Biocompatibility of Inks: Complete Guide to USP Class VI & ISO 10993

Lately, many friends have been asking whether there are biocompatible inks available. So, what exactly is biocompatibility? And what standards does ink need to meet to be considered biocompatible? Let's dive in and learn more.

1. What is Biocompatibility?

Biocompatibility is a core concept in the fields of biomaterials science and medical device evaluation. It refers to the ability of a material to perform with an appropriate host response in a specific physiological environment. This concept covers the two-way dynamic process of the material's effect on the biological system (such as toxicity, immune response) and the biological system's effect on the material (such as degradation, corrosion).

To put it simply and plainly:

• Biocompatibility = Whether a material (such as plastic, metal, or ink) will "cause trouble" when placed inside or in contact with the human body.

• If it doesn't cause trouble (no toxicity, no irritation, no allergy, no rejection), it is considered to have good biocompatibility.

2. What are the standards for ink biocompatibility and what are the differences?

In the medical device and biomaterials field, biocompatibility assessment is an indispensable step before a product can be marketed. Currently, the two most commonly used global biocompatibility standard systems are the United States Pharmacopeia (USP) and the ISO 10993 series of standards. Although both are used to evaluate the interaction between materials and biological systems, they have significant differences in their origins, scopes of application, evaluation methods, and regulatory positioning. This article will analyze the differences between these two major standards from multiple dimensions, providing a reference for medical device R&D and regulatory affairs professionals.

2.1. Standard Origins and Historical Background

2.1.1. Origin of USP Biocompatibility Standards

The biocompatibility standards of the United States Pharmacopeia (USP) originally stemmed from the need to evaluate pharmaceutical packaging materials. USP's biological tests for plastics were initially designed for pharmaceutical packaging materials, with core chapters including <87> (Biological Reactivity Tests, In Vitro) and <88> (Biological Reactivity Tests, In Vivo). These tests were first used to evaluate the compatibility of drug containers and packaging materials with drug formulations and were later extended to the medical device field.

USP classifies the biocompatibility of plastics into six classes (Class I to Class VI), with Class VI being the highest level, requiring the most comprehensive in vivo tests. This classification system originated from the biological assessment of the suitability of plastic materials for use in drug containers.

2.1.2. Origin of ISO 10993 Standards

ISO 10993 is a series of standards specifically developed by the International Organization for Standardization (ISO) for the biological evaluation of medical devices. The first part of this standard (ISO 10993-1) was first published in the 1990s, establishing the core concept of "biological evaluation within a risk management process."

Unlike USP, which originated from pharmaceutical packaging, ISO 10993 has focused on medical devices since its inception, covering a complete evaluation system from cytotoxicity to chronic systemic toxicity. Currently, ISO 10993 has been adopted by major medical device regulatory bodies worldwide, including the US FDA, the EU MDR, and China's NMPA.

2.2. Differences in Standard Positioning and Core Concepts

2.2.1. Standard Positioning: Material Standard vs. Medical Device Standard

The most fundamental difference lies in their standard positioning:

USP is essentially a pharmacopoeia, and its biocompatibility chapters exist as part of the material specification. When a material claims to "meet USP Class VI," it means the material itself has passed the specified biological tests.

ISO 10993, however, is a set of standards dedicated to medical devices. Its core, ISO 10993-1, emphasizes "evaluation and testing within a risk management process." ISO 10993 does not pre-assign a "class" to a material. Instead, it requires manufacturers to determine the biological endpoints needing assessment based on the specific nature of the medical device's contact with the body (type of contact, duration of contact).

2.2.2. Evaluation Concept: Fixed Classification vs. Risk-Based Approach

USP adopts a fixed classification system: After a material passes a specific combination of in vitro and in vivo tests, it is placed into a class from I to VI. Class VI requires passing three in vivo tests: acute systemic toxicity, intradermal irritation, and muscle implantation.

ISO 10993 adopts a risk-based approach: According to ISO 10993-1:2018, Annex A, manufacturers need to analyze the medical device's contact with the body (surface contact, external communicating, implant) and contact duration (≤24h, 24h-30d, >30d) to determine the biological endpoints that require assessment. This model is more flexible and scientifically sound—not all medical devices require the full battery of tests.

3. Differences in Test Methods

3.1. USP's Main Test Methods

USP's biocompatibility tests are mainly concentrated in the following chapters:

• USP <87> Biological Reactivity Tests, In Vitro: Primarily includes cytotoxicity tests, using elution methods (agar diffusion or filter diffusion) to assess the effect of a material on mammalian cells. The details of the cytotoxicity test method in USP <87> differ from those in ISO 10993-5.

• USP <88> Biological Reactivity Tests, In Vivo: Includes three types of tests—intradermal irritation test, acute systemic toxicity test, and muscle implantation test. A material that passes all three tests can be classified as Class VI.

• USP <661> Plastic Packaging Materials: Besides biological tests, it also includes physicochemical tests, such as analysis of extracts.

3.2. ISO 10993 Test Method System

ISO 10993 is a family of standards consisting of over 20 parts, covering a comprehensive range of biological evaluation methods:

3.3. Key Differences in Test Methods

Although there is some overlap in the biocompatibility tests covered by the two standards, differences exist in technical details:

• Cytotoxicity Tests: Both ISO 10993-5 and USP <87> include cytotoxicity testing, but the specific procedures and evaluation criteria differ. ISO 10993-5 includes various methods (e.g., MTT assay, agar diffusion, direct contact), while USP <87> offers a relatively limited selection of methods.

• Design of In Vivo Tests: The in vivo tests in USP <88> are relatively simplified and primarily target the material itself; in vivo tests in ISO 10993 (e.g., implantation tests) focus more on the final device and clinically relevant implantation sites.

• Requirements for Chemical Characterization: ISO 10993-18 emphasizes the role of chemical characterization in biological evaluation, reflecting the modern toxicological risk assessment philosophy—first analyze the material's composition, then conduct targeted testing based on the analysis results.

4. Regulatory Application and Market Access

4.1. FDA's Stance

Although the USP is the official pharmacopoeia of the United States, the FDA favors ISO 10993 in medical device review. The FDA updated its guidance "Use of International Standard ISO 10993-1" in 2020, clearly accepting ISO 10993 as the basis for the biological evaluation of medical devices. Regarding USP Class VI, the FDA does not consider it sufficient evidence for marketing a medical device. Even if a material passes USP Class VI testing, if used in a medical device, a full biological evaluation according to the requirements of ISO 10993-1 is still necessary.

4.2. Global Regulatory Acceptance

• European Union: The Medical Device Regulation (MDR) explicitly requires compliance with the ISO 10993 series.

• China: The GB/T 16886 series identically adopts ISO 10993.

• Japan: MHLW notifications require reference to ISO 10993.

• Other Countries: ISO 10993 is generally accepted as the standard for biological evaluation of medical devices.

USP standards have relatively limited direct citation in global medical device regulations and are more often used as reference data provided by material suppliers.

4.3. Market Value of USP Class VI

Although USP Class VI is not decisive in medical device regulation, it still holds significant value in industry practice:

• Initial Material Screening Tool: A supplier providing a USP Class VI certificate can serve as an initial reference for material selection.

• Reduces Development Risk: Using materials already certified to USP Class VI can reduce uncertainty at the material level.

• Industry Practice Acceptance: For some low-risk medical devices or combination products, USP Class VI data can support biocompatibility claims.

The USP and ISO 10993 biocompatibility standards represent two different evaluation concepts and regulatory positions. USP originated from pharmaceutical packaging evaluation, uses a fixed classification system (Class I-VI), and is suitable for standardized evaluation at the material level. ISO 10993 is specifically designed for medical devices, uses a risk-based endpoint evaluation model, and is the internationally accepted standard for biological evaluation of medical devices.

For medical device manufacturers, understanding the difference is crucial: USP Class VI can be used as a reference for material screening, but it cannot replace the finished product biological evaluation required by ISO 10993. In the context of global registration, following the risk management path of ISO 10993-1, combined with the specific test methods of the various parts of ISO 10993, is the correct strategy to ensure products meet international regulatory requirements.

As medical device materials continue to innovate and regulatory requirements evolve, ISO 10993 is also constantly updated (e.g., the publication of the 2025 version of ISO 10993-1), emphasizing the combination of scientific evidence and risk management. Manufacturers need to continuously monitor standard updates to ensure their biocompatibility evaluation strategies always comply with the latest regulatory requirements.