Stability testing demonstrates how the quality of a drug substance or drug product may be influenced by temperature, light, humidity and other environmental factors, and is used to show shelf life within recommended storage conditions. Studies to evaluate any physical, chemical, biological, and microbiological attributes that may change during storage can be complex and costly.
This article discusses the regulatory expectations and guidance documents for drug stability testing, and provides practical approaches to stability testing of both small- and large-molecule drug substances, including a risk-based approach to testing for different stages of the product lifecycle. Special considerations for evaluating the impact that temperature excursions, vibration and other environmental factors may have on the drug product during shipping are also included.
Almost all regulatory requirements for drug stability testing are clearly described in guidelines. Tests within good manufacturing practice (GMP) regulations for specific product applications e.g. in-use stabilities, are outlined, and there are more detailed and specific recommendations that fall under best practices. GMP regulations are very similar throughout the world, and require a pharmaceutical product to have an expiration date, determined by appropriate stability testing. They also require a written stability testing program that specifies sample sizes and test intervals based on statistical criteria; controlled storage conditions; validated and specific test methods; and that an adequate number of drug production batches are tested. Stability testing of the product in its marketed container or closure is also required.
Application Requirements
In investigational applications, regulations require information to be submitted supporting drug substance and drug product stability during pre-clinical and clinical testing, and data are to be submitted consistent with the phase of study.
With respect to new drug applications (NDAs), submissions for approval by the regulatory authorities are required to contain data from stability studies conducted on both the drug substance and drug product, in support of the product expiration date. For abbreviated applications, such as those for new generic drugs, stability data must be included on the specific batch (es) used to conduct the pivotal bioavailability or bioequivalence study. The data must demonstrate that the generic has pharmaceutical equivalence to the branded product by having a comparable stability profile.
There has been considerable harmonization across GMP regulations, with ICH guidelines now the globally accepted gold standard, and the 2009 WHO guidance and Annex being the most current with respect to climatic zones III and IV -‘hot and dry’, and ‘hot and humid’, respectively. Additionally, stability plans today must include attention to shipping and distribution practices. ‘Stability’ itself is not just a requirement of the regulations: the stability testing operations are a ‘window’ into the whole development program of the product and the assurance of quality.
Which is Best, a No-Risk or a Lean Stability Test Strategy?
It may not, however, be practical to implement a completely no-risk approach to stability testing that guarantees product approval in all markets: there will always be tension between this approach and a ‘lean stability’ one in which testing resources are used in the most efficient and economical way possible. These science- and risk-based stability strategies are here to stay and are securing more converts each year, for example the International Consortium for Innovation and Quality in Pharmaceutical Development (IQ Consortium) is considering forming a working group on Lean Stability. It is essential that the pharmaceutical industry and the regulatory bodies collaborate to generate meaningful risk-based guidance that meets both the scientific and regulatory requirements for stability data. The question is how to balance taking reasonable risk with the demands of a working environment in which risk is not always rewarded. However, to ensure additional and unnecessary testing is avoided, confirmation and guidance of appropriate levels of stability testing can be given by regulatory authorities.
There is a continuum of risk that can be taken, ranging from the purely no-risk one, to the fully lean stability model. In the no-risk case, there is often the need to consider possible extra testing requirements for smaller markets other than the major ones of the USA, Europe and Japan. Such wider programs may result in there being fewer queries about drug substance or product quality but may require the pharmaceutical company to add ‘non-value-added’ stability testing to the program.
Lean stability testing, on the other hand, focuses on the highest-risk attributes of a product and on time points, making the most efficient use of resources by leveraging statistics, scientific tools and modeling, but there is the possibility of delaying approval. Project teams need to create different strategies with different costs and risks and present them to their internal sponsors. Risk mitigation strategies also need to be considered.
Stability Data Ensure Effective and Safe Products
Stability data are not only important in ensuring successful drug substance and product manufacture, as the supply chain for medicinal products and substances is itself highly regulated, with SOPs giving information about the procedures to be followed. Qualified equipment must be used for transportation as well. Obviously, during manufacture, the control and monitoring of manufacturing steps and process conditions is controlled, and any deviations from standards registered and evaluated; continuous improvement is a natural consequence of such activities. When transporting drug material, however, it has to be determined whether there is any risk for substance or product stability, and alongside the API, excipient quality and stability also needs to be taken into consideration.
Drug substance stability has to be considered throughout the drug development process, from the pre-clinical stage to final product approval. Analytical development, forced degradation studies and bulk API stability studies form the basis of pre-clinical work, with Phase I studies covering further analytical development and method validation, initial formulation stability studies, and stress tests. For container characterization, extractables studies have to be performed in order to detect potential risks of compounds leaching into the product, and help to choose the best container material. Typical studies performed in Phase II and III range from comparator release and stability studies, through to in-use and compatibility studies to registration stability and the completion of final method validation. Phases II and III are also the stages in which transportation stability studies should take place. Finally, after market approval, specific leachables studies and follow-up stability tests are performed.
Obviously, the stability of products will need to be tested under different conditions depending on where the product is to be shipped. Due to high variations over climatic zones, transportation simulation studies need to be adapted to guarantee quality of drug products and drug substances reflect local market stability requirements. The World Health Organization identifies four climatic zones – temperate (Zone I), subtropical and Mediterranean (Zone II), hot and dry (Zone III) and hot and humid (Zone IV).
Transportation: Its Effects on Drug Quality
So what risks does the pharmaceutical company need to be aware of during transportation? It needs to be aware of mechanical influences such as pressure variation, vibrations, and physical impacts, and climatic influences such as temperature variation, humidity and light. Chemical influences include gases and cross-contamination by other goods, while biological influences include microbial contamination and pest infiltration. Criminal factors also have to be considered, for example manipulation of goods and burglary.
There are a number of physical changes that may also occur in materials as they are transported, for example water condensation on the surface may lead to changes in physical or chemical properties of the drug substance or product. Humidity changes can affect the hardness of the tablets for example, and phase separation of suspensions can occur. Similarly, there may be precipitation effects with injectable solutions or parenterals. For large molecules, such as proteins, aggregation and denaturation may be a problem, and for medical devices, changes in functionality can lead to overdosing effects of drug may occur due to malfunctions of the device. An important question is, therefore, is it desirable to have warning information on the label in order to ensure safe transport?
In formulation development, is it important to make improvements to give a stable product that have reduced influence by temperature variations? This is important because globalization of pharmaceutical supply means that packaging of products may take place in local markets, that is, in different countries, which means it is necessary to have safe transportation systems. While distribution within local markets is managed by the pharmaceutical company or by a contracted partner, it is the responsibility of the manufacturer to ensure safe transportation during the distribution process.
According to the WHO ‘Guide to Good Storage Practice for Pharmaceuticals, Technical Report 2003,’ “Materials and pharmaceutical products should be transported in such a way that storage conditions are maintained” but transportation conditions are not similar to those of long-term storage. For example, storage is usually performed under homogenous temperature conditions, while temperatures may vary during transportation; storage is more controlled, with defined temperature and humidity ranges, whereas there is no control of these parameters during transportation with the exception of products which have to be transported a lower temperature – for example between 2 to 8°C - extreme variations in conditions being possible. In addition, storage is a long-term phenomenon requiring detailed documented records while transportation usually does not require major documentation of the procedures followed. Also worth noting is that in storage, data are evaluated in accordance with ICH guidelines, but there remains a question as to whether product stability is ensured within any distribution practices used.
Special Conditions
Temperature excursion studies demonstrate the influence of extreme conditions on product quality, for example, by conducting tests on samples maintained at temperatures up to 50°C and a relative humidity of 75%, or stored at temperatures as low as -20°C.
Temperature cycling studies show the effects of temperature variation, simulating changes from day to night and from sunny to dull conditions. For these tests, a study (one batch in the final container) employing the final product formulation should be sufficient, however, temperature excursion studies could be added to a global stability design in order to detect the influence of product stability. Temperature cycling conditions include low-to-high excursions such as 4 days at 5°C followed by 3 days at 40°C, for example; or freeze-thaw testing, a typical cycle being 5 days at -20°C and 2 days at 25°C. It is quite common to perform cycle testing before carrying out long-term stability studies.
Biological molecules present their own challenges in transportation stability testing, particularly due to their potential to denature and lose activity during shipment. Due to their sensitivity, biologicals are usually stored between 2 and 8°C or transported at -20°C to -60°C.
Conclusion
Stability studies are an essential and vital part of drug development and necessary throughout all phases, with stringent timelines for analytical testing. It is not uncommon that unexpected stability data may arise that can impact on the development program so it is critical for researchers to take rapid and effective action that minimizes the risk to their timelines, and satisfies the relevant regulatory authorities. A long term view on potential risks to drug product stability is recommended so that any deviances and effects caused by temperature excursions or agitation during shipment are identified in early development, rather than late phase stages. All through development, the goal is a safe and effective product.