Nitrosamines

Nitrosamines are organic compounds formed by the reaction of secondary or tertiary amines with nitrosating agents (e.g. nitrites). Their general chemical structure consists of a nitroso group (-NO) bound to an amine. Typical representatives are N-nitrosodimethylamine (NDMA) and N-nitrosodiethylamine (NDEA).

Properties:

- Carcinogenic: Many nitrosamines are genotoxic and carcinogenic.

- High stability: They are chemically stable and can be difficult to detect in small quantities.

- Formation under certain conditions: They are formed under heat, moisture or acidic conditions.

Nitrosamines can enter pharmaceutical products in various ways. The main sources include:

1. Synthesis processes: Use of nitrosating substances or amine sources in the manufacture of active ingredients.

2. Packaging materials: Chemical reactions between components of primary packaging materials and pharmaceuticals.

3. External inputs: Contamination by the environment or water.

Primary packaging materials such as rubber stoppers, plungers and vials are particularly critical as they are in direct contact with sensitive dosage forms and can therefore act as potential sources of nitrosamines.

Rubber stoppers:

Rubber stoppers used in vials often contain additives such as vulcanizing agents, plasticizers or stabilizers. These additives can resemble amines or release amines themselves. Under certain conditions, these amines can form nitrosamines with nitrogen oxides or nitrites that occur during sterilization or storage.

Typical reactions:

- Secondary amines (from the rubber) + nitrosating agents → nitrosamines

Critical factors:

- Temperature: High temperatures during autoclaving or sterilization promote nitrosamine formation.

- Moisture: Favors the chemical reaction between amine and nitrosating sources.

Risk examples:

- NDMA formation due to N-nitrosation of rubber additives containing dimethylamine.

Plunger (piston):

Plungers in prefilled syringes are often made of elastomeric materials that contain additives similar to rubber stoppers. During prolonged contact with the drug, small amounts of amines or nitrosamines can be released from the material and contaminate the drug.

Challenges:

- Direct contact with highly sensitive liquid medicines.

- Interactions between plunger materials and active ingredients.

Vials:

Although glass vials themselves are not sources of nitrosamines, they can contribute indirectly to contamination. For example, residues from cleaning or coating processes may contain amines or nitrite compounds. In addition, the packaging system as a whole (vial + rubber stopper + drug) can form nitrosamines through interactions.

In view of the risks, regulatory authorities around the world have introduced measures to control and minimize nitrosamine contamination. Strict requirements apply, particularly with regard to primary packaging materials.

EU guidelines:

The European Medicines Agency (EMA) requires a comprehensive risk assessment for nitrosamines in medicinal products. This also includes primary packaging materials that come into contact with the product.

US FDA:

The FDA requires manufacturers to identify all potential sources of nitrosamines, including packaging materials, and implement strategies to minimize risk.

ISO standards:

ISO standards for primary packaging materials include guidelines for material selection, testing and documentation to minimize the risk of chemical contamination, including nitrosamines.

Several measures are taken to reduce the risk of nitrosamine formation by primary packaging materials:

Material selection and optimization:

- Use of nitrosamine-free elastomers: Manufacturers are increasingly focusing on materials that do not contain secondary or tertiary amines.

- Avoidance of critical additives: Substances that serve as nitrosamine precursors are replaced or removed.

Sterilization and production controls:

- Optimization of sterilization conditions: Lower temperatures and less aggressive processes reduce the likelihood of nitrosamine formation.

- Control of nitrite sources: Use of nitrite-free cleaning agents and processes.

Testing and monitoring:

- Release testing: Regular testing of rubber stoppers and plungers for nitrosamines.

- Stress tests: Simulation of storage conditions to investigate possible reactions between pharmaceuticals and packaging materials.

Packaging design:

- Barrier coatings: Use of PTFE or other inert materials as a barrier between the drug and the packaging material.

- Double packaging: Minimizing direct contact of pharmaceuticals with potentially reactive materials.

Challenges:

- Costs: Switching to nitrosamine-free materials and processes requires considerable investment.

- Technological hurdles: New materials must offer the same mechanical and chemical properties as existing elastomers.

- Regulatory adjustments: Different requirements in different regions make it difficult to implement global solutions.

Future prospects:

Research is focusing on the development of innovative materials that are completely nitrosamine-free while meeting the stringent requirements for primary packaging materials. Examples include:

- Silicone-based materials instead of elastomers.

- Nanotechnological coatings as a barrier against chemical reactions.

- Circular economy: Reuse and recycling of packaging materials to minimize exposure to additives.

Nitrosamines pose a significant challenge for the pharmaceutical industry, particularly in connection with primary packaging materials such as rubber stoppers, plungers and vials. These materials can contribute to contamination through additives or interactions with pharmaceuticals. The strict regulatory requirements and potential health risks make it necessary to carefully select, review and optimize materials and processes. With innovative materials, improved manufacturing processes and close collaboration between industry and regulatory authorities, the risk of nitrosamine contamination can be further minimized in the future.