Bioblog: USP Class VI

What is USP CLASS VI?

The United States Pharmacopoeia (USP) is an independent, science-based public health organization. Its purpose is to establish standards for medications, food ingredients and healthcare technologies.

It generates biocompatibility protocols for plastic and polymeric materials to test the suitability of these materials intended for use in fabricating containers and accessories thereto, for use in parenteral preparations, and for use in medical devices, implants, and other systems [1].

USP 88 is designed to determine biological response of animals to elastomerics, plastics, and other polymeric material with direct or indirect patient contact, or by the injection of specific extracts prepared from the material under test.

According to the number of tests approved and to the conditions of each one, the polymers are classified according 6 different plastic classes. Details of the assays and the classification can be seen at Figure 1 and Table 1 [2].

 USP 88 explains guidelines and tests for devices that are conformed by medical plastics, polymers, and elastomers, also known as biomaterials.

This biomaterials are subjected to in-vivo testing, classified in three main areas: acute systemic toxicity, intracutaneous reactivity and short-term implantation test (summarized at Figure 2 [3], [4]. The approval of this tests is considered a pharmaceutical approval for biomaterials, but many authorities see it only as a minimum requirement.

The in vivo tests (USP 88) are designed to determine the biological response of animals to elastomeric, plastics and other polymeric material with direct or indirect patient contact, or by the injection of specific extracts prepared from the material under test.

Systemic injection test

Designed to evaluate systemic responses to the extracts of materials under test following injection into mice.

It consists of injecting each of the five mice in a test group with a sample or the blank.

Intracutaneous test

Designed to evaluate local responses to the extracts of materials under test following intracutaneous injection into rabbits.

Implantation test

Designed for the evaluation of plastic materials and other polymeric materials in direct contact with living tissue. The test specimens are placed into needles as the delivery system for implantation.

Which is the difference between USP 88 and USP 87?

USP 88 is conducted when the material tested passes USP 87.

USP 87 describes test methods (see Figure 3) to estimate the biocompatibility of plastic medical materials while conducting in-vitro testing. It is designed to determine the biological reactivity of mammalian cell cultures following contact with elastomeric plastics and other polymeric materials with direct or indirect patient contact or of specific extracts prepared from the materials under test [5]. It is used as screening prior to conducting in-vivo testing.

Agar diffusion

The agar layer acts as a cushion to protect the cells from mechanical damage while allowing the diffusion of leachable chemicals from the polymeric specimens. Extracts of materials that are to be tested are applied to a piece of filter paper.

Direct contact test

This test is designed for materials in a variety of shapes. The procedure allows for simultaneous extraction and testing of leachable chemicals from the specimen with a serum-supplemented medium. The procedure is not appropriate for very low- or high-density materials that could cause mechanical damage to the cells.

Elution test

The procedure allows for extraction of the specimens at physiological or non-physiological temperatures for varying time intervals. It is appropriate for high-density materials and for dose-response evaluations. It is appropriate for high-density materials and for dose-response evaluations.

Are USP 87 and USP 88 the unique procedures for determining biocompatibility?

For a more restrictive classification, there are materials that require the ISO-10993 testing [6], that includes assays that can be seen in the Figure 4.

Although some tests overlap, the minimum requirements for testing are usually different. One of the differences is that ISO 10993 is more strict than the USP 88 because is conformed by more assays [4]. It is also possible to do part of the tests of the ISO 10993 in function of what is needed for the product qualification.

USP standards for systemic injection and intracutaneous test are nearly identical to ISO 10993 standards for acute systemic toxicity and irritation/ intracutaneous reactivity, respectively. The implantation test also has much common with the standards in part 6 of ISO 10993 [7].

Which biocompatibility testing is required?

It depends to a large extent on the application and therefore also on the application period of the finished product. ISO 10993 is designed for medical products that remain permanently or for a very long time in the human body, so for shorter applications, a USP Class VI or even a lower USP Class certification is often sufficient.

At Venair, all our tubing has a Validation Guide upon request, as can be seen in Table 3.

Table 3. Compliance and biocompatibility before gamma dose.

References

[1]       “USP Class VI | Foster Corporation.” [Online]. Available: https://www.fostercomp.com/stewardship/usp-class-vi/. [Accessed: 24-Feb-2021].

[2]       C. D. Negri, “Designación de la clase USP de plásticos y otros polímeros - Eurofins.” [Online]. Available: https://cdnmedia.eurofins.com/spain/media/1039/md-15-esp_-_usp_plasticos_bpt_rev_2.pdf. [Accessed: 24-Feb-2021].

[3]       USP, “USP88 Biological reactivity.” [Online]. Available: https://www.drugfuture.com/Pharmacopoeia/usp35/PDF/0094-0098 %5B88%5D Biological Reactivity Tests, In Vivo.pdf. [Accessed: 24-Feb-2021].

[4]       “Biocompatibility - A benchmark for USP Class VI - Reichelt Chemietechnik Magazin.” [Online]. Available: https://www.rct-online.de/magazin/biokompatibilitaet/. [Accessed: 05-Mar-2021].

[5]       The United States Pharmacopeia, “USP 87 Biological Reactivity test in vitro,” vol. 87, no. 36, p. 1832, 2013.

[6]       “Biocompatibility Planning Tool (BioPT) - Pacific BioLabs.” [Online]. Available: https://pacificbiolabs.com/biocompatibility-planning. [Accessed: 24-Feb-2021].

[7]       Biometrics, “Biocompatibility Guide,” p. 11, 2011.