Classification of Plastics
Plastics and other polymers intended for use in medical devices, implants or other systems associated with a medical process, must be shown to be suitable for use in the intended applications. USP Biological Reactivity Tests, in Vivo offers guidance to the testing required to meet the individual classification sought. Through exposure to different extract vehicles at different temperatures, the response of the material defines the level of classification and is directly related to the intended use of the material.
The test methods designated for use in the classification of plastics, elastomers, or other polymers are Systemic Injection, Intracutaneous Injection, and Implantation.
Biocompatibility; ISO 10993, USP
Biocompatibility is the process of evaluating materials used in the manufacture of medical devices. It consists of a number of tests designed to provide assurance that the final product, when used as indicated, will be safe. When a material is being considered for use in a final product, the appropriateness of its use should be assessed and documentation should be made of the evaluation.
While some materials have been tested, other materials and chemical components have not. The manufacturer of a medical device is obliged to evaluate the product for possible adverse responses before release into the marketplace is allowed.
The type of testing needed for any given material/device is determined by the intended patient contact and the duration of that contact. The ISO series of guidance documents for biocompatibility (ISO 10993), and the United States Pharmacopoeia , offer the direction needed to determine which test methods may be most appropriate.
Cytotoxicity; ISO 10993-5, USP
Definition: the degree to which an agent/material possesses a specific destructive action on certain cells.
The characteristics of the sample are used to determine the method to be used – extract, direct contact, indirect contact – when conducting the cytotoxicity test. The sample is exposed to mammalian cell cultures (L929 cells) by extract, direct or indirect contact. After the appropriate incubation time for the method used, the cytotoxic effect is evaluated.
Agar diffusion: designed for polymeric materials. The thin agar layer protects the cells from damage while allowing any leachable chemicals to diffuse to the cell culture.
Direct Contact: allows for the simultaneous extraction and testing of leachable chemicals, not appropriate for very low or high density materials that could cause mechanical damage to the cells.
MEM elution: designed for polymeric materials, allows for extraction at physiological or non-physiological temperatures, appropriate for high density materials and for dose response evaluations.
USP – specifies duplicate testing
ISO – specifies triplicate testing
Sensitization; ISO 10993-10, USP
This process explores the potential of a material or product to cause a sensitizing effect or allergenic reaction in a patient over an extended period of exposure. Two methods are followed at Geneva Labs: the Guinea Pig Maximization Test (GPMT) and the Closed Patch Test.
GPMT – The maximization test is the most sensitive. Extracts using 0.9% saline and cottonseed oil are prepared from the product. The test is performed in a series of three stages extending over a period of 4 weeks.
Closed Patch Test, a.k.a. Standard Buehler Test – This test is used primarily for products / materials that will have direct skin contact. It is performed in a series of phases over a period of 5 weeks.
Irritation / Intracutaneous Reactivity; ISO 10993-10, USP
Irritation – determines the likelihood of a material, device, or their extract to cause irritation. Sites chosen for the test exposure should be the most appropriate for the indicated use (skin, eye, mucosal membrane) of the material or device.
Intracutaneous injection – evaluates tissue reaction to extracts made from the device, used when the irritation tests are inappropriate for the use of the device, i.e.; devices having blood or compromised tissue contact.
Systemic Toxicity; ISO 10993-11, USP
Definition: toxicity that is not limited to adverse effects at the site of contact between the body and a device.
An extract of the material or product item is prepared following either ISO guidance or USP standards. ISO 10993 requires utilizing extract vehicles that are polar (0.9% sodium chloride) and non-polar (vegetable oil). In addition to 0.9% sodium chloride and vegetable oil, USP indicates that extracts be prepared with polyethylene glycol and alcohol in sodium chloride solution.
Acute systemic toxicity; indicated for product items with limited (<24 hours) patient exposure
Ten subjects (5 test and 5 control) each receive an injection of the indicated extract and control vehicle. The test and control subjects are monitored for any systemic reaction; weights are checked and recorded daily.
Subacute systemic toxicity; indicated for product items with prolonged (24 hours to 30 days) patient exposure
This test is designed to determine systemic effects occurring after multiple exposures. 20 subjects (10 test and 10 control) each receive an injection of the indicated extract and control vehicle at daily intervals. Daily health observations of the test subjects and controls, with weekly monitoring of weights, are performed. Gross necropsy, with weights of specified organs, is analyzed.
Subchronic and chronic systemic toxicity test methods are followed for materials that do not have a history of testing, either in the use for products in the intended application, or for permanent patient exposure. If either of these test methods are indicated for your product, Geneva Labs will work with an outsource facility to provide you with the needed information.
Genotoxicity; ISO 10993-3
This testing evaluates the possibility that a material may cause a toxic modification or alteration of the structure or function of genetic material.
Genotoxic chemicals are those which are capable of causing damage to DNA. Such damage can potentially lead to the formation of a malignant tumor, but DNA damage does not lead inevitably to the creation of cancerous cells.
The most common test procedures are the Ames Test and the Mouse Lymphoma Assay. A positive response in any of the in vitro tests requires additional in vivo assays or a presumption that the material is mutagenic.
Implantation; ISO 10993-6, USP
The intent of the Implantation Test is to assess the response a test article may have on the tissue of a test subject. The nature of the test article will determine the means of implant, surgical vs. needle. The test article and control are implanted into the paravertebral muscle of three test subjects. The implanted material remains in place for the indicated time based on intended patient exposure. The implant test is followed by a histopathological evaluation by a board certified veterinary pathologist.
The required time of exposure to the test subject is based on the intended duration of patient contact. The time frames may range from 7 days (limited exposure; <24 hours) to 52 weeks (permanent exposure).
Hemocompatibility; ISO 10993-4
Testing for hemocompatibility measures the level of interaction between the material(s) and the blood. Interactions with artificial materials begin after the initial contact with the blood. Adsorption of plasma proteins with the device surface initiates foreign-surface thrombosis.
Initially, for devices externally communicating with direct or indirect blood contact, the following testing should be considered: hemolysis, coagulation, thrombosis and immunology (complement activation).