Product Stability Data

The stability data that should available at the time of preapproval inspection include 

Calibration of equipment This is a routine requirement, and the FDA inspectors may not review these data if they find that the firm is in general good compliance with the cGMP. However, these data should be updated and current at all times. 

Developing stability data for an ANDA product generally requires fewer laboratory studies than those required with an NCE. The primary goal of an ANDA should be to mimic the stability profile of the innovator product, barring any intellectual property issues that might prevent the generic manufacturer from formulating a sim- 

The general principles of process validation involve prospective process validation (also called premarket validation), retrospective process validation, revalidation, and 

Retrospective validation involves using the accumulated in-process production and final product testing and control (numerical) data to establish that the product and its manufacturing process are in a state of control. Valid in-process results should be consistent with the drug products final specifications and should be derived from previous acceptable process average and process variability estimates, where possible, and determined by the application of suitable statistical procedures, that is, quality control charting, where appropriate. The retrospective validation option is selected when manufacturing processes for established products are considered to be stable and when, on the basis of economic considerations and resource limitations, prospective qualification and validation experimentation cannot be justified. 

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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 validation protocol and report may also include the product stability data or a summary and documentation concerning cleaning and analytical validation. 

For related products, stability data need only be submitted for products taken internally. 

The purpose of stability testing is to assess the effects of temperature, humidity, light, and other environmental factors on the quality of a drug substance or product. The data produced are used to establish storage conditions, retest periods, shelf loss, and to justify overages included in products for stability reasons. The most useful equation relating temperature and reaction rate is the Arrhenius equation. This equation (27) may be integrated and rewritten as Eqs. (31) and (32). 

Once a product gains FDA approval for marketing, the sponsor should maintain a readily retrievable profile of commercial batches. This includes individual batch release data and stability data. These data should be compiled throughout the year and tabulated prior to the anniversary of NDA approval for submission in the annual product report to FDA. By maintaining an ongoing database, which is reviewed as new information is added, changing trends in the data can be observed and management notified if any of these trends are unfavorable. 

Where antioxidants or antimicrobial preservatives are used, the finished product release specification will need to include identification tests and assays for these two types of excipient. The shelf life specification should also include a specification for assay for antimicrobial preservatives. Stability data will be required for both antioxidants and antimicrobial preservatives in the finished product, and in addition the preservative efficacy of the formulated product should be examined over its shelf life and by means of appropriate in-use stability tests. Preservative efficacy data should also be presented at the lower limit of the preservative assay. 

Currently the main application of interest for parametric release is to replace the sterility test as a control method in appropriate cases (given the limited value of that test to predict sterility assurance due to statistical considerations, although it is also pointed out that a sterility test provides a final opportunity to identify a major failure, although other means should provide a more reliable way of detecting such failures). The concept is applicable to well-founded methods of sterilization where the product stability is known and development data have identified the critical process parameters. The measured parameters should be such as to ensure that correct processing of the batch provides sufficient assurance that the sterility assurance level intended has been achieved. 

There has been a large number of field trials of transgenic crops that accumulate recombinant proteins, but the results of only a few have been reported so far. Of particular interest for the future are reports of detailed trial protocols that address confinement concerns multi-location, multi-year performance and stability data environmental impact and non-target impact studies and GLP production. The impact of production conditions on extraction efficiency and product quality are also significant issues that should be addressed through field-testing. 

As the stability data can be affected by many factors like formulation, manufacturing, storage conditions, in-process and GMP controls, analytical methods, and process validation, the biggest challenge is to figure out the source of the variability in the stability results. At least three batches of the drug substance or product are required to establish the acceptance criteria for future production batches as a measurement... 

Today, in the United States, the FDA is responsible for examining safety and efficacy data before an antibiotic or synthetic chemical may be commercialized for livestock use. This includes studies on formulations, product stability, conventional and genetic toxicity, environmental safety, metabolism, residue studies in target animals, studies on antibiotic resistance in gut microflora and on salmonella shedding in target animals. Similar requirements are part of registering these products in overseas markets. In general, after a product is discovered in the laboratory, many... 

Once the optimal formulation and processing method have been determined and the most suitable packaging configuration decided, product stability tests may be commenced. The aim is to determine a shelf life and provide data that demonstrate the product s continued quality under the conditions of manufacture, storage. 

Cartwright AC. Stability data. In Cartwright AC, Matthews BR, eds. International Pharmaceutical Product Registration Aspects of Quality, Safety and Efficacy. Chichester EUis Horwood, 1994 206-45. 

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