Comprehensive Testing and Verification

Dissolution refers to the compounds that migrate from any material in contact with the product to a suitable solvent under certain time and temperature conditions, directly manifested as 'non-volatile residue (NVR)'. The NVR determination method is a designated validation method for food contact materials specified in the US 21CFR, and it is also a designated testing method for dissolution specified in the US Pharmacopeia USP <661>. The GB9685-2008 "Hygienic Standards for the Use of Additives in Food Containers and Packaging Materials" formulated by the Chinese Ministry of Health also specifies the use of this method. Therefore, the NVR method is the most commonly used dissolution validation method.

The company's compatibility verification uses the "comprehensive verification method" that best meets GMP requirements. PDA Report No. 26 states that the typical chemical compatibility table provided by the manufacturer can only serve as a starting point for further testing, and additional tests should be conducted by the user. Common chemical compatibility tests include integrity, tensile strength, NVR, leachables, particles, flow rate, optical or scanning electron microscopy (SEM), burst pressure, filter membrane thickness, and O-ring size. It is recommended to use these tests in combination, as a single test may not detect subtle incompatibilities.

Bacterial survival verification is to ensure that the materials in contact with the liquid can effectively control and prevent the survival and reproduction of bacteria. The biological indicator for sterilizing filtration specified in the Chinese Pharmacopoeia is Brevundimonas dimininuta (defective pseudomonas, ATCC 19146). Generally, it is the most reasonable to directly inoculate the challenge bacteria in the test liquid. However, some liquid materials may have bactericidal effects on the challenge bacteria. In this case, the bactericidal effects need to be eliminated by rinsing the filter membrane and selecting alternative liquid for bacterial challenge.

The reference standards for bacterial challenge are ASTM F838-05, PDA Report No. 26, and the "Pharmacopoeia of the People's Republic of China" sterilization method of "filtration sterilization". ASTM F838-05 specifies that the bacterial challenge level for sterilizing grade filters should be ≥ 107 CFU / cm. The "Pharmacopoeia of the People's Republic of China" specifies that the LRV value should be > 7. It is important to emphasize that the LRV value here refers to the bacterial retention capability of the filtration process, which needs to consider process parameters such as membrane area, batch size, filtration time, and maximum pressure difference, not just the bacterial challenge level of the filter.

Adsorption verification refers to the process of evaluating the adsorption properties of materials in contact with liquids. It is part of the quality assurance of liquids, especially sensitive drug components. The adsorption effect of filters on the effective components of the drug solution may affect the quality of the drug. Therefore, it is sometimes necessary to choose a membrane material with minimal adsorption or exclude the adverse effects of adsorption by pre-saturation. The methods for adsorption verification include simulated contact method, simulated filling method, and weighing method.

After using the filter, integrity testing should be performed. GMP specifies three methods for integrity testing: bubble point, diffusion flow, or pressure maintenance. Standard reagents (such as water) or process fluids can be used as wetting liquids, which require verification of the product wetting integrity testing parameters. The verification principle is based on the differences in surface tension or other physical parameters between different fluids, and the standards for product wetting integrity testing are obtained through statistical methods.

During the use of filters, particles may be released. This validation can confirm the amount of particles released from the filter into the drug, or the filter's interception performance through standard particle challenges. Through such validation, product quality can be improved, potential risks can be reduced, and the safety and purity of the final product can be ensured. At the same time, it also ensures that the product complies with relevant regulations and industry standards.