Validation cost controls

Regardless of whether the costs of unnecessary and unproductive validation efforts represent a significant portion of a laboratory s annual expense or a small decimal of its budget, managers have a fiduciary responsibility to control costs. If that responsibility is not exercised patients costs ultimately rise, a portion of needy patients are financially excluded from a beneficial treatment, and investors who might otherwise have funded valuable research and development efforts put their money in an Internet stock instead. Cost control isn t just good business it s good altruistic policy as well. 

Not every marketing process supported by a computer system would fall within the scope of regulatory scrutiny. Computer systems such as forecasting applications, cost control systems, and systems that are used to purely support only financial or accounting activities may not need to be validated at all. However, each of these systems is stiU expected by industry regulators to undergo some form of formal documented regulatory assessment to determine whether or not this is the case. 

In short, most pharma companies assure the quality and product safety related to their laboratories, but are overzea-lous in meeting regulatory requirements to the detriment of cost controls. The responsible segment of the industry is doing more than it needs to do and is spending too much time and too many resources on the validation of LIMS. 

There are four cost-control strategies that if taken together can significantly control the cost of validation. Laboratory information management systems (or other regulated... 

After a satisfactory verification film is produced, an assembly may be fabricated specifically for destructive inspection to validate that the verification film was accurate. This correlation allows the use of verification film rather than more expensive destructive inspection for future changes such as duplicate tool fabrication and tool or detail modification. Simple assemblies are usually not destructively inspected because of high confidence that the verification film is entirely representative of the expected bondlines. Complex or large parts may not be destructively inspected because of the cost of the details and assembly time. In these cases other means of validating the verification film are used. Meticulous pre-bond detail and post-bond assembly thickness measurements may be sufficient to prove bondline thickness control. Ultrasonic inspection and X-ray photography (discussed previously) may be sufficient to prove that details are in the correct places and bonds are good. 

Figure 1.8. Schematic frequency distributions for some independent (reaction input or control) resp. dependent (reaction output) variables to show how non-Gaussian distributions can obtain for a large population of reactions (i.e., all batches of one product in 5 years), while approximate normal distributions are found for repeat measurements on one single batch. For example, the gray areas correspond to the process parameters for a given run, while the histograms give the distribution of repeat determinations on one (several) sample(s) from this run. Because of the huge costs associated with individual production batches, the number of data points measured under closely controlled conditions, i.e., validation runs, is miniscule. Distributions must be estimated from historical data, which typically suffers from ever-changing parameter combinations, such as reagent batches, operators, impurity profiles, etc.

Step (6) can be broken down as given in Table 2.7. If the hardware and its operation is under control, and some experience with similar problems is available, experiments need only be carried out late in the selection process to prove/disprove the viability of a tentative protocol. Laboratory work will earnestly begin with the optimization of instrumental parameters, and will continue with validation. In following such a simulation procedure, days and weeks of costly lab work can be replaced by hours or days of desk work. 

To be useful to those concerned with choices in the allocation of health and social care resources, the data for economic evaluations need to be timely, relevant, credible and accurate (Davies, 1998). As a minimum, the costs associated with the interventions should be estimated from activity data, which quantify resources used, and price or unit cost data. Often evidence from well-controlled prospective trials with high internal validity is required to establish whether differences in economic end points are directly attributable to the interventions. However, the economic evaluations of acetylcholinesterase inhibitors estimated costs from retrospective analysis of available datasets Qonsson et al, 1999b), analysis of published literature (e.g. Stewart et al, 1998) and expert opinion (e.g. O Brien et al, 1999 Neumann et al, 1999). This means that it is not clear whether differences in costs were due to the anticholinesterase inhibitors or to other factors such as availability of services in different areas, the living situation of the patient, or disease severity. 

Obviously, GMP requirements, especially extensive personnel training, calibration, qualification and validation, enhanced documentation, extensive cleaning and sanitation, and sharpened in-process control must considerably influence process organization and output. All these GMP-related activities are costly and time consuming, and will result in decreased productivity and increased production costs. On the other hand, a quality assurance system contributes to consistent production with a lower number of rejected batches and complaints. 

The inherent reproducibility or imprecision of the method will have been determined as part of the validation procedure. This information can then be applied to the internal quality control programme which is designed to identify the intrusion of a bias (inaccuracy) and/or an alteration in the reproducibility of the assay. Programs for Internal quality control are most extensively developed for clinical laboratories because of the availability of suitable RMs in large batches and at an affordable cost although some level of IQC is appropriate to aU work carried out at a continuing basis see Section 6.2. 

Final methods are developed for transfer to operational quality control (QC) laboratories for the release testing of production batches. Additionally, the methods are intended to be applied during Registration Stability studies and for the release of the DP or DS validation batches during the pre-approval development stage. The analytical methods should last for the entire product lifetime therefore, the aim of final method development is to generate fast, robust, reliable, and transferable HPLC methods (preferably isocratic and at low cost). 

The critics of government-imposed price controls on pharmaceutical products do have a valid point. As long as the price ceilings are set above the incremental cost of producing these products, manufacturers will be tempted to sell at whatever those controlled prices are, because they earn at least a positive margin toward the recovery of fixed costs. The problem is that the price ceilings may be set at levels far below fully allocated fixed costs per unit. If every payer followed that strategy, pharmaceutical companies would soon become insolvent. 

Endocrine diseases and their treatment have a major impact on health throughout the world, particularly in terms of diabetes, thyroid disease, steroid therapy, and control of fertility. Most endocrine therapy is simple and relatively cheap, but a clear understanding of their actions and uses is essential for safe and cost-effective treatment. In this chapter we will focus mainly on well established and validated endocrine therapies that are widely used throughout the world, with briefer mention of drugs that have recently been introduced. In the sections that follow we outline the major issues in the current clinical pharmacology of endocrine disease, covering each of the major endocrine systems in turn. 

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