Stability Testing For Shelf-Life & Meeting Acceptance Criteria Over Time

Stability testing is utilized to determine if the quality of a drug substance or drug product is altered over time by various environmental factors, such as light, temperature, and humidity. A drug “substance,” often referred to as an Active Pharmaceutical Ingredient (API), is defined as the unformulated material that may subsequently be formulated with excipients to produce a dosage form. A drug “product” is the formulated mixture of the drug substance and excipients comprising the final marketed dosage form.

For a drug substance, stability testing determines the “re-test period,” the timeframe during which the drug substance is expected to remain within its specification, and therefore can be used in the manufacture of a drug product. After the established re-test period has elapsed, a drug substance can only be used if additional specification testing is performed, the substance meets specifications, and the substance is distributed soon after meeting acceptance criteria.

For a drug product, stability testing determines the shelf-life of the product by establishing the duration for which the product is safe to use and retains therapeutic value.

During a stability study, materials are stored at various temperature and humidity conditions and samples are pulled at predetermined time points and subjected to a battery of tests that may include: an identification test, assay, physical tests, microbiological limits, and preservative effectiveness testing, using appropriately validated methods and/or recognized compendial methods.  Acceptance criteria are stipulated before initialization of the study, and if a product fails to meet specifications at any time point, the stability study may be halted and restarted after reformulation or other modifications have occurred.

The primary stability testing guidance document for drug substances and products marketed in Japan, Europe, and the United States is the International Conference on Harmonization (ICH) of Technical Requirements for Registration of Pharmaceuticals for Human Use, ICH Harmonized Tripartite Guideline, Stability Testing of New Drug Substances and Products – Q1A(R2).

For a drug substance stability study, the ICH guidance recommends utilizing a minimum of three batches of product.  The batches should be manufactured to a minimum of pilot scale. A “pilot scale” batch is one produced by a procedure fully representative of and simulating that to be applied to a full production scale batch. The substance should be stored and tested using the same packaging and materials as the intended finished product.

For a drug product, data from stability studies should be provided on at least three primary batches of the same formulation and packaged in the same container closure system as intended for distribution. Two of the three batches should be at least pilot scale batches, and the third one can be smaller if justified. Batches of the drug product should be manufactured using different batches of the drug substance.

Stability testing can also be used to determine acceptance criteria for release testing. Specifications that remain stable throughout stability storage and evaluation may not need to be included in release testing, whereas more fluctuating measurements may suggest requiring either batch-by-batch or periodic testing of the ready-for-market drug product before distribution.

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