Stability studies are crucial for drug development, from early clinical trials to the product registration. An in-depth knowledge of the stability of pharmaceutical drug substances and final products is essential to ensure product quality throughout its shelf life.
In this article, Mathieu Fournier, Chief Scientific Officer at Neopharm Labs, explores the various stability studies conducted in the pharmaceutical industry.
The Degradation Pathway
The understanding of the degradation pathway of a drug is key to ensure proper stability results interpretation through all the steps of a drug product development.
The role of stress studies is to help to identify the likely degradation products and establish degradation pathways, either for an Investigational New Drug (IND), during clinical phases or for a New Drug Application (NDA/ANDA). Effects of temperature, humidity, light (photostability), oxidation and pH are usually investigated to cover the most common degradation pathways to develop and validate suitable analytical procedures.
When needed, using this forced degradation approach, degradation products can also be identified using mass spectrometry following isolation & purification.
Support Drug Product Development
The degradation profile observed during the stability testing of a drug product in development can be a tool of significant value to identify the most impactful factors affecting the product stability (temperature, humidity, light, oxidation, pH).
Applying the knowledge derived from the analysis will help to adjust the manufacturing process, the formulation (pH, excipients, humidity, coating, etc.), and/or the packaging device to ensure reliable long-term stability for each drug product.
The understanding of the degradation profile is a tool of great value to fasten and minimize the costs of a drug product development.
Clinical Phases Requirements
For Phase 1 clinical trials, US FDA recommends the “initiation of a stability study using representative samples of Phase 1 Investigational drug to monitor the stability and quality of Phase 1 Investigational drug during the clinical trial”.
During Phase 2 clinical trials, FDA requires the submission of a description of the stability performance to support the clinical study. This should include suggested tests, analytical procedures, acceptance criteria, time points for each test, and storage conditions. The duration of the study should be long enough to cover the expected duration of the clinical trial.
It is also encouraged to carry out stress studies during this phase because such studies provide critical information governing the choice of stability-indicating procedures to be used in real-time studies.
In Phase 3, conducting stability study is a requirement to monitor product stability and provide marketing application data. As Phase 3 stability studies are often used for product registration, a formal stability protocol usually developed to satisfy all regulatory requirements.
Conducting stress studies is part of this stage’s requirements to demonstrate the inherent stability of the drug substance, its degradation pathways, and the capabilities and suitability of the proposed analytical methods.
The stability requirements for NDA/ANDA are clearly explained in ICH guidelines Q1A(R2) to Q1E. The WHO also published a stability guideline in 2018 with more details for MAHs considering global registration.
A formal stability protocol becomes a regulatory and compliance requirement for product registration. The 21 CFR 211,166 (a) states this protocol should minimally include:
- Sample size and test intervals based on statistical criteria considering each of the attributes examined to assure valid estimates of stability.
- Storage conditions for samples retained for testing.
- Reliable, meaningful, and specific test methods.
- Testing of the drug product in the same container closure system as that in which the drug product is marketed.
- Testing of drug products for reconstitution during the time of dispensing (as directed in the labelling) and after they are reconstituted.
When conducting stability studies on a drug product, each different dose strength and container size need to be tested unless bracketing or matrixing is used. A minimum of three pilot-scale batches of the final formulation manufactured must be produced and tested for compliance with identical quality standards, specifications, and container closure systems than the proposed commercial drug product.
Considering the complete long-term stability study results may not be available at the time of the submission of the files for a New Drug Submission (NDA), the dossier must include stability results for three pilot scale batches with at least six months of accelerated stability and the long-term results available (usually six months too). A statistical approach can be used to predict the drug product shelf life considering the Arrhenius law to extrapolate the accelerated stability results to the long-term storage conditions.
To ensure the global stability of the drug product through all its supply chain support, thermocycling (such as freeze-thaw) and transportation studies may be required depending on each product’s behaviour and logistics. Additionally, an in-use study should be submitted to support the in-use label storage conditions and in-use period.
Commercial Stability Requirements
Following approval, sponsors are expected to conduct stability studies on at least one lot per strength and per packaging configuration under long-term conditions each year the product is manufactured. Failing to prove commercial stability might lead to product recalls and/or field alerts.
Additional stability testing may be required to support post-approval modifications, such as manufacturing process, composition in formulation, immediate packaging, and manufacturing of APIs. In these circumstances, long-term and accelerated programs must be initiated to demonstrate the impact of the changes made on the marketed drug product.
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