Pharmaceutical manufacturing processes

Pharmaceutical manufacturing processes often consist of a series of unit operations, each intended to modulate certain properties of the materials being processed. To ensure acceptable and reproducible modulation, consideration must be given to the quality attributes of incoming materials and their process-ability for each unit operation. During the last 3 decades, significant progress has been made in developing analytical methods for chemical attributes (e.g., identity and purity). However, certain physical and mechanical attributes (e.g., particle shape, size distribution, inter- and intra-particulate bonding) of pharmaceutical ingredients are relatively difficult to characterize, and adverse effects due to inherent quality variability are often not recognized until after manufacture. Establishing effective standards or specifications for physical attributes of raw (e.g., excipients) and in-process materials poses a significant challenge because of the complexities of such attributes (e.g., particle shape and shape variations within a sample) and because of difficulties related to collecting representative powder samples for testing. It is well known that powder sampling procedures can be prone to sampling errors.

Formulation design strategies exist that provide robust processes that are not adversely affected by minor differences in physical attributes of raw materials. Because these strategies are not generalized and are often based on the experience of a particular formulator, the quality of these formulations can only be evaluated by testing samples of in-process materials and end products. Currently, these tests are performed off line after preparing collected samples for analysis. Different tests, each for a particular quality attribute (e.g., content uniformity, moisture content, dissolution rate), are needed because such tests only address one attribute of the active ingredient following sample preparation (e.g., chemical separation to isolate it from other components). During sample preparation, other valuable information pertaining to the formulation matrix is often lost. Several new technologies are now available that can acquire information on multiple attributes with minimal or no sample preparation. These technologies provide an opportunity to assess multiple attributes, often nondestructively.

Currently most pharmaceutical processes are based on time defined end points (e.g., blend for 10 minutes). However, in some cases, these time defined end points do not completely take into consideration physical differences in raw materials (e.g., excipients). Processing difficulties can arise that result in failure of the product to meet specifications, even if certain raw materials conform to established specifications.