Pharmaceutical products delivered in multidose containers require in-use stability studies. Moreover, those pharmaceutical products requiring dilution or reconstitution prior to use also require in-use stability studies. In-use stability can be described as how well a pharmaceutical product remains stable during in-use within a particular closure system.
During the in-use period, the pharmaceutical product remains within its physical, chemical, and microbiological specifications and retains its safety, efficacy, and performance.
Crucial parameters during in-use stability study may include the following:
- Effect of the dilution factor
- Effect of the dilution media
- Hold-times
- Adsorption to surfaces
- Shear-forces during application
- Effect at the injection site
- Silicone oil contact
- Extractable volume
- Reconstitution
Objective
The purpose of in-use stability testing is to establish - where applicable - a period of time during which a multidose product can be used whilst retaining quality within an accepted specification once the container is opened.
Scope
This refers to medicinal products in multidose containers which - by nature of their physical form and chemical composition - due to repeated opening and closing, may pose a risk to its content with regard to microbiological contamination, proliferation and/or physicochemical degradation once the closure system has been breached.
Introduction
- No specific guidance is available on defining test design and conduct of studies to be undertaken to define in-use shelf life in a uniform fashion. This blog attempts to define a framework for selection of batches, test design, test storage conditions, test parameters, test procedures etc., taking into consideration the broad range of products concerned.
- The registration dossier for a multi-dose product should include either the in-use stability data on which the in-use shelf life is based or a justification why no in-use shelf life is established.
- This justification can also be based on experimental results.
Selection of Batches
- A minimum of two batches, at least pilot scale batches, should be subjected to the test. At least one of the batch should be chosen towards the end of its shelf life. If such results are not available, one batch should be tested at the final point of the submitted stability studies.
- The batch number, date of manufacture and size of each batch should be stated.
- The container and closure of the product and, if present, the medicinal device should be equivalent to that proposed for marketing.
- If the product is to be supplied in more than one container size or in different strengths, the in-use stability test should be applied to the product which presents the greatest susceptibility to change.
- The choice of the tested product should always be justified.
Test Design
- The test should be designed to simulate the use of the product in practice taking into consideration the filling volume of the container and any dilution/reconstitution before use.
- At intervals comparable to those which occur in practice appropriate quantities should be removed by the withdrawal methods normally used and described in the product literature.
- Sampling should take place under normal environmental conditions of use.
- The appropriate physical, chemical and microbial properties of the product susceptible to change during storage should be determined over the period of the proposed in-use shelf life.
- Testing should be performed at intermediate time points and at the end of the proposed in-use shelf life on the final remaining amount of the product in the container.
Test Storage Conditions
- The product should be stored under the conditions as recommended in the product literature (Summary of Product Characteristics and Patients Information Leaflets) throughout the in-use stability test period.
Test Parameters
- The physical, chemical, and microbial properties of the product should be monitored.
- Physical: color, clarity, closure integrity, particulate matter, particle size
- Chemical: active substance assay(s), antimicrobial preservative and antioxidant content(s), degradation product level(s), pH
- Microbial: Total viable count, sterility
Analytical Procedures
- The analytical procedures used in the study should be described and fully validated. Stability-indicating assays should be employed.
Presentation of the Results
- The results should be summarized and tabulated. If relevant, the results should be presented graphically.
Tags
Quality Control
