Endotoxins are lipopolysaccharides (LPS) found in the outer cell wall of Gram-negative bacteria. They only get onto a medical device through microbial growth or bacterial cell fragments.

Its main features are:

• Purely microbial origin
• It is not a material property of the product.
• Although they are critical for the patient, they can be fully controlled through production processes.

Consequently, endotoxins are clearly process contaminants and not material risks.

More about endotoxins

In practice, endotoxins are often mistakenly associated with ISO 10993, for example in the context of a supposed "pyrogen test according to ISO 10993." However, this association is incorrect in terms of both content and standards.

Why?

ISO 10993 assesses material risks, i.e., potential hazards arising from the chemical or biological nature of a material. 

Endotoxins, on the other hand, are produced by:

• Cleanliness of raw materials.
• Production environment.
• Handling of water, rinsing solutions, and cleaning processes.
• Handling and packaging.
• Sterilization and logistics.

All these aspects are process- and hygiene-driven and not material-related.

Consequences:

• ISO 10993 is not applicable.
• The evaluation of endotoxins is not a biocompatibility test.

The ISO 10993 classification system includes:

• Cytotoxicity
• Sensitization
• Irritation
• Systemic toxicity
• Material chemistry (ISO 10993-18)

Endotoxins do not fit in here because:

• Endotoxins are not a property of the material.
• They are not based on extractable substances.
• They are not influenced by material composition.
• Endotoxins arise exclusively as a result of process hygiene.

This makes it clear:

Endotoxins are a GMP issue—but not a biocompatibility issue.

Endotoxin control is an integral part of:

• Quality assurance
• Hygiene and cleanliness concepts
• Cleaning validations
• Sterilization processes
• Environmental monitoring

Acceptable methods for the quantitative detection of endotoxins:

• LAL test (Limulus amebocyte lysate)
• rFC test (recombinant factor C)
• MAT (monocyte activation test)

Possible relevant standards and regulations: 

• Pharmacopoea Europaea (Ph. Eur.) Chapter 2.6.14 – Bacterial Endotoxins
• United States Pharmacopeia (USP) <85> – Bacterial Endotoxins Test
• ISO 11737‑3 – Sterilization of medical devices – Microbiological methods – Part 3: Guidance on detection limit for endotoxins 

These methods are internationally recognized. 

Endotoxins do not belong in ISO 10993, but rather in a structured quality and hygiene management system. They are process-controllable contaminants whose risk can be managed through appropriate production, cleaning, and sterilization processes.