Container-closure system marketing

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

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. 

The formal validation is often completed after the PAI, where three-batch process validation will be conducted in accordance with the protocol approved during the preapproval inspection. The primary objective of the formal process validation exercise is to establish process reproducibility and consistency. Such validation must be completed before entering the market. The formal validation studies continue through packaging and labeling operations (in whole or in part), so that machinability and stability of the finished product can be established and documented in the primary container-closure system. 

To Support Product Development. In addition to supporting the use of clinical trial materials, stability studies are carried out on both the API and different formulations in different container-closure systems to guide the development of the final formulation and container-closures. Stability studies may be carried out on either the formulation to be marketed or a representative formulation to evaluate different API suppliers, drug product manufacturing processes and sites, and drug product container-closures. 

Sometimes container-closure development is not complete when the registration stability studies are initiated. Firms may then include multiple container-closure systems in the registration stability study and choose the one(s) to be used for the marketed product based on the results of the stability study. Although this means additional work, it is usually preferable to a delay in the start of the stability study. 

Marketed product stability studies are required to provide assurance that the drug product continues to exhibit reproducible quality over its shelf life and that accumulated minor changes over time have not adversely affected the product. These studies are initiated annually on one batch of each marketed product in each marketed container-closure system using the approved stability protocol. 

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. ... 

Describe the proposed container/closure system(s) in which the drug product is to be marketed. Safety closure systems should be detailed. 

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. 

The dry powders that are reconstituted in their marketed container need not be sterile however, the possibility of an interaction between the packaging components and the reconstituting fluid can t be discarded. Although the contact time will be relatively short when compared to the component/dosage form contact time for liquid-based oral dosage forms, it should still be taken into consideration when the compatibility and safety of the container closure system are being evaluated. 

Solids For solids that must be dissolved or dispersed in an appropriate diluent before being injected, the diluent may be in the same container closure system (e. g., a two-part vial) or be part of the same market package (e.g., a kit containing a vial of diluent). 

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. 

The container-closure system should be the same as what will be used for the market. 

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... 

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