It is the purpose of this chapter to provide standards for plastic materials and components used to package medical articles (pharmaceuticals, biologics, dietary supplements, and devices). Definitions that apply to this chapter are provided in the Preservation, Packaging, Storage, and Labeling section of the General Notices and Requirements. Standards and tests for the functional properties of containers and their components are provided in general chapter Containers—Performance Testing 671.

In addition to the standards provided herein, the ingredients added to the polymers, and those used in the fabrication of the containers, must conform to the requirements in the applicable sections of the Code of Federal Regulations, Title 21, Indirect Food Additives, or have been evaluated by the FDA and determined to be acceptable substances for the listed use.

Plastic articles are identified and characterized by IR spectroscopy and differential scanning calorimetry. Standards are provided in this chapter for the identification and characterization of the different types of plastic, and the test procedures are provided at the end of the chapter. The degree of testing is based on whether or not the container has direct contact with the drug product, and the risk is based on the route of administration.

Plastics are composed of a mixture of homologous polymers, having a range of molecular weights. Plastics may contain other substances such as residues from the polymerization process, plasticizers, stabilizers, antioxidants, pigments, and lubricants. These materials meet the requirements for food contact as provided in the Code of Federal Regulations, Title 21. Factors such as plastic composition, processing and cleaning procedures, surface treatment, contacting media, inks, adhesives, absorption and permeability of preservatives, and conditions of storage may also affect the suitability of a plastic for a specific use. Extraction tests are designed to characterize the extracted components and identify possible migrants. The degree or extent of testing for extractables of the component is dependent on the intended use and the degree of risk to adversely impact the efficacy of the compendial article (drug, biologic, dietary supplement, or device). Resin-specific extraction tests are provided in this chapter for polyethylene, polypropylene, polypropylene terephthalate, and polypropylene terephthalate G. Test all other plastics as directed under Physicochemical Tests in the section Test Methods. Conduct the Buffering Capacity test only when the containers are intended to hold a liquid product.

Plastic components used for products of high risk, such as those intended for inhalation, parenteral preparation, and ophthalmics are tested using the Biological Tests in the section Test Methods.

Plastic containers intended for packaging products prepared for parenteral use meet the requirements under Biological Tests and Physicochemical Tests in the section Test Methods. Standards are also provided for polyethylene containers used to package dry oral dosage forms that are not meant for constitution into solution.

Scope

Background

High-Density Polyethylene

Infrared Spectroscopy— Proceed as directed under Multiple Internal Reflectance in the section Test Methods. The corrected spectrum of the specimen exhibits major absorption bands only at the same wavelengths as the spectrum of USP High-Density Polyethylene RS.

Differential Scanning Calorimetry— Proceed as directed under Thermal Analysis in the section Test Methods. The thermogram of the specimen is similar to the thermogram of USP High-Density Polyethylene RS, similarly determined, and the temperature of the endotherm (melt) in the thermogram of the specimen does not differ from that of the USP Reference Standard by more than 6.0.

Heavy Metals and Nonvolatile Residue— Prepare extracts of specimens for these tests as directed for under Physicochemical Tests in the section Test Methods, except Sample Preparation that for each 20.0 mL of Extracting Medium the portion shall be 60 cm2, regardless of thickness.

Components Used in Contact with Oral Liquids— Proceed as directed under Buffering Capacity under Physicochemical Tests in the section Test Methods.

Low-Density Polyethylene

Infrared Spectroscopy— Proceed as directed under Multiple Internal Reflectance in the section Test Methods. The corrected spectrum of the specimen exhibits major absorption bands only at the same wavelengths as the spectrum of USP Low-Density Polyethylene RS.

Differential Scanning Calorimetry— Proceed as directed under Thermal Analysis in the section Test Methods. The thermogram of the specimen is similar to the thermogram of USP Low-Density Polyethylene RS, similarly determined, and the temperature of the endotherm (melt) in the thermogram of the specimen does not differ from that of the USP Reference Standard by more than 8.0.

Heavy Metals and Nonvolatile Residue— Prepare extracts of specimens for these tests as directed for Sample Preparation under Physicochemical Tests in the section Test Methods, except that for each 20.0 mL of Extracting Medium the portion shall be 60 cm2, regardless of thickness.

Components Used in Contact with Oral Liquids— Proceed as directed under Buffering Capacity under Physicochemical Tests in the section Test Methods.

Scope

Background

heavy metals— Containers meet the requirements for Heavy Metals under Physicochemical Tests in the section Test Methods.

nonvolatile residue— Proceed as directed for Nonvolatile Residue under Physicochemical Tests in the section Test Methods, except that the Blank shall be the same solvent used in each of the following test conditions: the difference between the amounts obtained from the Sample Preparation and the Blank does not exceed 10.0 mg when water maintained at a temperature of 70 is used as the Extracting Medium; does not exceed 60.0 mg when alcohol maintained at a temperature of 70 is used as the Extracting Medium; and does not exceed 225.0 mg when hexanes maintained at a temperature of 50 is used as the Extracting Medium. Containers meet these requirements for Nonvolatile Residue for all of the above extracting media. [note—Hexanes and alcohol are flammable. When evaporating these solvents, use a current of air with the water bath; when drying the residue, use an explosion-proof oven.]

Scope

Background

extracting media—

Periodic Acid Solution— Dissolve 125 mg of periodic acid in 10 mL of water.

Dilute Sulfuric Acid— To 50 mL of water add slowly and with constant stirring 50 mL of sulfuric acid, and allow to cool to room temperature.

Sodium Bisulfite Solution— Dissolve 0.1 g of sodium bisulfite in 10 mL of water. Use this solution within 7 days.

Disodium Chromotropate Solution— Dissolve 100 mg of disodium chromotropate in 100 mL of sulfuric acid. Protect this solution from light, and use within 7 days.

Standard Solution— Dissolve an accurately weighed quantity of ethylene glycol in water, and dilute quantitatively, and stepwise if necessary, to obtain a solution having a known concentration of about 1 µg per mL.

Test Solution— Use the Purified Water extract.

Procedure— Transfer 1.0 mL of the Standard Solution to a 10-mL volumetric flask. Transfer 1.0 mL of the Test Solution to a second 10-mL volumetric flask. Transfer 1.0 mL of the Purified Water Extracting Medium to a third 10-mL volumetric flask. To each of the three flasks, add 100 µL of Periodic Acid Solution, swirl to mix, and allow to stand for 60 minutes. Add 1.0 mL of Sodium Bisulfite Solution to each flask, and mix. Add 100 µL of Disodium Chromotropate Solution to each flask, and mix. [note—All solutions should be analyzed within 1 hour after addition of the Disodium Chromotropate Solution.] Cautiously add 6 mL of sulfuric acid to each flask, mix, and allow the solutions to cool to room temperature. [Caution–Dilution of sulfuric acid produces substantial heat and can cause the solution to boil. Perform this addition carefully. Sulfur dioxide gas will be evolved. Use of a fume hood is recommended.] Dilute each solution with Dilute Sulfuric Acid to volume, and mix. Concomitantly determine the absorbances of the solutions from the Standard Solution and the Test Solution in 1-cm cells at the wavelength of maximum absorbance at about 575 nm (see Spectrophotometry and Light-Scattering 851), using as the blank the solution from the Purified Water Extracting Medium: the absorbance of the solution from the Test Solution does not exceed that of the solution from the Standard Solution, corresponding to not more than 1 ppm of ethylene glycol.

Multiple Internal Reflectance

Apparatus— Use an IR spectrophotometer capable of correcting for the blank spectrum and equipped with a multiple internal reflectance accessory and a KRS-5 internal reflection plate.1 A KRS-5 crystal 2-mm thick having an angle of incidence of 45 provides a sufficient number of reflections.

Specimen Preparation— Cut two flat sections representative of the average wall thickness of the container, and trim them as necessary to obtain segments that are convenient for mounting in the multiple internal reflectance accessory. Taking care to avoid scratching the surfaces, wipe the specimens with dry paper or, if necessary, clean them with a soft cloth dampened with methanol, and permit them to dry. Securely mount the specimens on both sides of the KRS-5 internal reflection plate, ensuring adequate surface contact. Prior to mounting the specimens on the plate, they may be compressed to thin uniform films by exposing them to temperatures of about 177 under high pressures (15,000 psi or more).

General Procedure— Place the mounted specimen sections within the multiple internal reflectance accessory, and place the assembly in the specimen beam of the IR spectrophotometer. Adjust the specimen position and mirrors within the accessory to permit maximum light transmission of the unattenuated reference beam. (For a double-beam instrument, upon completing the adjustments in the accessory, attenuate the reference beam to permit full-scale deflection during the scanning of the specimen.) Determine the IR spectrum from 3500 to 600 cm–1 for polyethylene and polypropylene and from 4000 to 400 cm–1 for PET and PETG.

Thermal Analysis

General Procedure— Cut a section weighing about 12 mg, and place it in the test specimen pan. [note—Intimate contact between the pan and the thermocouple is essential for reproducible results.] Determine the thermogram under nitrogen, using the heating and cooling conditions as specified for the resin type and using equipment capable of performing the determinations as specified under Thermal Analysis 891.

For Polyethylene— Determine the thermogram under nitrogen at temperatures between 40 and 200 at a heating rate between 2 and 10 per minute followed by cooling at a rate between 2 and 10 per minute to 40.

For Polypropylene— Determine the thermogram under nitrogen at temperatures ranging from ambient to 30 above the melting point. Maintain the temperature for 10 minutes, then cool to 50 below the peak crystallization temperature at a rate of 10 to 20 per minute.

For Polyethylene Terephthalate— Heat the specimen from room temperature to 280 at a heating rate of about 20 per minute. Hold the specimen at 280 for 1 minute. Quickly cool the specimen to room temperature, and reheat it to 280 at a heating rate of about 5 per minute.

For Polyethylene Terephthalate G— Heat the specimen from room temperature to 120 at a heating rate of about 20 per minute. Hold the specimen at 120 for 1 minute. Quickly cool the specimen to room temperature, and reheat it to 120 at a heating rate of about 10 per minute.

Biological Tests

Physicochemical Tests

Testing Parameters—

Extracting Medium— Unless otherwise directed in a specific test below, use Purified Water (see monograph) as the Extracting Medium, maintained at a temperature of 70 during the extraction of the Sample Preparation.

Nonvolatile Residue— Transfer, in suitable portions, 50.0 mL of the Sample Preparation Extract to a suitable, tared crucible (preferably a fused-silica crucible that has been acid-cleaned), and evaporate the volatile matter on a steam bath. Similarly evaporate 50.0 mL of the Blank in a second crucible. [note—If an oily residue is expected, inspect the crucible repeatedly during the evaporation and drying period, and reduce the amount of heat if the oil tends to creep along the walls of the crucible.] Dry at 105 for 1 hour: the difference between the amounts obtained from the Sample Preparation Extract and the Blank does not exceed 15 mg.

Residue on Ignition 281— [note—It is not necessary to perform this test when the Nonvolatile Residue test result does not exceed 5 mg.] Proceed with the residues obtained from the Sample Preparation Extract and from the Blank in the test for Nonvolatile Residue above, using, if necessary, additional sulfuric acid but adding the same amount of sulfuric acid to each crucible: the difference between the amounts of residue on ignition obtained from the Sample Preparation Extract and the Blank does not exceed 5 mg.

Heavy Metals— Pipet 20 mL of the Sample Preparation Extract, filtered if necessary, into one of two matched 50-mL color-comparison tubes. Adjust with 1 N acetic acid or 6 N ammonium hydroxide to a pH between 3.0 and 4.0, using short-range pH paper as an external indicator, dilute with water to about 35 mL, and mix.

Buffering Capacity— Titrate the previously collected 20-mL portion of the Sample Preparation Extract potentiometrically to a pH of 7.0, using either 0.010 N hydrochloric acid or 0.010 N sodium hydroxide, as required. Treat a 20.0-mL portion of the Blank similarly: if the same titrant was required for both the Sample Preparation Extract and the Blank, the difference between the two volumes is not greater than 10.0 mL; and if acid was required for either the Sample Preparation Extract or the Blank and alkali for the other, the total of the two volumes required is not greater than 10.0 mL.