Stable partners

If the scientists responsible for drug discovery are the 'star-performers' in pharmaceutical science, then those performing stability studies deserve the nomination for 'best supporting actors'. They don't attract much attention, but without reliable stability studies and shelf-life testing, there would be no drugs on the market and no viable pharmaceutical industry to speak of.

That said, a stability study is something of a misnomer as its purpose is to detect signs of instability, and sometimes to create the conditions whereby any instability in the product or its packaging might be encouraged, accelerated and otherwise brought to light.

As such, stability studies are not only concerned with the shelf life of the end product, but accompany and support all phases of drug development. This includes specific studies required to support progress through to the various phases of clinical trials. After all, if the drug can't be produced in a form that can be effectively packaged, distributed, stored and administered, its efficacy is largely immaterial. That being the case, stability studies play a much greater role in drug development than many people realize. Though largely routine and time consuming, and, therefore, an ideal candidate for contracting out, stability studies are integral to the drug development process. Therefore, the choice of partner laboratory is a significant decision for a pharmaceutical manufacturer, not least because it has implications for the speed and cost of bringing drugs to market.

Storage and testing

There are essentially two aspects to the stability study, at least in terms of facilities and expertise. The first of these is appropriate storage of the drugs for the period of the study and the second is the testing for degradation, spoilage, contamination and so on. While it is possible to separate the two by choosing different laboratories to store and test, there are clear advantages in having both disciplines under the same roof.

Technical challenges of storage

Appropriate storage facilities will include all rooms, chambers, ovens, fridges and freezers that can provide controlled environments of temperature, humidity and light as appropriate to the specific drug substance or product being challenged. In accordance with the International Conference on Harmonisation (ICH) guidelines, these facilities must be validated initially to confirm operation to the required tolerances and thereafter monitored continuously during use. Revalidation is performed as an assurance of continued performance. However, equipment failure can occur and as such back-up facilities are recommended to prevent long-term excursions from the specified conditions. In the case of short-term excursions, an investigation into the effects on the stability results will be required.

Despite the ICH requirement for validation there is little actual guidance on how the validation should be performed. The validation protocol is, therefore, one of the key areas for assessing the quality of the laboratory entrusted with sample storage. Indeed, the rigour of the initial validation process, the robustness of in-use monitoring and the frequency of revalidation will all impact on the reliability of a stability study.

The specific conditions chosen for storage will depend on the aspect of stability that is being assessed. Long-term storage conditions will differ from accelerated testing conditions, or stress testing conditions. Depending on the market and manner in which the drug is likely to be used, it may make sense to perform storage at the more extreme conditions of temperature and humidity, 30?°C and 65% relative humidity (RH), as specified in Q1F for long-term storage.

For multidose products that have an extended use period and will have the pack integrity broken on opening, it may be advisable to also conduct in-use stability testing from which an in-use product shelf life can be established. While it is not always necessary to set an in-use shelf life, the decision not to do so must be justified and fully substantiated.

An example of the type of product where in-use testing is sensible is one where a moisture-proof seal is used on a pack containing several days' treatment. CPMP/QWP/2934/99 gives guidance on the in-use stability testing of human medical products.¹ It refers specifically to products that: "Due to repeated opening and closing, may pose a risk to its contents with regard to microbiological contamination, proliferation and/or physicochemical degradation once the closure system has been breached."

The storage regime should, as far as possible, simulate the actual use of the product and include testing at intermediate time points throughout the proposed shelf life period. Such tests might be physical (assessing changes to colour, clarity, particle size, etc.), chemical (assaying the active substance, degradation products, pH, etc.) and microbiological (total viable count, sterility, spoilage).

Stability testing

The specifics of the testing regime, in terms of frequency and nature of tests required, are governed by a variety of factors. These include, but are not limited to, the particular characteristics of the product and whether it is a new drug or existing product. In the latter case, the use of existing stability data may be permissible.

Needless to say, there is a vast range of chemical, microbiological, physical and microscopy tests that may need to be evaluated to assess the stability of a pharmaceutical product and its packaging. Any contract research company (CRO) performing such studies will need to be equipped with considerable analytical resources and expertise.

Key to the success of outsourcing stability studies is the relationship/partnership between the client and CRO. It involves a high degree of trust and mutual support. The client must be willing to share potentially commercially sensitive information with the CRO, including technical transfer of analytical methods. The CRO must be fully communicative throughout the course of the trial and particularly vigilant to identify and communicate any out of trend/out of specification (OOT/OOS) observations.

From the CRO's perspective, openness may simply be a matter of regular communication and a readiness to respond to client questions. However, modern IT systems permit greater transparency through a web-enabled LIMS, which may allow clients to access and assess the progress of their projects.

In the case where progress is halted, perhaps by the reporting of OOT/OOS results, there are potentially serious cost implications for the drug manufacturer — another area where the choice of CRO could prove significant. A CRO with investigative abilities as well as routine testing capability will certainly be able to save a client time and money, especially when investigating OOS results. Investigative analysis will provide critical information to the client and help determine the course of action to be taken.

Bracketing and matrixing

The CRO may also be able to save money for the client by careful bracketing and/or matrixing of the stability study. Bracketing describes the design of a stability schedule such that at any time point only the samples on the extremes are tested, for example, the minimum and maximum dosage forms, or smallest and largest pack sizes. Clearly, bracketing has an inherent assumption that intermediate conditions are covered by the extremes.

Matrixing is a statistical design of a stability schedule so that only a subset of the total number of samples is tested at any specified time. At subsequent set times, a different subset of the samples will be tested, with the aim that all samples are tested at some point during the lifetime of the study. Clearly, where an OOT/OOS situation occurs, samples not scheduled for testing can be tested to provide supplementary data to support or negate the continuance of the stability trial. In any event, matrixing can be applied to samples where there already exists a high degree of certainty concerning their stability. In all cases, scientific and often statistical justification of the matrix design is required.

Both bracketing and matrixing seek to reduce the resource required for a stability study without compromising data quality and patient safety.

Stress and light

Stress testing is typically targeted at determining the stability of the drug substance. According to the ICH definition, stress testing "helps to determine the intrinsic stability of the drug substance by establishing degradation pathways to identify the likely degradation products and to validate the stability indicating power of the analytical procedure used". Photostability testing is seen as an integral part of stress testing and may be pertinent to the testing of drug substances and drug products. Indeed, the ICH gives specific guidance (in Q1B) for photostability testing.²

An experienced CRO can help to define the specific stress parameters to be applied to the test material. Such variables may include temperature, humidity, pH, oxidation and light. The CRO may also be able to suggest appropriate tests for identifying the degradation products, which may be unanticipated and difficult to isolate/identify.

Conclusion

There are many more aspects to stability studies than appear at first sight. Their duration and the long periods of inactivity between each round of testing can suggest that stability testing is more about the waiting than the testing. The name too can also create the expectation of stability and the absence of anything to report, whereas as noted above, the study is principally concerned with detecting instability.

As such, stability studies play a key role in drug development and in getting new drugs to market. The scientists playing the role of 'best supporting actors' are not mere walk-ons, but an essential part of the drug development team, a fact which both the client and CRO should not take for granted when stability studies are being outsourced.

References

Peter Rooney is a technical manager (pharmaceuticals) at RSSL Pharma (UK).

1. www.emea.eu.int/pdfs/human/qwp/293499en.pdf

2. www.ich.org/LOB/media/MEDIA412.pdf