Elastomeric closures for containers used in the types of preparations defined in the general test chapter Injections 1 are made of materials obtained by vulcanization (cross-linking) polymerization, polyaddition, or polycondensation of macromolecular organic substances (elastomers). Closure formulations contain natural or synthetic elastomers and inorganic and organic additives to aid or control vulcanization, impart physical and chemical properties or color, or stabilize the closure formulation.

This chapter applies to closures used for long-term storage of preparations defined in the general test chapter Injections 1. Such closures are typically used as part of a vial, bottle, or pre-fill syringe package system.

This chapter applies to closures formulated with natural or synthetic elastomeric substances. This chapter does not apply to closures made from silicone elastomer; however, it does apply to closures treated with silicone (e.g., Dimethicone, NF). When performing the tests in this chapter, it is not required that closures be treated with silicone, although there is no restriction prohibiting the use of siliconized closures.

This chapter also applies to closures coated with other lubricious materials (e.g., materials chemically or mechanically bonded to the closure) that are not intended to, and in fact do not provide, a barrier to the base elastomer. When performing the tests, closures with lubricious nonbarrier coatings are to be tested in their coated state.

The following comments relate solely to closures laminated or coated with materials intended to provide, or in fact function as, a barrier to the base elastomer (e.g., PTFE or lacquer coatings). It is not permissible to use a barrier material in an attempt to change a closure that does not meet compendial requirements to one that does conform. Therefore, all Physicochemical Tests apply to the base formula of such closures, as well as to the coated or laminated closure. To obtain Physicochemical Tests results, the tests are to be performed on uncoated or nonlaminated closures of the same elastomeric compound, as well as to the laminated or coated closure. The Functionality Tests apply to and are to be performed using the laminated or coated elastomeric closure. Biological Tests apply to the lamination or coating material, as well as to the base formula. Biological Tests may be performed on the laminated or coated closure, or they may be performed on the laminate/coating material and the uncoated or nonlaminated closures of the same elastomeric compound. In the latter case, the results are to be reported separately. The base formula used for physicochemical or biological tests intended to support the compendial compliance of a barrier-coated closure should be similar to the corresponding coated closure in configuration and size.

For all Elastomeric Closures for Injection 381 tests performed on any closure type, it is important to document the closure being tested, including a full description of the elastomer, and any lubrication, coating, laminations, or treatments applied.

This chapter states test limits for Type I and Type II elastomeric closures. Type I closures are typically used for aqueous preparations. Type II closures are typically intended for nonaqueous preparations and are those which, having properties optimized for special uses, may not meet all requirements listed for Type I closures because of physical configuration, material of construction, or both. If a closure fails to meet one or more of the Type I test requirements, but still meets the Type II requirements for the test(s), the closure is assigned a final classification of Type II. All elastomeric closures suitable for use with injectable preparations must comply with either Type I or Type II test limits. However, this specification is not intended to serve as the sole evaluation criteria for the selection of such closures.

It is appropriate to use this chapter when identifying elastomeric closures that might be acceptable for use with injectable preparations on the basis of their biological reactivity, their aqueous extract physicochemical properties, and their functionality.

The following closure evaluation requirements are beyond the scope of this chapter:

The manufacturer of the injectable product (the end user) must obtain from the closure supplier an assurance that the composition of the closure does not vary and that it is the same as that of the closure used during compatibility testing. When the supplier informs the end user of changes in the composition, compatibility testing must be repeated, totally or partly, depending on the nature of the changes. Closures must be properly stored, cleaned for removal of environmental contaminants and endotoxins, and, for aseptic processes, sterilized prior to use in packaging injectable products.

Elastomeric closures are translucent or opaque and have no characteristic color, the latter depending on the additives used. They are homogeneous and practically free from flash and adventitious materials (e.g., fibers, foreign particles, and waste rubber.)

Closures are made of a wide variety of elastomeric materials and optional polymeric coatings. For this reason, it is beyond the scope of this chapter to specify identification tests that encompass all possible closure presentations. However, it is the responsibility of the closure supplier and the injectable product manufacturer (the end user) to verify the closure elastomeric formulation and any coating or laminate materials used according to suitable identification tests. Examples of some of the analytical test methodologies that may be used include specific gravity, percentage of ash analysis, sulfur content determination, FTIR-ATR test, thin-layer chromatography of an extract, UV absorption spectrophotometry of an extract, or IR absorption spectrophotometry of a pyrolysate.

Elastomeric closures shall conform to biological, physicochemical, and functionality requirements both as they are shipped by the closure supplier to the injectable product manufacturer (the end user), and in their final ready-to-use state by the end user.

For those elastomeric closures processed by the supplier prior to distribution to the end user, the supplier shall demonstrate compendial conformance of closures exposed to such processing and/or sterilization steps. Similarly, if elastomeric closures received by the end user are subsequently processed or sterilized, the end user is responsible for demonstrating the continued conformance of closures to compendial requirements subsequent to such processing and/or sterilization conditions (i.e., in their ready-to-use state). This is especially important if closures shall be exposed to processes or conditions that may significantly impact the biological, physicochemical, or functionality characteristics of the closure (e.g., gamma irradiation).

For closures that are normally lubricated with silicone prior to use, it is permissible to perform physicochemical testing on nonlubricated closures, in order to avoid potential method interference and/or difficulties in interpreting test results. For closures supplied with other lubricious nonbarrier coatings, all tests are to be performed using the coated closure.

For closures coated or laminated with coatings intended to provide a barrier function (e.g., PTFE or lacquer coatings), physicochemical compendial tests apply to the uncoated base elastomer, as well as to the coated closure. In this case, suppliers are responsible for demonstrating physicochemical compendial compliance of the coated closure, as well as of the uncoated closure, processed or treated in a manner simulating conditions typically followed by the supplier for such coated closures prior to shipment to the end user. The uncoated closure subject to physicochemical tests should be similar to the corresponding coated closure in size and configuration. End users of coated closures are also responsible for demonstrating the continued physicochemical compendial conformance of the coated closure, processed or treated in a manner simulating conditions typically employed by the end user prior to use.

In all cases, it is appropriate to document all conditions of closure processing, pretreatment, sterilization, or lubrication when reporting test results.

Table 1 summarizes the testing requirements of closures, and the responsibilities of the supplier and the end user.

Two stages of testing are indicated. The first stage is the performance of an in vitro test procedure as described in general test chapter Biological Reactivity Tests, In Vitro 87. Materials that do not meet the requirements of the in vitro test are subjected to the second stage of testing, which is the performance of the in vivo tests, Systemic Injection Test and Intracutaneous Test, according to the procedures set forth in the general test chapter Biological Reactivity Tests, In Vivo 88. Materials that meet the requirements of the in vitro test are not required to undergo in vivo testing.

Type I and Type II closures must both conform to the requirements of either the in vitro or the in vivo biological reactivity tests. [Note—Also see the general information chapter The Biocompatibility of Material Used in Drug Containers, Medical Devices, and Implants 1031. ]