Scale-up of production

A historic summary of the development of the product serves many purposes. The foremost purpose is to apprise the investigators of the scope of inspection. The investigators learn more about the product from the history of its development than from the analysis report of the finished product. This shows the awareness of the firm about the development process. This document should include a description of the API, the formulation, and the analytical methods. These sections should be clearly marked or presented in separate binders. The summary section should highlight how the biobatch is linked to the full-scale batch with respect to validation and scale-up of production. This section also offers an opportunity for the firm to address the issues that it considers critical. 

Concern related to PCNs began in workplace settings with occurrences of chloracne, jaundice, liver disease, and death noted from prior to scale-up of production until PCN substitutes became popular (reviewed by Hayward (1998) [12]). Occupational exposures were reported as recently as 1989 [8]. Environmental contamination by PCNs was first observed in the 1970s in sediments near industrial sites [13], in air, water, and soil near sites of PCN manufacture and use [14,15], and in fish [16] and fish-eating birds [17,18]. 

Transgenic plant systems have the potential to produce recombinant proteins on a commodity scale (Kusnadi et al., 1997) due to the low cost of growing plants and because scale-up of production simply requires sewing seeds over a greater field area. As such they offer almost unlimited scalability (Giddings, 2001). It is estimated by Kusnadi et al. (1997) that transgenic plants can produce pharmaceutical proteins at between 10 and 50-fold lower cost than microbial fermentation systems, and 1,000 times lower than mammalian cell culture systems (Hood et al., 2002). 

Microfabrication technology used to manufacture microreactors also introduces many advantages, most notably the ability to rapidly and cheaply mass-produce devices. The low cost of microfabricated devices makes it possible for these devices to be disposable, a characteristic desirable for many medical applications. Rapid scale-up of production by operating many microreactors in parallel can also be accomplished. Microfabrication also presents the opportunity for complete systems in a single monolithic device or systems on a chip as microreactors are incorporated with chemical sensors and analysis devices, microseparation systems, microfluidic components, and/or microelectronics. 

For increasing the capacity of preparative work, two methods have proved to be popular, viz., cyclic automatic operation and increasing the column diameter. These two principles, alone or in combination, should permit the scaling up of production-scale throughputs, but this aim has not yet been realized. 

When only small quantities of product are required, scale-up of production via roller bottles in a laboratory robot assisted facility may be feasible, but this approach is susceptible to contamination. Moreover, ensuring uniform environmental conditions throughout a multitude of bottles is not a trivial task. Control of a small stirred tank bioreactor is more readily accomplished. The kinetics of product formation in animal cells can often be represented in terms of the Luedeking-Piret model (see Section 13.1.5). 

With the growing interest in the SILP technology and the success of these novel materials in catalysis and gas purification, the scale-up of production capacity becomes an important issue. Recently, large batches of SILP materials have been synthesized using fluidized bed spray-coating techniques as shown in Figure 4.7... 

Figure 18.14 Scale-up of production with a 16-channel module, (a) Schematic of the microchannels on a chip. Labels b and w specify the inlet positions for black and white IBA, respectively. The aqueous phase is infused from the inner 16 inlets, arranged circularly, (b)...

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