Stability Testing – the Basics

When obtaining a quote for manufacture of an investigational medicinal product (IMP), the requirement to provide data for the new dosage form are all too often not considered, and this can be a costly oversight. Clinical research involving placebos or comparator products are likely to require modification of a dosage form of a product to render it indistinguishable from another product (for example – over encapsulation or film coating of a product). Alternatively, the packaging of a product has to be changed for concealment purposes.

Modifying Medicines May Alter Original Quality Characteristics

Annex 13 of the Good Manufacturing Guide stipulates: If a product is modified, data should be available (e.g. stability, comparative dissolution, bioavailability) to demonstrate that these changes do not significantly alter the original quality characteristics of the product. Where a product has been repackaged in a different container that may not offer equivalent protection or be compatible with the product, a suitable use-by-date, taking into account the nature of the product, the characteristics of the container and the storage conditions to which the article may be subjected, should be determined by or on behalf of the Sponsor of a clinical trial. Such a date should be justified and must not be later than the expiry date of the original package. Furthermore, there should be compatibility of expiry dating and clinical trial duration. This additional data is obtained via carrying out stability studies on the new dosage form.

About Stability Studies

Stability studies evaluate the appearance and physical attributes (e.g. colour, caking, hardness, phase separation, re-suspendibility), potency, and purity of a drug product throughout its stated shelf-life and are essential to determine the quality of a modified or repacked drug product. Stability testing should be conducted on the dosage form packaged in the container closure system proposed to be used in the clinical trial. The testing paramaters will vary with different dosage forms; stability studies should include testing of those attributes of the pharmaceutical product that are suseptible to change during storage and are likely to influence quality, safety and efficacy.

Types of Stability Testing

Commonly, two types of stability tests are employed: real-time stability tests and accelerated stability tests. Real-time tests store the product at recommended storage conditions and monitor the product until it fails the specification. Real-time stability should typically be done at 0, 3, 6, 9, 12 months on the first year, every 6 months on the second year and once every year afterwards. In accelerated stablity studies, the product is stored at elevated stress conditions (such as temperature and humidity). Accelerated stability testing should at the minimum be done at 0, 3 and 6 months. Degredation at the recommended storage conditions can then be predicted by using known relationships between the acceleration factor and the degredation rate.

Stability Test Requirements for Clinical Trial Medication

Stability studies are mandated by regulatory agencies across the globe. They determine the shelf-life and provide evidence that the quality of a drug product, over time and under the influence of various environmental conditions, remains acceptable for the duration of its stipulated shelf-life. Both current GCP and EU GMP guidelines explicitly state that it is the responsibility of a clinical trial’s Sponsor to determine how the stability of the product will be affected and what shelf-life should be assigned. According to EU Guidelines the shelf-life of the IMP can be based on extrapolation provided that stability studies are conducted in parallel to the clinical trial and throughout its duration. When planning a clinical trial involving medication it is therefore necessary to factor in the cost of any required stability studies and implications from a reduced shelf-life. Any reduction of shelf-life and restriction of storage conditions will require a notification of a Clinical Trial Authorisation substantial amendment to the regulatory agency.

Furthermore, a stability study can be costly to undertake and test results may require the trial medication to be prepared in several manufacturing campaigns thereby significantly impacting total cost of manufacture. The Sponsor and the IMP manufacturing company therefore need to have procedures in place on decisions on stability programs for IMPs. With careful planning of the right medication solution (i.e. blinding approach, dosage form and packaging) it is, however, possible to optimise manufacturing and stability requirements and keep costs under control. Sponsors, investigators and trial managers should therefore keep this requirement in mind and seek additional guidance when planning their research.