USP Class VI

Definition and Classification (USP-NF ⟨88⟩, “Biological Reactivity Tests, In Vivo”)

USP Class VI is a bioreactivity classification for plastics and elastomers according to the US pharmacopeia (USP, United States Pharmacopeia) in chapter USP-NF ⟨88⟩. What is meant is a material-related screening: it tests whether a material in defined in vivo tests (animal testing) does not cause unacceptable acute harmful reactions. As a result, the classification answers primarily the question of whether a material reacts biologically conspicuously in the short term when it is extracted or implanted under defined conditions.

For sealing technology, USP Class VI is frequently relevant when seals, diaphragms, or hoses are used in pharmaceutical or bioprocess-related media and material contact with product or cleaning media plays a role. The classification, however, does not replace an application-related safety assessment of a specific component, because contact duration, contact type, process chemistry, and operating conditions are not fully represented.

What Does “USP” Mean and What Does “Class VI” Stand For?

USP is a reference work that describes requirements and test methods for drugs, excipients, and certain materials. Class VI within USP ⟨88⟩ is a pass/fail test framework: a material is considered Class VI when it passes the three intended sub-tests without unacceptable acute reactions. In practice, Class VI is often cited as a quality feature, yet the statement is always tied to the specific test setup — particularly to extraction conditions and temperature.

Test Setup According to USP ⟨88⟩: Three Sub-Tests and What They Assess

USP ⟨88⟩ combines extract tests (assess leachable substances) with an implantation test (assesses tissue reaction to the material itself). The tests target acute systemic effects, local irritations, and local tissue reactions. As a result, a pragmatic picture of the short-term biological reactivity of a material arises, which is used in many procurement specifications for sealing materials.

Systemic Injection Test (Acute Systemic Toxicity)

Systemic means that the entire organism can react. In this test, material extracts are administered to identify acute toxic effects. For sealing materials, this is an important perspective, because not only the polymer itself is relevant but also additives or degradation products that can pass into the extraction medium under test conditions.

Intracutaneous Test (Local Irritation)

Intracutaneous (also intradermal) means injection into the skin. Extracts are used here too. What is assessed is the local irritation effect at the injection site. Translated into practice, the test checks whether leachable substances can trigger a short-term local inflammation or irritation reaction.

Implantation Test (Tissue Reaction to the Material)

In the implantation test, the material itself is placed into tissue, and the tissue reaction is then assessed. This part is important for the classification because it considers direct contact and not only extracts. For seals, this nevertheless does not provide a statement about wear particles in operation or about long-term effects, because the test is designed for defined conditions and observation periods.

Extraction and Extraction Temperature: Why “…-50°/…-121°” Is Part of the Specification

An extract arises when a material is leached in a liquid. In the process, extractable substances (e.g., additives, residual monomers, or low-molecular constituents) can pass into the medium. These extracts are then tested in the Systemic Injection Test and the Intracutaneous Test. Extraction is therefore central, because biological reactions are frequently triggered by dissolved substances and not by the pure polymer body.

The extraction temperature influences the quantity and type of dissolved substances. Higher temperatures often increase mobility and solubility and can thereby bring more substances into the extract. Therefore, the USP Class VI specification is in practice frequently linked to a temperature — for example as Class VI-50° or Class VI-121°. Without this specification, it remains unclear how strict the extraction was and how well the test matches the real process.

What Is an “Extract” and Why Is Extraction Performed?

Extracts are the test matrix when leachable substances are to be assessed. For seals, this is obvious, because formulations frequently contain plasticizers, fillers, cross-linkers, processing aids, or stabilizers that can pass into contact media under certain conditions. Extraction simulates this mechanism in a controlled way and makes it measurable in the test.

Why Extraction Temperature Co-Determines the Classification

Temperature is a critical test parameter, because it co-determines the loading of the material in the test. A classification at 121 °C can under some circumstances capture more potentially leachable substances than at 50 °C. For specification in sealing technology, what therefore matters is which temperature is stated and whether it matches the process — for example SIP/CIP steps (sterilization/cleaning) or real operating temperatures.

Significance for Sealing Technology and Distinctions (Hydraulics/Pneumatics, USP ⟨87⟩, ISO 10993, Specification)

In sealing technology, USP Class VI is required primarily where material contact with sensitive media has to be documented — for example in pharmaceutical processes or laboratory applications. In hydraulics and pneumatics, by contrast, the classification usually plays a subordinate role, because functional parameters such as compression set, extrusion resistance, friction, wear, and media resistance are in focus there. In pharmaceutical applications too, these functional properties remain decisive — yet they are not described by USP ⟨88⟩.

What USP Class VI Covers and What It Does Not

USP Class VI assesses short-term biological reactivity under defined test conditions. This covers an important but limited risk class. For seals, it is sensible to delimit the statement cleanly, so that requirements are not overinterpreted.

Covered (core statement):

• Acute biological reactivity via extracts (systemic and local)
• Local tissue reaction upon material implantation

Not covered (to be clarified separately):

• Long-term toxicity, sensitization, and many chronic effects
• Application-related product safety for a specific contact type and contact duration
• Sealing function and operational durability (pressure, temperature cycling, extrusion)
• Tribological effects such as abrasion and particle formation
• Chemical resistance in real media and cleaning chemicals

USP ⟨87⟩ vs. USP ⟨88⟩ and When ISO 10993 Makes Sense

USP ⟨87⟩ describes in vitro tests (cell tests), USP ⟨88⟩ in vivo tests (animal model) for biological reactivity. Which standard is sensible depends on what the material or component is used for and how long as well as in what kind of contact.

ISO 10993 is particularly relevant when an application- and contact-related biological evaluation is required, as is customary in the medical device environment. There, contact type (e.g., skin, blood, tissue) and contact duration are systematically included in the test strategy. In sealing technology, ISO 10993 can therefore be complementary or primary depending on the application case, while USP Class VI tends to be used as a material-related verification in the pharmaceutical environment.

How a Reliable Specification Is Formulated

A usable specification must be formulated so that it is verifiable and clearly defines the test framework. In practice, a compact but complete requirement helps that at least names: the referenced USP chapter, the Class VI classification, the extraction conditions (including temperature), and the verification via a test report.

As a formulation, the following is frequently required in spirit: compliance with USP-NF ⟨88⟩ Class VI including Systemic Injection, Intracutaneous, and Implantation Test, in each case with documented extraction conditions and temperature. Particularly with safety-critical applications, it can be sensible to supplement the specification with application-near tests and an expert evaluation.