Controlling Endotoxins Contamination during Pharmaceutical Production

Controlling Endotoxins Contamination during Pharmaceutical Production: Sampling Plans, Test Methods, and Method optimization

Endotoxins are substances that elicit a fever when contacting blood or cerebrospinal fluid (brain and central nerve system). Endotoxins are a part of the cell wall of gram-negative bacteria, consequently endotoxin contamination is always linked to bacterial contamination.

They are very resistant to most sterilization processes like steam, EtO or radiation sterilization, and disinfection methods. Obtaining endotoxin free end-products should therefore mainly be based on preventing introduction of contamination rather than removal or destruction. Understanding the effect the manufacturing process has on endotoxin contamination is therefore of utmost importance.

Endotoxin free pharmaceuticals, like sterile pharmaceuticals, cannot be assured simply by end product testing. Therefore, it is important to be aware of the possible contamination sources, and limit and control the introduction of endotoxins through these sources. The identification, sampling and testing of endotoxin contamination sources should be part of a formal endotoxin sampling plan.

When considering a sampling plan for the control of endotoxins, one must consider all possible sources of contamination. From this knowledge Critical Control Points (CCP) should be identified. CCPs can be defined as places in the process where endotoxin can either be added to or eliminated from the system. Testing and setting limits of identified intermediate CCPs will provide the drug or device manufacturer with a significant measure of risk control.

In conclusion, endotoxin sampling plans and testing schemes are an essential part for the manufacturing of endotoxin free end-products. Sampling plans should be based on knowledge of the production process and the origin and characteristics of endotoxins.