Physiochemical Testing For Plastics Used In Injectables
How are plastic materials used in injectable products?
Many product-packaging systems use elastomeric materials. Elastomeric materials are plastics that can resume their original shape after experiencing tension or compression. Plastics are used in injectable products such as vials, bottles, prefilled syringes, flexible bags, and blow-fill-seal containers. Stoppers, cap liners, plungers, needle shields, tip caps, seal liners, and injection ports are all examples of injectable product components that utilize plastics. Any plastic with direct or transient contact with a pharmaceutical product or medical product formulation must pass certain regulatory requirements before being used as a device or packaging material. Polymer coatings also fall under the assessment criteria for elastomeric materials. Information on these polymers’ composition, manufacturing, and use can be found in USP 1381.
What are the regulatory tests needed for the elastomeric packaging used in injectables?
As mentioned earlier, elastomerics (a subset of plastics) in direct or indirect contact with a medical or pharmaceutical product must be assessed for their safety before use. Plastic materials can vary widely in their purity, meaning that intentionally or unintentionally added elements exist in manufactured plastics. Thus, baseline physiochemical and biological reactivity requirements for plastics used in injectable packaging-delivery systems must be met, in addition to functional requirements. Depending upon the elastomeric material, USP 1663 extractables testing may be needed. Overall, safety tests for elastomeric plastics fall under two primary categories: package integrity testing (e.g., functionality, seal quality, and leak testing) and cytotoxicity testing (e.g., biological reactivity and physiochemical testing).
What are cytotoxicity and cytotoxicity testing?
Cytotoxicity refers to molecules and compounds that are poisonous to living cells. Cytotoxins are often chemical but can also be from natural or biological sources. Cytotoxicity testing evaluates the biological reactivity of mammalian cells and tissues to contact with elastomeric plastics, excipients, and other materials that will come in direct or indirect patient contact during medical product use. Cytotoxicity is significant as it evaluates the biological effects of a sample’s leachable chemicals. The types of cytotoxicity testing to perform for your medical device or product depend upon the final product, the final product’s intended use, and the materials the final product is made of and packaged within. In-vitro USP 87 methods of cytotoxicity testing include direct contact, agar diffusion, and elution testing. In-vivo USP 88 methods of cytotoxicity testing include intracutaneous injection, systemic, and implantation testing. Most medical devices and products will only require in-vitro cytotoxicity testing.
In many ways, physiochemical testing is a cytotoxicity pre-test for plastic materials. Due to their physicochemical properties, certain plastics can be excluded from use prior to in-vitro cytotoxicity testing. Physiochemical tests for type I and type II elastomers are described below.
What types of plastic (elastomeric) materials are used in injectable products?
Plastics used for injectables come in two primary classifications: type I and type II elastomeric components. Type I elastomeric closures are preferred and meet specific appearance, absorbance, and reducing substance requirements. Type II elastomeric closures are suitable for special uses (e.g., repeated hypodermic needle piercings for syringe refiling). However, type II elastomers do not meet type I criteria. Instead, type II materials meet alternative criteria for their intended use.
What physiochemical tests do pharmaceutical-grade plastics undergo?
Sample Preparation: First, whole elastomeric components with a 100 ± 10 square centimeters surface area are placed into a wide-necked glass flask. If the surface area mentioned above is not possible with uncut elastomers, use uncut elastomeric components that will most closely approximate 100 ± 10 square centimeters. Next, the elastomeric samples are covered with water so that the volume of purified water is approximately two milliliters of water per centimeter squared of the elastomer’s surface area. Then weigh the water-covered elastomers in the flask. Next, cover the glass flask and heat the immersed elastomers in an autoclave so that a temperature of 121 ± 2°C is reached and held for thirty minutes. Then slowly cool the immersed elastomers to room temperature. Purified water is then added to bring the immersed elastomers to their original mass. This solution is shaken and used for the physiochemical tests described below. Purified water is used as a negative control for these tests.
#1: Appearance (Turbidity & Opalescence) Testing
Procedure: Turbidity can be determined visually or with a calibrated turbidimeter. Particle-free water must be used to create all solutions for appearance testing. A formazin stock solution is made by combining a hydrazine sulfate and a hexamethylenetetramine solution. The formazin stock solution must stand for two days before use. A formazin standard suspension is made by diluting fifteen milliliters of the formazin stock suspension with particle-free water until a volume of one liter is reached. Use the formazin stock suspension to prepare reference suspensions A-D. Details on reference suspension preparations can be found in Table 1 of USP 381. For testing, six identical test tubes made of transparent glass are filled with the solutions listed below:
- sample solution
- particle-free water
- reference suspension A
- reference suspension B
- reference suspension C
- reference suspension D
For evaluation, compare the solutions in diffuse daylight against a black background or a turbidimeter with a particle-free water blank.
Acceptance criteria: For type I elastomers, the sample solution should not be more opalescent than reference suspension B. Alternatively, the measured turbidity of the sample solution should not be more than reference suspension B (6 nephelometric turbidity units (NTU) or formazin turbidity units (FTU)). For type II elastomers, the sample solution should not be more opalescent than reference suspension C. Alternatively, the turbidity of the sample solution should not be more than reference suspension C (18 NTU/FTU). Note that reference suspension A and reference suspension D should be 3 NTU and 30 NTU, respectively.
#2: Color Testing
Procedure: Prepare a color standard by diluting 3.0 milliliters of matching fluid O with 97.0 milliliters of diluted hydrochloric acid (10 ± 0.5%). Next, fill two clear, identical tubes: one tube with sample solution and the second tube with the color standard. Compare the liquids in daylight against a white background.
Acceptance criteria: The sample solution must not be more intense (in color) than the color standard.
#3: Acidity/Alkalinity Testing
Procedure: Acidity and alkalinity are determined using bromothymol blue solution. The bromothymol blue solution is made with bromothymol blue powder, 0.02 M sodium hydroxide, alcohol, and purified water. Twenty milliliters of prepared sample solution and 0.1 milliliters of Bromothymol blue solution are combined for testing. If the solution is yellow, the test solution is titrated with 0.01 N sodium hydroxide until a blue endpoint is reached. If the solution is blue, the test solution is titrated with 0.01 N hydrochloric acid until a yellow endpoint is reached. If the solution is green, it is already at a pH of seven, and no titration is needed. Use purified water as a blank. If the purified water is not green, correct the sample test results by subtracting or adding the volume of titrant required for the purified water.
Acceptance criteria: Green indicates a neutral solution. Not more than 0.3 milliliters of 0.01 N sodium hydroxide produces a blue color, while not more than 0.8 milliliters of 0.01 N hydrochloric acid produces a yellow color. Generally, elastomers with high acidity or alkalinity should be avoided.
#4: Absorbance Testing
Procedure: Absorbance testing must be performed within five hours of preparing the elastomeric sample solution. Once the sample solution is made, it is passed through a 0.45-micron filter. The absorbance of the filtrate is evaluated in a spectrophotometer at wavelengths between 220 to 360 nanometers. Purified water is used as a blank.
Acceptance criteria: For type I elastomers, the acceptance criterium is not more than 0.2. Whereas for type II, it is not more than 4.0.
#5: Reducing Substances Testing
Procedure: Absorbance testing must be performed within four hours of preparing the elastomeric sample solution. First, one milliliter of diluted sulfuric acid is added to twenty milliliters of sample solution and twenty milliliters of 0.002 M potassium permanganate. This solution is then boiled and allowed to cool. Then a single gram of potassium iodide is added before titrating the solution with 0.01 M sodium thiosulfate. Finally, perform a titration using twenty milliliters of purified water and record the difference in the volume of the 0.01 M sodium thiosulfate solution required to reach a neutral pH. A quarter milliliter of starch solution TS is the indicator for both titrations.
Acceptance criteria: For type I elastomers, the difference between titration volumes must be not more than three milliliters of 0.01 molar sodium thiosulfate. For type II elastomers, the difference between titration volumes must not be more than seven milliliters of 0.01 molar sodium thiosulfate.
#6: Volatile Sulfides Testing
Procedure: Elastomeric samples are processed differently for this physiochemical test. Instead of using the sample stock solution, elastomeric components (cut or uncut) with a total surface area of 20 ± 2 centimeters square are placed in a 100-mL flask. Then fifty milliliters of a 20-gram/liter citric acid solution is added. A control solution is made by dissolving 0.154 milligrams of sodium sulfide in fifty milliliters of a 20-gram/liter citric acid solution. Place a piece of lead acetate paper over the mouth of the sample and control solutions, and weigh it down. Heat the flasks in an autoclave to 121°C and hold for thirty minutes. Cool to room temperature before evaluating for stains.
Acceptance criteria: A black stain on the paper produced by the test solution is not more intense than any stain produced by the control solution.
#7: Ammonium Testing
Procedure: Prepare an alkaline potassium tetraiodomercurate solution in water. Then mix one volume of this solution with an equal volume of a sodium hydroxide solution. Dilute five milliliters of elastomer sample solution with water to fourteen milliliters. Then add 0.3 milliliters of alkaline potassium tetraiodomercurate solution. Wait five minutes before assessing the sample solution with an ammonium standard solution.
Acceptance criteria: After five minutes, the yellow color in the test solution is no darker than the Ammonium standard solution.
Summary
Overall, many product-packaging systems use plastic materials known as elastomers. Elastomeric plastics are used in injectable products such as vials, bottles, prefilled syringes, flexible bags, and blow-fill-seal containers. Stoppers, cap liners, plungers, needle shields, tip caps, seal liners, and injection ports are all examples of injectable product components that utilize plastics. Any plastic with direct or transient contact with a pharmaceutical product or medical product formulation must pass certain regulatory requirements before being used as a device or packaging material. Safety tests for elastomeric plastics fall under two primary categories: package integrity testing (e.g., functionality, seal quality, and leak testing) and cytotoxicity testing (e.g., biological reactivity and physiochemical testing). This article describes seven physiochemical tests performed on elastomeric closures intended for needle piercing. These physiochemical tests are appearance, color, acidity-alkalinity, absorbance, reducing substances, volatile sulfides, and ammonium testing. All in all, ensure you choose a contract manufacturing organization that can support you with appropriate physiochemical testing for your unique parenteral or injectable product needs.
MycoScience is a contract manufacturing organization specializing in sterile syringe and vial filling. MycoScience also offers Preservative Efficacy Testing, Cytotoxicity Testing, Bioburden Testing, Cleaning Validations, Microbial Aerosol Challenge Testing, Accelerated Aging, Microbiology Testing, EO Residual Testing, Bacterial Endotoxin Testing, Package Integrity Testing, Sterilization Validations & Environmental Monitoring services medical devices and allied industries. MycoScience is an ISO 13485 certified facility.
References
Michael J. Akers. Sterile Drug Products Formulation, Packaging, Manufacture, and Quality. Drugs and the Pharmaceutical Sciences. Informa Healthcare. 2010.
United States Pharmacopeial Convention. <87> Biological Reactivity Tests, In Vitro. Rockville, MD, USA. 2021. (USPC <87>).
United States Pharmacopeial Convention. <88> Biological Reactivity Tests, In Vivo. Rockville, MD, USA. 2021. (USPC <88>).
United States Pharmacopeial Convention. <381> Elastomeric Components In Injectable
Pharmaceutical Product Packaging/Delivery Systems (USPC <381>).
United States Pharmacopeial Convention. <1207> Package Integrity Evaluation- Sterile Products. Rockville, MD, USA. 2021. (USPC <1207>).
