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As compounds become more complex in nature and biological ingredients are more widely used, stability testing approaches must follow suit and provide flexibility for developers.
According to market research, the global pharmaceutical analytical testing outsourcing market is projected to have strong growth from 2020 to 2027 (1). Drivers of this growth include an increase in demand for biopharmaceuticals, biosimilars, and analytical drugs, in addition to a general requirement for bio/pharma companies to streamline operations and reduce costs.
To learn more about the criticality of stability testing throughout drug development, potential differences with small versus large molecules, regulatory requirements, and future trends, BioPharm International spoke with Ramesh Jagadeesan, senior director of analytical development, Recipharm; and Karin Kottig, manager contract service analytics, Vetter Development Services.
BioPharm: Could you elaborate on the importance of stability testing throughout the various development steps of drug products?
Jagadeesan (Recipharm): Stability testing is one of the most crucial steps in the development of new drug products. By performing a series of analyses, testing programs can determine how long a product will maintain the properties and characteristics it possessed at the time of manufacture. The effect of environmental factors (such as temperature, light, and humidity) on a formulation’s purity, efficacy, and structure is evaluated over time to define both its shelf-life and the necessary storage conditions. This information is vital for the regulatory approval of a new medicine.
Stability studies are conducted during all phases of drug development. They typically start at the preclinical stage of drug development and continue through Phase I–Phase III clinical trials to support formulation development, and to satisfy the regulatory requirements for clinical trials. However, the purpose of the studies and regulatory requirements vary depending on the product type, the phase of the program, and the intended markets.
The first stage of stability testing usually takes the form of forced-degradation studies. These studies help to identify the ideal formulation from a host of different candidates to take forward for further testing. The aim of this is to understand the primary degradation products of a molecule and aid analysts in selecting the best methods for further stability tests, which mimic real-life storage in different global regions. Long-term stability studies will subsequently be initiated and validated on both the API and the drug product.
In short, the aim of the stability testing process is to produce data that demonstrates whether any physical, chemical, or microbiological changes affect the efficiency and integrity of a pharmaceutical product. This helps to ensure medicines are safe and effective, irrespective of where in the world they are supplied.
Kottig (Vetter): Stability studies are an essential and vital part of drug development. They are necessary throughout all phases with stringent timelines for analytical testing. The purpose of the studies is to prove how the quality of an API or drug product changes over the course of time while under the influence of environmental conditions such as temperature, humidity, or light. Stability studies also support the determination of the re-test date of the active ingredient, shelf-life of the drug product, suitable packaging materials, and recommended storage conditions.
With respect to new drug applications, submissions for approval by regulatory authorities are required to contain data from stability studies conducted on both the drug substance and the drug product. During drug development, this assessment is performed with the help of a variety of well-designed stability studies in the different development phases. During early development, stability studies are performed on technical batches as well as on clinical samples. These include, for example, stress and accelerated studies of the drug substance and product to support setup of formulation, selection of primary packaging, and production process. In later phases, transport and cycling studies as well as long-term and accelerated studies with registration batches are realized. All data are compiled to generate the expiration date of the drug and, finally, to obtain the market authorization.
After product launch, follow-up stability studies of market batches are conducted on a regular basis. The studies are also necessary after post-approval changes. In this way, they significantly influence the entire lifecycle of a product. Ultimately, they are essential to provide a drug and thus the health of the patient by supplying a stable product with consistent quality.
BioPharm: Are there specific differences in terms of stability testing for small-molecule versus large-molecule products?
Kottig (Vetter): From complex and highly sensitive substances to vaccines and biotechnologically produced proteins, the manufacturing of drug products demands a high-degree of expertise and flexibility to perform all the necessary and product-specific processes prior to the independent completion of the final product. Thus, stability testing required for ensuring a product is fit for use are adapted on a case-by-case basis.
The increasing number of biologics in clinical development has had a significant impact on analytical methods and has brought forth new scientific challenges. When it comes to injectables, biologics are placed into a small volume of liquid that often requires a very high concentration. This leads to unique stability issues related to aggregation, viscosity, and thermal degradation. And, while still relatively complex, it is usually a straightforward process to demonstrate the identity, correct content, and purity of small-molecule drugs and the correlated products. The evaluation of the quality of a biological, large-molecule product requires much more complex analytical and bioanalytical methods.
From my point of view, the increased focus on particulate matter is also correlated to large-molecule products as they are often very sensitive. Aggregation, as well as interactions with other components such as excipients and packaging material, for example, could lead to increased particulate matter formation. These particulates will then be analyzed with different analytical methods.
Jagadeesan (Recipharm): The development of an appropriate stability testing program typically considers the specific nature of the product being evaluated. Based upon the constituent compounds and knowledge of how they are impacted by storage and environmental conditions, the degradation dynamics of small-molecule products are predictable. The rise of newer, large-molecule drugs developed using biotechnology has brought new scientific challenges for stability testing.
The greater complexity of large-molecule products, combined with more batch-to-batch variance and specialized storage conditions, makes typical stability study conditions unsuitable. To this end, bespoke stability testing programs need to be designed for each product. Biopharmaceuticals are generally highly concentrated and/or less soluble, which increases the likelihood that the API will precipitate during stability studies. Clear, quality data surrounding this process are essential to ensuring regulatory compliance.
In addition, small-molecule degradation pathways are more predictable and shelf-life specifications are set based on the toxicological studies. Whereas, with biopharmaceuticals, degradation pathways are much more unpredictable, and they differ for different proteins. For example, some parenteral biologics administered for patients are highly concentrated, so they may precipitate during the stability studies.
Biopharmaceuticals are often only stable over a very limited temperature range, meaning that excursions/temperature deviations outside the optimum storage conditions can have a significant impact on stability. To this end, they should be stored within an extremely narrow temperature range to avoid an impact on biological activity. Testing the stability of such sensitive products in a range of temperatures needs to be carefully planned to take actual storage conditions into consideration. Additionally, the stability of proteins often calls for other analytical methods other than the liquid chromatography that is frequently used for small organic molecules.
BioPharm: What are the regulatory expectations for stability testing?
Jagadeesan (Recipharm): The International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH) has established stability testing guidelines that provide comprehensive guidance on registration stability requirements for new drug applications in the ICH regions. These guidelines recommend different testing protocols for climatic zones around the globe. For example, storage stability tests can range from temperatures as low as -80 °C to 40 °C, with relative humidity up to 75%. The ICH guidelines have been adapted by many regulatory agencies including the European Medicines Agency (EMA) and FDA for its abbreviated new drug applications pathway.
There are, however, marked differences in the specific stability data required by authorities in each market. As a result, testing programs should be developed with the specific market in mind. For example, despite authorities in the United States and European Union adopting the same standards, they set different microbiological limits for stability tests. In addition, some assessments that can be omitted in the US are mandatory in the EU and vice versa.
Stability testing of pharmaceutical products is mandatory for regulatory approvals. If a product fails to meet the standards prescribed by the ICH, as well as those defined by the World Health Organization, the product will not be granted approval for commercialization. Planning, execution, and completion of studies in given timelines plays a major role in securing approval and ensuring a product reaches patients.
Kottig (Vetter): Drug stability is not simply a requirement of the regulations. Rather, stability testing operations are a ‘window’ for the development program of the product and the assurance of quality. Practically all regulatory requirements for drug stability testing are clearly described in [good manufacturing practices] GMP guidelines. Today, stability plans include far more than just the determination of an expiration date for a pharmaceutical product. They also require a written stability testing program that specifies sample sizes and test intervals, controlled storage conditions, validated and specific test methods, and specifications. Furthermore, requirements stipulate that an adequate number of drug production batches are tested. In addition, it is mandatory to perform stability testing of the product in its marketed container or closure system.
There has been considerable harmonization of regulatory guidelines, with the ICH pharmaceutical stability guidelines now recognized as the globally accepted industry standard. ICH provides practical guidance on the amount and the type of drug substance and drug product stability data needed to support marketing applications. The included quality guidelines Q1A–Q1F have made a major contribution to increasing the quality of pharmaceuticals and are applicable for small molecules. Generally speaking, they apply to large-molecule products as well. ICH Q5C takes into consideration the specific characteristics of biotechnological/biological products. These large-molecule products are typically more sensitive than small-molecule products and require complex analytical methods to demonstrate that their molecular conformation is maintained during shelf life. For example, a potency assay is required to prove biological activity is maintained. Usually, more than one analytical method is needed to prove purity of the product.
BioPharm: As molecules in development become more complex and difficult to deal with, what trends do you predict may impact the industry over the next 5–10 years in the area of stability testing?
Jagadeesan (Recipharm): As the demand for biopharmaceuticals increase, even more efficient methods will need to be in place for the assessment of protein activity. This makes it necessary to have access to more analytical technology compared to when handling small molecules, where liquid chromatography can fulfill most analytical needs.
A great challenge in product development is the time it takes to ensure stability. There is a significant need for methods that enable the prediction of the stability of a formulation at an early stage as this will allow companies to shorten development timelines and reduce the risk of unforeseen challenges later on in stability studies.
While APIs are growing in complexity, there is also a trend towards more complex formulations, such as nanoparticles, microemulsions, and amorphous formulations to give acceptable solubility and bioavailability. For these formulations, physical-chemical characteristics, in particular solid-state characteristics, are very important; hence, this leads to the need for more physical-chemical characterization during stability studies.
Kottig (Vetter): When addressing the challenges of increased complexity of molecules in development in combination with even shorter timeframes for drug development and smaller batch sizes, the pharmaceutical and biotech industry should collaborate with regulatory bodies to generate meaningful risk-based guidance. Holistic approaches will require good data management and integrated systems to collect, manage, and process data to effectively support stability analyses in the future.
Felicity Thomas is the European editor for BioPharm International.
Vol. 33, No. 3
When referring to this article, please cite it as F. Thomas, “Stability Testing: The Crucial Development Step,” BioPharm International 33 (3) 2020.