Non-GMP and GMP Stability Studies of Biopharmaceuticals Meeting Regulatory Standards, Ensuring Patient Safety, and Maintaining Product Quality and Efficacy

A drug substance or drug product lacking stability can result in degradation, making a life-saving drug less efficacious, forming adverse-reaction-creating byproducts, or reducing shelf life and increasing storage complexity.

Therefore, stability studies assessing how a drug is impacted by environmental factors over time, ensuring it maintains its intended potency, purity, and physical properties, are critical to drug development, patient safety, regulatory compliance, and successful commercialization.

A Closer Look at Biopharmaceutical Stability Studies

Stability studies, conducted at various phases of development, systematically evaluate how long a biopharmaceutical product maintains its quality, safety, efficacy, and integrity under specified storage and stress conditions. These studies are critical to drug development, ensuring that products meet regulatory requirements and the drug’s handling and packaging needs are well understood so that the drug performs as intended throughout its determined shelf life.
A stability-indicating profile is generated to assess the stability of a drug. This profile consists of several analytical methods designed to evaluate key quality attributes during stability studies:

• Potency and content—Methods that indicate therapeutic capability/biologic activity (binding of target molecules, enzymatic activity)
• Purity and Impurity—Methods that indicate chemical stability and purity (aggregation, degradation, isoforms, glycosylation, stoichiometry, process-related impurities)
• Microbiology—Methods that indicate microbiological safety (Bioburden, Bacterial Endotoxin, sterility, CCIT)
• Physical properties—Methods that indicate key physical parameters (pH, osmolality, visual inspection, etc.)

Overview of Stability Study Regulatory Guidelines

Although it is well understood today that a drug’s physical and chemical stability is a critical quality attribute on par with the criticality of understanding purity, solubility, chemical identification, molecular weight, and microbiological purity, that was not always the case. The first publications discussing pharmaceutical stability were released in the 1950s, and broadly, no regulatory requirements governing stability existed until 1993.¹

The stability regulatory framework in use today for active pharmaceutical ingredients (APIs) and finished pharmaceutical products (FPPs) was established in the mid-1990s to early 2000s by the publication of ICH Q1A-F, Q3A-B, Q5C, and Q6A-B by the International Conference on Harmonization of Technical Requirements of Pharmaceuticals for Human Use (ICH) along with the World Health Organization (WHO).²

Stability Study Protocols and Retest Intervals

Directed by ICH guidelines, a stability program must begin with a stability study protocol that outlines the analytical procedures, testing parameters, storage conditions, and testing intervals that will be used to evaluate the stability of a drug substance or drug product over time.
Additionally, ICH documentation provides specific guidelines for accelerated and long-term retest intervals. Long-term testing intervals are generally every three months in the first year, every six months in the second year, then annually. Common initial intervals for accelerated and stress testing are zero, three, and six months. These intervals help build a stability profile over time, allowing developers to assess degradation rates and determine shelf life. However, testing intervals must be modified as necessary, and more frequent intervals might be required at various stages of development for drugs with known instability or sensitivities.
While ICH guidelines primarily guide stability study protocols, they are often adapted to fit the specific drug, and phase-appropriate protocols are employed to meet the maturing program’s needs as the product moves through the phases of development. Like virtually all development activities, stability studies become substantially more robust in later phases of development.

Phase-Appropriate Stability Studies: The Roles of Non-GMP and GMP Studies

Non-GMP studies of drug substance and drug product obtained from a pilot batch or toxicology batch are regularly performed to support preclinical development activities and provide first insights into the expected stability profile of later GMP drug substance or drug product.
Less stringent and allowing for more flexibility in design, non-GMP stability studies permit quick process changes, and rapid adjustments to testing methods, which often evolve as the drug development process advances. Data generated in non-GMP studies is exploratory and used for internal decision-making rather than regulatory submissions.
On the other hand, GMP stability studies are conducted using rigorous regulatory standards to assess the long-term stability of a final product. They are ultimately used to determine shelf life, storage conditions, packaging, and container closure. Importantly, GMP stability studies also generate data critical to successful regulatory filings.
Post-market approval stability studies are also conducted under GMP conditions and requirements and are essential to ongoing quality assurance programs. These studies, often called post-approval stability (PAS) studies, are conducted after a drug has received regulatory approval and has been released to the market to ensure that the product and its manufacturing process remain stable, effective, and safe throughout its entire marketed shelf life in real-world conditions.
Finally, minor variability can occur across production batches despite utilizing a well-established and characterized manufacturing process. Post-market stability studies monitor production batches to ensure that stability profiles remain consistent.

Different Types of Stability Studies and Their Roles

Various types of stability testing—long-term stability testing, accelerated and stress stability testing, stress/forced degradation testing, primary packaging compatibility, and in-use stability testing—are used to evaluate multiple aspects of a drug’s stability under different conditions. Each type has a specific purpose and provides unique insights into the stability profile of a drug product.

• Long-term stability testing assesses the drug’s stability under normal, recommended storage conditions over an extended period. This testing simulates real-world storage conditions to support shelf life and expiration date determination.
• Accelerated and stress stability testing evaluates a drug’s stability under more extreme storage conditions to speed up degradation processes, allowing developers to predict the long-term stability of the drug product in a shorter time frame. Data from accelerated conditions are often extrapolated using the Arrhenius equation, which relates temperature and degradation rates. These calculations allow for an estimated prediction of stability under normal conditions.
• Stress testing or forced degradation testing exposes the drug product to extreme conditions like high heat, freeze-thaw cycles, light exposure, and chemical exposure to identify its degradation pathways and establish suitable storage guidelines.
• Primary packaging material compatibility testing assesses the drug’s stability in different primary packaging materials such as vials, cartridges, and syringes.
• In-Use stability testing simulates the period after the product has been opened, including the bedside application. Testing is often conducted at room temperature, and for products requiring reconstitution (e.g., lyophilized powders), the stability of the reconstituted product is tested under normal handling conditions. Bedside application of clinically relevant drug product dilutions is simulated using appropriate infusion bags, tubing, and needles or spikes.

Drug Product Stability Testing: Tests and Approaches

Drug product stability studies involve a range of tests and analytical methods to ensure the drug’s quality, safety, and efficacy over time. Each test evaluates different aspects of the drug’s stability under specific conditions and provides insights into its shelf life, degradation patterns, and optimal storage requirements. While not a comprehensive list, some of the most common types of stability tests are included below:

Stability Testing Is Central to Coriolis Pharma’s Formulation Development Success

Coriolis is driven by the mission to support the development of transformative therapeutics that save and improve the quality of patient lives. Stability, as well as a biotherapeutic’s quality, effectiveness, and global regulatory approval, are central to achieving this mission.
While small-molecule therapeutics are reasonably known and understood entities, increasingly complex and novel biologic modalities require experts dedicated to continually evolving methods and techniques to rise to the challenges of ensuring stability and overall therapeutic product quality. Coriolis Pharma’s team of experts is committed to applying our exceptional formulation and analytical capabilities to the pursuit of developing and manufacturing stable and effective therapeutics, no matter how complex. With a legacy of scientific excellence and a commitment to innovation, we continue evolving our capabilities to meet the industry’s ever-changing needs.

References

1. Carstensen, J. T., & Rhodes, C. T. (2018). A history of the physical and chemical stability of pharmaceuticals: A review.
2. National Center for Biotechnology Information. (2022). Pharmaceutical stability testing: Current practices and challenges. PubMed Central.