Addressing critical issues from EMA review requirements on nitrosamines
When the European Medicines Agency first issued its communication on the presence of nitrosamines in human medicines, there was significant confusion and uncertainty in companies. Specifically, the health authorities had issued a requirement that companies review their products for the possible presence of nitrosamines, have appropriate control strategies to prevent or limit the presence of nitrosamine impurities and, where needed, improve manufacturing processes. However, the requirements for the process, known as a “call for review”, lacked references and analytical methods to comply with the provisions.
To address the uncertainty and improve contact between companies and regulatory agencies, EMA set up the Nitrosamine Implementation Oversight Group (NIOG), which acts as the main interface between pharmaceutical companies, EMA and national regulatory agencies in the scientific and regulatory development of nitrosamines. NIOG activities include:
Step 1: Risk evaluation
The risk assessment is a multidisciplinary exercise and requires the involvement of experts from several departments (R&D, manufacturing, engineering, quality control and quality assurance).
First, it is necessary to analyze each step of both the synthesis of the active substance and the manufacture of the finished product. In addition, the risk assessment must also consider the information provided by manufacturers/suppliers of raw materials, solvents, reagents, excipients, and primary packaging materials. The widespread opinion among companies is that this collection of data from suppliers has been one of the greatest difficulties with the evaluation process. This has mainly been due to the fact that many suppliers, particularly early on, did not have the appropriate knowledge and were not used to receiving such requests. To meet the requests of their customers, they had to invest both time and money, and today most are able to provide the information requested.
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Step 2: Confirmatory testing
If step 1 resulted in identifying the risk of nitrosamine presence, companies had to perform further confirmatory testing on the products and report any confirmed presence of nitrosamines as soon as possible. Different approaches were applied: perform a screening on the main nitrosamines, develop and validate specific analytical methods for the determination of nitrosamines, or a combination of these approaches in the event of the presence of one or more nitrosamines.
The development of analytical methods suitable for detecting and quantifying the single nitrosamines was one of the most critical aspects for several reasons: it is a non-routine activity for the internal laboratory (e.g. lack of specialized personnel), the equipment is not available to support the technique, such as liquid chromatography–mass spectrometry (LC-MS) or MS-MS; the difficulty in handling the sample (interference and contamination, purification, concentration), given the presence of trace nitrosamines (parts per billion or sub-ppb); handling of uncommon materials used during analysis (e.g. deuterated internal standard).
Step 3: Update marketing authorizations
When the presence of nitrosamines is confirmed, companies must mitigate the risk by implementing an action plan which may include several changes to the marketing authorizations. These changes are managed by submitting variations via standard regulatory procedures.
The mitigation of the presence of nitrosamines is a further challenge for companies, mainly due to the additional costs that arise when implementing an action plan that typically requires investment in analytical equipment, changes in the product composition and/or in the manufacturing process, and the resulting impact on production and release of the finished product. In some cases, these steps can result in companies withdrawing the product as the expected costs for risk mitigation are not sustainable.