Closures container-closure system

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

Vacuum retention determines the ability of an elastomeric closure to maintain vacuum in a container-closure system when vacuum retention is a requirement. In certain instances it impacts on the long-term stability of a parenteral system. 

Other development studies that will need to be considered include the choice of the dosage form and formulation in terms of the route of administration and the usage (and usage instructions) being suitable. The choice of the container-closure system and any dosing device also needs to be considered in this context. Data may be derived from the literature or from specific studies. 

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. 

Development pharmaceutics information is intended to cover a number of aspects related to the active ingredient(s), excipients, container-closure system, and the finished (drug) product. These aspects will be considered individually below. 

The integrity of the container and its closure should be discussed. Factors such as child resistance or tamper evidence, etc., should be discussed. The PhEur includes a requirement for certain types of product to be supplied in tamper proof container-closure system-s—which is not possible if the product is to be used by a patient ... 

For sterile products, particular attention should be paid to the choice of an appropriate method of sterilization. Wherever possible a terminal sterilization process should be applied to the product in its final container-closure system, as suggested in the Ph Eur. The preferred options include steam sterilization, dry heat sterilization, and irradiation using the Ph Eur listed conditions (saturated steam at 121°C for 15 minutes dry heat at 160°C for 120 minutes irradiation with an absorbed dose of not less than 25 kGy). Where these cannot be used, the application must include justification for the alternative procedure adopted on the understanding that the highest achievable sterility assurance level should be achieved in conjunction with the lowest practicable level of presterilization bioburden. There is guidance in the form of decision trees as to the preferred options for sterilization method to be applied ... 

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

Waterman et al. [103] determined the theoretical rate of oxygen permeation through a standard 30-cc bottle when stored in a well-sealed container. This equated to an uptake of 0.2 mMol of oxygen per year. In addition to permeation through the container walls, the key vulnerability in any container-closure system is the closure. With screw-topped closures leakage can be significant. Hence for... 

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. 

Guidance for industry, container closure systems for packaging human drugs and biologies, chemistry, manufacturing and control documentation, Food and Drug Administration, 1999. 

Stability data should be generated on at least three primary batches, which should be manufactured to a minimum of pilot scale by the same synthetic route and manufacturing process as the production batches. The quality of the API placed on a formal stability program should be similar to the quality of the material to be made on a commercial production scale. The container closure system must be the same or simulate the packaging proposed for storage and distribution of marketed product. 

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