Commercial-scale Manufacturing Research Articles

Fulvestrant: From the Laboratory to Commercial-Scale Manufacture

The development of a commercial manufacturing process for fulvestrant (the active ingredient in ‘Faslodex’) is described. Key steps in the synthesis are stereoselective 1,6-addition of an organocuprate to a steroidal dienone followed by copper-mediated aromatisation of the A-ring. The strategy for dealing with noncrystalline intermediates is outlined. The production of drug substance of acceptable quality is critically dependent on limiting the formation of key impurities. The origin of these impurities is discussed, and measures to prevent or control their formation are described.

Ultra scale‐down studies of the effect of shear on cell quality; Processing of a human cell line for cancer vaccine therapy

Whole cell therapy is showing potential in the clinic for the treatment of many chronic diseases. The translation of laboratory-scale methods for cell harvesting and formulation to commercial-scale manufacturing offers major bioprocessing challenges. This is especially the case when the cell properties determine the final product effectiveness. This study is focused on developing an ultra scale-down method for assessing the impact of the hydrodynamic environment on human cells that constitute the therapeutic product. Small volumes of a prostate cancer cell line, currently being developed in late phase II clinical trials as an allogeneic whole cell vaccine therapy for prostate cancer, were exposed to hydrodynamic shear rates similar to those present in downstream process, formulation and vial filling operations. A small scale rotating disc shear device (20 mL) was used over a range of disc speeds to expose cells to maximum shear rates ranging from 90 x 10(3) to 175 x 10(3) s(-1) (equivalent maximum power dissipation rates of 14 x 10(3) to 52 x 10(3) W kg(-1)). These cells were subsequently analyzed for critical cell quality attributes such as the retention of membrane integrity and cell surface marker profile and density. Three cell surface markers (CD9, CD147, and HLAA-C) were studied. The cell markers exhibited different levels of susceptibility to hydrodynamic shear but in all cases this was less than or equal to the loss of membrane integrity. It is evident that the marker, or combination or markers, which might provide the required immunogenic response, will be affected by hydrodynamic shear environment during bioprocessing, if the engineering environment is not controlled to within the limits tolerated by the cell components.

Scalable Recombinant Adeno-Associated Virus Production Using Recombinant Herpes Simplex Virus Type 1 Coinfection of Suspension-Adapted Mammalian Cells

Recombinant adeno-associated virus (rAAV) production systems capable of meeting clinical or anticipated commercial-scale manufacturing needs have received relatively little scrutiny compared with the intense research activity afforded the in vivo and in vitro evaluation of rAAV for gene transfer. Previously we have reported a highly efficient recombinant herpes simplex virus type 1 (rHSV) complementation system for rAAV production in multiple adherent cell lines; however, production in a scalable format was not demonstrated. Here we report rAAV production by rHSV coinfection of baby hamster kidney (BHK) cells grown in suspension (sBHK cells), using two ICP27-deficient rHSV vectors, one harboring a transgene flanked by the AAV2 inverted terminal repeats and a second bearing the AAV rep2 and capX genes (where X is any rAAV serotype). The rHSV coinfection of sBHK cells produced similar rAAV1/AAT-specific yields (85,400 DNase-resistant particles [DRP]/cell) compared with coinfection of adherent HEK-293 cells (74,600 DRP/cell); however, sBHK cells permitted a 3-fold reduction in the rHSV-rep2/capX vector multiplicity of infection, grew faster than HEK-293 cells, retained specific yields (DRP/cell) at higher cell densities, and had a decreased virus production cycle. Furthermore, sBHK cells were able to produce AAV serotypes 1, 2, 5, and 8 at similar specific yields, using multiple therapeutic genes. rAAV1/AAT production in sBHK cells was scaled to 10-liter disposable bioreactors, using optimized spinner flask infection conditions, and resulted in average volumetric productivities as high as 2.4 x 10(14) DRP/liter.

GAIN AND LOSS IN MALARIA WAR

THE FRUSTRATING BATTLE against malaria took two steps forward and one step back last week. New ventures targeting more affordable and effective treatments were launched, but they came on the heels of a setback in the antimalaria drug pipeline. The Institute for OneWorld Health has signed on Sanofi-Aventis and Amyris Biotechnologies to develop a low-cost semisynthetic route to artemisinin, the active pharmaceutical ingredient (API) in a range of malaria drugs. The API is currently extracted from the sweet wormwood plant, and the companies say a nonseasonal source would help stabilize the supply and price of malaria treatments. The goal is to design a commercial-scale manufacturing process that will turn out enough API to treat 200 million people—about 40% of the population that contracts malaria each year. The project builds on technology developed by University of California, Berkeley, professor Jay Keasling, who developed a microbial system to produce artemisinin through fermentation. “This collaboration...

Ontological informatics infrastructure for pharmaceutical product development and manufacturing

Informatics infrastructure plays a crucial role in supporting different decision making activities related to pharmaceutical product development, pilot plant and commercial scale manufacturing by streamlining information gathering, data integration, model development and managing all these for easy and timely access and reuse. The foundation of such an infrastructure is the explicitly and formally modeled information. This foundation enables knowledge in different forms, and best manufacturing practices, to be modeled and captured into tools to support the product lifecycle management. This paper discusses the development of ontologies, Semantic Web infrastructure and Web related technologies that make such an infrastructure development possible. While many of the issues addressed in this paper are applicable to a wide spectrum of molecular-based products, we focus our work on the development of pharmaceutical informatics to support Active Pharmaceutical Ingredient (API) as well as drug product development as case studies to illustrate the various aspects of this infrastructure.

An Adventure in Catalysis: The Story of the BP Fischer–Tropsch Catalyst from Laboratory to Full-Scale Demonstration in Alaska

This article describes the development of BP's Fischer–Tropsch catalyst from the early days of laboratory scale preparations and microreactors right through to commercial scale manufacture and installation in BP's new $86 million demonstration facility in Nikiski, Alaska. For those who were involved in the early work and who have remained with the project through to its latest phase, this has truly proved to be an Adventure in Catalysis.

Thermogravimetric studies of binary and ternary systems containing salicylic acid, sodium salicylate, sodium carbonate and sodium hydrogen carbonate. Part II

The mechanism of thermal decomposition of binary and ternary systems containing salicylic acid, sodium salicylate and disodium salicylate sesquihydrate, sodium carbonate and sodium hydrogen carbonate were studied by means of thermogravimetric and differential thermal analysis. The possibility was demonstrated of analyzing ternary systems containing three unreactive or three reactive components. The results can be useful for monitoring the course of the commercial-scale manufacture of sodium salicylate and for checking declared compositions of salicylate mixtures.