Closure Systems

A container closure system is the sum of packaging components that together contain and protect the dosage form. This includes primary packaging components and secondary packaging components, if the latter are intended to provide additional protection to the drug product. A packaging system is equivalent to a container closure system. 

The term quality refers to the physical, chemical, microbiological, biological, bioavailability, and stability 

An extraction profile is the analysis (usually by chromatographic means) of extracts obtained from a packaging component. A quantitative extraction profile is one in which the amount of each detected substance is determined. 

The manner and frequency with which it is necessary to open and close the vessel largely determines the design of the closure. In the case of columns 

In the case of pressure vessels which must be opened and closed frequently (such as batch extractors for example) a more convenient closure system is required and, in order to avoid long down times a quick closure system is then desirable. A distinction must be made between closures which provide an opening of diameter equal to the full vessel diameter (which are required when the material to be extracted is loaded in removable baskets) and those which do not. The latter are adequate if the vessel is to be charged with fluid or, in some cases, bulk solids (see chapter 5). Some of the available designs for quick closures are listed below. 

Designs based on a screw cap with inner or outside threads. 

Due to the complicated stress ratio, quick closure systems have to be very carefully designed using the method of finite elements. In some cases permission to use the system may only be granted if the computed tension is confirmed experimentally using a wire strain gauge. 

The importance of using mechanical or electronic safety systems in conjunction with quick closure systems should not be underestimated. These prevent the pressure vessel from being opened while it is still under pressure (see also chapter 5). 

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Justification of Specification 3.2.S.5Reference Standards or Materials 3.2.S.6Container Closure System 3.2.S.7Stabillty... 

Changes to a closure system that does not affect quality of the drug product... 

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 ... 

Final cover systems are another important component of waste containment systems used at landfills. While liner systems are installed beneath the waste, final cover (or closure) systems are installed over the completed solid waste mass. For hazardous waste landfills, 40 CFR 264 requires that the landfill be closed with a final cover system that meets certain performance criteria, most notably, that they have a permeability less than or equal to the permeability of any bottom liner system or natural subsoils present. U.S. EPA guidance documents517 recommend that final cover systems for hazardous waste landfills consist of at least the following, from top to bottom ... 

The ability of the closure system to withstand considerable stresses due to the impact of settlement. 

Figure 26.30 shows details of a gas vent pipe system. The two details at the top left of the illustration show close-ups of the boot seal and flange seals located directly at the interface of the SWCR system with the FMC. To keep the vent operating properly, the slope of the closure system should... 

Filter layers, frost penetration, and cap-liner connections are other factors to consider in designing the closure system for a hazardous waste landfill. Before using geotextiles for filter layers in closures, one should conduct pressure tests and clogging tests on the material. Freeze-thaw cycles probably have little effect on membranes, but their impact on clay is still not known. Because of this lack of knowledge, membrane and clay layers should be placed below the frost penetration layer. Finally, a cap membrane should not be welded to the primary FML. Differential settlement in the cap can put tension on the cap membrane. In such a situation, the seam could separate and increase the potential for integration of the surface water collection system into the LDS. 

H. Container and Closure System L Drug Substance Stability... 

An example of the possibilities for plastics to respond to a specific problem is the replacement of almost 100% of the stoppers, capsules, joints and other closure systems used for pharmaceutical products. The replacement of glass is the most-significant opportunity for the development of thermoplastics but new possibilities could appear in medical self-care systems and blood sample tubes. A 50-70% increase in the use of plastics should come from existing mass-produced and low-cost products. Let us quote, for example ... 

Several dosage forms carry an increased risk of degradation or adjunct formation. Products such as injections and aerosols are more likely to interact with volatiles or extractables from packaging and closure systems. Tablets have the potential to form adjuncts with excipients (specifically, lactose has been shown to form adjuncts in tablets). Non-CFC propellants in aerosols have a large number of impurities that typically do not interact with drug substances, but the potential for these interactions does still exist. Creams, ointments, lotions, and other such products will each have specific interactions that should be considered while evaluating the impurity profile of a drug product. 

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... 

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