Effects of ampoule leaking
Ampoule includes plastic ampoule and glass ampoule, which are generally filled with sterile liquid preparations. Ampoules may be filled with sterile air or nitrogen through ampoule filling machine. The purpose of the nitrogen-filled process is to inhibit the growth of aerobic bacteria on the one hand and to prevent oxygen-sensitive products from being oxidized on the other hand. Once the ampoule is leaked, oxygen and microorganisms in the air will invade the container, so that the product filled inside may be oxidized, affecting the stability of the product; after the invasion of microorganisms, if the filled product is suitable for the growth of microorganisms, microorganisms will multiply rapidly, thus laying hidden dangers for the safety of patients' lives.
The traditional leak detection method of ampoule and disadvantages
The traditional leak detection method of the ampoule is mainly the color water method and the microbial challenge method. These two methods are generally subjective, qualitative, and destructive test methods. The color water method is suitable for product-filled ampoules and can be used for the detection of production step; The microbial challenge method is more used for the detection of empty containers themselves and is suitable for verification. Although these two methods have been used by the industry for many years, their shortcomings are also relatively obvious. The disadvantages of the color water method are tested destructive, low sensitivity results subjective, time-consuming and laborious, and non-traceable; The disadvantages of the microbial challenge method are test destructive, time-consuming and laborious, non-traceable, and high leakage rate when the leakage channel is a tortuous path. Currently, the U.S. FDA prefers to replace the traditional two methods with physical quantification.
Leak detection method selection of ampoule
The physical quantitative methods suitable for ampoule leak detection include the vacuum attenuation method, laser method, and high voltage discharge method. The vacuum attenuation method is suitable for all kinds of ampoules, the laser method is suitable for nitrogen-filled ampoules, and the high-pressure discharge method is suitable for ampoules with internally filled liquid conductivity ≥5μS/cm.
Development and Validation of Ampoule Leak Detection Method
Taking the high-voltage discharge method as an example, the leakage detection method of the high-voltage discharge method needs to optimize the parameters such as high voltage settings and test sensitivity settings. The optimized parameters must ensure that the results are reproducible, that the target aperture can be detected, and that the accuracy is high. After the parameter optimization, the method verification is required, including the verification of items such as detection limits.
Ampoule leakage standards established
Taking the high-voltage discharge method as an example, to formulate the leakage standard one parameter needs to be set: voltage. The voltage reading should be set to ensure that various degrees of leakage can be detected. The correlation between the voltage reading and the size of the leakage hole can be achieved by laser punching. The formulation of the ampoule leakage standard is ultimately reflected in the size of the leak hole, and the setting of the final pore size internal control standard needs to consider the risk of microbial invasion, and it is necessary to give priority to the pore size that can prevent microbial invasion, and at the same time to avoid false positives. According to international practice, the set aperture internal control standard usually reaches at least 5 microns of pore size. The actual set aperture size is also required in conjunction with the specific product specification type.