Wisdom For Polyethylene vol.34
34. Nitrosamines in Pharmaceutical Packaging
2025-12-04
Nitrosamines have attracted significant attention in the pharmaceutical industry as compounds with carcinogenic risk.
In this article, from the perspective of a film manufacturer, we explain the mechanisms of nitrosamine formation in packaging materials, identify risk factors, and discuss effective management measures.
In particular, we highlight how the selection of raw materials and the use of additive-free LDPE bags can effectively reduce risk.
In this article, from the perspective of a film manufacturer, we explain the mechanisms of nitrosamine formation in packaging materials, identify risk factors, and discuss effective management measures.
In particular, we highlight how the selection of raw materials and the use of additive-free LDPE bags can effectively reduce risk.
Nitrosamines Currently Highlighted in the Pharmaceutical Industry
We examine risk control measures from the standpoint of a film manufacturer.
As is widely known, nitrosamines are problematic because some compounds within this class are confirmed to have carcinogenic potential.
Examples include N-nitrosodimethylamine (NDMA) and others.
Examples include N-nitrosodimethylamine (NDMA) and others.
Challenges in Addressing Nitrosamines in Packaging Materials
How should we address nitrosamines in the packaging materials we manufacture?
The first consideration is whether we have evidence data that certifies “nitrosamine-free” status.
However, in practice, it has become clear that achieving this is not straightforward.
The first consideration is whether we have evidence data that certifies “nitrosamine-free” status.
However, in practice, it has become clear that achieving this is not straightforward.
Background on Nitrosamine Formation
Nitrosamine contamination involves numerous factors, making it a highly complex and troublesome issue in the pharmaceutical industry.
Nitrosamines are known to form through reactions between amines and nitrogen oxides.
These amines are widely used in everyday life and industrial applications, including pharmaceuticals, electronics, pesticides, and additives.
Secondary amines are also present in seafood, making them a very familiar presence.
Nitrosamines are known to form through reactions between amines and nitrogen oxides.
These amines are widely used in everyday life and industrial applications, including pharmaceuticals, electronics, pesticides, and additives.
Secondary amines are also present in seafood, making them a very familiar presence.
Complicating Risk Factors
Because nitrosamines can form when commonly encountered amines react with nitrogen oxides, the issue becomes even more complex.
The core problem in the pharmaceutical and packaging industries can be summarized as follows:
Risks in the Packaging Process
As mentioned, nitrosamines form through reactions between amines and nitrogen oxides.
If residual amines are present as impurities in the contents and are exposed to nitrogen oxides during the manufacturing process, there is a risk of nitrosamine formation.
If residual amines are present as impurities in the contents and are exposed to nitrogen oxides during the manufacturing process, there is a risk of nitrosamine formation.
To put it bluntly, even nitrogen oxides released from packaging containing APIs or intermediates can be a risk. Similarly, if amines are present in packaging used in environments potentially contaminated with nitrogen oxides during production, this also constitutes a risk.
Necessity of Risk Management
Even if the contents themselves are stable and contain no nitrosamines, components in the packaging or contamination during the production process can trigger nitrosamine formation.
Therefore, it is essential to manage the risk to this level.
In simplified terms:
Amine + (Nitrogen Oxide) = Nitrosamine
It is necessary to thoroughly manage the substance in the parentheses (nitrogen oxides).
Moreover, if amines are not present in the packaging material, the potential for formation is further reduced.
Moreover, if amines are not present in the packaging material, the potential for formation is further reduced.
Examples of Substances Requiring Control
Representative substances that may lead to nitrosamine formation in the presence of amines include:
- Sodium nitrite
- Nitrous acid
- Nitrite salts
- Nitric acid
- Nitric oxide
- Dinitrogen trioxide
- Dinitrogen tetroxide
- Nitrocellulose
This list is not exhaustive.
Risks from Recycled Raw Materials
According to the EMA (European Medicines Agency), recycled, purified, and regenerated raw materials also carry contamination risks and require management.
Thus, packaging materials must be managed not only for the substances listed above but also for recycled, purified, regenerated sources, and amines.
Difficulty of Management
In practice, the number of substances requiring management is large, making it extremely time- and labor-intensive to ensure safety.
Typically, polybags used by end users are made from LLDPE (linear low-density polyethylene).
LLDPE polybags may contain metallic catalysts, antioxidants, antiblocking agents, lubricants, and, depending on application, antistatic agents or colorants.
Managing all these substances for nitrosamine risk represents a very high hurdle.
LLDPE polybags may contain metallic catalysts, antioxidants, antiblocking agents, lubricants, and, depending on application, antistatic agents or colorants.
Managing all these substances for nitrosamine risk represents a very high hurdle.
Moreover, the number of substances requiring control may increase in the future, making the investigation time-consuming.
Direction for Strengthening Control
How can control be strengthened?
The key is to minimize the raw materials used.
Instead of using multiple types of raw materials (additives, etc.), standardizing to a single material allows the control scope to be limited and investigation targets to be focused, enabling concentrated management.
The Option of Additive-Free LDPE Bags
In polybag terms, this approach corresponds to “additive-free LDPE bags.”
LDPE (low-density polyethylene) can be produced by radical polymerization under high temperature and high pressure without catalysts, enabling the production of pure polybags without additives.
LDPE (low-density polyethylene) can be produced by radical polymerization under high temperature and high pressure without catalysts, enabling the production of pure polybags without additives.
However, simply using additive-free raw materials is not enough.
Raw materials come in various grades, and selecting the purest materials is critical.
Accumulated experience and data are the most important knowledge in determining purity and cleanliness.
Raw materials come in various grades, and selecting the purest materials is critical.
Accumulated experience and data are the most important knowledge in determining purity and cleanliness.
Our company offers the ASO Clean Polybag Series, produced from carefully selected, completely additive-free LDPE raw materials, with a long track record of supply to pharmaceutical manufacturers.
Production is performed on dedicated manufacturing lines with standardized procedures in an ISO Class 6 cleanroom, minimizing the risk of secondary contamination and ensuring safe use.
Production is performed on dedicated manufacturing lines with standardized procedures in an ISO Class 6 cleanroom, minimizing the risk of secondary contamination and ensuring safe use.
Summary
Nitrosamine contamination risk is an unavoidable issue in pharmaceutical packaging.
Key points for management include:
Key points for management include:
- Control both amines and nitrogen oxides
- Minimize raw materials to reduce the number of substances requiring control
- Select low-risk packaging materials such as additive-free LDPE bags
These measures allow long-term and stable safety assurance.
Although this article focuses on nitrosamines, in an environment of increasingly strict chemical management, choosing high-quality polybags made from additive-free LDPE and produced in a cleanroom contributes to strengthened container and packaging management for users.
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