Outsourcing stability studies is the best option for pharmaceutical firms. Handing these routine, but vital studies over to experts with established capacity reduces costs and lets in-house staff focus on drug R&D.
The aim of a stability study is, as the name suggests, to determine the stability of a drug formulation. Testing takes into consideration the impact of a variety of environmental factors, including temperature, light, and humidity.
The International Conference on Harmonization (ICH) provides detailed recommendations for stability testing in guideline Q1A (R2)1, which has been adopted by many regulatory agencies including the EMA and the U.S. FDA.
Regional Regulatory Variation
While this framework exists, specific testing requirements vary considerably between markets, even those that share it as a standard.
For example, the microbiological limits used in the U.S. differ from those in Europe. It is, therefore, vital that the stability studies are tailored to the market for which the pharmaceutical product is destined, which requires detailed knowledge of what data is acceptable and what is not.
One example is bracketing and matrixing, which is an ICH backed statistical analysis-based means of reducing the number of tests required during stability testing2.
Bracketing and matrixing is accepted by regulators in the U.S. and Europe; however, it is not accepted in South Korea. As a result, pharmaceutical firms targeting Korea will need to include additional experiments in their stability testing programs.
Likewise, Korean regulators usually require a minimum of three batches to be tested in order to determine an expiry date for a drug product. In other markets, fewer batches are often required as statistical methods are permitted.
Market knowledge is also critical to the development of a stability testing program in regards to the range of the conditions tested. Understanding the climatic conditions of the territory in which a drug will be sold is key to determining how it needs to be tested.
For example, if the country has a very high average temperature, it is imperative to conduct studies that test the stability of a product in the appropriate conditions.
To take factors like temperature and humidity into account, the ICH varies the testing conditions it recommends.
Under the ICH guidelines, countries are grouped into different climatic zones. The idea is that manufacturers can use these zones to determine the type of testing that is likely to be required in a particular market and include it in their programs.
Small or Large Molecule Testing
The type of drug being tested also has a considerable impact on its stability testing program. In general, small molecule, chemical-based pharmaceuticals are more straightforward to test than biopharmaceuticals based on proteins, cells, or nucleotides
For small molecule drugs, the degradation dynamics are predictable based on the constituent compounds and knowledge of how they are impacted by storage and environmental conditions. For large molecule drugs, degradation pathways vary considerably, which means stability testing programs need to be bespoke for each product.
Additionally, large molecule formulations are generally highly concentrated, which increases the likelihood the active pharmaceutical ingredient (API) will precipitate during stability studies. Understanding this process and the impact it is likely to have on stability is critical to generating the quality of data that regulators demand.
Thermal stability is another factor that is particularly important for biopharmaceuticals. Biopharmaceuticals usually are only stable over a very limited temperature range. Excursions—temperature deviations outside the optimum storage conditions—can have a significant impact on stability. Testing the stability of such sensitive products in a range of temperatures needs to be carefully planned to take actual storage conditions into consideration.
The Role of Outsourcing
Conducting an effective stability testing program requires expertise in a number of fields. Such programs also require considerable investment to set up the required stability chambers, and to maintain them during the desired assessment periods.
Fortunately for the pharmaceutical industry, there are contractors with established capacity and expertise in undertaking this sort of work. And, in addition to accessing knowhow and reducing costs, outsourcing to a CDMO allows the pharmaceutical developer to focus on doing what it does best: developing pharmaceuticals.
Selecting the CDMO that best meets a pharmaceutical company’s stability testing needs is a critical process. It is vital that the contractor has both up to date information about regulations in the destination market, and the requisite capacity to successfully carry out the program.
For instance, it is fairly straightforward to ascertain if the CDMO has a current good manufacturing practice (cGMP) compliant facility, as well as instruments that meet with 21 CFR guidelines.
Response time is another important factor to consider. The ideal CDMO is able to perform the stability studies as accurately and quickly as possible. Any delays are likely to impact the pharmaceutical customer significantly as, in many markets, regulatory approval is contingent on the provision of stability data as part of the submission.
Transparency is equally important. It is vital that the contractor communicates any out-of-specification (OOS) results to its customer as quickly and openly is possible. Any failure can have a serious impact on a development program and, in the most extreme cases, require that tests are repeated. The additional costs associated with repeat testing can be significant. Likewise, retests can considerably lengthen time to market.
Another important consideration is the scale of your project and company. It is vital the CDMO is capable of providing services that are suitable. For example, a small pharma company that lacks any internal capacity is likely to need a contractor that can provide everything from sample receipt to reporting, ideally at a single site to improve oversight and minimize costs.
In contrast, a large pharmaceutical company may have some capacity in-house and may, therefore, require a more bespoke service.
Stable, but Not Static
The field of pharmaceutical stability testing is rapidly evolving as pharmaceutical firms look to new markets, drugs become more complex and regulators demand better quality, and more extensive data.
For an R&D focused company, it is important to consider the benefits of outsourcing a stability program to a CDMO with capacity, expertise, and experience. The capacity guarantees the correct tests will be carried out in a timely manner, while the expertise means the program will be planned effectively with the specific destination market in mind. Finally, the CDMO’s experience will ensure that any unexpected occurrences are managed in an effective and appropriate manner.
References http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1A_R2/Step4/Q1A_R2__Guideline.pdf  http://www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q1D/Step4/Q1D_Guideline.pdf
About the Author
Dr. Ramesh Jagadeesan, Ph.D is the sr. director of analytical development at Recipharm. He has 20 years of experience in analytical research and development, and has authored numerous research publications in the areas of analytical development, controlled release technology, and stability studies. He is an expert in stability studies for NCE, ANDA, commercial, and clinical stability.