When it comes to medical device testing, there never seems to be a shortage of misconceptions related to the biocompatibility of medical device materials.
An example of this is a comment I recently heard from a client: “My materials are all Class VI, so I don’t think I’m worried about biocompatibility.” This client is not alone. In fact many medical device manufacturers and suppliers struggle with this one. “Class VI” is a common shortcut designation for medical-grade safety. But what does it mean?
What is USP Class testing?
“Class VI” means USP Plastic Class VI, one of six designations for plastics from General Chapter of the United States Pharmacopeia and National Formulary (USP-NF). In this chapter, a set of tests for determining basic safety are laid out, along with guidelines for how to test and how to certify a material to USP Plastic Class I-VI. The table below shows what is needed for each class:
USP Classification of Plastics (USP Biological Reactivity Tests, In Vivo)
|Systemic injection test – injection in test model 1||Sodium chloride (intravenous)||X||X||X||X||X||X|
|Alcohol saline (intravenous)||X||X||X||X||X|
|Polyethylene glycol (intraperitoneal)||X||X||X|
|Vegetable oil (intraperitoneal)||X||X||X||X|
|Intracutaneous test – injection in test model 2||Sodium chloride (intravenous)||X||X||X||X||X||X|
|Alcohol saline (intravenous)||X||X||X||X||X|
|Polyethylene glycol (intraperitoneal)||X||X|
|Vegetable oil (intraperitoneal)||X||X||X|
|Implantation test – strips implanted in test model 2||None||X||X|
The three tests are
1) Systemic injection (also called acute systemic toxicity). The test article is extracted in up to four vehicles (saline, vegetable oil, alcohol saline, and polyethylene glycol) and injected intravenously or intraperitoneally, according to the vehicle type, into test model 1. Test model 1 is observed for three days for signs of toxicity or death. After the three days, the extracts are rated as passing or failing depending on whether any test models died or showed significant reaction to the extracts.
2) Intracutaneous reactivity. The test article is extracted in the same four vehicles and injected intracutaneously into five sites on each of two test models. The test models are scored at 24, 48, and 72 hours and an overall score calculated. The test and control sites are compared to determine whether a significant reaction occurred.
3) Muscle implantation. The test article is implanted in the muscle tissue of two test models. After five or seven days, the implantation sites are scored macroscopically and compared to controls to determine whether a significant reaction occurred.
What do these tests tell us? Systemic injection gauges general toxicity of the extract—whether it will cause general malaise, weight loss, or other whole-body problems. Intracutaneous reactivity determines whether the extract is a local irritant. And muscle implantation evaluates whether the test article itself will cause a reaction at the cellular level.
What needs USP Class testing?
USP Class testing was originally intended only for polymers (mainly containers for injections). Technically, the classification does not apply to containers for oral or topical products, non-polymers, or elastomers—though chapter does include instructions for the latter: they are to be tested in the systemic and intracutaneous tests using saline and sesame oil only. However, we have had requests for USP Class testing on various materials, including filters, elastomers, and multicomponent devices.
The different Class designations are intended to mimic the end use of the material: “These tests are directly related to the intended end-use of the plastic articles. The choice of extractants is representative of the vehicles in preparations with which the plastics are likely to be in contact. “ (USP ) For example, only Classes IV and VI include the implantation test. This can arguably be considered the most stringent test, and is appropriate for materials that will become actual implantables. If your device will only ever be in contact with skin, you may not want to worry about whether your raw materials have been tested to Class IV or VI; but if your device is an implant, USP Class IV or VI materials are a prudent choice.
What does USP Class testing mean for your product?
While USP notes that these tests can be used for medical devices, regulatory agencies of the world generally will not accept a USP certificate in lieu of ISO 10993 testing. USP Class testing is most commonly used to designate a raw material as safe for use in manufacturing medical devices.
Certification for each of these classes is available from CROs (and MROs). By far the most common is Class VI. It is the most comprehensive and stringent, encompassing implantation plus extract tests that include not only the standard polar and nonpolar extracts required in ISO 10993-12 for finished devices, but two additional extracts to mimic possible drug carriers. Class VI is now the gold standard for medical-grade raw materials of all types. However, Classes I-V still have extensive value. All Class I-V certifications have been tested to USP-approved standards and methods and have been proven to be safe.