Stability testing in plain terms

A certificate of analysis describes a material on the day it was tested. Stability testing is how a manufacturer finds out what the same material will look like in six months, two years or five. The results set the storage conditions printed on the label and the date after which the material should no longer be relied on. For pharmaceutical substances and products, the core guidance is ICH Q1A(R2), Stability Testing of New Drug Substances and Products, with ICH Q1B covering exposure to light.

What a stability study is

A stability study places samples from defined batches into storage chambers held at controlled temperature and humidity, then pulls samples at scheduled times and tests them. The tests usually include appearance, assay, related impurities and degradation products and, depending on the material, water content or other properties expected to change. Each pull is compared with the starting result and with the specification.

The tests must be stability-indicating: able to detect the changes the material actually undergoes. An assay method that cannot separate the substance from its own degradation products would report a steady result for a material that is breaking down. Establishing which degradation products form, and confirming that the method sees them, is therefore done before the formal study starts.

Stress testing comes first

Stress testing, also called forced degradation, deliberately exposes material to conditions harsher than it should ever see in storage: high temperature, high humidity, acid, base, oxidizing agents and intense light. The aim is not to predict a shelf life. It is to learn how the substance breaks down, and to produce the degradation products that the analytical methods then have to separate and measure.

Storage conditions

ICH Q1A(R2) defines standard storage conditions so that studies are comparable. The main ones are:

• Long-term: 25°C and 60 percent relative humidity, or 30°C and 65 percent relative humidity, depending on the climatic zone the material is intended for.
• Intermediate: 30°C and 65 percent relative humidity, used when accelerated results show significant change and the long-term condition is the cooler one.
• Accelerated: 40°C and 75 percent relative humidity, used to reveal changes sooner than long-term storage would.

Materials meant for refrigerated or frozen storage are studied at those temperatures instead, with accelerated conditions set correspondingly lower. Each condition carries a tolerance, and the chambers are monitored continuously, because a study run in a chamber that drifted out of range does not support the conclusion drawn from it.

Long-term studies are typically tested every three months in the first year, every six months in the second, and once a year after that. Accelerated studies run for six months with at least three time points, including the start and the end.

From data to a date

Stability data are evaluated for trends. Where a result changes over time, the trend is projected forward to the point at which the material would fail its specification, with statistical allowance for variability. ICH Q1A(R2) allows limited extrapolation beyond the period actually observed under long-term conditions, but only where the data and their analysis justify it.

Two kinds of date come out of this work. A retest date applies to substances: after it, the material should be tested again and, if it still meets specification, it can be used. An expiry date, or shelf life, applies to finished products and to some substances: after it, the material is not used, regardless of what a fresh test might show. The distinction is worth knowing, because the two are often confused on labels and certificates.

Studies are run on several batches, usually at least three, to show that the result is a property of the process rather than of one good batch. Material is stored in the same container and closure it will be supplied in, because packaging governs exposure to moisture, oxygen and light. A material that is stable in sealed glass may not be stable in a permeable bag.

Stability work does not stop when a date is set. Long-term studies continue in order to confirm it, and an ongoing program tests production batches over their life. When a material’s process, formulation or packaging changes, the effect on stability has to be assessed again.

What it means for storage

The storage instruction on a label — a temperature range, protection from light, keep tightly closed — is a summary of the conditions under which the stability data were generated. The retest or expiry date holds only under those conditions. A material stored outside them is no longer covered by the evidence behind its date, even if nothing about it looks different.