in the molecule associated with an increase or decrease in carcinogenic potency and can be applied to any concerned molecule. The Carcinogenic Potency Categories range from Class 1 (high) to Class 5 (low) and are described in detail in EMA Questions and Answers, Appendix 2.
• Approved AIs derived using the CPCA approach are published in EMA Questions and Answers, Appendix 1, alongside AIs for N-nitrosamines established using conventional substance-specific animal carcinogenicity data available. The TD50 (Median Toxic Dose) is used to derive a substance-specific limit for lifetime exposure according to the ICH M7(R2) guideline.
• A test procedure for an enhanced AMES test protocol was published in EMA Questions and Answers, Appendix 3, in July 2023. A negative result in a GLP-compliant enhanced AMES test allows control of the nitrosamine at 1500 ng/day, which is equivalent to a low carcinogenic potency.
• Understanding of the risk factors associated with the quality of water used during manufacture has advanced during the review period. If purified water or water for injection is used in the manufacture of the API or finished product, it is important to understand the process used to purify the source water. There are alerts for levels of nitrites associated with the use of anion exchange resins combined with oxidizing agents such as chloramine, which are used for disinfection.
• Limited information has been available on the levels of nitrites in commonly used excipients. Therefore, a database was created in 2020 containing data donated by pharmaceutical organizations on the nitrite concentrations in common excipients, measured with validated analytical procedures. The collated data is useful for categorizing the potential risk posed by a variety of common excipients mainly used in solid dose oral formulations.
• The EMA has recently observed that APIs controlled by CEPs and ASMFs may be used in different finished products, potentially with different formulations, manufacturing processes, and indications. Therefore, to mitigate levels of nitrosamine impurities, a given finished product may need a particular quality of API, with additional tests or tighter limits, compared to the Ph. Eur. monograph of that substance, e.g., tighter limits for vulnerable amine impurities that may be converted to nitrosamines during formulation and storage of the finished product.

Step 2: Rigorous Confirmatory Testing for Nitrosamine Presence

Expertise in compilation, format, content, evaluation, and review of the Step 2 report, including completing the response templates. PLG can recommend contract laboratories using analytical methodology to test nitrosamines. The availability and sensitivity of the analytical methods have greatly improved since the original testing may have been carried out. Therefore, interpretation of the results of confirmatory testing may require updating, with reference to the Limit of Quantitation of the method (LOQ), the Acceptable Limit based upon total daily intake, and the 10 % and 30 % threshold limits thereof.

Step 3: Updating Marketing Authorization to Ensure Safety

If the nitrosamines risk has changed, the dossier controlling the API may need to be updated (ASMF or CEP update) and/or the Marketing Authorization Application (MAA) dossier by variation. PLG can prepare a CEP dossier revision according to the updated CEP 2.0 procedure implemented in September 2023, along with a recommendation of a suitable variation submission strategy (single variations or appropriate groupings) for the finished product. Coordinating between the MAH and the API and/or finished product manufacturer or CMO to obtain the technical information for the presentation of the change is part of the service provided by PLG.

Authors:

Stephen Jones

CMC Specialist

Regulatory Affairs