The "USP 88 Biological reactivity tests, in vivo" standard, published by the American Pharmacopoeia (USP), describes test methods for determining biological reactivity.
The following tests are designed to determine the biological responses of animals to elastomeric, plastic, and other polymeric materials, either through direct or indirect patient contact or by injection of specific extracts prepared from the material being tested. It is important to have the specific surface area readily available for extraction. If the surface area of the sample cannot be determined, 0,1 g of elastomer or 0,2 g of plastic or other material is used per mL of extraction fluid. Furthermore, care must be taken to avoid contamination with microorganisms and other foreign substances when preparing materials to be injected or dripped.
This standard describes three tests:
The first two tests (systemic injection test and intracutaneous test) are used for elastomeric materials, particularly for elastomeric caps that demonstrate significant biological reactivity according to the “USP 87 Biological reactivity tests, in vitro” standard. These two tests are used for plastics and other polymers. In addition, a third test, the implantation test, is used to assess the suitability of these materials for use in the manufacture of caps and their accessories, in parenteral preparations and medical devices, implants, and other systems.
In a world where pharmaceuticals and medical devices are heavily regulated, ensuring product safety and efficacy is paramount. The United States Pharmacopoeia (USP) plays a critical role in establishing quality control standards, particularly for injectable products and related medical devices. USP 88 addresses a specific but vital concern: the potential for particulate contamination caused by components nesting during manufacturing and packaging. This section is important for manufacturers of glass, plastic, or other materials used in syringes, vials, and other administration systems, as it helps mitigate risks that could compromise patient safety.
The USP 88 standard focuses on the physical interactions between nested components, such as pre-fillable syringes or cartridges, and the particles they may generate. These particles, often microscopic, can migrate into injectable medications, posing serious health risks. This standard remains a cornerstone of compliance with FDA guidelines, aligning with international pharmacopoeias such as the European Pharmacopoeia and the Japanese Pharmacopoeia.
Particulate matter (PM) refers to mobile, undissolved particles unintentionally present in solutions, excluding gas bubbles. In injectable products, PM can come from various sources: raw materials, manufacturing equipment, environmental contaminants, or, most importantly, the interlocking process of medical devices. Interlocking occurs when multiple components, such as syringes or vials, are stacked on top of or interlocked for efficient storage and transport, a common practice to reduce costs and space.
During interpenetration, friction between surfaces can create particles such as glass fragments, rubber pieces, or plastic debris. If these become involved in the final drug product, they pose significant hazards. Studies and regulatory reports emphasize that even invisible particles (those smaller than 100 µm) can cause inflammation, embolism, tissue damage, or immunogenic reactions during injection.
The FDA has issued more than 100 recall notices in recent years for injectable drugs contaminated with particles, mostly based on packaging interactions. The USP 88 standard directly addresses this problem by providing standard tests to measure and limit nesting-derived particles, ensuring devices are essentially free of such contaminants.
The USP 88 standard includes procedures for evaluating particle formation resulting from nesting, complementing broader standards such as “USP 788 Particulate matter in injections” and “USP 787 Invisible particulate matter in therapeutic protein injections.” While the USP 788 standard focuses on the end-use drug product, the USP 88 standard targets device components in the supply chain.
The basic elements of the USP 88 standard are as follows:
This standard emphasizes that all injectable preparations must be designed to exclude particulate matter and that nesting tests must simulate real-world assembly conditions.
The USP 88 standard details two fundamental methods for evaluating nesting-derived particles and ensuring repeatability and accuracy:
Samples are prepared by inverting the units 20 times to suspend the particles, and at least 10 units are tested per batch. For large volume parenterals (at least 25 mL), the limits are scaled accordingly (e.g., a maximum of 600 particles at least 10 µm).
For many years, our organization, with its competent and experienced staff, has been understanding the needs of its clients, providing the advanced testing services they require, and assisting in the establishment, implementation, and improvement of management systems. Within this framework, we also provide testing services to businesses in accordance with the "USP 88 Biological reactivity tests, in vivo" standard.
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