Drug product manufacturing variables

Raw materials are normally accepted as being of useable quality based on two pieces of evidence. One is a certificate of analysis (COA) supplied by the supplier. This COA will often contain only analytical tests that are considered to have an impact on process robustness. This is probably one of the biggest variables causing lack of process robustness and therefore variability in both drug substance and drug product manufacture. 

Independent of existing intra-lot variability, a sample size of six dosage units is generally recognized to suffice the needs of quality control (QC). In very early development less than six specimens may be used to create data, but as soon as possible tests should be run with at least n = 6. It is advisable to create statistically valid and sound data for manufacturing prototypes even at very early phases of development, in order to be able to identify formulations/batches with unwanted dissolution behavior. In the early phases of a drug product s development, formulations may not be of acceptable stability. This means that stability phenomena may mask... 

Cui Y. Song X. Chuang K. Venkatramani C. Lee S. Gallegos G. Venkateshwaran,T. Xie, M. Variable selection in multivariate modeling of drug product formula and manufacturing process. Journal of Pharmaceutical Sciences, 2012, in press. 

Control procedures are not established to monitor the output/validate the performance of manufacturing processes that may be responsible for causing variability in the characteristics of the drug product. 

Retrospective validation involves using the accumulated in-process production and final product testing and control (numerical) data to establish that the product and its manufacturing process are in a state of control. Valid in-process results should be consistent with the drug products final specifications and should be derived from previous acceptable process average and process variability estimates, where possible, and determined by the application of suitable statistical procedures, that is, quality control charting, where appropriate. The retrospective validation option is selected when manufacturing processes for established products are considered to be stable and when, on the basis of economic considerations and resource limitations, prospective qualification and validation experimentation cannot be justified. 

Control procedures shall be established to monitor output and to validate performance of the manufacturing processes that may be responsible for causing variability in the characteristics of in-process material and the drug product. Such control procedures shall include, but are not limited to the following, where appropriate [2] ... 

The pharmaceutical industry manufactures dosage forms in large-scale formulations. The decision to scale up is based on the economics of the production process related to costs of materials, personnel, equipment, and control [2], To reduce costs of wastes and to obtain high-quality and efficacious drug products, the strategic plan to be applied during the process has to be developed carefully. In fact, the variables that affect product quality are identified and understood in the process instead of tested into the final product [3],... 

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