Container closure systems stability data

Information on the analytical reference standard Description of the container/closure system Stability data... 

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. 

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. 

Stability studies during the IND phase provide not only assurance of the quality of clinical trial material but also the basis for the drug product development program. Stability data are used to evaluate different formulations, methods of manufacture, and container-closure systems, as well as to determine storage requirements, expiration dating periods, and specifications. 

Another consideration is whether zero-time data for a batch in one container-closure may be used for the same batch in a different container-closure system. This would depend on the amount of time between packaging of the product and zero-time as well as the stability profile of the product. The data generated for zero-time for a batch in one type of container-closure are usually also used to evaluate the same batch in the same container-closure under different storage conditions. 

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. 

An adequate number of batches of each drug product shall be tested to determine an appropriate expiration date and a record of such data shall be maintained. Accelerated studies, combined with basic stability information on the components, drug products, and container-closure system, may be used to support tentative expiration dates, provided full shelf-life studies are not available and are being conducted. Where data from accelerated studies are used to project a tentative expiration date that is beyond a date supported by actual shelf-life studies, there must be stability studies conducted, including drug product testing at appropriate intervals, until the tentative expiration date is verified or the appropriate expiration date determined. 

Container and closure systems for sterile products must be capable of withstanding process conditions, storage, and transport without compromizing the sterility of the product. This has been recently emphasized by the FDA, which has omitted a former obligation to provide data from the Test for Sterility in stability program for new sterile products in favor of verifying the microbial integrity of the container-closure system. ... 

Data from stability studies should be provided on at least three primary batches of the drug product. The primary batches should be of the same formulation and packaged in the same container closure system as proposed for marketing. The manufacturing process used for primary batches should simulate that to be applied to production batches and should provide product of the same quality and meeting the same specification as that intended for marketing. 

Where long term data are not amenable to statistical analysis, but relevant supporting data are provided, the proposed shelf life can be up to one-and-a-half times, but should not be more than 6 months beyond, the period covered by long term data. Relevant supporting data include satisfactory long term data from development batches that are (/) made with a closely related formulation to, ( /) manufactured on a smaller scale than, or (/7/) packaged in a container closure system similar to, that of the primary stability batches. 

Stability testing A brief description of the stability study and the test methods used to monitor the stability of the drug product packaged in the proposed container/closure system and storage conditions should be submitted. Preliminary tabular data based on representative material may be submitted. Neither detailed stability data nor the stability protocol need to be submitted. 

This section, as previously discussed, frequently poses problems leading to delays in NDA approval. Particular attention should be paid to the development of adequate data from studies conducted with commercial formulations packaged in container/closure system(s) to be marketed. It is critical that adequately validated analytical methods be used as early as possible in the investigational phases of drug development—no later than the initiation of phase 3 studies. Common defects in stability studies submitted to the FDA reflect the lack of acceptable long-term or short-term accelerated stability data to support the approval of an expiration date for the product. Another common problem occurs when studies are conducted using only one container size, yet the sponsor is... 

Thus, it is no longer acceptable for the formulator to delay this compatibility testing until later in the development programme. The key message is for the formulator to test early and ensure equivalence of the whole product throughout the development cycle. Leachables are specifically mentioned data on their identity and concentration in the product and placebo are required through the shelf life and also under accelerated stability test conditions. Information should be submitted on source, chemical composition and physical dimensions of the container closure system, together with control and routine extraction tests. Acceptance criteria are also required. 

All previously described analytical tools and specifications are used to describe the quality of a biopharmaceutical. In terms of use, it is important to know how stable the product itself and its formulation are, and which specific handling conditions or precautions must be estabhshed. Stabihty studies are conducted to generate the corresponding data [26]. These studies address (apart from temperature and humidity) light exposure, interaction with the container/closure system (e.g., vials or ready-to-use syringes) and also in-use stability, for examples in case of dissolved lyo-philisates. 

Interactions with Closure Systems. Elastomeric and plastic container and closure systems release leachable compounds into the liquid dosage form, such as nitrosamines, monomers, plasticizers, accelerators, antioxidants, and vulcanizing agents [44], Each type of container and closure with different composition and/or design proposed for marketing the drug or physician s samples has to be tested and stability data should be developed. Containers should be stored upright, on their side, and inverted in order to determine if container-closure interactions affect product stability [6,45]. 

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