How To Control Endotoxins In Medical Products
What is an endotoxin?
The “endo” in endotoxin refers to something that is within. The “toxin” component of endotoxin relates to something poisonous. When we combine these definitions, endotoxins are poisons from within. Indeed, endotoxins are deadly to humans because they trigger the innate immune system and produce fever when released within the human body. Endotoxins come from the cell walls of gram-negative bacteria. The endotoxins themselves are molecules with both a fat component and a complex sugar component. Complex sugars are also known as polysaccharides. The presence of fat and sugar components is why endotoxins are also known in scientific literature as lipopolysaccharides (LPS). Endotoxins are the most ubiquitous pyrogenic contaminants for medical devices or products. However, there are other types of pyrogens.
Three Ways To Control Endotoxins In Medical Products
The simplest and most effective way to reduce endotoxin levels in medical products is to control the gram-negative bacteria levels. Manufacturers use three types of control (indirect, process, and direct control) to keep endotoxin content at safe levels. Endotoxin prevention through the control of product components (such as raw materials, water, excipients, packaging materials, equipment, and the manufacturing environment) is known as indirect control. Manufacturing operators also fall under indirect control as they are often primary contributors to the microbe content of the manufacturing environment. Endotoxins are also limited through process control. Process controls monitor endotoxin levels before and after established processing steps (known as critical control points) to ensure no increase in endotoxin levels resulting from various processes involved in the creation and packaging of the product. If indirect and process control methods are not enough, direct control methods for endotoxins are used. Direct control processes involve the destruction or removal of endotoxins. Direct control methods for reducing endotoxins can be applied to product streams, equipment, and primary packaging materials. Both direct control and process control methods for endotoxin control must be validated to ensure consistent results for reducing or maintaining a low level of endotoxin burden within the product and product-package system.
Indirect Control of Endotoxins
Part of indirect control is preventing any gram-negative microbes from proliferating and increasing in concentration during manufacturing. Materials from natural sources or with high water activity are at the greatest risk of gram-negative microbe exposure and proliferation. On the other hand, glass, plastic containers, and elastomeric closures have the lowest endotoxin levels due to their manufacturing requirements. Water is a common raw material, especially for the manufacturing of parenteral products. Water is possibly the highest risk material for endotoxin contamination. As a result, water quality, generation, and distribution must be properly validated and controlled to prevent biofilm formation. If biofilms form, Gram-negative bacteria can contribute significantly to the endotoxin load of the end product.
If gram-negative microbes are sufficiently limited through indirect control, endotoxin removal in downstream product processes will not be necessary. One way of regulating endotoxin levels in raw materials and packaging is to audit packaging suppliers to confirm that they are performing consistent and documented control over their manufacturing processes. Specifically, bioburden and endotoxin control should be a component of a vendor audit as microbial levels and microbe type directly affect endotoxin concentration in materials.
Process Control of Endotoxins
Product process control involves identifying critical control points (CCP) where endotoxins are introduced in the process or removed as a result of a process.
Process control measures include but may not be limited to the following:
- Control of manufacturing practices. Endotoxin control is a part of cleaning validation procedures. Manufacturers avoid the use of materials where endotoxin limits cannot be controlled whenever possible. Clean product-contact equipment is stored dry to avoid Gram-negative bacterial proliferation.
- Hold times during manufacturing. Holding conditions are validated to ensure microbial proliferation does not occur during holding times.
- Environmental control. Aseptic and good manufacturing practices can be used to control endotoxin levels. Any standing water after cleaning is to be removed from the space. Operators must be trained to reduce their microbial impact and wear proper protective clothing (gowns, masks, gloves, etc.). Disinfecting practices are implemented to reduce the possibility of microbial proliferation in critical areas.
- Endotoxin monitoring. Endotoxin limits at CCP get to be assessed regularly for quality control and risk mitigation. Further, if any changes to the process (such as new sources for raw materials or equipment) occur, endotoxin levels must be monitored when these changes have been made.
Direct Control of Endotoxins
As mentioned earlier, processes used for direct control of endotoxins must be validated to ensure that endotoxins are removed or reduced to safe levels. Direct control methods are also known as depyrogenation methods. When deciding on which depyrogenation method to use, an assessment of current manufacturing processes and materials is needed to confirm where endotoxins are being introduced. From there, the easiest way for endotoxin removal can be determined. Depyrogenation methods include dry heat, chemicals, filtration, or physical removal. The depyrogenation methods available for any application depend upon the effects of depyrogenation treatment on the materials or process itself. In many cases, the use of dry heat or chemicals is not a viable option. Depyrogenation methods require adequate validation and ongoing monitoring as a part of process controls to ensure endotoxins are consistently removed at the desired levels. As with most modifications to a process, direct depyrogenation methods often increase the cost of production and can result in complications or reduction in product process output for previously optimized processes.
Summary
Overall, indirect, process, and direct control methods can be used to control endotoxin levels for medical products. Direct control methods are the most aggressive and difficult to implement since they involve removing or destroying endotoxins from a product or process. Endotoxin control is important for ensuring medical devices and products are free of toxins and safe for patient use. Make sure you choose a contract testing organization that can support you with appropriate endotoxin testing for your unique medical device or product needs.
Ethide Labs is a contract testing organization that specializing in Bacterial Endotoxin Testing. Ethide Labs also offers Microbiology Testing, Sterilization Validations, Bioburden Testing, Package Integrity Testing, Cytotoxicity Testing, Environmental Monitoring and EO Residual Testing services for medical device companies and allied industries. Ethide is an ISO 13485 certified facility.
References
United States Pharmacopeial Convention. <1228> Depyrogenation. Rockville, MD, USA. 2021. (USPC <1228>).
