Pharmaceutical containers consist of a container and a closure. Plastic containers may consist of polymers that upon extraction do not alter the stability of the contained product or do not exhibit toxicity. The biocompatibility testing requirements for drug containers are stated under Injections 1 and Containers 661. As directed in these chapters, the plastic or other polymeric portions of these products are tested according to the procedures set forth under Biological Reactivity Tests, In Vitro 87. A plastic or other polymer that does not meet the requirements of Biological Reactivity Tests, In Vitro 87 is not a suitable material for a drug container. Materials that meet the in vitro requirements qualify as biocompatible materials without the need for further testing and may be used in the construction of a drug container. If a class designation (classes I–VI) for plastics or other polymers is desired, the appropriate testing procedures are performed as discussed in the section In Vivo Testing and Class Designation.

Elastomeric closures are closures that can be pierced by a syringe and maintain their integrity because of their elastic properties. Elastomeric materials may be composed of several chemical entities including fillers, pigments, plasticizers, stabilizers, accelerators, vulcanizing agents, and a natural or a synthetic polymer. These materials are used for manufacturing a product with the desired elastomeric physical properties, and they frequently demonstrate biological reactivity—cellular degeneration and malformation—when tested with in vitro cell cultures.

The biocompatibility of an elastomeric material is evaluated according to the two-stage testing protocol specified in the Biological Test Procedures under Elastomeric Closures for Injections 381. Unlike plastics or other polymers, an elastomeric material that does not meet the requirements of the first-stage (in vitro) testing may qualify as a biocompatible material by passing the second-stage (in vivo) testing, which consists of the Systemic Injection Test and the Intracutaneous Test described under Biological Reactivity Tests, In Vivo 88. No class or type distinction is made between elastomeric materials that meet the requirements of the first stage of testing and those that qualify as biocompatible materials by meeting the second-stage requirements. Elastomeric materials are not assigned class I–VI designation.

Evaluation of the biocompatibility of a whole medical product is often not realistic; thus, the use of representative portions or extracts of selected materials may be the only practical alternative for performing the assays. When representative portions of the materials or extracts of the materials under test are used, it is important to consider that raw materials may undergo chemical changes during the manufacturing, processing, and sterilization of a medical product. Although in vitro testing of raw materials can serve as an important screening procedure, a final evaluation of the biocompatibility of a medical product is performed with portions of the finished and sterilized product.

The preparation of extracts is performed according to the procedures set forth under Biological Reactivity Tests, In Vitro 87 and under Biological Reactivity Tests, In Vivo 88. Extractions may be performed at various temperatures (121, 70, 50, or 37), for various time intervals (1 hour, 24 hours, or 72 hours), and in different extraction media. The choice of extraction medium for the procedures under Biological Reactivity Tests, In Vitro 87 includes Sodium Chloride Injection (0.9% NaCl) or tissue culture medium with or without serum. When medium with serum is used, the extraction temperature cannot exceed 37. In vivo extraction medium includes the choices described under Biological Reactivity Tests, In Vivo 88 or the solvent to which the drug or medical device is exposed.

When choosing extraction conditions, select the temperature, solvent, and time variables that best mimic the “in use” conditions of the product. The performance of multiple tests at various conditions can be used to simulate variations in the “in use” conditions. Although careful selection of extraction conditions allows the simulation of manufacturing and processing conditions in the testing of raw materials, an evaluation of the biocompatibility of the product is performed with the finished and sterilized product.

The procedures described under Biological Reactivity Tests, In Vitro 87 include an Agar Diffusion Test (indirect contact test), a Direct Contact Test, and an Elution Test (extraction test). The sample is biocompatible if the cell cultures do not exhibit greater than a mild reactivity (Grade 2) to the material under test, as described under Biological Reactivity Tests, In Vitro 87. The Agar Diffusion Test is designed to evaluate the biocompatibility of elastomeric materials. The material is placed on the agar overlay of the cell monolayer, which cushions the cells from physical damage by the material and allows leachable chemicals or materials to diffuse from the elastomer and contact the cell monolayer. Extracts of elastomeric materials are tested by placing the filter paper saturated with an extract of the elastomer on the solidified surface of the agar. The Direct Contact Test is designed for elastomeric or plastic materials that will not physically damage cells with which they are in direct contact. Any leachable chemicals diffuse from the material into the serum-supplemented growth medium and directly contact the cell monolayer. The Elution Test is designed to evaluate the extracts of polymeric materials. The material may be applied directly to the tissue culture media.

The performance of either the Agar Diffusion Test or the Direct Contact Test in combination with the Elution Test is the preferred testing protocol. Extraction of the product or materials for the Agar Diffusion Test or the Elution Test is performed as described in the Preparation of Extracts.

According to the injection and implantation requirements specified in Table 1 under Biological Reactivity Tests, In Vivo 88, plastics and other polymers are assigned a class designation between class I and class VI. To obtain a plastic or other polymer class designation, extracts of the test material are produced according to the specified procedures in various media. To evaluate biocompatibility, the extracts are injected systemically and intracutaneously into mice and rabbits. According to the specified injection requirements, a plastic or other polymer may initially be graded as class I, II, III, or V. If in addition to injection testing, implantation testing using the material itself is performed, the plastic or other polymer may be classified as class IV or class VI.

Guidance on comparing a medical device or an implant to previously marketed products is provided by the Biocompatibility Decision Flowchart (see Figure 1.* )

Fig. 1. Biocompatibility flowchart

as adapted from the FDA's Blue Book Memorandum #G95-1. The purpose of the flowchart is to determine whether the available data from previously marketed devices are sufficient to ensure the safety of the device under consideration. As indicated by the flowchart, the material composition and the manufacturing techniques of a product are compared to those of the previously marketed products for the devices that come in direct contact with the body. In addition, the flowchart requires an evaluation of the toxicity of any unique material that has not been used in predicate devices. Responses to the questions posed in the flowchart lead to the conclusion that either the available data are sufficient or additional testing is required to ensure the safety of the product. When additional testing is required, guidance on the identification of appropriate testing procedures is provided in the section Test Selection Matrix.

To facilitate the identification of appropriate testing procedures, medical devices are divided and subdivided, as shown in Table 2,

Table 2. Classification and Examples of Medical Devices

according to the nature and extent of their contact with the body. Major categories of medical devices are surface devices, external communicating devices, and implant devices. These are then further subcategorized. Some examples of medical devices and implants belonging to each of the subcategories are also presented in Table 2.

The matrix provides guidance on the identification of appropriate biological testing procedures for the three categories of medical devices: tests for Surface Devices (see Table 3), tests for External Communicating Devices (see Table 4), and tests for Implant Devices (see Table 5). Each category of devices is subcategorized and then even further subdivided according to the duration of the contact between the device and the body. The duration of contact is defined as (A) limited (less than 24 hours); (B) prolonged (24 hours to 30 days); or (C) permanent (more than 30 days). The biological effects that are included in the matrix are cytotoxicity, sensitization, irritation or intracutaneous reactivity, systemic toxicity, subchronic toxicity, genotoxicity, implantation, hemocompatibility, chronic toxicity, carcinogenicity, reproductive or developmental toxicity, and biodegradation. The general chapters that contain toxicity testing procedure for these biological effects are indicated in Table 1.

Each subcategory in the matrix has an associated panel of testing requirements. Generally, the number of tests in the panel increases as the duration of the contact between the device and the body is extended and as the device or implant comes in closer contact with the circulatory system. Within several subcategories, the option of performing additional tests beyond those required should be considered on a case-by-case basis. Specific situations such as use of permanent implant devices or external communicating devices for pregnant women have to be taken into consideration in the manufacturer's decision to include reproductive or developmental testing. Guidance on the identification of possible additional testing procedures is provided in the matrix for each subcategory of medical devices.