Meeting Stability Testing Expectations In Today's Complex Pharma Landscape
By Daniel Galbraith, Director of Global Product Characterization, MilliporeSigma
The biopharma industry is constantly advancing and innovating, but what does this mean for processes? Standard approaches are not viable long term due to regulatory changes, more cutting-edge drugs, and new markets. Stability testing is one area that may be considered a victim of the status quo, and this can be misleading because higher expectations are being placed on data quality. Specifically, the regulatory demands are focused on extensive and in-depth analysis more than ever before. This amplifies the responsibility of drug developers to evaluate testing and optimize processes, resulting in complex processes for manufacturers to confirm the quality, efficacy, and safety of drug formulations. A framework for stability studies exists; however, specific testing requirements vary considerably between markets. So, how can drug developers mitigate risks, avoid costly mishaps, and stay current? Let’s explore these questions and their impacts.
Stability Testing In A Changing Market
Measuring aggregates is foundational to stability testing and is a good example of how testing has changed over the years. Aggregates can be a simple accumulation of a few molecules together or can be a much larger complex of many thousands that can be seen by the naked eye. Aggregation not only reduces the amount of available active drug to affect treatment, but in some circumstances, aggregates can provoke a serious immune response. In the past, aggregates were estimated solely by a visual inspection by a laboratory technician. As technology has advanced, so have methods. One can now fully elucidate each type of aggregate in relationship to size and shape. In addition, clinical studies have pointed to which aggregates, and under which circumstances, are of concern to patients. As a result, regulators are asking deeper questions, such as:
- Are aggregates at a safe level?
- How much does the level of aggregates increase over time with your drug?
- Does the number of aggregates increase after several years, or do they disappear?
What was once a check-the-box procedure in standard stability testing now requires a deeper understanding of the molecule, how it behaves, and, most importantly, what effect it has on the patient.
Variety of Modalities
Next, we must consider the diversity of drugs in today’s market. It’s important to remember during stability testing that one size does not fit all. The principle of the study is the same, which is to understand what the drug’s expected safe length of storage is by exposing the drug to different conditions and monitoring it over time. However, the analytical packages will vary because the critical quality attributes of each drug will be different. For example, monoclonal antibody drugs and antibody drug conjugates (ADCs) are two very similar drug modalities, but monoclonal antibodies can last up to three years while an ADC, on the other hand, has an expected shelf life of only 12 months. For the latter, one would profile the checkpoints within a year rather than the standard three-month intervals for up to three years. The characterization of an ADC also requires substantially more analytical characterization of the intact molecule and the breakdown products than the naked antibody. As a result, these studies can be completely different. Biosimilars are another example of how different drug types require different approaches, as the stability study must show that the degradation of a biosimilar molecule is the same as the degradation of the innovator drug. In other words, biosimilars must begin and end “life” just as the innovator drug does. Therefore, the analytical profiling of the breakdown products in a biosimilar stability study will be more expansive than the innovator drug being compared.
Overall, the more we learn about new drugs before clinical trials, the better we understand how they function and what can be done to make them more effective. This safeguards your product, satisfies regulators, and ultimately, gets your drug to patients faster.
Developing a Stability Protocol
Before moving into Phase 1 clinical trials, a drug must have at least three months of stability testing data available, which is why a protocol is so important. Questions to be considered when developing your stability protocol include:
- How much of a drug will be made?
- How much is needed for a stability study?
- What methods will be used to determine stability?
- Which batch will be used for testing?
The methods selected must be validated and ready for use as soon as the drug is available. One key component of a validated assay is reference material. This sets a basis for the analytics and allows reporting of the data. Methods will need to be developed on the reference material before the actual drug is available. These steps are completed within 6 to 12 months before the first clinical trial begins. As soon as the prototype drug is available, the reference provides the comparison that will be submitted to the regulatory agency for permission to release to the clinic. Stability testing will continue throughout the duration of the clinical trial with the reference material used at each time point. So, if you have a clinical trial that lasts for 24 months, you must make sure you have enough materials and the analytical testing capabilities available for a two-year period.
Accelerated & Long-Term Stability Studies
An accelerated stability study is useful for formulation development, establishment of stability-indicating methods, and comparability. These are performed by exposing a drug to extremes, such as very high temperatures, freeze-thaw, agitation, high pH, low pH, and light exposure, in order to examine the breakdown products of the molecule. This type of test can identify whether anything unusual or potentially dangerous occurs that might prevent the drug from going into clinical trials . This information is also useful to assess risk when a batch experiences a temperature excursion, as the accelerated stability study will show how much of an impact that excursion has on the drug’s efficacy or safety.
As you move into later phases, the patient pool gets bigger and the timeline for treatment is longer, requiring more data on the long-term stability of multiple batches of a drug to show consistent stability over time. Specifically, regulators want to see the breakdown pathway of a drug to know what happens as it decomposes and the implication of that breakdown, such as:
- aggregation
- fragmentation
- deamidation
- oxidation
This information details the biological activity of the drug, eventually determining its shelf life. Stability testing also includes examination of the container closure. This dye test indicates the length of time a drug can be stored without leakage from within the container or from outside into it. For example, plastic containers may shrink or change during freezing.
Once clinical trials are complete and a drug enters the market, oversight of the drug and its safety continue with post-licensure monitoring. Drug manufacturers must collate any information from medical professionals to determine if there are adverse effects reported after treatment or any heightened risk factors that could lead to other complications. If an event occurs or something about the manufacturing process or formulation of the drug changes, stability testing should be conducted again to determine if these changes have any impact on shelf life.
Regardless of the phase, stability testing does not have a pass or fail baseline, it simply offers insight into how a drug behaves under certain conditions and over time. This helps put necessary restrictions on the drug to ensure it is only available to patients when it is safe and effective. Partnering with a company with the expertise and capabilities to properly execute stability testing provides access to a wide array of technologies and experience, enabling you to achieve your first-to-market goals, a key advantage in today’s competitive market.