Contract Endotoxin Testing Services

Get details on our contract bacterial endotoxin testing services:

Routine Endotoxin Detection for Non-release Applications
Our contract endotoxin testing services are designed to fulfill all pharmacopeia requirements. All testing is performed using customer-requested methods for submitted samples. Our optimized formulations provide increased sensitivity, greater linearity, and superior interference resistance. Endotoxin testing formulations are offered with a comprehensive range of buffers and accessories, providing numerous options for resolving interferences with difficult-to-test products.

Available Methods:

• Endosafe^® Kinetic Chromogenic Cartridge Technology
• Traditional LAL Kinetic Chromogenic Assay
• Endosafe^® Trillium™ Recombinant Cascade Reagent (rCR)
• LAL Kinetic Turbidimetric Assay
• Gel-Clot LAL

Product Validation: One and Three Lots
Before performing product release testing, we offer validation testing for up to three product lots. This meets standard validation requirements and accounts for any variability between lots.

Product Release Testing
Partner with us during this crucial part of ensuring drug product quality and safety. Regulatory bodies such as the U.S. Food and Drug Administration (FDA) and the European Medicines Agency (EMA) require lot release tests for each biopharmaceutical batch.

Stability Testing
Test your product for stability after exposure to a variety of environmental factors such as temperature, humidity, and light, and ensure your BET, pyrogen, or MAT method is robust and detecting contamination appropriately. 

Depyrogenation Validation
We offer a wide variety of studies to help with depyrogenation validation, from oven validation to stopper washing endotoxin reduction. They use specifically contaminated articles to verify a 3-log reduction in endotoxin content. We can also contaminate specific devices or articles with an adequate contamination value or provide ready-to-use endotoxin indicators as preferred. With a capacity of more than 200 devices per day, all returned devices, articles, or indicators can be assayed within 72 hours of receipt, avoiding production delays.

On-Site Bacterial Endotoxin Training
We can partner with you to create and facilitate tailored endotoxin training courses to meet your specifications, ensuring your team stays up-to-date with the most current BET methods.

Bacterial Endotoxin Assay Protocol Writing
Standard Operation Procedure (SOP) and protocol writing assistance is available to help our customers create a procedure specific to your operation, including the activities necessary to complete tasks in accordance with your standards and regulations.

Interference Screen with Trillium™ rCR
Test your product for inhibition and enhancement profiles within a range from neat to its maximum valid dilution (MVD) with either Trillium recombinant cascade reagent (rCR) vials or cartridges.

Product Specificity with Trillium™ rCR

Offered for either one or three lots of products tested at three concentrations. This method suitability will lower the barrier to implementation, speed up approval and implementation processes, and save time and cost of performing all aspects of validation.

Endosafe BET Proficiency Testing Program
For more information, please contact your local Charles River Representative or email [email protected]. 

Rabbit Pyrogen Test (RPT)

RPT remains a viable mammalian test model when testing for non-endotoxin pyrogens and a variety of products for which LAL is limited. One-time pyrogen testing may also be required by regulatory authorities to support routine use of endotoxin tests. All in vivo rabbit pyrogen tests are performed according to USP, European, and/or Japanese Pharmacopeia.  

*The European Pharmacopoeia Commission (EPC) has decided to eliminate the Rabbit Pyrogen Test (RPT) from its monographs. The revised texts omitting the RPT and the new chapter, Pyrogenicity (5.1.13), will be published in Supplement 11.8 of the Ph. Eur., with an implementation date of 1 July 2025.

Monocyte Activation Testing (MAT)

As an alternative to the Rabbit Pyrogen Test (RPT) for pyrogen detection, and for samples where Limulus Amebocyte Lysate (LAL) testing is not suitable (e.g., drugs that affect body temperature regulation, drugs that cause immunological reactions, some blood-derived products, or products that could contain pyrogens other than just endotoxin), we offer an in vitro pyrogen test service with the Monocyte Activation Test (MAT) in accordance with the European Pharmacopoeia regulations (EP 2.6.30). The MAT is based on the human reaction to pyrogens that cause a fever and may be used as an alternative to the rabbit pyrogen test. This method can be used to detect a wide range of pyrogens, including Gram-positive and Gram-negative organisms, parasitic, viral, and other biological pyrogens (e.g., yeast). When required, our scientific staff can work with clients to develop other approaches to the MAT to satisfy testing objectives.

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In the US, the main guidance is found in the FDA's Guidance for Industry: Pyrogen and Endotoxins Testing: Questions and Answers. 

Much of the information contained in the original 1987 FDA Guide is now covered by USP chapters <85> and <161>, as well as ANSI/AAMI ST72:2019, which is referenced in the latest guide from 2012. While the 1987 FDA Guide has been retired, some of the information is not covered by more current guidance so it is still often cited. The United States Pharmacopeia chapters <85> and <161>, and ANSI/AAMI ST72:2019 are not regulatory in themselves, however the 2012 guidance document specifically references them as accurate. USP is harmonized with the European Pharmacopeia and the Japanese Pharmacopeia, so they present the same overall information. 

The LAL endotoxin testing methods of Gel-clot, Kinetic Turbidimetric, and Kinetic Chromogenic are considered compendial, validated methods, so the method itself does not need to be validated as would an alternative method. Suitability tests, known collectively as a 3 Lot Product Validation should be completed to assure suitability of your product to the chosen method and dilution. 

Yes, end users will have to perform the appropriate validation, which is currently an alternative method validation globally. We offer a primary validation package and contract test services for those requiring support.

The acceptance criteria for LAL endotoxin testing assays are as follows: 

Gel-clot – The labeled sensitivity of the LAL reagent must be verified by obtaining an endpoint that is with 50-200% of the labeled sensitivity using endotoxin standards. The Negative Water Controls must be negative. For samples, the endpoint correlating to the sample’s endotoxin value must be below the sample’s endotoxin limit, and Positive Product Controls must be positive. 

Kinetic Endotoxin Test – The correlation coefficient (R-Value) of the standard curve must be greater than the absolute value of 0.980. The Negative Water Controls must contain less endotoxin than the lowest tested endotoxin standard. For samples, the endotoxin value must be below the sample’s endotoxin limit, and the Positive Product Controls must recover between 50-200% of the spiked endotoxin. 

There are multiple methods used for bacterial endotoxin testing. Gel-clot, Kinetic Turbidimetric, Kinetic Chromogenic, and Endosafe LAL cartridge technology (which falls under the Kinetic Chromogenic category) are all considered compendial endotoxin test methods, validated methods for LAL endotoxin testing of any product. 

The kinetic chromogenic method measures the absorbance of light in LAL reagent to determine if endotoxin is present by visible color changes. The degree of color and the rate at which the color appears is directly proportional to the amount of endotoxin within the sample. 

The chromogenic method is user-friendly and can be automated, which decreases the amount of time required to perform the test, allows more LAL assays to be completed per unit of time and calculations can be performed simply. Both of our Endosafe cartridges uses a kineitic chromogenic method. 

The kinetic turbidimetric method is a modified extension of the Gel-clot test. It measures the change in turbidity over time. The LAL reagent is altered so it is unable to form a solid clot when exposed to endotoxin. The amount of endotoxin present is inversely proportional to the reaction time. 

In addition to LAL, we offer Endosafe^® Trillium^®, an animal-free optimized kinetic chromogenic recombinant cascade reagent (rCR). Curated to simulate the natural LAL reaction, the formulation and composition of Trillium includes the three critical biological proteins (recombinant Factor C, recombinant Factor B, and recombinant proclotting enzyme) and a specific concentration of key components. 

Specific suitability studies should be performed to show that the chosen endotoxin testing method is appropriate for your specific products. Although not always the case, as a general rule, colored samples will show less interference to the Kinetic Turbidimetric assay, and turbid or cloudy samples will show less interference to the Kinetic Chromogenic assay. Neither color nor turbidity would affect the Gel-clot endotoxin test method. 

Gel-clot Endotoxin Test – For a reagent qualification, the Standard Curve and Negative Water Control should be run in quadruplicate. For a routine assay the Negative Water Control, Standard Curve, Negative Product Control, and Positive Product Control may be run in duplicates. 

Kinetic Endotoxin Test – For a reagent qualification, the standard curve and Negative Water Control should be run in triplicate with average replicates turned off. For a routine endotoxin test, the Negative Water Control, Standard Curve, Negative Product Control, and Positive Product Control may be run in duplicates, or in the desired number of replicates. 

You may find more information on our Endosafe technical resources page.