Functionality Testing vs. Physiochemical Testing For Medical-Grade Plastics
How are plastic materials used in injectable products?
Many product-packaging systems use medical-grade polymers and 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 functionality tests?
Functionality tests are a subset of package integrity tests. Package integrity testing assesses how well a package stays complete and undivided to keep wrapped objects protected and sterile. Package integrity and container-closure integrity are terms that are used interchangeably. These terms are the same, depending upon the definition of container-closure integrity. In the past, container–closure integrity referred to a package that had passed or could pass a microbiological challenge test. However, package integrity and container-closure integrity are synonymous under the USP 1207 definition of container-closure integrity. In the context of package integrity and package integrity testing, a product package is considered both the product packaging and the product. Package integrity testing includes leak testing, seal quality testing, and other assessments such as the functionality testing described below.
What are physiochemical tests?
In many ways, physiochemical testing is a cytotoxicity pre-test for plastic materials. Certain plastics can be excluded from medical use due to their physicochemical properties. Thus, physiochemical tests can save time and money on cytotoxicity testing. Physiochemical tests for type I and type II elastomers are described below.
What are the regulatory tests needed for medical-grade packaging used in injectables?
As mentioned earlier, medical-grade plastics in direct or indirect contact with a medical or pharmaceutical product must be assessed for safety before use. Plastic materials can vary widely in their purity, meaning that intentionally or unintentionally added elements exist in manufactured plastics. Thus, physiochemical and cytotoxicity requirements for medical-grade plastics 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., cytotoxicity and physiochemical testing).
What are the functionality tests pharmaceutical-grade plastic materials undergo?
Functionality tests are performed on plastic closures that a hypodermic needle will pierce. These tests ensure that the plastic closures can adequately seal product containers and provide effective product delivery through needles. Self-sealing functionality tests are needed only for multi-dose containers. The elastomeric plastic closures being tested should mimic those used in the final product-package system, including any terminal sterilization processes (e.g., steam, ethylene oxide) or surface modifications (e.g., siliconization, fluoropolymer coatings). Multiple 21-gauge hypodermic needles with a 12° long-bevel are used for the following functionality tests.
#1: Penetrability Testing
Procedure: Ten vials are filled with water and fit with elastomeric closures. Closures are then examined by measuring the force required to pierce the plastic closure with a sterile hypodermic needle repeatedly.
Acceptance criteria: Piercing force is no greater than ten Newtons for each closure.
#2: Fragmentation Testing
Procedure: Fragmentation testing for dry preparations involves first fitting twelve clean vials with plastic closures. For liquid preparations, twelve vials are filled with water within four milliliters of their capacity before being fit with closures. All vials stand for sixteen hours after preparation. Next, a hypodermic needle is used to inject one milliliter of water and remove one milliliter of air. The water injection and air removal process is completed four times for each elastomeric closure, piercing in a new location with each injection and using a new needle for each closure. Once all four piercings are complete, vial liquid is filtered through a membrane with a pore size of half a micron or less. Rubber fragments visible to the naked eye are then counted after filtration for each of the twelve vials.
Acceptance criteria: No more than five fragments with a diameter greater than 50 microns (μm) are visible. Particles can be examined microscopically for size verification.
#3: Self-Sealing Capacity Testing
Procedure: Ten vials are filled with water and fit with elastomeric closures. Closures are then pierced ten times each with a new hypodermic needle. Each needle piercing is at a different location on each plastic closure. Next, all ten vials are immersed in a 0.1% (1 gram/Liter) methylene blue solution for forty minutes. The external pressure is reduced by 27 kilo Pascals for the first ten minutes before being restored to atmospheric pressure for the remaining thirty minutes of immersion. Finally, the vials are removed, rinsed, and visually inspected for any trace of blue within the filled vials.
Acceptance criteria: All vials contain no trace of blue solution.
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: Reducing substances 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, stoppers, cap liners, plungers, needle shields, tip caps, seal liners, and injection ports are all examples of injectable product components that utilize medical-grade 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 medical-grade 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 three functionality tests and seven physiochemical tests performed on plastic closures. These functionality tests are penetrability, fragmentation, and self-sealing capacity testing. Self-sealing capacity testing is only needed for multi-dose containers. The physiochemical tests described 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 package integrity and toxicity testing for your unique implantable device or injectable 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>).
