Operational issues

In the following sections, the operational issues that must be considered to operate a viable, flexible stability program for excipients, drug substances, and drug products will be presented. 

Although individual organizations may refer to the development phases differently, for the purpose of this discussion a product will go through four phases during its life cycle. 

During the various phases of development, the specific need for stability data changes. 

Phase IV occurs after product approval and launch and the typical stability studies are focused on the marketed product stability program. These studies are conducted to assure that the product continues to meet the stability requirement for the approved expiration date. Therefore, these studies are conducted at the label storage conditions only. However, if new strengths, packages, or formulations are being developed, these studies would be conducted at accelerated storage conditions also. 

Not only is it important to consult these guidelines for structuring your stability program, but it is also important to be aware of other additional specific requirements of the various governing agencies. For example, the FDA published a draft stability guidance document, which included the ICH requirements and also defined and interpreted the ICH guidelines to include information they specifically require (e.g., site-specific stability). 

Hydroprocessing - especially hydrocracking - is exothermic. Effective control of produced heat is the primary concern of designers, owners and operators of hydrocracking units. In modem units, a high flux of recycle gas provides a sink for process heat. It also promotes plug flow and the transport of heat through the reactors. Most licensors recommend that the ratio of recycle gas to makeup gas should exceed 4 1. 

During design, limits on temperature rise (Tise = Tom - T ) set the size of catalyst beds and determine the number and location of quench zones. During operation, when feeds (and maybe catalysts) are different, the Tnse is also different - sometimes dangerously different. A sudden spike in Tnse can lead to a temperature runaway or temperature excursion. These are dangerous. The rates of cracking reactions increase exponentially with temperature - the hotter they get, the faster they get hot. In a few cases, temperature mnaways have melted holes in the stainless steel walls of hydrocracking reactors. This is remarkable, because the walls were more than 8 inches (20 cm) thick. 

The best way to stop a temperature excursion is to de-pressure the unit by venting recycle gas through a special valve at the CHPS. This decelerates all hydrocracking reactions by rapidly reducing H2 partial pressure in the reactors. De-pressuring can also lead to catalyst mal-distribution, decreased 

Due to the presence of hydrogen, leaks in hydroprocessing units often cause fires. Such fires can be devastating, if not deadly. The replacement of a reactor and the reconstruction of other equipment damaged by the accident can take 12 months. The cost of lost production can exceed US 50 million. Safety concerns are responsible for several operating constraints, such as  

Leading licensors of hydroprocessing technology are listed in Table 15. 

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The SSHO will usually eonduet daily inspeetions to determine if operations are being eondueted in aeeordanee with the HASP, other host eontraet requirements, and OSHA regulations. The SSHO is assigned to the PM for the duration of the projeet, but reports direetly to the HSM with operational issues. An open dialogue is kept between the SSHO and supervisory personnel of the projeet to make sure that safety issues are quiekly addressed and eorreetive aetion is taken. 

A young scientist said, I have never seen a complex scientific area such as industrial ventilation, where so little scientific research and brain power has been applied. This is one of the major reasons activities in the industrial ventilation field at the global level were started. The young scientist was right. The challenges faced by designers and practitioners in the industrial ventilation field, compared to comfort ventilation, are much more complex. In industrial ventilation, it is essential to have an in-depth knowledge of modern computational fluid dynamics (CFD), three-dimensional heat flow, complex fluid flows, steady state and transient conditions, operator issues, contaminants inside and outside the facility, etc. 

Abstract This chapter embodies two sections. In the first section a survey of the state of the art of azo-dye conversion by means of bacteria is presented, with a focus on reactor design and operational issues. The relevance of thorough characterization of reaction kinetics and yields is discussed. The second section is focused on recent results regarding the conversion of an azo-dye by means of bacterial biofilm in an internal loop airlift reactor. Experimental results are analyzed in the light of a comprehensive reactor model. Key issues, research needs and priorities regarding bioprocess development for azo-dye conversion are discussed. 

Consequently, we have to touch upon at least some operational issues to define our approach to the ways and means of constructing models of metabolism. At the most basic level, surveying the current literature, we face a strong dichotomy between a quest for elaborate large-scale models of cellular pathways and minimal (skeleton) models, tailored to explain specific dynamic phenomena only. 

CE has suffered from an assortment of common operator errors, which in turn have characterized the technique as not being robust. Like any analytical piece of equipment, there can be hardware and chemistry/operator issues. CE requires a keen background and user knowledge of the technique so as to avoid common problems that may initially be diagnosed as instrumental issues. For the early user of CE, the table below lists some common problems followed by their root causes and corrective actions. Following the suggested corrective actions should help the beginner get the maximum performance out of the CE instrumentation. 

Detecting explosives in complex environments requires very sensitive and specific analyzers. Though MS offers excellent detection limits and resolutions (e.g., sensitivity and specificity), general-purpose laboratory instrumentation is not ideally suited for detecting trace levels of explosives in the presence of large abundances of potential interferent compounds. Furthermore MS has traditionally required a skilled operator not only to acquire data but to interpret it. MS developments have tended to focus on the performance issues and less so on the operational issues. 

Third, as the anthrax vaccine experience reveals, both DoD acquisition personnel and the contractors hired by DoD have not always possessed the technical and managerial expertise for working with FDA. Interactions with FDA, especially in licensing-related efforts, involve a complicated three-way relationship among DoD, the private contractor, and FDA. This relationship is quite unlike either the two-way relationship between DoD and defense contractors involved in the procurement of weapon systems or the two-way interaction between FDA and a private drug firm. The policy and operational issues about how to manage these three-way relationships have yet to be worked out. 

From an industrial viewpoint there are several drivers that need to be satisfied before a catalyst can be successfully implemented in production plants. Technically there have been various challenges to be met including the synthesis of the requisite ligands, catalyst sensitivity to the environment in which it is applied, reproducibility in product enantiomeric excess (ee) and yield, feasibility in the use of commercial solvents and IP issues around freedom to operate . All these issues have been factors that have influenced commercial exploitation. An example of how one or more of these factors can decide the selection of a catalyst system was described by Hawkins,where Pfizer s selection of the Degussa DEGUPHOS catalyst system over the technically superior DUPHOS system in the synthesis of a Candoxatiil intermediate (shown in Figure 1.1) was decided by royalty payments and freedom to operate issues. 

Each process owner is required to work closely with his or her QA counterpart. This ensures design and operational issues are clearly reviewed and approved by a representative from the quality assurance function, a regulatory expectation. The quality assurance counterpart must be familiar with the process, understand documentation supporting the process, and able to convey what approval the Quality... 

Recommendation 3-la. The Army should develop criteria and a schedule for resolving design and operational issues raised in the 1998 report, Using Supercritical Water Oxidation to Treat Hydrolysate from VX Neutralization, that have not yet been resolved for supercritical water oxidation operation at Newport. These issues include materials of construction, fabrication methods, system plugging, pressure let-down, and the duration of successful continuous pilot-scale operations. 

Ferrara M, De Gennaro L. The sleep inertia phenomenon during the sleep-wake transition theoretical and operational issues. Aviat Space Environ Med 2000 71 843-848. 

Florian Budde is a director of McKinsey, based in the Frankfurt office and with two years experience in the Seoul office. He is co-leader of the European chemicals practice and has served a large number of chemical clients on strategic, organizational, and operational issues, with an emphasis on capital market-oriented corporate strategy. He holds a PhD in physical chemistry from the Fritz-Haber-Institut der Max-Planck-Gesellschaft/Freie Universitat Berlin, and has worked as a researcher in the Physical Science department of IBM s T. J. Watson Research Center in New York. 

Bernd Heinemann is a principal in the Munich office of McKinsey. He is a member of the chemicals practice and co-leader of the German corporate finance practice. Bernd Heinemann has served many chemical clients on strategic and operational issues, with a focus on corporate finance and manufacturing. He holds a diploma in physics from RWTH Aachen and an MBA from Sloan School, MIT. 

Overview The message in these examples is that reactors in this exothermic irreversible reaction system should not necessarily be designed for the maximum temperature. Operability issues should be considered. Designing for a lower temperature gives a larger reactor with more heat transfer area that is more controllable. 

There are other issues with HPGe detectors, which have made their use for this application problematic. The most obvious operational issue is the requirement for... 

Clearly, the design and operations issues are interdependent and must be considered simultaneously. 

Over the last few decades many alternative column configurations and operation have been suggested for batch distillation. The features and characteristics of such configurations have been briefly presented in Chapter 2 with process models of different degree of complexity in Chapter 4. The flexibility and operational issues of some of these configurations will be presented in this chapter. 

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