The purpose of stability testing is to provide evidence on how the quality of a drug substance or drug product varies with time under the influence of a variety of environmental factors, such as temperature, humidity and light, and to establish a retest period for the drug substance or a shelf life for the drug product and recommended storage conditions.
The stability of a pharmaceutical product is a critical aspect of the Quality Target Product Profile (QTPP) and is investigated throughout the various
stages of a product’s development and lifecycle. With use of scientific first principles and knowledge of the mechanisms of degradation, together with previous experience gained from the stability testing of similar dosage forms, it is possible to develop a
pharmaceutical product and its container closure system to avoid obvious stability issues and increase
the likelihood of an acceptably long retest period or shelf life, and establish acceptable storage conditions.
The stability of a pharmaceutical product is complex, often being dependent on multiple physical, chemical and microbiological factors that may or may
not interact with each other, such that an acceptable stability profile can never be fully predicted – in short, this complexity means that stability testing of
a pharmaceutical product is a necessary part of any development programme.
The design of a stability study depends on the stage of product development and what knowledge about a product’s stability profile is being sought.
Types of stability studies
1. Preformulation studies
In the preformulation stage, the physicochemical properties of the active substance are fully characterized.
Stress testing or forced stability studies expose the active substance, both solid
and solubilized forms, to extreme conditions over a short period (e.g. 14–28 days): elevated temperature (e.g. 50°C, 60°C or 70°C); elevated humidity (e.g. 60%, 75%, 85% or 90% relative humidity); acid and base hydrolysis (e.g. 0.01 N to 1 N acid/base); oxidation (e.g. 0.3% to 3% hydrogen peroxide) and
photolysis (e.g. 1.2 x 106 lux hours).
Regulatory or pharmacopoeial authorities do not prescribe formal
conditions for stress testing. Conditions should be selected to obtain a degradation level of approximately 10%, although this level may vary from one
company to another, and from one active substance to another.
The aim of these studies is to degrade the active substance to elucidate the likely degradation mechanisms and pathways, which is useful for the development of the container closure system and the
formulation of the drug product. Of course, where an existing active substance is used, this information
may be derived from published literature sources.
Stress testing or forced stability studies are also used to validate and demonstrate that the analytical
methods are stability indicating.
2. Binary mixes
Once the degradation pathway is known, this knowledge, together with any previous development experience and scientific first principles, can be used to carefully select suitable excipients to be
formulated with the active substance in the drug product.
Binary mixes of the active substance and
excipient can then be used to confirm excipient compatibility. Binary mixes are usually a 1:1 ratio of the active substance and excipient in either a powder blend/compact or an aqueous slurry mixture (to investigate the effect of moisture), although it may be more scientific for the ratio to mimic the
levels likely to be used in the formulation.
Tertiary mixes, where an additional excipient is added to the binary mix, may also be used. These mixes are
then subject to testing at accelerated conditions (e.g. 40°C/75% relative humidity, 40°C/85% relative humidity or 50°C, and light) for a short period (1–3
months), with evaluation of the mixes for changes in appearance, content and degradation products.
Alternatively, thermal methods, such as differential scanning calorimetry, can be used to detect interactions between the active substance and excipients.
The benefit here is that there is no need for stability studies, so the cycle time and sample consumption are much reduced; however, the data can be difficult
to interpret, false positives/negatives are frequently encountered and the outcome is sensitive to sample preparation.
3. Formulation and container development
A drug product may undergo several stages of formulation development. The first formulation stage may be for preclinical studies or phase I (first in humans) clinical trials, where the product may be a simple parenteral injection or an early prototype formulation.
Formulation, manufacturing and container closure development studies may be performed further to
develop the formulation and the container closure system for phase II (first in patients) clinical studies.
The formulation, manufacturing process and container closure system are then further optimized to arrive at the final formulation and container closure system for the large-scale phase III (pivotal) clinical studies (the data from which form the basis for marketing
authorization applications to regulatory authorities) and eventual commercialization.
Stability testing of the different formulations is performed at appropriate stages to support the
development programme, as well as to provide stability data to support the clinical trial (regulatory authorities require demonstration that clinical trial
supplies are appropriately stable and are safe to be administered to volunteers).
The types of stability study can range from forced degradation or stress
testing of the drug product (principally to validate the analytical methods as stability indicating, but can also provide useful information on potential interactions with excipients within a formulated product), accelerated testing (which can give an indication of the likely long-term stability of different development formulations) and long-term or real-time testing (on prototype laboratory-scale or small pilot scale development batches) to formal stability studies (Table 49.1) on the exact formulation and container closure system that is intended to be marketed.
Bulk intermediate and final drug product (i.e. before it is packaged into the marketed container closure system) stability also needs to be monitored
to support holding times during product
Temperature cycling studies (from less than 0°C to 40°C) should be performed for inhalation, nasal and transdermal products, as well as suspensions, creams and emulsions (even solutions, in some cases).
Temperature fluctuations can encourage precipitation and/or particle growth, which can have a significant effect on the quality and efficacy of these products.
The performance of inhalation and nasal products at low temperature also needs to be characterized.
The manufacturer must select the most appropriate type of study to gain the maximum amount of useful information on the stability of the drug product,
while making the most efficient use of the formulation, manufacturing, analytical, stability cabinet storage, financial and time resources at its disposal.
Stability testing forms a significant part of a development programme both financially and in time, so it is important to get it right first time.
4. Postauthorization stability studies
The licensing of a pharmaceutical product is not the end of stability testing. If stability studies on commercial-scale batches have not been provided
during the licensing submission, regulatory authorities will require the manufacturer to provide a commitment to stability-test the first three commercial-scale batches to confirm the retest period/ shelf life once the product is commercialized. The manufacturer has to notify the authorities immediately
if the commercial-scale stability data do not agree with those previously provided in the Marketing
Authorisation application, and do not conform to the agreed shelf life and storage conditions.
Pharmaceutical products are likely to undergo many changes during their lifecycle. It is quite common for manufacturers to amend the drug product formulation or change the manufacturing process and equipment, change suppliers of active substances/
excipients, change the manufacturer of the drug product or change the container closure system. It is also common for manufacturers to change the retest
period or shelf life and storage conditions to suit the marketing requirements of the product. All these
changes will need to be submitted to the regulatory authorities and supported by stability studies if a variation is sought to the marketing authorization.
5. GMP and good distribution practice
GMP requires the stability of a marketed product to be monitored during its shelf-life to determine whether the product remains, and can be expected to remain, within its licensed specifications under its labelled storage conditions (Medicines and Healthcare products Regulatory Agency, 2017). This requires manufacturers to initiate an ongoing or rolling stability programme, in which at least one batch per year of product manufactured, of every strength and every primary packaging type is included, unless otherwise justified. The stability study design can be different
from that used for licensing purposes, but must generate sufficient stability data to permit trend analysis so that changes in the stability profile can
The stability of the product during transportation from the manufacturer(s) to the wholesaler(s) and finally the pharmacy also needs be verified, as the
recommended storage advice applies to both static and mobile (during transportation) storage (Medicines and Healthcare products Regulatory Agency, 2017).
Certain pharmaceutical products may be susceptible to temperature ‘spikes’ (the temperature suddenly deviates from and quickly recovers to within the target range) or ‘plateaus’ (the temperature lies
outside the range for an extended time before eventual recovery), which can have different effects. Products
requiring ‘cold-chain’ transportation (i.e. refrigerated or frozen) are highly susceptible to temperature excursions.
This may require simulated transportationbstudies, accelerated testing or temperature/humidity
cycling studies to be performed if this information cannot be gleaned from development or formal stability studies.