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The importance of capability and capacity of a CDMO partner to deliver drug substance and product testing should never be underestimated, considering the increasing complexity of compounds in development.
Stability testing of medicines is a vital component of bringing a drug to market. While there are universal standards and guidance from the International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use (ICH), each drug product requires a bespoke program-particularly as new chemical entities (NCEs) are becoming increasingly complex.
Contract development and manufacturing organizations (CDMOs) have an important role to play in drug product testing. Not only can CDMO partners provide expertise capabilities and capacity to perform the potentially numerous tests required for product commercialization, but an end-to-end partner can offer accelerated assessment programs to help predict long-term stability and planning for late-stage programs. To discuss the significance and best practices of stability testing, as well as the key role of an outsourcing partner, Pharmaceutical Technology spoke with Zhen Liu, executive director of analytical services at WuXi STA.
PharmTech: How important is stability testing during the various drug development steps?
Liu (WuXi STA): Stability testing, as a mandatory requirement for the filing of investigational new drug (IND) applications and new drug applications (NDA), is naturally a critical component of any drug development program. Tests are required throughout all phases of development from the preclinical stage to post-product launch. (Table 1)
Early stage testing focuses on the stability of the drug molecules. For example, the initial stages can use studies with severe conditions to get an initial idea of degradation products (impurities) that need to be monitored in subsequent studies. Initial studies can also provide data to help develop the formulation, packaging, and storage conditions required at late phases.
Table 1: List of tests required at each phase of development. (Table is courtesy of Zhen Liu, executive director of analytical services at WuXi STA.)
Phases of drug development
Stability testing focus
Stability of drug substance to understand the molecule characteristic and select the most stable drug physical form
Preclinical to IND
Informal and formal stabilities on drug substance and drug product for IND submission
Predict re-test period for drug substance and select appropriate storage conditions for drug substance and drug product
Validation of analytical methods and specification limits
Clinical to NDA
Formal stability studies to accumulate data. Packaging screening might be needed
Formal stability studies for registration batches and PPQ batches for drug product shelf life assignment
Formal stability repeated for new formulation or packaging and change in climate zone
PharmTech: Can you explain stability testing for drug product versus drug substance?
Liu (WuXi STA): In the case of drug product, the use of stability testing determines the re-test date of the clinical trial materials and shelf-life of the commercial product. The finished drug product requires multiple tests to verify its safety and efficacy. A variety of different techniques are used to establish the stability of each drug product based on its dosage form. These can span from simple techniques such as appearance, disintegration, and pH determination to more complex testing requiring chromatography coupled with mass spectrometry.
For example, in the case of oral solid drugs, appearance, assay, degradants, dissolution properties, water content, and microbial testing are usually performed. Whereas for injectable products, additional tests are required for pH, insoluble particulate matter, and sterility.
Unlike drug products (which are dependent upon formulation, the dosage form etc.), the tests for drug substances are relatively standard-including appearance, assay, impurities, water, and physical characterizations.
PharmTech: What are the regulatory expectations for stability testing?
Liu (WuXi STA): Globally, the regulatory standards are quite similar as most authorities are using the ICH guidelines, which provides in-depth recommendations for stability testing (1). The ICH pharmaceutical stability guidelines have been implemented by many regulatory agencies such as the US Food and Drug Administration, the European Medicines Agency (EMA), and the Chinese National Medical Products Administration (NMPA). Additionally, recommendations about different testing protocols per climate condition are also in place, with countries grouped into different climatic zones to best determine the type of testing needed.
There are some slight differences in the ICH guidelines for small and large molecules. Although both follow ICH Q1 guidelines, biologics also follow an additional guideline for stability testing-ICH Q5C. This additional ‘layer’ includes information on the properties of biologics, storage conditions, and testing frequencies.
PharmTech: Which approach to stability testing is considered the best?
Liu (WuXi STA): As previously mentioned, stability testing programs are well defined and there are standardized protocols to follow according to the ICH requirements. But several factors may shape the program, including the properties, dosage form, and packaging of the product.
In fact, packaging is a major component of stability testing. Smaller biotech companies often use similar packaging in early stability tests that best mimic the expected commercial packaging to save time and cost. In most cases this will be fine, but it does run some risks of the packaging failing the stability tests and so an alternative packaging needs to be retested before the NDA can be filed. Large companies often opt to select two or three different packaging types to run stability tests in parallel, then select the most appropriate packaging based on these results.
PharmTech: What benefits can companies gain from using an outsourcing partner for stability testing?
Liu (WuXi STA): There are a wide range of benefits by outsourcing stability testing. The ideal CDMO partner would have significant capacity to be able to perform the full set of stability studies quickly. For some stability programs, the testing number could be very large at a certain period of time. It may require tens or hundreds of the drug product samples to be tested in a short period of time, because each product needs to be tested for four to five items, with different strengths, batches, in different storage conditions, and in different packaging configurations. Vast resources are required to run a full program like this, including significant human resources and multiple equipment lines to complete on time.
Another benefit of partnering with an experienced CDMO is to leverage expertise, which is important in investigative testing when there are unknown impurities during the stability testing. It is critical to understand as much as possible about impurities, structure, and quality, to determine if product safety may be affected. For example, if the impurity is found to be genotoxic then it will increase the safety risk. Therefore, the ability to run investigative tests in-house is valuable.
Some companies will contract with different providers for drug substance or drug product testing, but it can be beneficial to perform all stability testing at one site. This simplifies the stability testing process, as it is often easier to compare impurity profiles and other stability data generated by the same company with the same methods and equipment. This is even more important for drugs in late-stage development where consistency and quality of data are paramount.
PharmTech: As molecules in development become more complex and difficult to deal with, what trends do you foresee becoming apparent over the next 5–10 years?
Liu (WuXi STA): One trend being witnessed is more companies using short-term stability tests during early-phase development to help predict the product’s long-term stability. These short-term studies include ASAP (accelerated stability assessment program) studies, forced degradation, etc. to collect data to predict the long-term stability. For example, we have an ASAP program we found more useful than traditional forced degradation studies. We use it to determine stability of the product under 7–10 different conditions. This process takes about three to four weeks, but the data generated is used to develop a model that can predict the product’s stability for up to one or two years. Developing these predictive models requires a combination of hardware, software, and expertise. Formal, long-term stability testing is still required as per the ICH guidelines, but these early predictive tests can help establish a high degree of confidence that the compound (drug substance form and formulation) will have long-term stability.
Another trend relates to the ICH guidelines for stability conditions based on designated climate zones. In the past, a product entering a new market would have separate stability testing designed for the different climate conditions. However, to achieve desired stability, one single change to specifications for drug substance or drug product might cause many product development steps to be repeated. Now, companies want to be ready to launch globally as soon as possible so they design one program that includes the storage conditions across their target markets.
More generally-speaking, many larger, more complex molecules are coming through the pipeline-such as peptides and oligonucleotides-necessitating that CDMOs are able to conduct more complex stability testing regimens than in the past.
1. EMA, ICH Topic Q1A(R2): Stability Testing of New Drug Substances and Products, ema.europa.eu, Guidance Document (August 2003).