Starts off with Definitions:
A Blank is the extract fluid without test article in it, using a vessel identical to the vessels containing test article. The purpose of this is defined to eliminate effects stemming from the vessel, vehicles or process.
A certified reference material is accompanied with a certificate establishing traceability to specific values.
An exaggerated extraction is one that intentionally produces more chemical entities being released than would be under simulated use conditions.
Experimental controls are used to validate a procedure.
An extract is the liquid that is the product of extracting a test material or control.
Homogeneous is a uniform structure or composition and yields predictable responses.
A negative control yields a non reactive result. Now specifies blanks, vehicles, and reference materials.
A positive control yields a reactive result.
A reference material are well characterized materials that are used for calibration of apparatus or demonstrates the suitability of the test system to produce predictable responses both negative or positive.
A simulated use extraction uses conditions that mimic product use scenarios for the purpose of evaluating potential hazard to the end user under routine use.
A test material is that which is subdivided for testing.
A test sample is the extract of the subdivided sample or the subdivided sample itself.
Experimental controls shall be used in biological evaluations to validate a test procedure and to compare results between materials. Then can be negative and or positive controls.
Test Material: Should be the final product or representative samples from final product or materials processed in the same manner as the final product.
Test samples and reference materials shall be handled in a manner to prevent contamination. Manufacturing residues are considered integral to the final product. If the sample is sterile and the test requires sterility they should be handled aseptically. If sterilization is part of the use of the sample it should be sterilized by the manufacturer prior to testing. If cleaning is part of the sterilizing process then the cleaning procedure should be considered.
When cutting a sample, consideration should be given to exposing previously unexposed surfaces. Tools shall be clean to prevent contamination. When a whole device cannot be extracted, each individual material shall be proportionally represented in the test sample.
Coated products should be tested with the coating on the substrate. If connections, joints or seals are present in the final form they should be included in the test sample.
Differing materials in one device could have synergies or interactions and this should be considered in choosing the test sample. The test sample should be selected to maximize the exposure to those materials that have a potential for a biological reaction.
Preparation of extracts:
Containers to be inert and of a size to minimize headspace and precautions taken to prevent contamination. Borosilicate tubes with caps with inert liners such as PTFE.
A Blank is the extract fluid without test article in it, using a vessel identical to the vessels containing test article. The purpose of this is defined to eliminate effects stemming from the vessel, vehicles or process.
A certified reference material is accompanied with a certificate establishing traceability to specific values.
An exaggerated extraction is one that intentionally produces more chemical entities being released than would be under simulated use conditions.
Experimental controls are used to validate a procedure.
An extract is the liquid that is the product of extracting a test material or control.
Homogeneous is a uniform structure or composition and yields predictable responses.
A negative control yields a non reactive result. Now specifies blanks, vehicles, and reference materials.
A positive control yields a reactive result.
A reference material are well characterized materials that are used for calibration of apparatus or demonstrates the suitability of the test system to produce predictable responses both negative or positive.
A simulated use extraction uses conditions that mimic product use scenarios for the purpose of evaluating potential hazard to the end user under routine use.
A test material is that which is subdivided for testing.
A test sample is the extract of the subdivided sample or the subdivided sample itself.
Experimental controls shall be used in biological evaluations to validate a test procedure and to compare results between materials. Then can be negative and or positive controls.
Test Material: Should be the final product or representative samples from final product or materials processed in the same manner as the final product.
Test samples and reference materials shall be handled in a manner to prevent contamination. Manufacturing residues are considered integral to the final product. If the sample is sterile and the test requires sterility they should be handled aseptically. If sterilization is part of the use of the sample it should be sterilized by the manufacturer prior to testing. If cleaning is part of the sterilizing process then the cleaning procedure should be considered.
When cutting a sample, consideration should be given to exposing previously unexposed surfaces. Tools shall be clean to prevent contamination. When a whole device cannot be extracted, each individual material shall be proportionally represented in the test sample.
Coated products should be tested with the coating on the substrate. If connections, joints or seals are present in the final form they should be included in the test sample.
Differing materials in one device could have synergies or interactions and this should be considered in choosing the test sample. The test sample should be selected to maximize the exposure to those materials that have a potential for a biological reaction.
Preparation of extracts:
Containers to be inert and of a size to minimize headspace and precautions taken to prevent contamination. Borosilicate tubes with caps with inert liners such as PTFE.
Temperature and times:
37oC +/- 1oC for 24 hours +/- 2 hours
37oC +/- 1oC for 72 hours +/- 2 hours
50oC +/- 2oC for 72 hours +/- 2 hours
70oC +/- 2oC for 24 hours +/- 2 hours
121oC +/- 2oC for 1 hour +/- 0.1 hour
A statement that extract conditions above are intended to for risk estimation and that simulated clinical conditions need to be described and justified.
Standard surface area can be used to determine volume of extract. The area is both sides but excludes indeterminate surface irregularities. When surface area cannot be determined then a mass to volume ratio shall be used.
Extract ratios:
For a thickness less than half a millimeter a 6 cm2 per 1 ml with a 10% tolerance should be used. For a thickness of a half to 1 millimeter a 3 cm2 per 1 mL with a 10% tolerance should be used. Examples of materials for these ratios are tubing walls, sheets, film slabs and small molded items.
For a thickness greater than 1 mm a ratio of 1.25 cm2 per 1 with a 10% tolerance should be used on larger molded items. Irregularly shaped solid devices should use a 0.2 gram per 1 ml ratio for powders, pellets, foam and non-absorbent materials. Low density irregularly shaped products such as membranes should use a 0.1 gram per 1 ml ratio.
A description of how to extract absorbent materials is outlined. The absorbent capacity should be determined per gram and extracted at 0.1 gram per 1 ml beyond the absorptive capacity of the sample.
Materials should be cut to enhance submersion in the extract liquid. Sizes of 10 mm x 50 mm or 5 mm x 25 mm are suggested. But, laminates, coated substrates and elastomers should be extracted intact.
Both polar and nonpolar evaluations have to be performed.
Polar vehicle examples are water, physiologic saline, cell culture media without serum.
Non polar vehicle examples are vegetable oils such as cottonseed oil, sesame oil or oleum naturale
Alternate vehicle examples 5% ethanol in saline or water, polyethylene glycol 400 diluted to physiological osmotic pressure, dimethylsulfoxide and cell culture media with serum.
The extracts shall be performed under agitation. Extracts should be used within 24 hours, otherwise stability data is required.
The pH of the extract should not be adjusted.
The extract should not by standard practice be centrifuged, filtered or have suspended particulates removed. If these are performed then they should be reported.
Hazard Identification: Exaggerated extraction conditions should be considered. Solvents should not cause more than slight softening of a polymer. The solvent then needs to be removed prior to a bioassay. Manufacturing processes and residues should be considered.
Test samples that cure in situ shall represent the point of exposure and maximum curing time.
37oC +/- 1oC for 24 hours +/- 2 hours
37oC +/- 1oC for 72 hours +/- 2 hours
50oC +/- 2oC for 72 hours +/- 2 hours
70oC +/- 2oC for 24 hours +/- 2 hours
121oC +/- 2oC for 1 hour +/- 0.1 hour
A statement that extract conditions above are intended to for risk estimation and that simulated clinical conditions need to be described and justified.
Standard surface area can be used to determine volume of extract. The area is both sides but excludes indeterminate surface irregularities. When surface area cannot be determined then a mass to volume ratio shall be used.
Extract ratios:
For a thickness less than half a millimeter a 6 cm2 per 1 ml with a 10% tolerance should be used. For a thickness of a half to 1 millimeter a 3 cm2 per 1 mL with a 10% tolerance should be used. Examples of materials for these ratios are tubing walls, sheets, film slabs and small molded items.
For a thickness greater than 1 mm a ratio of 1.25 cm2 per 1 with a 10% tolerance should be used on larger molded items. Irregularly shaped solid devices should use a 0.2 gram per 1 ml ratio for powders, pellets, foam and non-absorbent materials. Low density irregularly shaped products such as membranes should use a 0.1 gram per 1 ml ratio.
A description of how to extract absorbent materials is outlined. The absorbent capacity should be determined per gram and extracted at 0.1 gram per 1 ml beyond the absorptive capacity of the sample.
Materials should be cut to enhance submersion in the extract liquid. Sizes of 10 mm x 50 mm or 5 mm x 25 mm are suggested. But, laminates, coated substrates and elastomers should be extracted intact.
Both polar and nonpolar evaluations have to be performed.
Polar vehicle examples are water, physiologic saline, cell culture media without serum.
Non polar vehicle examples are vegetable oils such as cottonseed oil, sesame oil or oleum naturale
Alternate vehicle examples 5% ethanol in saline or water, polyethylene glycol 400 diluted to physiological osmotic pressure, dimethylsulfoxide and cell culture media with serum.
The extracts shall be performed under agitation. Extracts should be used within 24 hours, otherwise stability data is required.
The pH of the extract should not be adjusted.
The extract should not by standard practice be centrifuged, filtered or have suspended particulates removed. If these are performed then they should be reported.
Hazard Identification: Exaggerated extraction conditions should be considered. Solvents should not cause more than slight softening of a polymer. The solvent then needs to be removed prior to a bioassay. Manufacturing processes and residues should be considered.
Test samples that cure in situ shall represent the point of exposure and maximum curing time.
