In the WHO Technical Report Series, No. 953, 2009 Annex 2 Stability Testing of Active Pharmaceutical Ingredients and Finished Pharmaceutical Products section 2.2.10, In-use Stability Testing is defined as:
“The purpose of in-use stability testing is to provide information for the labelling on the preparation, storage conditions and utilization period of multi-dose products after opening, reconstitution or dilution of a solution, e.g. an antibiotic injection supplied as a powder for reconstitution.”
Like many guidance statements, WHO Stability Guidelines appear simple enough to understand, but then reality sets in. How can a laboratory study be designed to execute potential real world uses of a product for a hospital or clinic? How many lots of product are needed to meet expectations of the regulatory authorities? Which batch(es) should be used in the in-use stability testing studies? What analytical testing should be performed and at what time points should the testing be performed?
Multi-use injectable products by their intended use can pose a risk to their contents with regard to microbiological contamination, proliferation and/or physicochemical degradation once the closure has been breached. Once the closure has been breached the integrity of the product is an important quality issue. The following describes an example of an in-use stability study for a lyophilized injectable product. Other approaches to in-use stability studies can be taken depending on the intended use of a product. However, the intent of an in-use stability study is to simulate the use of the product in practice taking into consideration the filling volume of the container, any dilution/reconstitution before use, the hold time before use and various diluents that could be used for administration. The analytical team at Alcami has the advantage of also having a formulations development team that can set up the study and prepare the samples. The cooperative efforts between a formulation development team and an analytical team lead to successful projects.
Good preparation for an in-use study will ensure proper execution to achieve its goals. Items that should be in place prior to study execution are:
The in-use study should follow a protocol that has been approved by management and quality.
Validated test procedures should be in place. For example, the testing should include tests for appearance/clarity, pH, assay for potency, assay for impurity/related substances and particulate matter. Do not assume that every testing procedure can be performed as written. Methods for potency and impurities may need adjustments to sample preparations scheme or HPLC injection volumes to account for the different sample concentrations. These method modifications should be described in the study protocol and approved.
Knowledge of how the product has been used in the clinical trials or how the reference product has been used in a clinical setting is necessary. This information will determine syringes, IV bags, diluents and transfer lines that will be needed. This information will also describe how the product is reconstituted, storage conditions prior to use and during use, and what would be the longest time prior to use.
The details of the in-use stability testing procedures are typically described in the study protocol. Management and quality can assist in answering questions about the details to ensure successful testing.