Stability data helps pharmaceutical firms to forecast demand and plan manufacturing, packaging and logistics. In addition, complying with regulations also requires a detailed understanding of drug stability.
Different regulatory authorities have differing data requirements and testing rules. All of this means that developing an effective stability study programme is an important yet increasingly complex task for a pharmaceutical firm, particularly if it supplies multiple markets.
In this article, Dr Ramesh Jagadeesan, Senior Director, Analytical Development, at Recipharm, discusses emerging trends in stability testing and explains how working with the correct service partner can streamline and accelerate the process.
Role of stability studies
Stability studies are defined in International Conference on Harmonisation of Technical Requirements for Registration of Pharmaceuticals for Human Use (ICH) guideline Q1A (R2).
According to the guideline — which has been adopted by regulators such as the US Food and Drug Administration (FDA) and the European Medicines Agency (EMA) — the aim of stability testing is to demonstrate “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.”
Put simply, a stability testing programme allows the pharmaceutical manufacturer to determine the optimum storage conditions and expiry date of a drug substance or drug product.
Globalisation and markets
National and regional drug regulatory agencies usually require stability data prior to granting marketing approval, which means testing is usually conducted in parallel with clinical development. The difficulty is that the specific stability data required by authorities in each market differs. As a result, testing programmes have to be developed with the specific market in mind.
For example, even though authorities in the US and European Union have adopted the same standards, they set different microbiological limits for stability tests. Some assessments that can be omitted in the US are mandatory in the EU and vice versa. And outside of the major markets, understanding the nuances of a country’s stability testing requirements is equally important.
South Korea is a good example. In Korea, regulators do not accept the bracketing and matrixing approach, which is a statistical analysis method used by authorities in the US and Europe to reduce the number of tests required.
Likewise, Korean regulators require that a minimum of three product batches are tested to determine the expiration dates. In other markets, fewer batches are often required as statistical methods are preferred.
Climatic conditions and sample transport
Regional climate characteristics and logistics infrastructure also impact drug stability and therefore need to be included in stability testing programmes. To take these factors into account, the testing conditions recommended by ICH vary depending on the temperature and humidity in the destination market.
ICH has assigned countries into different climatic zones. The idea is that manufacturers can use these zones to determine the type of testing regulators in a particular market are likely to request and include it in their programmes. Sample logistics are also an important criterion for some regulators, with regulatory agencies in some countries requesting that the stability study is conducted at the final packaging site.
Dr Ramesh Jagadeesan
Small molecule versus biopharmaceutical
Beyond regulatory and environmental considerations, it is also necessary to keep the specific nature of the product in mind when developing a stability testing programme. In this regard, the biggest driver of change is the continuing growth of the large molecule drug market, because such products differ markedly from traditional chemical-based pharmaceuticals.
For example, for small molecules, degradation pathways are predictable, which means that shelf-life specifications can be set based on toxicological studies. In the case of biopharmaceuticals, degradation pathways are unpredictable, which means extensive testing is usually always required.
In addition, because parenteral biologics are administered in highly concentrated dosages, there is a likelihood that some degree of precipitation will take place during stability studies. This occurrence needs to be planned for during the programme development stage.
Also, biopharmaceuticals are usually highly susceptible to temperature fluctuations; indeed, most have very narrow thermal stability profiles. Clearly, this needs to be kept in mind when deciding at which temperature storage conditions the product should be tested.
Outsourcing complexity
Given the growing complexity of stability testing, it is understandable that many pharmaceutical companies are choosing to outsource such work. CDMOs have the infrastructure and expertise to help clients ensure their testing programmes are relevant, cost-effective and as streamlined as possible.
For example, there is considerable cost involved in setting up stability chambers for different customised conditions. Likewise, it is expensive to maintain stability chambers, which are energy intensive and require back-up generators. Outsourcing stability testing activities to a trusted CDMO that has established capacity is clearly more cost-effective than developing such capabilities in-house.
Expertise is also a factor. A CDMO with a history of providing stability testing services is often better placed than a pharmaceutical company that conducts testing on a per product basis. Hiring a CDMO also allows in-house pharmaceutical company staff to focus on what they do best, namely R&D rather than routine testing.
Outsourcing also reduces the risk of bias. A services firm is less likely to allow bias to impact its test results in favour of a candidate product.
Points to consider when hiring a CDMO
As illustrated, stability studies are a critical part of the drug development and approval process. Choosing the correct CDMO to conduct such testing is critically important. The ideal approach is to use a list of criteria to assess the potential CDMO’s capabilities before deciding.
Turnaround time is one criterion. How quickly a CDMO can develop a stability testing programme based on information provided by the customer is a good illustration of how engaged and responsive it is likely to be throughout the process.
Likewise, transparency is important. It is critical that a contractor keeps an open channel of communication with the sponsor, particularly in the event that out-of-specification (OOS) results occur. CDMO capacity and infrastructure are also worth taking into consideration. It is vital that the contractor has a cGMP standard facility and instruments that comply with 21 CFR guidelines.
Summary
It is vital to have a detailed understanding of a drug’s stability in a range of environmental conditions that match the target markets. It is also critical to understand the specific requirements of regulators in the target market at the earliest possible stage to facilitate the effective development of a stability testing programme.
CDMOs can help pharmaceutical manufacturers to ensure that the stability of products is tested in a timely, cost-efficient manner, which can have a significant impact on the duration of the approval process.
