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The Importance of Stability Studies in Pharmaceuticals

Stability studies in pharmaceuticals are performed from early development through regulatory approval and commercialization. Understanding the stability and shelf-life of a pharmaceutical drug product (DP, or Finished dosage form) and drug substance (DS or active pharmaceutical ingredient, API) is a critical quality component to ensure the safety and efficacy of the product throughout its lifecycle.

Stability studies typically begin at the preclinical stage of drug development and continue through clinical trials to support formulation development and satisfy the regulatory requirements for clinical trials, approval, and commercialization. Stability studies have the primary objective of ensuring DP and DS retain their potency, purity, and other quality attributes throughout the product’s shelf life to ensure the safety and efficacy of the drug. The purpose of stability testing is to provide evidence on how the quality of a DS or DP varies with time under the influence of a variety of environmental factors, such as temperature, humidity, and light, and to establish a retest period for the drug substance or shelf life for the drug product. Shelf life can be influenced by many factors, including the intrinsic stability properties of the active ingredient, the choice and level of the excipients in the formulation, the drug product manufacturing process, and the selection of the container closure components, and packaging design.

Understanding the Objectives of Stability Studies

Stability studies are performed to support multiple objectives at each of the product development stages. As pre-formulation, formulation, and pilot stability data is generated, the studies typically advance from exploratory studies to identify a formulation and initial storage condition to confirmatory studies to justify shelf-life for a regulatory filing and product approval. The goals of stability studies include: identifying the most stable drug candidate, identifying the drug degradation mechanisms and chemical pathways, supporting GLP non-clinical studies, determining appropriate DS and DP storage conditions, estimating shelf-life of formulation candidates, evaluating alternate drug product packaging, evaluating proposed shipping conditions, extending shelf-life, and more.

It is important to understand the criticality of developing and selecting the appropriate analytical methods to evaluate DS and DP stability to ensure product potency and purity. Analytical methods must be stability-indicating that can detect the change with time in the chemical, physical or microbiological properties of the DS or DP. These methods are specific so that the content of active ingredients and degradation products can be determined accurately without interference from formulation excipients.

Forced degradation and stress testing techniques are typically employed by exposing the DS and DP to conditions that exceed those used for accelerated stability testing and that the product is typically exposed. Degradation is intentionally achieved by exposing the drug to pH extremes (acid and base), heat (elevated temperatures, i.e. 80°C), oxidizing agents (e.g., hydrogen peroxide), light (UV and visible) and other extreme conditions. This intentional degradation of the API must be detected in the selected analytical methods to ensure that the methods are stability indicating. ICH publishes Guidelines on the development and validation (Q2 and Q14) of appropriate analytical methods.

Early Stage Studies

CMC Pharmaceuticals routinely performs stability studies in our lab. Early in the drug development process stability studies are performed to identify drug candidates that have better stability characteristics than alternatives and to ensure the selected compound(s) have sufficient stability characteristics for an adequate shelf-life. The purpose in this phase of development is to identify the most stable drug candidate to ensure feasible commercialization

Stability studies are also executed early in development to determine chemical degradation pathways (e.g., hydrolysis, oxidation, light mediated, etc.) of the active pharmaceutical ingredient. An understanding of the degradation mechanisms is critical to advance to the next stage of development that identifies a stable formulation for the drug product for use in non-clinical or clinical studies. Understanding the degradation mechanism is used to identify and evaluate stabilizing strategies of the drug product (e.g.,, minimizing hydrolysis, protecting from light, eliminating oxygen with inert gas overlays or oxygen scavengers).

Late Stage Stability Evaluations

The purpose of the stability studies in late development is to establish, based on testing a minimum of three batches of DS or DP, a re-test or shelf-life period that is applicable to all future batches. ICH has published Guideline Q1E, “Evaluation for Stability Data” to provide recommendations on how to use stability data to propose shelf life in a registration application. ICH Q6A and Q6B Guidelines should be consulted for recommendations on the setting and justification of acceptance criteria, and ICH Q1D should be referenced for recommendations on the use of full- versus reduced-design studies. The Q1E guideline describes when and how extrapolation can be considered when proposing shelf life for a drug product that extends beyond the covered available data from stability studies under the long-term storage condition.

A systematic approach should be adopted in the presentation and evaluation of the stability information. The stability information should include, as appropriate, results from the physical, chemical, biological, and microbiological tests, including those related to particular attributes of the dosage form (for example, dissolution rate for solid oral dosage forms). When extrapolating stability data to determine drug product dating, shelf life can be no longer than the time when the 95% confidence limits (CL) of the regression line first intersect the acceptance criteria. This analysis should be done for each attribute to determine the earliest time the regression line intersects with the acceptance criteria; the proposed shelf life can be no longer than this time. It is important to ensure that sufficient stability data is available to support extrapolation.

CMC Pharma Helps You Navigate Stability Studies

CMC Pharma has expertise in performing stability studies throughout every stage of drug product development. These studies can initially be exploratory to learn about the intrinsic stability of the drug compound, select developable compounds for further development, and evaluate formulation approaches to support commercialization. As drug development programs mature and near completion of clinical trials, stability studies become more confirmatory to support and justify a shelf-life and product approval. The team at CMC Pharma can help design and guide you through these studies. Contact Us today!