Lot release testing

The CE applications described in this chapter have been validated according to the guidelines of the ICH, and are currently being used in routine lot-release testing and stability monitoring of selected marketed protein therapeutics. 

Various types of validation generally required in biopharmaceutical manufacturing include process validation, facility and equipment validation, analytical method validation, software validation, cleaning validation and expression system characterization. Combined with other elements of cGMP, including lot release testing, raw material testing, vendor quality certifications, and vendor audits, the quality of product can be consistently assured. 

Polymerase chain reaction (PCR)-based assays amplify a specific target DNA which can be used in a variety of analytical applications. Quantitative PCR has been used for lot release testing, the detection of viral contaminants (both in raw material testing as well as in-process control), the quantification of endogenous retroviruses in cell cultures, host cell DNA quantification, and the determination of genetic stability in cell lines [13-15]. 

Table 8.2 Commonly Used HPLC-based Tests for Characterization and Lot Release Testing of Biotherapeutics...

II. In Vitro Release Documentation. The in vitro release rate of a lot of the dosage form prepared by the new/modified process should be compared with the in vitro release rate of a recent lot of comparable age of the dosage form prepared by the prechange process. The median in vitro release rates (as estimated by the estimated slope from each cell, see VII) of the lots prepared by the two processes should be demonstrated to be within acceptable limits, using the testing procedure described in section VII (IN VITRO RELEASE TEST) below. 

Metered valves are critical to the functionality of this dosage form, and a thorough understanding of this component is essential. Table 3 shows some tests conducted on metered valves. Footnoted items are special tests performed for valve characterization, not necessarily for individual lot release. 

The FDA s lot release regulations allow the agency to require manufacturers to submit samples of any licensed biological products for testing [24], Manufacturers must submit to CBER representative samples of each lot, a lot release protocol, and a summary of the test results. Lots may not be released until CBER authorizes an official release. However, CBER does not require lot release in all circumstances. 

It is also desirable to have predictive tests that are rapid and are grounded by benchmarking with older exposure-based tests. Rapid validated tests are necessary for quality control and lot release inspection. Often the results of such tests are needed within hours. Cabinet exposure testing that requires days or weeks is obviously impractical. 

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