Endotoxin Limits And Calculations For Medical Devices And Combination Products
What is the difference between combination products and medical devices?
Combination products are products comprised of a merge of two or more regulated classes. Examples of combination products are drug devices, biologic devices, drug-biologics, or drug-biologic combination devices. Combination products can also be separate products from different regulated classes packaged together in a single package as a kit or single entity product (such as a pre-filled syringe). Some medical devices may be devices alone. Other medical devices may be combination products.
The FDA considers your product a device if it meets the Section 201 (h) criteria from the Food, Drug, and Cosmetic Act. Section 201 (h) reads:
“Per Section 201(h) of the Food, Drug, and Cosmetic Act, a device is:
An instrument, apparatus, implement, machine, contrivance, implant, in vitro reagent, or other similar or related article, including a component part, or accessory which is:
- recognized in the official National Formulary, or the United States Pharmacopoeia, or any supplement to them,
- intended for use in the diagnosis of disease or other conditions, or in the cure, mitigation, treatment, or prevention of disease, in man or other animals, or
- intended to affect the structure or any function of the body of man or other animals, and which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and
which does not achieve its primary intended purposes through chemical action within or on the body of man or other animals and which is not dependent upon being metabolized for the achievement of its primary intended purposes. The term “device” does not include software functions excluded pursuant to section 520(o).”
Calculating Endotoxin Limits for Combination Products
A manufacturer can propose, with appropriate justification and data, unique limits for regulatory submissions for combination products. When proposing limits ensure your have appropriate in-vitro bacterial endotoxin testing or in-vivo bacterial endotoxin testing. You can find endotoxin limits for drugs and biologics HERE.
If you plan to justify particular endotoxin limits for your combination product, consider the following:
# 1: If the combination product is a drug-device combination
Drug-device combination products, such as pre-filled syringes, may be tested as a filled unit. In this case, pre-filled syringes will use the endotoxin limit for the drug component. Pre-filled syringes use the endotoxin limits for the drug component because the combined drug-device endotoxin total should not exceed the endotoxin limits for the drug component. Additionally, the endotoxins contributed by the container (the device component) are eluted with the drug product during sample preparation. Thus, they are accounted for in the product’s total endotoxin limit during testing.
#2: If the combination product is two drugs to be administered simultaneously
Sometimes combination products are two drugs administered simultaneously (such as intravenous (IV) or intramuscular (IM) injections). If medications are administered simultaneously, the endotoxins contained in the combination of both doses may not exceed the drug endotoxin limit of 5 endotoxin units (EU) per kilogram (kg) per hour (hr) for IV or IM injections. In the case of an Intrathecal (IT) injection, the drug limit is 0.2 EU/kg/hr.
#3: If the combination product is a kit containing multiple components that are administered as a single entity
Sometimes combination products are kits containing multiple components administered as a single entity (such as a lyophilized product, a diluent, and a syringe). In these cases, the endotoxin content of the kit may not exceed the drug endotoxin limit of 0.2 EU/kg/h for IT injections or 5 EU/kg/hr for IV or IM injections.
Overall, when justifying unique limits for your combination product, make sure to consider the set endotoxin limits for drugs, devices, and biologics. The endotoxin limits for medical devices are detailed below.
Calculating Endotoxin Limits for Medical Devices
The assigned endotoxin limit for medical devices is 20 EU per device. The exceptions to this rule are medical devices that come in contact with cerebrospinal fluid and devices that contact the anterior segment of the eye. Cerebrospinal fluid contacting devices have stringent limits of 2.15 EU per device. Devices that contact the anterior segment of the eye are further restricted and cannot exceed 0.2 EU per milliliter or 0.2 EU per device. Endotoxins for medical devices are not measured directly, but the device is soaked, and device extracts are tested. As a result, the endotoxin limit for a device’s extract is expressed in EU/mL. This limit is converted to EU per device using the extract’s total volume. The endotoxin limit for an extract is:
Endotoxin Limit = (K×N)/V
K = where endotoxin limit per device
N = number of devices represented in the pool
V = total volume of solvent used for device extraction
Although bacterial endotoxin tests may test primary packaging components such as vials or stoppers for endotoxins, these packaging components are not considered medical devices. Some medical devices are liquids (such as dialysis fluid) or solids (such as enzymes). The endotoxin limit is calculated for these products as if the device were a drug.
If your medical device or combination product has endotoxin limits that are too high, endotoxin controls and depyrogenation studies are available to reduce a product’s endotoxin concentration. For liquid or biologic components of combination products, depyrogenation by filtration is the best way to remove endotoxins.
Summary
Overall, the endotoxin limit for a medical device is 20 endotoxin units (EU) per device. The exceptions to this rule are medical devices that come in contact with cerebrospinal fluid and devices that contact the anterior segment of the eye. Cerebrospinal fluid contacting devices have stringent limits of 2.15 EU per device. Devices that touch the anterior part of the eye are further restricted and cannot exceed 0.2 EU per milliliter or 0.2 EU per device. Combination products, such as drug devices, drug-biologic devices, or drug-biologics may be assigned unique endotoxin limits based on data-driven justifications. For drug devices that are pre-filled syringes, two drugs administered simultaneously, or kits, the endotoxin limits are based on the drug component. Overall, when justifying unique limits for your combination product, make sure to consider the set endotoxin limits for drugs, devices, and biologics.
Ethide Labs is a contract testing organization that specializes in Bacterial Endotoxin Testing. Ethide Labs also offers Bioburden Testing, Environmental Monitoring, Sterilization Validations, Microbiology Testing, EO Residual Testing, Package Integrity Testing & Cytotoxicity Testing services for medical device companies and allied industries. Ethide is an ISO 13485 certified facility.
References
Food And Drug Administration. How To Determine If Your Product Is A Medical Device. December 2019.
United States Pharmacopeial Convention. <1085> Guidelines On The Endotoxins Test. Rockville, MD, USA. 2021. (USPC <1085>).
