USP <671> Container Performance Testing provides standards for evaluating the functional properties of packaging systems used for solid oral dosage forms (SODFs) and liquid oral dosage forms (LODFs), though tests can be applied to packages intended for other dosage forms where appropriate. The critical performance metrics under test are water vapor transmission (permeation) and spectral transmission (light resistance), applicable if the container is intended to protect contents from light. The most current version was published by the USP Effective December 1, 2020 and multiple dose containers such as bottles and closure, single unit containers such as individual blisters or stick packs, and unit-dose containers such as blister cards with multiple cavities. Over the past 7 years, at least four new test procedures have been approved, previous methods have been altered, and specifications are purposefully vague – allowing flexibility for manufacturers and repackagers to define suitable containers for a given product. In some cases, test method titles and numbers have changed, even if the procedure has not, adding to the confusion. These factors make navigating the specific test requirements, methods, and results challenging.

Understanding the spirit of the test, the reason for performing it, and the numerous variables that can impact the validity of results and usefulness of the data are all critical to successful implementation of USP <671>. The CS Analytical Team has decades of experience in USP container qualification testing and can assist with determining and executing the most suitable test plan for your specific container system.

Spectral Transmission – often referred to as “light percent” testing, this test is required for those container or package systems that are intended to provide protection from light or offered as light resistance. Testing requires the use of a UV-Visible Spectrophotometer fitted with special device for measuring light transmission of plastic drug containers.

Summary of USP <671> Container Performance Testing Key Points

  • There are eight (8) different Permeation Methods that may be applicable based upon dosage form, package type, material of construction, and study goals.
  • The most current revision to the USP <671> General Chapter is effective as of December 1, 2020.
  • All methods referenced are applicable to manufacturers (i.e. Drug or Product Manufacturers).
  • The basis of the USP <671> Moisture Vapor Transmission Rate (MVTR) Test Methods reference the ASTM D7709 “Standard Test Methods for Measuring Water Vapor Transmission Rate (WVTR) of Pharmaceutical Bottles and Blisters”. Classification methods do not reference the ASTM.
  • USP <671> Makes direct reference to USP <659> and USP <1671> as these chapters provide support information for the test methods outlined.
  • Depending on specific method, results are reported as an MVTR for Methods 1, 2, 3, 4 or as “Meets/ Does Not Meet” specifications for certain classifications in Methods 5, 6, 7, 8.

Procedural highlights and applicability of each USP <671> Permeation Method are detailed below.

MVTR Tests

Method One

Method 1, also called barrier protection, is applicable to multiple unit solid oral dosage form (SODF) plastic container (bottles) and closures with or without induction seals. Test sample size equals 15 containers and closures. Typically, testing is performed according to anticipated conditions of manufacture: if an induction seal is intended as part of the package system, it will be applied, and closures are torqued to assigned USP value based upon closure inner diameters or according to the final assembly specification. However, other study configurations may be performed to evaluate conditions of storage and use, such as broached seals or variable torque conditions.

Desiccant used is anhydrous calcium chloride in granular form. Standard total test time is 35 days in storage at 40oC / 75% RH with standard 7 day weighing intervals at day 0, 7, 14, 21, 28, 35. MVTR Results are reported in average mg/day/container and must include the standard deviation of the 15 samples.

Method Two

This method is similar to Method 1 and also referred to as barrier protection, but is applicable to solid oral dosage form (SODF) single unit or unit-dose blister cards that are constructed of high barrier or ultra-high barrier materials. Sample size is 10 Test Units, with a test unit being defined as a minimum of 10 cavities. However, some test configurations benefit from additional cavities in a test unit, especially ultra-high barrier packaging such as foil-foil blisters, where up to 30 cavities may be included in a single test unit. Sorting out the actual required number of blister cards to be used is dependent on the total number of cavities per card and anticipated moisture transmission. As such, each configuration should be considered on an independent basis.

USP Reference Standard Desiccants (molecular sieves of different sizes to fit different cavities) are sealed into each cavity of a blister card. Standard total test time is 35 days in storage at 40oC / 75% RH with standard weighing times at day 0, 7, 14, 21, 28, 35, though both weighing intervals and total test times may be modified to improve test sensitivity, especially in the case of ultra-high barrier packaging. The time between the first two timepoints, typically day 0 to day 7, is defined as the equilibrium period. MVTR Results are reported in average mg/day/cavity and must include the standard deviation of the 10 samples (test units).

Method Three

This method is similar to Methods 1 and 2, but is applicable to solid oral dosage form (SODF) single unit or unit-dose blister cards that are constructed of low barrier materials, which quickly allow for desiccants to become saturated at test temperature and humidity conditions.  Sample size is 10 Test Units with a test unit being defined as a minimum of 10 cavities. Sorting out the actual required number of blister cards to be used is dependent on the total number of cavities per card and should be considered on an individual basis.

USP Reference Standard Desiccants (molecular sieves of different sizes to fit different cavities) are sealed into each cavity of a blister card. Total test time is 2 days (48 hours) in storage at 40oC / 75% RH with weigh times at day 0 and day 2. Longer test durations are likely to result in desiccant saturation, ultimately yielding meaningless results. Additional weighings within this shortened period are more likely to create variation than valuable data. MVTR Results are reported in average mg/day/cavity and must include the standard deviation of the 10 samples (test units).

Method Four

Method 4 is applicable to solid oral dosage form (SODF) single unit or unit-dose blister cards that are constructed of low barrier, high barrier or ultra-high barrier materials, but relies on measuring the rate of moisture egress from water filled samples, as opposed to ingress to desiccant filled samples in Methods 1-3. Sample size is 10 Test Units with a test unit being defined as a minimum of 10 cavities. However, some test configurations benefit from additional cavities in a test unit, especially ultra-high barrier packaging such as foil-foil blisters, where up to 30 cavities may be included in a single unit. Sorting out the actual required number of blister cards to be used is dependent on the total number of cavities per card.

In place of desiccant, water is used to fill the blister cavities prior to sealing. All weights must be taken with samples in a glove box that must maintain 25% RH. Standard total test time is 35 days in storage at 40oC / 25% RH with weigh times at day 0, 7, 14, 21, 28, 35, though both weighing intervals and total test times may be modified to improve test sensitivity, especially in the case of ultra-high barrier packaging. Because performance will not degrade the way desiccant becomes saturated, low-barrier containers can be properly measured over time assuming sufficient water is present in the cavity at test start. MVTR Results are reported in average mg/day/cavity and must include the standard deviation of the 10 samples (test units).

Classification Tests

Method Five

Method 5 is a required classification test for multiple unit solid oral dosage form (SODF) plastic packages; either those without an impervious (induction) seal, or those that will have an end-use and storage period with an open (broached) induction seal. Test sample size equals 17 total containers and closures with 10 sample defined as test samples, 2 defined as controls, and 5 containers used for volume determination. Closures must be torqued shut to the assigned USP value based upon closure inner diameters, though custom torque values can be applied to reflect actual manufacturing conditions.

Desiccant used is 4-8 mesh anhydrous calcium chloride. Total test time is 14 days in storage at 23°C / 75% RH with weighing timepoints at day 0 and day 14. Moisture vapor transmission results are calculated in mg/day/liter and based upon calculations, containers are reported as meeting or not meeting specifications for “tight” or “well-closed” classifications.

Method Six

Method 6 is a required classification test for multiple unit solid oral dosage form (SODF) plastic packages with an impervious seal, such as induction seal liners. The method may also be applied to evaluate permeation specifically through the bottle as opposed to the composite system. In place of an induction seal, other impervious seals may be utilized (glass plate and wax mixture) and when an induction seal is used, the closure can be removed to improve overall test precision. Test sample size equals 17 total containers and closures with 10 sample defined as test samples, 2 defined as controls and 5 containers used for volume determination.

Desiccant used is 4-8 mesh anhydrous calcium chloride. Total test time is 14 days in storage at 23°C / 75% RH with weighing timepoints at day 0 and day 14. Moisture vapor transmission results are calculated in mg/day/liter and based upon calculations, containers are reported as meeting or not meeting specifications for “tight” or “well-closed” classifications. Specifications to meet these standards are more stringent than those found in Method 5.

Method Seven

Method 7 is a classification test applicable to solid oral dosage form (SODF) single unit or unit dose containers, whether low barrier, high barrier, or ultra-high barrier. The actual number of cards to be used is dependent on the number of cavities per card, but also the materials of construction and anticipated moisture vapor transmission. However, the method requires not less than 4 packs (blister cards) and least a total of 10 units (in this case, a unit is a single cavity).

The desiccant used are typically molecular sieve in pellet form and sealed in each cavity of the blister card. A corresponding number of blister cards are sealed empty to act as control samples. Storage requirements are 23oC / 75% RH with weights taken every 24 hours or suitable intervals.  Moisture vapor transmission results are calculated in mg/day/cavity and based upon results, the blister card is a assigned a classification of A, B, C or D according to the package’s ability to meet specifications for each class.

Method Eight 

Method 8 is a classification test applicable to multiple unit liquid oral dosage form (LODF) containers and operates on the principle of moisture egress from water-filled packages as opposed to moisture ingress in desiccant filled packages. Test sample size equals 12 total containers and closures with 10 sample defined as test samples and 2 defined as control samples that will be filled with glass beads. Closures must be torqued shut to the assigned USP value based upon closure diameters, though custom torque values can be applied to reflect actual manufacturing conditions.

Water is used to fill the containers. Total test time is 14 days in storage at 25oC / 40% RH with weighing timepoints at day 0 and day 14. Moisture vapor transmission results are expressed as a percent of weight loss. Based upon results, containers are classified as “tight” if the assigned specification is met.