USP recently added a new chapter “1469” on nitrosamine impurities to the U.S. Pharmacopeia. With this addition, USP intends to help both the Authority and pharmaceutical manufacturers assess the presence of nitrosamine impurities and implement appropriate control strategies and analytical procedures.
This chapter is aligned with current scientific and regulatory approaches developed to ensure appropriate control of nitrosamine impurities by eliminating or reducing their presence in drug substances and drug products. Thus, the approach described ensures product quality with respect to safety.
BRIEF OVERVIEW OF THE NEW CHAPTER: <1469> nITROSAMINE IMPURITIES
The new chapter has a more substantial structure articulated in nine paragraphs:
- INTRODUCTION: clarifies the reasons why the presence of nitrosamines represents a significant concern and lists the main possible sources of nitrosamines
- NITROSAMINE IMPURITIES: provides a detailed list of nitrosamines relevant to the pharmaceutical industry, including additional chemical information for each entry. It also positions nitrosamines from the ICH M7 perspective.
- SOURCES OF NITROSAMINES: provides a general overview on how nitrosamines are formed and could end up in pharmaceutical products. It also indicates the risk factor associated (by observation or evaluation) with each of these sources
- NITROSAMINES RISK ASSESSMENT – DEVELOPMENT OF A CONTROL STRATEGY: provides recommendations on how to perform the nitrosamines risk assessment and the development of a control strategy to ensure that the nitrosamine presence is avoided or at least reduce to levels below acceptable intake.
- LIMITS OF NITROSAMINES: details the approach used to determine daily acceptable intake levels of nitrosamines and the criterion used to calculate concentrations limits and the maximum daily dose of the drug substance.
- TESTING FOR THE PRESENCE OF NITROSAMINES: upon completion of the risk assessment, specify the possibility of performing exploratory testing to confirm the conclusions of the risk assessment and proposed control strategy.
- TEST METHOD PERFORMANCE CHARACTERISTICS OF NITROSAMINE METHODS: provides guidance on the verification process, the procedures being implemented in the laboratory, and the validation of alternative procedures.
- ANALYTICAL PROCEDURES: describes the four procedures validated or verified in USP laboratories
- ADDITIONAL SOURCES OF INFORMATION: contains references to analytical procedures that are currently on the websites of regulatory agencies in the United States (FDA) and Europe (EDQM).