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B R O C H U R E

ProductLife Group Offers Flexible Solution to Address Nitrosamine Risk Assessment

In response to the detection of nitrosamine impurities in several medicines, the European Medicines Agency (EMA) has issued a notification specifying its risk assessment requirements. The notification comes after authorities were made aware that nitrosamines, including N-nitrosodimethylamine (NDMA), were found in a number of blood pressure medicines and later in batches of a medicine used to treat heartburn. NDMA and N-nitrosodiethylamine are classified as probable human carcinogens.

The agency’s notification—EMA/189634/2019, dated 19 September 2019—establishes a two-step process for marketing authorisation holders (MAHs). First, a marketing authorisation holder must carry out a risk-based assessment of each authorised human medicinal product containing chemically synthesised active pharmaceutical ingredients (APIs). The risk evaluation for each product should be submitted before 26 March 2020 to the European agencies. MAHs were advised to prioritise products so as to determine the sequence in which their products should be evaluated.

In the event that any products get identified as at risk during phase one, MAHs must conduct confirmatory testing of those products. All such testing and submissions of required changes in manufacturing authorisations must be concluded by 26 September 2022. MAHs must also inform competent authorities immediately if nitrosamine impurities are confirmed during testing.

The agency has flagged a case-by-case assessment to determine what needs to be done to reduce or remove risks posed to patients. However, companies should follow the approach taken with the assessment of elemental impurities—as set forth in the ICH Q3D guideline on elemental impurities, which requires that companies demonstrate that their products adhere to the limits on 24 heavy metals in four risk classes.

The amount of work involved, especially for MAHs with large product portfolios, is huge—and the time to meet EMA’s requirements is limited.

End-to-End Risk Assessment SupportProductLife Group has extensive expertise in handling all aspects of the review, risk evaluation, confirmatory testing, and document management required by EMA’s nitrosamine contamination notification. Our team supports clients with:

ProductLife Group specialises in helping international life sciences organisations more effectively get their products and therapies to market by providing those clients with functional support across all of the regulated stages of the product life cycle—from development to launch, to postmarketing.

Performing successfully for more than 25 years, ProductLife Group has an established global presence in Europe, the Middle East, Asia Pacific, Africa, Latin America, and North America. We deliver services via an innovative, platform-and-hub operating model, enabling our clients to achieve continuous improvement, increased quality, enhanced performance, reduced risk, better compliance, and overall cost benefit. That approach, combined with our collaborative, partnership-oriented culture, empowers life sciences organisations to realise the commercial potential of their own international operations.

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• Chemical expertise in the form of a chemistry, manufacturing, and control consultant who is responsible for performing the chemical risk assessment

• Toxicological and medical expertise in the form of a medical pharmacology consultant who is responsible for performing the medical risk assessment from treatment data, posology, and the chemical risk assessment

• Data and document management expertise in the form of a documentation expert who performs data collection and conducts follow-up with manufacturers to get accurate information on drug substances, excipients, and packaging materials

• Management expertise in the form of a project manager who oversees all aspects of the risk assessment, follow-up testing, and submission of changes

A Flexible, Just-in-Time SolutionBecause the issue of possible nitrosamine contamination does not lend itself to a one-size-fits-all approach, ProductLife Group offers a flexible solution to meet the various challenges and requirements each client faces. To start with, our team of experts communicates and interacts with suppliers and laboratories to collect and update data for APIs, excipients, and packaging. Data flow can be managed either in the client’s environment or in ProductLife Group’s depending on client preference.

Our team of chemical and medical experts prepares risk assessment reports, beginning with an update of the first risk assessment—with new data from suppliers when available—after which the team updates the risk assessment reports based on test results of the APIs and finished product. The team also updates and implements prioritised protocols in compliance with the regulatory changes and carries out literature searches and analysis when required. Again, ProductLife Group offers the flexibility of either using our own risk-analysis templates or adopting and, if necessary, updating the client’s format.

To ensure that the testing addresses EMA’s provisions, ProductLife Group can define and optimise the testing strategy to reduce the risk the MAH faces. The team can also prepare and file all variations. In addition, the team can manage the entire life cycle of a nitrosamine risk assessment by handling the integration of a new manufacturer and assessing any change of process to APIs, excipients, packaging, or contract manufacturing organisations.

9 MAH data 9 Supplier data

9 Nitrosamines risk assessment 9 Strategy to define the risk

9 Approved varations or implemented strategy to decrease risk

9 Coordination as well as document and data management

9 Nitrosamines risk assessment

9 Supplier ’s and manufacturer’s data

9 Laboratory analysis

9 Variations 9 Project management

Suppliers and

Laboratory

Marketing Authorisation

Holders

Nitrosamines Process