Source of Nitrosemine - Review Article

A comprehensive analysis of the factors that can contribute to nitrosamine levels exceeding safety limits in pharmaceutical products. I've organized the potential causes into eight major categories, each with five specific contributing factors:

Raw Materials

• Nitrite-contaminated excipients
• APIs with vulnerable amine groups
• Inadequate vendor qualification
• Nitrite in processing water
• Insufficient raw material testing

Manufacturing Process

• Acidic process conditions (pH < 5)
• Use of nitrosating agents
• High processing temperatures
• Recycled solvents contamination
• Inadequate GMP controls

Formulation

• Reactive excipient combinations
• Lack of antioxidants/inhibitors
• Formulation pH promotes nitrosation
• Incompatible preservatives
• Poor formulation design

Storage & Packaging

• Nitrocellulose in packaging
• High humidity storage
• Elevated temperature conditions
• Printing inks containing nitro compounds
• Extended shelf-life

Analytical Methods

• Insufficient method sensitivity
• Inadequate validation
• Matrix interference effects
• Lack of reference standards
• Equipment limitations

Quality Control

• Inadequate sampling plan
• Insufficient stability testing
• Ineffective change control
• Poor staff training
• Ineffective OOS investigations

Regulatory Compliance

• Outdated regulatory filings
• Missed regulatory updates
• Inconsistent global standards
• Delayed implementation of controls
• Inadequate PAS submissions

Risk Assessment

• Incomplete risk assessment
• Improper PCPC categorization
• Failure to evaluate multiple nitrosamines
• Insufficient product lifecycle management
• Inadequate degradation pathway assessment

Understanding these multifaceted causes is essential for implementing effective preventive and corrective measures across the pharmaceutical manufacturing process.

The diagram highlights that nitrosamine control requires a comprehensive approach spanning from material selection to analytical testing, quality systems, and ongoing risk management.