á381ñELASTOMERIC CLOSURES FOR INJECTIONS
An elastomeric closure may be of synthetic or natural origin.It is generally a complex mixture of many ingredients.These include the basic polymer,fillers,accelerators,vulcanizing agents,and pigments.The properties of the elastomeric closure are dependent not only upon these ingredients,but also on the processing procedure,such as mixing,milling,dusting agents used,molding,and curing.
Factors such as cleansing procedures,contacting media,and conditions of storage may also affect the suitability of an elastomeric closure for a specific use.Evaluation of such factors should be made by appropriate additional specific tests to determine the suitability of an elastomeric closure for its intended use.Criteria for the selection of an elastomeric closure should also include a careful review of all the ingredients to assure that no known or suspected carcinogens,or other toxic substances are added.

Definition— An elastomeric closureis a packaging component that is,or may be,in direct contact with the drug.

Biological Test Procedures
Two stages of testing are indicated.The first stage is the performance of in vitro tests according to the procedures set forth in chapter á87ñ,Biological Reactivity Tests,In Vitro.Materials that meet the requirements of the in vitro tests are not required to undergo further testing.Materials that do not meet the requirements of the in vitro tests are subjected to the second stage of testing which is the performance of in vivo tests,i.e.,the Systemic Injection Testand Intracutaneous Test,according to the procedures set forth in chapterBiological Reactivity Tests,In Vivo á88ñ.

Physicochemical Test Procedures
The following tests are designed to determine pertinent physicochemical extraction characteristics of elastomeric closures.Since the tests are based on the extraction of the elastomer,it is essential that the designated amount of surface area of sample be available.In each case,the specified surface area is available for extraction at the designated temperature.The test methods are devised to detect the majority of expected variations.
Extraction Solvents—
A: Purified Water.
B: Drug product vehicle (where applicable).
C: Isopropyl alcohol.
Apparatus—
Autoclave— Use an autoclave capable of maintaining a temperature of 121±2,equipped with a thermometer,a pressure gauge,and a rack adequate to accommodate the test containers above the water level.
Oven— Use an oven,preferably a forced-draft model,that will maintain an operating temperature of 105±2.
Reflux Apparatus— Use a suitable reflux apparatus having a capacity of about 500mL.
Procedure—
Preparation of Sample— Place in a suitable extraction container a sufficient number of elastomeric closures to provide 100cm2of exposed surface area.Add 300mLof purified water to each container,cover with a suitable inverted beaker,and autoclave at 121±0.5for 30minutes.[NOTE—Adjust so that the temperature rises rapidly,preferably within 2to 5minutes.]Decant,using a stainless steel screen to hold the closures in the containers.Rinse with 100mLof purified water,gently swirl,and discard the rinsings.Repeat with a second 100-mLportion of purified water.Treat all blankcontainers in a similar manner.
Extracts (with use of Extraction Solvent A)— Place a properly prepared sample,having an exposed surface area of 100cm2,in a suitable container,and add 200mLof purified water.Cover with a suitable inverted beaker,and extract by heating in an autoclave at 121for 2hours,allowing adequate time for the liquid within the container to reach the extraction temperature.Allow the autoclave to cool rapidly,and cool to room temperature.Treat the blankcontainer in a similar manner.
Extracts (with use of Extraction Solvent Bor C)— Place a properly prepared sample,having an exposed surface area of 100cm2,in a suitable Reflux Apparatuscontaining 200mLof Extraction Solvent,and reflux for 30minutes.Treat the blankin a similar manner.
Turbidity— [NOTE—Use Extractsprepared with Extraction Solvent A,B,or C.]Agitate the container,and transfer a sufficient quantity of Extract,diluted with Extraction Solvent,if necessary,to a cell.Measure the turbidity in a suitable ratio turbidimeter (see Spectrophotometry and Light-Scattering á851ñ)against fixed reproducible standards.*The turbidity is the difference between the values obtained for the blank and the sample expressed in Nephelometric Turbidity Units (NTU),an arbitrary linear numerical scale expressing a haze range from absolute clarity to the zone of turbidity.
Reducing Agents— [NOTE—Use Extractsprepared with Extraction Solvent A.]Agitate the container,transfer 50mLof sampleextract to a suitable container,and titrate with 0.01Niodine VS,using 3mLof starch TSas the indicator.Treat the blankextract in a similar manner.The difference between the blankand the sampletitration is expressed in mLof 0.01Niodine.
Heavy Metals á231ñ— [NOTE—Use Extractsprepared with Extraction Solvent Aor B.]Transfer 20mLof the blankand the sampleextracts to separate color-comparison tubes.Transfer 2,6,and 10mLof Standard Lead Solutioninto separate color-comparison tubes,add 2mLof 1Nacetic acid to each tube,and adjust the volume to 25mLwith purified water.Add 10mLof freshly prepared hydrogen sulfide TSto each tube,mix,allow to stand for 5minutes,and view downward over a white surface.Determine the amount of heavy metals in the blankand in the sample.The heavy metals content is the difference between the blankand the sample.
pH Change— [NOTE—Use Extractsprepared with Extraction Solvent Aor B,adding to extractsobtained with Solvent Asufficient potassium chloride to provide a concentration of 0.1%.]Determine the pHof sampleextracts Aand Bpotentiometrically,performing blank determinations with blankextracts Aand B,and making any necessary corrections.The pHchange is the difference between the blankand the sample.
Total Extractables— [NOTE—Use Extractsprepared with Extraction Solvent A,B,or C.]Agitate the containers,and transfer 100-mLaliquots of the blankand the sampleto separate,tared evaporating dishes.Evaporate on a steam bath to dryness (Extractsprepared with Extraction Solvent C)or in an oven at 100,dry at 105for 1hour,cool in a desiccator,and weigh.Calculate the total extractables,in mg,by the formula:
2(WU-WB),
in which WUis the weight,in mg,of residue found in the sample extract aliquot;and WBis the weight,in mg,of residue found in the blank solution aliquot.
*  Asuitable standard is available from the manufacturer of the instrumentation.