New Requirements for Drugs in Cold Storage and Drugs in Semipermeable Packaging

A new FDA document outlines stability data requirements for new molecular entities and related drugs.

A new draft for stability testing procedures of new drug substances and related products has been published by FDA. It includes some packaging-related provisions.

The revised guidance, "Q1A Stability Testing of New Drug Substances and Products," was published in the April 21, 2000, Federal Register (65 FR: 21446–21453). The document is the product of the Quality Expert Working Group of the International Conference on Harmonization (ICH) and will apply to products marketed in the United States, the European Union, and Japan.

The document outlines what should be included when submitting stability data in registration applications for new molecular entities and associated drug products. The major additions are conditions for drugs intended to be stored in refrigerators or freezers, and for those intended to be packaged in semipermeable containers. Details of testing for particular forms of packaging are not covered. The only distinction made among packages is between impermeable and semipermeable containers. The stability studies should be done with container-closure systems that are the same as or that simulate the packaging proposed for storage and distribution.

For a drug product, data from formal stability studies must be provided on at least three batches. Two of those batches should be pilot scale and a third can be smaller, but laboratory-scale batches are not acceptable. The evaluations should be done "under storage conditions that test the thermal stability and, if appropriate, its sensitivity to moisture or, for liquid products in semipermeable containers, the potential for solvent loss. The storage conditions and length of studies should be sufficient to cover storage, shipment, and subsequent use."

The goal of the tests is to determine whether there is significant change to the packaged product during testing. "Significant change" is defined as:


  • A 5% potency change from the initial assay value.
  • Any specified degradant exceeding its acceptance criteria.
  • Failure to meet acceptance criteria for appearance and physical properties, as appropriate to the product.
  • The pH exceeding acceptance criteria.
  • Dissolution exceeding acceptance criteria for 12 dosage units.

For a "general case" drug product, long-term studies (minimum 12 months' data required in the application) should be done at 25° ± 2°C and 60° ± 5% RH. For accelerated testing (minimum 6 months), conditions should be 40° ± 2°C and 75° ± 5% RH. When a "significant change" occurs at any time during accelerated testing, then testing at an intermediate storage condition should be conducted. Intermediate studies (minimum 6 months) should be conducted at 30° ± 2°C and 60° ± 5% RH.

However, if a drug product is stored in an impermeable container, that eliminates moisture sensitivity and solvent loss as concerns, and tests can be conducted under any relative humidity.

For a product intended to be stored in a refrigerator, long-term studies (minimum 12 months' data required in the application) should be done at 5° ± 3°C. Accelerated studies (minimum 6 months) should be conducted at 25° ± 2°C and 60° ± 5% RH. If significant change has occurred in the first three months, data should be supplied to cover use of the drug product outside the label storage condition. If significant change has occurred after 3 months but before 6 months of accelerated testing, the proposed shelf life should be based on the available long-term data.

For a product intended for storage in a freezer not colder than –20°C, the test condition (minimum 12 months' data required in the application) is –20° ± 5°C. Testing at an elevated temperature on a single batch should be conducted to support use of the drug product outside its proposed label storage condition. Products to be stored below –20°C are treated on a case-by-case basis.

Aqueous-based drug products packaged in semipermeable containers must be tested for potential water loss. The storage conditions for these tests should be: long term, 25° ± 2°C and 40° ± 5% RH; accelerated, 40° ± 2°C at not more than 25% RH; and intermediate, 30° ± 2°C at 60° ± 5% RH. A "significant change" in water loss is defined as more than 5% after 3 months at accelerated. This may be acceptable for some small single-dose products; if so, it should be justified in the application.

The label should bear a storage temperature range based on the stability studies, and terms such as ambient conditions and room temperature are unacceptable.

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