Best practices for the development, scale-up, and post-approval change control of IR and MR dosage forms in the current quality-by-design paradigm.

In this whitepaper, the Manufacturing Technical Committee of the Product Quality Research Institute provides information on the common, best practices in use today in the development of high-quality chemistry, manufacturing and controls documentation. Important topics reviewed include International Conference on Harmonization, in vitro-in vivo correlation considerations, quality-by-design approaches, process analytical technologies and current scale-up, and process control and validation practices. It is the hope and intent that this whitepaper will engender expanded dialog on this important subject by the pharmaceutical industry and its regulatory bodies.

Mechanisms of arm-tip regeneration in the sea star, Leptasterias hexactis.

Wound healing and regeneration following amputation of arm-tips of the sea star, Leptasterias hexactis, are described using light microscopy, SEM, TEM, and [3H] thymidine autoradiography. The process can be divided into a number of stages. Initially, the wound is closed by contractions of the stump-tip. Re-epithelialization then occurs through migration of epidermal cells from adjacent areas over the wound to form a thin wound epidermis. This is converted into a thicker, permanent covering in concurrence with the onset of cell cycle activity in the wound epidermis and adjacent epidermal regions. Histolysis and phagocytosis of damaged tissues occur beneath the new epidermis and a small connective tissue scar develops at the wound site within which muscle differentiates. At this time, elevated levels of [3H]thymidine incorporation are initiated in the sub-epidermal tissues of the arm-tip. A variety of differentiated cell types enter the cell cycle including cells of the parietal peritoneum, lining of the radial water canal, and the dermis. Cell division is accompanied by the development of a small new arm-tip complete with terminal ossicle, terminal tentacle, and optic cushion. The radial water canal, radial nerve, and perivisceral coelom extend by outgrowth into this newly developing tip. Accelerated growth of the regenerate then occurs in a zone just proximal to the new tip. There is no evidence of a blastema-like mass of rapidly dividing undifferentiated cells at the tip of regenerating arms. Arm-tip regeneration in this sea star may therefore be best described as a morphallactic-like process in which a true blastema is not formed, but in which scattered cell proliferation plays an essential role.