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Although stability testing programs for small-molecule drugs and biologics are often perceived as similar, stability programs for biologics are far more complex.
The purpose of stability testing programs is to ensure a drug product’s safety and efficacy remain within its specifications throughout the shelf-life. To develop suitable analytical methods to detect and quantify degradation products, drug manufacturers should conduct forced-degradation studies.
“Conduct proper analytical method development by understanding the drug substance degradation pathway,” says Shailesh Vengurlekar, SVP, quality and regulatory affairs, LGM Pharma. “Use validated stability-indicating test methods to perform testing at the scheduled time period.”
Stability programs and their practices can vary widely. These differences become more intricate when comparing stability testing of small molecules versus biologic drugs and how it impacts shelf life.
“A larger company that manufactures multiple products and batches must manage numerous stability studies with many more samples to analyze,” says Patrick Nieuwenhuizen, senior manager consultant, PharmaLex. “It can be more challenging to manage the volume of samples and testing compared to a smaller company with fewer products and fewer studies. Hence, you see larger companies are making more use of integrated software programs that can manage multiple stability studies.”
Regardless of company size, there are essential practices for stability testing that all companies should implement. From study design to testing completion, all companies should have a clearly defined process for stability, explains Anna Thabit-Jones, stability manager, PCI Pharma Services. To set up and manage a stability study, a detailed protocol is essential.
Nieuwenhuizen also notes that having a robust stability program is an essential practice for stability testing and shelf life. In addition, companies should have a scheduling system in place with adherence to testing the allocated time points within the study. There are many examples of companies receiving a regulatory citation for not having their stability program organized how it should be, Nieuwenhuizen adds.
According to Vengurlekar, all companies should follow the International Council for Harmonisation (ICH) guidelines to design a proper stability program and testing intervals.
Anis H. Khimani, PhD, senior strategy leader, pharma development, life science, PerkinElmer adds, “ICH Q1E guideline provides recommendations on how to use stability data generated in accordance with the principles detailed in the ICH guideline, Q1A(R2) Stability Testing of New Drug Substances and Products, to propose a retest period or shelf life in a registration application.”
For recommendations on the setting and justification of acceptance criteria, reference ICH Q6A and Q6B, Khimani specifies, whereas ICH Q1D is for the use of full- versus reduced-design studies.
Both small and large pharma organizations should consider addressing the critical quality attributes (CQAs), continues Khimani. CQAs could have an impact on purity, potency, drug release, stability, and safety. But for both small-molecule and biologic drugs, a QA review of protocols and establishment of methods and validation should be done. Khimani also confirms that a typical study can last up to two years based on the storage conditions and expected shelf life.
“A consistent and appropriate maintenance/calibration program for the stability chambers is also essential,” Thabit-Jones adds. “If you can’t trust your chambers to be working correctly and operating at the required temperature and humidity, then you can’t trust the data generated for any products stored. Depending on the size of the company’s stability program, effective sample inventory is also key to maintaining sample integrity. Testing should be conducted as soon as possible following the removal of the samples from the stability chamber. This is particularly important at the earlier time points and for accelerated conditions, as you want to capture the product stability at that point. Further degradation can occur over time.”
Although there are similarities in stability testing between small-molecule drugs and biologics, there are distinct differences as well.
“Issues associated with instability are potentially more significant and perhaps more likely to be observed with biologics than their small-molecule counterparts,” says Vengurlekar. “Biologics have a tendency to aggregate and are prone to degradation. Thus, the methods to accurately quantitate drug substance degradation differs between small-molecule and biologic drugs. To monitor various degradants from biologics, typically, analytical techniques such as Fourier-transform infrared, nuclear magnetic resonance, chromatography, mass spectrometry, and electrophoresis are used.”
Furthermore, stability tests are performed under controlled conditions (temperature and humidity) that match how the drug will be stored, which differ for small-molecule drugs and biologics.
“For small molecules, those conditions are typically set for 25 °C and 60% relative humidity,” says Arvind Srivastava, PhD, technical fellow, Avantor. “However, biologics may be lyophilized or stored as a liquid, and the more common condition is refrigerated at 2–8 °C. Humidity control is not generally required for biologics, but it may include additional conditions such as the orientation of the stored drug (upright or inverted). Agitation may also be applied because biologics can be sensitive to shear stress. Analytical techniques to monitor simple physical tests such as appearance, osmolality, particulates, and pH are usually the same for both small-molecule drugs and biologics. However, the technology utilized for purity and degradation products can be substantially different.”
In addition to storage conditions, CQAs for biologics must also focus on cell culture and production process parameters to ascertain the stability of the product along the entire workflow, states Khimani. Whereas, for small molecules, stability evaluation can be less complex.
Andrew Hanneman, PhD, scientific advisor, mass spectrometry laboratory at Charles River, adds, “In the development of biologics, specifically, an essential practice is the use of intelligent molecular design to avoid labile amino acids/sites in or around the protein’s active binding sites when practical. It is also important to initiate forced degradation investigations to support stability programs early on, even if they are not part of the formal stability program.”
One of the biggest misconceptions in stability testing—especially for late clinical or commercial products—is that the stability tests will produce a clear trend, notes Thabit-Jones, which is flat, increasing, or decreasing over time. However, some products may produce variable data points at each testing time-point and may not produce a clear trend until much later in the study.
“This makes it difficult to assess the likelihood of meeting the required shelf-life early on, and a deeper review of historical data can be required to support conclusions,” Thabit-Jones continues. “In addition, stability testing can sometimes be an ‘afterthought’ for some companies, but it is critical to collect data about product stability early on. The more data available, the easier it is to assess and investigate data that may be out of specification, out of trend, or out of expectation at later stages in the product life cycle.”
Another misconception is that stability testing is routine. While the testing techniques themselves are routine, every study is different and requires different testing, time-points, conditions, and final assessment, Thabit-Jones adds.
Although some people may perceive stability testing programs as similar for small-molecule drugs and biologics, stability programs for biologics are far more complex, confirms Srivastava.
“This is due to the complexity, degradation pathway, and mechanism of action differences between the two drug modalities,” Srivastava continues. “The degradation mechanism for small-molecule drugs is simple, typically involving hydrolysis and oxidation. Biologics, in comparison, can undergo a variety of physical and chemical degradation mechanisms, including unfolding, aggregation, fragmentation, surface absorption, particulate oxidation, deamidation, hydrolysis, and disulfide exchange. Additionally, potency can be extrapolated from the purity test for small molecules; but for biologics, a specific potency assay is mandatory in addition to a purity test.”
However, Nieuwenhuizen shares another perspective. As small molecules are better known, more stable, and less difficult to characterize than biologic drugs, it is a misconception that it would be easier to manage stability studies for small molecules, as the assays would be simpler for small-molecule drugs, Nieuwenhuizen explains. These assays for small molecules could be as complex as for biologics.
Providing an example for the complexity of assays for small molecules, Nieuwenhuizen says, “Potency assays for biologics [determine] the strength or assay in small molecules, in particular when the product is an antibody–drug conjugate (ADC), which is a combination of a [monoclonal antibody] coupled to a cytotoxic agent.”
How can drug manufacturers utilize all this stability testing data to ensure shelf life, and how soon should this data be collected? According to Thabit-Jones, stability data should be collected early on. The data should ideally guide product formulation and long-term storage.
“Trending and monitoring data at each time-point is essential to get a thorough understanding of how the product behaves over time. Companies should use this data to identify clear trends and understand what is unstable about the product,” Thabit-Jones says. “This may result in adjustments to the formulation to reduce the rate of degradation or allow storage at lower temperatures. The packaging type may also need to be reviewed where significant water intake is observed over time. Profile dissolutions will help in understanding delivery of the tablet/capsules once ingested and can guide adjustments in manufacture.”
Stability data can be used to monitor unintended drift in the manufacturing process, according to Srivastava. Early detection and corrective action can lead to a drug manufacturing process that facilitates a stable shelf-life.
“The quality and stability of raw materials and excipients also play a critical role on the stability and shelf-life of drug products,” Srivastava continues. “Small molecule and biologics manufacturers can work with their raw material suppliers to access stability data to assist with designing products with a stable shelf-life.”
Srivastava adds, “For both small and large molecules, partnering early on with trusted raw materials and excipients suppliers can help ensure quality and consistency of raw materials throughout the drug manufacturing process.”
Meg Rivers is a senior editor for Pharmaceutical Technology, Pharmaceutical Technology Europe, and BioPharm International.
Vol. 45, No. 10
Pages: 48, 50, 56
When referring to this article, please cite it as M. Rivers, “Determining Shelf Life: Reading the Stability Testing Data,” Pharmaceutical Technology, 45 (10) 2021.