Container closure systems testing

Testing of the drug product in the same container-closure system as that in which the drug product is marketed ... 

Microbiological aspects will need to be discussed, but the amount of information will depend on the type of product. For nonsterile products there will need to be a description of the microbiological attributes of the product and, if appropriate, a rationale for not performing microbial limit tests. For preserved products the selection of the antimicrobial preservatives will need to be discussed and the effectiveness of the selected system demonstrated. For sterile products there will need to be appropriate process validation data and information on the integrity of the container-closure system. 

Primary container-closure system-related data will need to cover storage, transportation, and use. The choice of materials of construction, their description, and the ability of the container-closure system to protect from moisture and/or light will need to be considered. The compatibility of the container-closure and its contents will need to consider sorption, leaching, and safety. The performance of the container-closure system will also need to be considered in terms of dose delivery from any associated device that is to be supplied as part of the product. Container-closure components will require adequate specifications covering description, identification, critical dimensional tolerances, and test methodology (including pharma-copeial and noncompendial methods). More data are likely to be required for liquid or semi-liquid products than for solid dosage forms. In the latter, product stability data and container-closure system specifications may suffice. 

The integrity of the container-closure system as a mierobial barrier should be assessed using a sensitive and adequately validated test. 

Areas and surfaces in a controlled environment that are in direct contact with products, containers, or closures and the microbiological status of which can result in potential microbial contamination of the product/container/ closure system should be identified. Once identified, these areas should be tested more frequently than non-product-contact areas or surfaces. Elements that are likely critical product contact points may include compressed air or nitrogen, room air, manufacturing equipment, tools, work surfaces, storage containers, conveyors, gloved hands of personnel, and water. 

Process simulation units shall not be required to be inverted at some point during the incubation period. All hlled units shall be sufficiently manipulated to assure the contact of all sterile surfaces by the growth media prior to incubation. Momentary inversion of test units shall be surfaces of the container/closure system. Reconciliation requirements of process simulation units shall be equivalent to the requirement for production. The target will be 100% reconciliation/accountability of all hlled units. Any excursion must be investigated and documented however, a variance is not an automatic invalidation of a process simulation test. Process simulation testing shall simulate normal production as closely as possible because its purpose is to assess the potential of contamination in units representative of normal production. 

Suitability refers to the tests and studies used and accepted for the initial qualification of a component, or a container closure system, for its intended use. Quality control refers to the tests typically used and accepted to establish that, after the application is approved, the components and the container closure system continue to possess the characteristics established in the suitability stud-... 

Testing on an assembled container closure system is usually performed by the applicant (or a testing laboratory commissioned by the applicant), and the test results are provided in the application. Such tests may include vacuum-leak testing, moisture permeation, and weight loss or media fill. Testing on an individual packaging component is typically performed by the manufacturer of the component and is reported via a DMF (see Section V). 

This test measures the water vapor permeation of a singleunit or unit-dose container closure system and establishes acceptance criteria for five standards (Class A-E containers). 

This test is intended for drugs being dispensed on prescription, but it has also been applied to the drug product manufacturer s container closure system. If the container closure system has an inner seal, it should be removed before testing. The results from this study reflect the contributions to water vapor permeation through the container and through the seal between the container and the closure. 

The application (or Type II DMF) should include a detailed description of the complete container closure system for the bulk drug substance as well as a description of the specific container, closure, all liners, inner seal, and desiccant (if any), and a description of the composition of each component. A reference to the appropriate indirect food additive regulation is typically considered sufficient to establish the safety of the materials of construction. The tests, methods, and criteria for the acceptance and release of each packaging component should be provided. Stability studies to establish a retest period for bulk drug substance in the proposed container closure system should be conducted with fillers or desiccant packs in place (if used). Smaller versions that simulate the actual container closure system may be used. 

FD-483 Observation. The firm failed to conduct a stability testing program using the current marketed container-closure system. Additionally the firm failed to establish a written stability test program that analyzes for impurities and degradants in their multiple products. ... 

Preventative Action. This observation could have been avoided by establishing a stability testing program SOP that specifies batches that are to be entered into the annual stability program, including all container-closure systems, and that requires that all commercial container-closure systems be tested. The stability program must include an evaluation of degradants and impurities if it is intended to assess stability. Additionally, a product-specific stability protocol should have been developed that specified the methods to be used. 

Container/Closure System. A description of the container and closure system and its compatibility with the drug substance should be submitted. The section should include detailed information concerning the supplier and the results of compatibility, toxicity, and biologic tests. Alternatively, a drug master file (DMF) may be referenced for this information. 

A description of all the container/closure system configurations for the drug to be marketed should be presented. In addition, stability data and any other information that support the suitability of the container/closure components, including specifications and test methods, should be indicated. 

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