Stability test conditions

Introduction

The evaluation of the different climatic conditions and the mean kinetic temperature (MKT) by each of the 194 WHO member states resulted in the recommended storage conditions for long-term stability studies (Fig. 49.2).

This results in some interesting discrepancies between the
meteorological conditions and the regulatory requirements. For example, Canada is meteorologically in
climatic zone I (temperate) but is in climatic zone IVA (hot and humid) from a stability testing perspective; northern Africa and the Middle East are typically
hot and dry (climatic zone III) but the long-term testing conditions are more humid (climatic zone IVA). The WHO long term stability testing conditions
do not necessarily correlate with climatic conditions, as the WHO conditions typically include a safety factor, but companies are required to use these
conditions to license their products.

Companies are allowed to use more harsh long-term testing conditions.

The intermediate storage condition is normally 30°C/65% relative humidity, unless this is the longterm storage condition, in which case there is no
intermediate condition.

The accelerated storage condition is 40°C/75% relative humidity.
These storage conditions describe the general case for testing pharmaceutical products. If the product is intended to be stored in a refrigerator, the long-term storage condition is 5°C ± 3°C and accelerated storage is 25°C/65% relative humidity, 30°C/65% relative humidity or 30°C/75% relative humidity. Products
intended for storage in a freezer have a long-term condition of −20°C; products that need to be stored below −20°C are treated on a case-by-case basis.

Where the drug product is stored in a semipermeable container closure system, long-term testing in lower humidity conditions (25°C/40% relative
humidity or 30°C/35% relative humidity) should be performed to determine the propensity of the product to lose water vapour through the plastic packaging, particularly if the product is intended
to be marketed in climatic zone III (hot and dry).

Alternatively, a higher storage humidity can be used, and water loss at the reference relative humidity can be derived through calculation. At 40°C, the
calculated rate of water loss during storage at not more than 25% relative humidity is equal to the measured water loss rate at 75% relative humidity multiplied by 3.0. Where the packaging is impermeable (e.g. glass ampoules), relative humidity is not
a concern.

1. Testing at accelerated and
intermediate conditions

Accelerated conditions are designed to be a moderately more stressful temperature and relative humidity environment than the long-term storage conditions, with intermediate conditions somewhere in the middle. Accelerated conditions should be differentiated from stress testing, where more extreme conditions may be used.

Pharmaceutical products are generally stable (in the order of years) at long-term storage conditions, and thus stability testing over this period presents a
practical problem for the manufacturer.

Testing at accelerated or intermediate conditions can significantly reduce the time taken to generate stability data, giving an early indicator of the stability of the pharmaceutical product.

Accelerated or intermediate stability data can also be used in the extrapolation of the available long-term
stability data to set longer retest periods or shelf lives than the period covered by the long-term data.

It is for this reason primarily that it is recommended to initiate stability testing at accelerated and/or intermediate conditions, in addition to long-term
conditions, in any formal stability study design.

The prediction of long-term stability from data obtained at accelerated conditions does have its limitations and it is acknowledged that shelf-life
estimates may have a high degree of uncertainty. To reduce this uncertainty, the concepts of a moisturecorrected Arrhenius equation (Eqn. 49.4) and an
isoconversion paradigm or model have been applied, together with a statistical design of experiment and analysis approach, to develop the Accelerated Stability Assessment Program (ASAP), which has improved the predictability of shelf life for a wide range of products (Waterman and Colgan, 2008; Waterman
et al., 2007).

The ‘isoconversion paradigm’ is essentially a model where the amount of degradation is kept approximately the same by adjustment of the time that the
product is exposed to different elevated temperature and humidity conditions (Table 49.3).

This overcomes some of the limitations of the empirically (experimentally) derived Arrhenius equation being unable to accurately reflect the complex individual molecular reactions involved in degradation (as described earlier).

For example, in a solid dosage form, active substance molecules can exist in an amorphous state or in crystalline domains, and may be adjacent to different excipients. Consequentially, the molecules may degrade at different rates as a function of the amount
of degradation. Often, only a small amount of active substance is in a very reactive form that will degrade, with the rest being relatively stable. If the
proportion of the reactive form changes with temperature and/or humidity, this can result in the degradation kinetics becoming very complex. This
exceeds the limitations of the Arrhenius equation, and thus can make prediction of stability at other conditions difficult.
If the amount of active substance converting to degradation products is kept the same, the proportions
of the different reacting species remain the same (isoconversion), and this compensates for the complex reaction kinetics.

The moisture-corrected Arrhenius equation is:

lnA = lnk – (EA/RT) + B (relative humidity)
….(Eqn. 49.4)

The influence of relative humidity on the degradation of an active substance can be understood in terms of the magnitude of the constant B, which can have values ranging from a low value of 0 to a high
value of 0.09. There is an exponential relationship between relative humidity and drug reactivity, such that a small change in humidity will result in a large
difference in stability and shelf-life prediction.

It is postulated that the influence of relative humidity on the rate of degradation is attributed to water increasing the mobility of the reacting species rather than being a direct reactant (hydrolytic reactions are not more susceptible to relative humidity).
ASAP can provide improved predicted shelf-life estimates with as little as 14 days’ stability testing, which is much faster than traditional accelerated testing, and thus is attractive to manufacturers developing pharmaceutical products and container
closure systems. The use of ASAP to set retest periods and shelf lives, and the associated storage conditions, is not currently accepted by regulatory authorities in Europe.

2. Long-term stability testing

A manufacturer must ensure that long-term stability testing is conducted on the product, as intended to be marketed, at conditions that represent the recommended storage conditions for the duration of the retest period or shelf life.

If the data are not available at the time of submission, then the manufacturer will need to provide commitments to provide the data if requested by the regulatory authorities, typically by continuing the
existing formal stability studies used in the initial regulatory submission. The GMP requirement to implement an ongoing long-term stability programme was discussed earlier.

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