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Pharmaceutical Technology BIOLOGICS AND STERILE DRUG MANUFACTURING 2018 59 capacity should be determined, and operations should fall within the validated ranges. Cell modification processes should be developed based on studies designed to show the effectiveness of those processes. Equipment, operating proce- dures, and processing conditions should be selected on the basis of those studies. Tests should be de- veloped to measure the effectiveness of the process. Standardized collection and washing equipment, processes, and procedures should likewise be se- lected based on the results of studies designed to evaluate their effectiveness. Data to show these processing steps perform as intended should be available. Processing times should be evaluated, and minimum and maximum times established. Issues such as cell degradation and pyrogen for- mation should be evaluated, as should any process f luid and equipment sterilization procedures. If controlled environments are necessary, validation studies should demonstrate their suitability. Processing, holding, and expiration periods should be evaluated and established to ensure product safety (i.e., freedom from objectionable levels of endotoxin and microbial contamination) and efficacy (i.e., viability and integrity of the pro- cessed cells). Because each "batch" is more or less unique, it is not possible to validate in a conventional man- ner. But it is possible to ensure the processing steps work reliably and do not compromise the harvested cells, and that the cell treatment process, whatever it is, has been evaluated and shown to be effec- tive. The principles of validation remain the same, but there may be some necessary interpretation to meet the requirements of the product. A consultation document published by the Eu- ropean Commission (18) and an FDA guidance document on human somatic cell therapy and gene therapy (19) provide useful information for developing validation studies for advanced therapy medicinal products. Lifecycle management Validation requirements change throughout the life of a product. Validation begins at the point it is determined a molecule of entity may have clini- cal significance. It ends when the product is no longer in the marketplace. At the beginning, the proposed molecule, drug substance, biologic, or API—however it is identi- fied—should be fully characterized, its synthesis routes defined, and any impurities identified and quantitated (13). Any purification procedures and processes, such as recrystallization, chromatography, and viral clearance or inactivation, should likewise be characterized and defined. Cell lines, fermenta- tion processes, and bioreactions must be fully de- fined and described. This information serves as the foundation for producing material for clinical stud- ies, initial regulatory filings such as investigational new drug applications (INDs) and biologics license applications (BLAs), and ultimately commercial production scale-up. Initially, development information can be kept in research or laboratory notebooks, but as clinical use becomes likely, formal development reports and initial validation work should be prepared, reviewed, and approved. Everything is interrelated, and de- tailed information is required to inform process de- velopment, scale-up, and commercial production. A product specification will be developed on the basis of initial development information. The product specification includes tests, ana- lytical procedures, and acceptance criteria defin-