FDA Puts a Leash on Stability Testing

The agency has finalized a guidance on stability testing of new, particulary sensitive veterinary medicines.

FDA's Center for Veterinary Medicine has finalized a guidance on stability testing of new biotechnological or biological veterinary medicinal products. The document, published March 26, is the companion to another guidance on stability testing of veterinary drug products that was finalized in September 1999. Both have been approved by the Veterinary International Conference on Harmonization (VICH) and apply to the United States, European Union, and Japan.

The drug guidance, the agency says, "applies in general" to biotechnological and biological veterinary products. But those products also need their own stability guidance because they are particularly sensitive to oxidation, light, temperature changes, and other factors and require stringent conditions for storage. The new guidance can be viewed at http://www.fda.gov/cvm/guidance/guide90.doc.

Where bulk material is being stored before formulation and final manufacturing, stability data must be provided on at least three batches of material stored under commercial manufacturing conditions. The batches should be stored in containers similar to the holding containers that will be used during manufacturing. Smaller containers may be acceptable if they are constructed of the same material and use the same type of container-closure system that will be used in manufacturing.

A minimum of six months of data should be submitted for products with storage periods greater than six months. For those with less than six months, the amount of data should be determined on a case-by-case basis.

When a product is to be distributed in batches differing in fill volume or mass, samples may be selected for the stability program based on a matrix program or by bracketing. Matrixing involves testing different fractions of samples at different sample points. It should not be used on samples with different container-closure systems or different strengths where it cannot be confirmed that they respond similarly under storage conditions. If matrixing is used, all differences in samples should be identified. Bracketing allows the firm to use only the largest and smallest container size in the stability program when the same strength and exact container-closure system is used for at least three fill contents. The agency may ask for extra data to demonstrate that all samples are represented by the results for the extremes.

Where the lack of interactions between the product and the container-closure system cannot be ruled out in liquid products (other than sealed ampoules), the stability studies should include samples maintained in the inverted or horizontal position as well as the upright position. This procedure aims to better determine the effects of the closure on product quality. Such data is needed for all container-closure systems that will be marketed.

Sterility testing or container-closure integrity testing should be minimal at the beginning and end of the proposed shelf life. Where it can be demonstrated that the proposed containers and storage conditions protect sufficiently against high and low humidity, stability tests at varying relative humidities are not necessary.

Storage temperatures for real-time stability studies may be confined to the proposed storage temperature, as most biological or biotechnological products need precisely defined storage temperatures.

Expiration dating should be based on real-time, real-temperature data. However, the agency "strongly" suggests performing studies under accelerated and stress conditions. Accelerated data can support the proposed expiration date, provide a preliminary assessment of scale-up and other manufacturing and packaging changes, or reveal the product's degradation profile. Stress-condition data can help determine the extent of product damage or degradation due to accidental exposure to harsh conditions during transportation.

The stability of freeze-dried products after reconstitution should be demonstrated for the conditions and maximum storage period as described on the package or insert, and that labeling should be in accordance with relevant national and regional requirements.

If a multiple-dose vial is used, the firm must demonstrate that the closure can withstand the conditions of repeated insertions and withdrawals and that the product retains its full potency and quality for the maximum period specified on the package or label.

The labeling should state specific storage recommendations, especially for products that cannot tolerate freezing. Where appropriate, recommendations for protection against light and humidity should also appear on the labeling.

Written comments on the final guidance may be submitted at any time to the Dockets Management Branch (HFA-305), FDA, 5630 Fishers Ln., Rm. 1061, Rockville, MD 20852.

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