Nitrosamine Impurities in Medicinal Products and APIs - the New FDA Guidance

"This Guidance is for immediate implementation". This instruction can be found directly under the title of the FDA's news Guidance for Industry entitled "Control of Nitrosamine Impurities in Human Drugs" - published in September 2020.

The immediate entry into force of this guideline is due to the urgent need for regulation, due to the fact that in the last 2 years since the discovery of the first cases of Nitrosamine impurities in Valsartan preparations, numerous other finished medicinal products with partially toxicologically questionable nitrosamine content have appeared. In the foreword, the authority points out that this guidance will come into force immediately without the usual deadline for comments and justifies this with the need to provide manufacturers of medicinal products and APIs with timely information to carry out risk assessments, analytical tests and other risk reduction measures regarding nitrosamine contamination.

The guidance document describes the current state of knowledge on this topic in 5 main chapters:

I. Introduction and II. Background

In a brief historical summary, the FDA describes their approach and the measures taken from the first discovery of contaminated Valsartan batches in 2018 to the present. This is followed by an explanation of the formation of nitrosamines using a general chemical reaction scheme (nitrosating reaction between primary or secondary amines) and the various root causes leading to nitrosamine contamination. The FDA emphasizes the importance of an exact knowledge of the supply chain (awareness of the supply chain) and thus also the control of suppliers and transport routes. This is the only way to effectively prevent brought-in contaminations.

III. Recommendations

Similar to the requirements applicable to the European Member States, the FDA also requires prioritisation of risk assessments according to the criteria

  • Maximum daily dose
  • Treatment duration
  • Therapeutic indication
  • Number of patients treated

Depending on the availability of new information and progress in knowledge, the FDA reserves the right to give higher priority to certain preparations with regard to risk analysis. For the risk assessment, the guidelines from ICH Q9 are to be applied.

Daily dose limits are given for six nitrosamine species commonly found in pharmaceutical preparations (highest limit of 96 ng/day for NDMA, lowest limit of 26.5 ng/day for NDEA, NMPA, NIPEA and NDIPA). These values are applicable when only one nitrosamine species is present. In the case of several nitrosamines that (based on a maximum daily dose of the medication in question of 880 mg) in total exceed the limit of 26.5 ng, the manufacturer has to contact the authority. If nitrosamines are detected for which no official daily dose limits exist, the risk must be evaluated according to the specifications of ICH M7(R1).

This section of the guidance also provides detailed recommendations to the manufacturers of APIs as well as to the manufacturers of finished medicinal products on the precautions to be taken to reduce the risk of nitrosamine contamination. In particular, the section addressed to API manufacturers describes in detail the precautions to be taken, taking into account the currently known sources of nitrosamines, such as specifics of chemical synthesis, catalysts, starting materials, raw materials and their supply chains, excipients, solvents, etc.

IV. Maintaining the Drug Supply and V. Reporting Changes to FDA

These chapters describe changes to be made in order to reduce risk and may result in limited availability of the product. The FDA provides clear guidance on communication and the reporting obligations of Drug Master File holders in cases of forced changes in the manufacturing process due to contamination. Furthermore, deadlines are defined for risk assessment, confirmatory testing and submission of changes. For example, manufacturers of medicinal products that are authorised or already on the market must complete the risk assessment within 6 months of the publication of this guidance (March 2021). A period of 3 years (September 2023) exists for confirmatory testing and notification of any necessary process changes. For products with pending applications, the risk assessment and any necessary confirmatory testing must be carried out quickly. For new applications, the FDA recommends that risk analysis and, if necessary, confirmatory review be completed before the application is submitted. If the application has already been submitted, an appropriate amendment to the application must be submitted as soon as possible.

In general, the FDA expects that the risk analyses will be completed within the timelines described in the guidance and will be available on request. It is not required to submit these risk analyses in a supplement. However, there is an obligation to submit a supplement in case of any changes to conditions established in the approved application in order to notify FDA of these changes.

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