Endotoxin Testing: From Finished-Device Limits to Component Controls Limits

If your finished medical device has an endotoxin limit of 20 EU/device, what limit should you set for each component? If every component has the full device limit, their combined endotoxin level could exceed it. An equal medical device component split may seem straightforward, but it can overlook important differences in materials, processing, and patient exposure.

Start by understanding how much endotoxin each component may contribute and how you control it. ISO 11737-3:2023 provides a framework for bacterial endotoxin testing (BET) of health care products, components and raw materials. It explains how to test for endotoxins. It does not set specific limits or explain how to divide a 20 EU limit among a device’s components.

This article explains the standard and offers practical tips. The 20 EU/device limit is only an example, not a universal limit set by ISO 11737-3. Before setting a limit, check the requirements for your device and the markets where it will be sold.

Start with the basics: what are you controlling?

A component acceptance limit and a finished-device limit have different purposes. The finished-device limit applies to the defined product and how it will be used. A limit for incoming components or work in progress helps control possible endotoxin sources before assembly is complete. A result below 20 EU/component does not, on its own, show that the finished device meets 20 EU/device.

For example, three components with 8 EU each would add up to 24 EU if all of their endotoxin remained in one finished device. Each component would be below 20 EU, but the total would exceed the example’s finished-device limit. This shows why you need to check both the measurement unit and the number of components used.

Know the difference between an assembled device and a kit

Before choosing a limit, define exactly what product or product unit you are assessing. A component used to make one finished device is not automatically the same as a separate health care product supplied in a procedure kit. Putting several products in one package also does not, by itself, tell you how to apply their endotoxin limits.

ISO 11737-3 covers product selection and the selection of product units. Your testing plan should identify the relevant parts that are in contact with the patient. It should also describe how the product is used and whether the claim applies to one product or a combination of products.

Table 1. Selection of product units for testing from ISO11737-3

Product	Packaging	Item for testing
a) One healthcare Product	One Sterile Barrier System	Individual health care product or applicable patient contact portion
b) Set: Components assembled into health care product at the point of use	One or more sterile barrier systems	All components or applicable patient contact portion
c) Number of identical health care products*	One sterile barrier system	Individual health care product or applicable patient contact portion
d) Kit: Procedure-related health care products*	Within a single sterile barrier system	Each type of health care product or applicable patient contact portion
e) Kit: Procedure-related health care products*	Health care products each in a sterile barrier that are combined in secondary packaging	Each type of health care product or applicable patient contact portion

*Manufacturers can choose to test the procedure-related health care products together to provide a single collective non-pyrogenic claim, however this is not required. Manufacturers that combine procedure-related health care products can support non-pyrogenicity by using supplier certification or by performing testing. 

Set component controls based on risk

One practical approach is to create an endotoxin budget. This means dividing the available finished-device allowance between components and process steps. It is an internal engineering and quality-control tool, not a method required by ISO 11737-3. It helps you clearly record and check your assumptions.

First, list the materials and process steps that could affect the relevant product surfaces. Consider supplier controls, process water, cleaning, handling, storage and assembly. Review past results and how much they vary, not just the average. Include components that could transfer contamination to parts or fluid pathways that contact the patient, even if those components do not contact the patient directly.

Next, check how many components are used in one device. Use a consistent basis when calculating their contributions. For a limit in EU/g, account for the mass used. For a limit in EU/component, account for the number of components. Dividing the allowance only by mass, surface area or component count needs supporting evidence. Do not assume that endotoxin is spread evenly.

Also, allow for endotoxin that may be added during later processing and for variation in the process. Base this allowance on evidence. Do not assume that later processing removes endotoxin unless you have demonstrated this for the actual process. When several sources share the allowance, component limits will often need to be lower than the finished-device limit. However, the standard does not set one numerical rule for all products.

A practical example: dividing a 20 EU/device allowance

Imagine a device with one housing, two connectors and one tubing segment. After reviewing the materials, process and data, the team assigns the example allowances below. These numbers only explain the approach. They are not ISO limits or specifications you can use without further assessment.

Contribution	Quantity per device	Example allowance	Total per device
Housing	1	4 EU/component	4 EU/device
Connectors	2	2 EU/component	4 EU/device
Tubing segment	1	6 EU/component	6 EU/device
Allowance for later processing	Not applicable	3 EU/device	3 EU/device
Remaining allowance	Not applicable	3 EU/device	3 EU/device

Table 2. Example of dividing 20 EU/device

The component allowances add up to 14 EU/device. Adding 3 EU/device for later processing gives a planning total of 17 EU/device. This leaves 3 EU/device below the example limit of 20 EU/device. The calculation is simple. The important work is showing that these allowances are suitable for the real product. A risk assessment can help in support of this decision.

This assumes that adding the contributions gives a suitable estimate without understating the total, and that the measurement methods are suitable. Differences in extraction, contamination that is not measured and process effects can affect this assumption. EU per component results help control the process. They do not automatically replace finished-device testing or prove that the finished device meets its limit.

Keep the control plan up to date

Do not file away the control plan after validation. Keep it linked to supplier results, manufacturing conditions and finished-device results. Section 8 of ISO 11737-3 covers routine testing, monitoring and interpretation of results. Section 9 covers maintaining the BET method.

Record the following in your control plan:

• The finished-device limit, why it was chosen and the product configuration it applies to.

• The relevant components, their quantities and the endotoxin that process steps may add.

• The reason and supporting data for each internal acceptance limit.

• The extraction method, reporting units, evidence that the method is suitable and the sampling plan.

• How component controls support finished-device checks and product release decisions.

• What to do when results show an unfavourable trend, exceed a limit, or when a supplier, material or process changes.

  
  

Share these expectations early so suppliers and laboratories work towards the same target. As you collect more data, you can review the allowances, identify new contamination sources and improve monitoring decisions. Base any changes on evidence and follow the relevant quality system and regulatory requirements. A series of passing results alone is not enough to justify a change.

Conclusion

Setting a component limit is not about finding one number in ISO 11737-3. It means linking a justified finished-device limit to a clear understanding of the product, a suitable test method and effective process controls.

If your device has an established limit of 20 EU/device, do not automatically allow 20 EU for every component or divide the limit equally without evidence. Define the product unit, assess possible endotoxin sources and set internal controls supported by data. Check that the testing plan can support these controls. Clearly separate your proposed allowances from the standard’s requirements.

A forward-looking endotoxin programme does more than check the finished product. It uses reliable results to identify risks earlier, improve discussions with suppliers and make manufacturing controls more consistent.

Reference

International Organization for Standardization. (2023). Sterilization of health care products—Microbiological methods—Part 3: Bacterial endotoxin testing (ISO Standard No. 11737-3:2023). https://www.iso.org/standard/76249.html