This may be useful
A vial washer is a relatively simple machine commonly used to clean containers during the manufacture of dosage form drugs. Some drug manufacturers only perform Installation Qualification (IQ) and Operational Qualification (OQ) of the machine as no regulatory requirements clearly state that the performance of the vial washer should be qualified. Although depyrogenation may be achieved using a heating tunnel or oven, if the washing process cannot remove chemical contaminants or particles, they will produce a pyretic response in humans or animals, although there are no pyrogens present. Some drug manufacturers may perform a qualitative trace study for coloring matter in washed vials using a white wiper to verify the performance of the washer, but it is not a quantitative method to reflect the actual performance of the washer for particles, endotoxin, and chemical contaminants.
21CFR Part 211.94 states: “Drug product containers and closures shall be clean and, where indicated by the nature of the drug, sterilized and processed to remove pyrogenic properties to assure that they are suitable for their intended use.”
The FDA Guideline for Dosage Form Drug Manufacturers also states:” Determine how containers and closures are handled and stored. Decide if the cleaning, sterilization, and depyrogenization are adequate, and have been validated.” So drug manufacturers have to evaluate the cleaning capability of the vial washer for endotoxin, as well as for chemical substance and particulate.
Then, where do you begin the validation?
The IQ/OQ of the machine should be performed prior to the Performance Qualification (PQ). As IQ/OQ is simple, and most drug manufacturers already have already conducted these tests, let’s focus on the topic of performance qualification
Before showing how we conducted the validation, it is better to give a brief description of our vial washer. Our automatic vial washers (LIBRA HYDRA1000-7-B) are designed to wash externally and internally many kinds of glass or plastic cylindrical containers. There are eight washing stations, plus two dripping stations equipped with independent connections to their respective circuits to prevent cross-contamination among the various media (compressed air for stations one and eight, recycled water for stations two and four, deionized water stations for five and six, and Water-for-Injection [wfi] for station seven). Each station has seven washing channels. When washing, the needles on each station enter the vials as the various media are sprayed. Each washing channel may have a different spray strength due to the distance of the spray nozzle from the utility supply point. Media spray time can be individually adjusted according to bottle size and production speed.
Two questions will help us design the PQ study:
• First, which parameters will affect the ability of the cleaning?
The ability of cleaning is largely dependent on vial size, media spray time, and pressure and washing speed. So each size of the vials will be subjected to the PQ study. To incorporate the worst case scenario into the validation studies, higher washing speed (+10%), shorter media spray time (-10%), and lower media spray pressure (-10%) than the pre-established washing cycle will be implemented during validation.
• Second, what’s the purpose of washing?
As mentioned above, the vial washer is used to clean the drug container to eliminate the contamination (endotoxin, chemical substance, particles etc.) from the container itself to ensure that the products produced meet expectations for purity, identity, safety, and quality. Thus decontamination studies for endotoxin, chemical contaminants, and particles should be performed. As the internal surface of the vial is product-direct-contact, a certain quantity of each contaminant will be placed into the vials, and washed in the vial washer. Then the quantity of contaminants in each washed vial will be determined, thus the reduction of contaminants can be obtained to verify the machine performance.
Questions may arise regarding the contamination level before washing and the acceptance level after washing. The initial contamination level of vials from qualified vendors was tested to set up the deliberate contamination level of the study. The initial contamination level was obtained by testing samples taken from three different production lots according to Military Standard 105E. In this case, for endotoxin, the initial level is quite low, and the depyrogenation process of dry heat will ensure the endotoxin reduction, so we use 1000-10,000EU as the initial level, and set acceptance criteria at three log reduction of 1000EU. For particle and chemical substance (free alkali), we double the data averaged from the test results of the initial contamination level testing. As any particle or chemical contaminants may affect the quality of the products, the acceptance criteria should be free of particles and chemicals for washed vials.