Inuse (Open Bottle) Stability Testing for Multidose Containers

 

INUSE (OPEN BOTTLE) STABILITY TESTING FOR MULTIDOSE CONTAINERS

 

The continued integrity of products in multidose containers after the first opening is an important quality issue. Repeated opening and closing, can pose a risk to its content with regard to microbiological contamination, proliferation and/or physicochemical degradation once the closure system has been breached.

 

The purpose of in use stability testing is to establish a period of time during which a multidose product may be used following the removal of the first dose of product from the container without adversely affecting the integrity of the product. 

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 batches 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. 

If the product is to be supplied in more than one container size or in different strengths, the inuse 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

As far as possible 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. If possible, 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 throughout the in-use stability test period. Any other storage conditions should be justified. 

Test parameters

The appropriate physical, chemical and microbial properties of the product susceptible to change during use should be monitored. The tests used must be appropriate to individual dosage forms, however, examples of parameter types which may need to be studied are given below:

Physical: colour, 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 

In-use stability data should be used to determine whether or not a declaration of an in-use shelf life and additional storage conditions are necessary. 

Labelling of the primary container

The in-use shelf life should be stated on the label. In addition (if space allows) there should be a space for the user to write the date of opening or the "use-by" date.