Lyophilization cycle

The Guide to Inspections of Lyophilization of Parenterals, published by the US Food and Drug Administration, July 1993, contains among others the chapters Lyophilization Cycle and Controls , Cycle Validation and Lyophilizer Sterilization/Design . 

Patapoff, T. W., Overcashier, D. E. Importance of freezing on lyophilization cycle development Biopharm March 2002. 

If the product is not freeze dried, the primary closure or stopper is applied shortly after completion of the filling process to better assure the sterility of the contents. When the product is to be lyophilized, the stopper may be partially inserted after filling and be fully seated after completion of the lyophilization cycle. Alternatively, the container could be left open and a stopper applied after completion of the drying. 

For several validations, we have implemented planned deviations of 10-15°C around the target temperature during primary drying and of 5-10°C for secondary drying. The products obtained from these extreme cycles complied with all specifications and the range of the temperature variations was satisfactory for most practical purposes. When the freeze-dried product can accommodate shelf temperature variations of 10°C or more, the lyophilization cycle can often be transposed without modifications to another lyophilizer. 

The validation of lyophilization cycles is a complicated issue because the process parameters and the characteristics of the product are closely interrelated. The process affects the final product, but the characteristics of the product undergoing lyophilization impact the dependent operating parameters, the freeze-drying pattern, and dictate the basic requirements for a successful process. This interdependence limits the opportunities of using placebo formulations and most of the validation runs must be performed with active product. The high cost and limited availability of some materials, as well as the need to validate the process under conditions that are representative of routine production, justify that part of the validation is performed in a concurrent fashion. The concurrent validation should then be completed by a retrospective review of the data accumulated for commercial batches, so as to track the reproducibility, the reliability, and the trends of the process over a longer period of time. 

Lyophilization technology, adapted from existing practices in formulating chemically synthesized drugs, was at first applied directly to proteins. However, research into refining the process for proteins was undertaken, and problems associated with protein stabilization and dosage form and lyophilization cycle devel-... 

Heller, M.C. Carpenter, J.F. Randolph, T.W. Protein formulation and lyophilization cycle design prevention of damage due to freeze-concentration induced phase separation. Biotechnol. Bioeng. 1999, 63, 166-174. 

Williams NA, Schwinke DL. Tow temperature properties of lyophilized solutions and their influence on lyophilization cycle design pentamide isothionate. J Pharm Sci Technol 1994 48 135-139. 

Perform controller security challenges to verify that lyophilization cycle parameters cannot be altered without appropriate supervisory control. 

T Patapoff, D Overcashier. The importance of freezing on lyophilization cycle... 

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