Inadequate stability may impair the purity, potency and safety of a pharma drug product. To safeguard patients, a reliable shelf life must be ascribed to a product during its development and commercialisation. A shelf life that is too
short can be problematic, and an unreliable or inconsistent shelf life can invite regulatory intervention. The correct evaluation of a drug product’s physicochemical stability requires an understanding of its physical and chemical properties, and numerous factors affect the final shelf life, including its chemical and physical stability during pre-clinical formulation, process development and packaging development, and how it is stored in fulfilment and after sale.
Aspects of stability testing
Pharma stability studies can be used to assess a drug substance, a formulation, a drug product, or a packaged product. Pre-clinical animal and human studies are used to determine a drug’s safety and efficacy. Identification, concentration and purity are defined as quality attributes. If a drug’s properties change during a stability study, the established safety and efficacy data may no longer be valid. Changes in drug stability could jeopardise patient safety by reducing dosage. Instability can produce toxic degradants.
Regulatory-compliant stability testing
Pharma products have a shelf life that determines how long they are safe and effective under specific storage conditions. The shelf-life is determined by several factors. Among these are the chemical stability of the Active Pharmaceutical Ingredients (APIs) in the chosen dosage form and whether any degradation products are potentially harmful to patients. Further, factors affecting an API’s bioavailability can shorten shelf life. These include degradation
of API potency, precipitation (for liquid dosage forms) and slowing of API release in the gastro-intestinal tract. Accelerating the ageing process by increasing temperature and relative humidity allows predictions of stability to be obtained more quickly, so that pharma development and production can proceed without waiting for the shelf life to expire. JMP supports stability testing in all these crucial phases and helps generate actionable data that conforms to regulatory requirements.
APIs, whether biological or small molecules, are susceptible to organic chemical degradation. Regulatory agencies require that such degradation products be assessed to correctly assign a shelf life to a product. The shelf life is limited by the time it takes for any degradation product to reach an unacceptable level or for the active ingredient to lose potency. Permitted amounts of degradants are based on the total daily intake of the API, and are described as reporting, identification, or qualification thresholds.
JMP stability-testing lifecycle
Stability testing comprises distinct phases in accordance with the developmental phase of the drug development lifecycle. JMP can analyse stability testing data from all these stages.
The discovery phase
The discovery phase determines the optimal stability. This phase focusses on the drug’s formulation and storage conditions. The container-closure system with which the product will come into contact is optimised, and the impact of critical excipients investigated. Design of experiments, linear regression, multiple regression, analysis of covariance, and non-linear regression are all required for this phase. Test results are compared to specifications using
simple linear regression.
Scatterplots are useful to explore the relationships between two periods, locate outlying or otherwise unusual values, and identify possible trends. Linear correlation measures the strength of any linear association between stability and time: The strength of the association is measured using Pearson’s linear correlation coefficient.
During the pre-clinical phase, stability profiles for drug substances and products are determined and reviewed. This gives an early indication of the stability profile of clinical batches, so that any process or product changes made since the discovery phase can be optimised. The statistical methods used in this phase include correlation, simple linear regression, analysis of covariance, non-linear regression and an assessment of comparability or equivalence.
Clinical phase
The clinical phase aims to assure that clinical batches have the same stability profile as the pre-clinical batches, so establishing the best stability conditions. A retest period for the drug substance and a shelf life for the drug product is established. This phase examines any recent changes in process or product conditions using correlation, simple linear regression, analysis of covariance, non-linear regression, estimation of mean and individual confidence intervals, extrapolation and an assessment of comparability or equivalence.
Commercial phase
The commercial phase identifies batches that are out of specification, and also addresses any changes to labelling. The statistical methods used include correlation, simple linear regression, analysis of covariance, non-linear regression, statistical intervals, control charts and an assessment of comparability or equivalence. JMP helps detect out-of-specification and out-of-test results and supports label changes needed to accommodate process and product modifications. JMP has a dedicated stability platform that caters for ICH Q1E testing and is in conformance with 21 CFR guidance. JMP allows you to conduct your stability programme according to the FDA’s cGMP guidelines in 21 CFR Part 211 and ensures the compliance of all data-related aspects of stability testing and the laboratory in which it is
carried out.
Resources
On demand Video – Pharmaceutical Product Stability
https://www.jmp.com/en_in/events/ondemand/technically-speaking/pharmaceutical-product-stability.html
Webinar – Stability Analysis Made Easier
In this webinar, you will learn about JMP’s regulatory complaint stability testing. JMP offers built-in stability testing capabilities designed to simplify the determination of expiration times in accordance with ICH guidelines.
https://www.jmp.com/en_ca/offers/stability-analysis-made-easier.html
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