Definition of process analytics

A broadly accepted definition of process analytics is difficult to capture as the scope of the methodology has increased significantly over the course of its development. What was once a subcategory of analytical chemistry or measurement science has developed into a much broader system for process understanding and control. Historically, a general definition of process analytics could have been  

Chemical or physical analysis of materials in the process stream through the use of an in-line or on-line 

This definition can be described as analysis in the process and is closely related to the traditional role of analytical chemistry in process control. The classical scope of a process analytical method is it to supplement the control scheme of a manufacturing process with data from a process analyzer that directly measures chemical or physical attributes of the sample. 

Typically, this definition is accompanied by the characterization of the measurement relative to the process as in-line (probe in direct contact with the sample inside the processing equipment), on-line (the sample is withdrawn from process via a sampling loop probe not directly part of processing equipment) and at-line (the sample is removed from process but measured in close proximity to process, within the timescale of processing). 

This previous definition had been broadened after the FDA s issue of the PAT guidance document to encompass aU factors influencing the quality and efficiency of a chemical or pharmaceutical manufacturing process. Driven by developments in Six-Sigma and operational excellence programs an extended definition included such items as  

This very wide definition can be summarized as the analysis of the process and has most recently been proposed in the pharmaceutical industry1 to encourage better use of the information content of classical process analytical methods for the improvement of process development and control. Particularly in the pharmaceutical industry, the acronym PAT for process analytical technology is often used to describe this newer definition of PA. 

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With the onset of the QbD initiative (see Section 2.3.4), first codified in the ICH Q8 document in 2006, the above-mentioned broader definition of process analytical technology has somewhat evolved into parts of the key elements of the broad definition of QbD, resulting in a partial retraction of the term PAT back... 

Implementation of process analytics in the pharmaceutical indusUy for continuous improvement purposes has received increased attention in recent years. Process analytics or PAT (see previous definition) has been identified as a key factor in continuous improvement initiatives and is seen as a central element of emerging regulatory strategies to enable these efforts as part of QbD. 

The most important factors for the entire process of equipment qualification and computer system validation in analytical laboratories are proper planning, execution of qualification according to the plan, and documentation of the results. The process should start with the definition of the analytical technique and the development of user requirement and functional specifications. For computer systems, a formal vendor assessment should be made. This can be done through checklists and vendor documentation with internal and/or external references. For very complex systems, it should go through a vendor audit. 

Further development of the mathematical description of the chromatographic process requires the definition of the analyte distribution function y/(c), or essentially the introduction of the retention model (or mechanism). 

FIGURE 2.1 Schematic definition of total analytical process (TAP). 

It is becoming more and more desirable for the analytical chemist to move away from the laboratory and iato the field via ia-field instmments and remote, poiat of use, measurements. As a result, process analytical chemistry has undergone an offensive thmst ia regard to problem solviag capabihty (77—79). In situ analysis enables the study of key process parameters for the purpose of definition and subsequent optimization. On-line analysis capabihty has already been extended to gc, Ic, ms, and ftir techniques as well as to icp-emission spectroscopy, flow iajection analysis, and near iafrared spectrophotometry (80). 

Section II introduces the formal framework for the definition anc description of process trends at all levels of detail qualitative, order-of magnitude, and analytic. A detour through the basic concepts of scale-spact filtering is necessary in order to see the connection between the concept o process trends and the classical material on signal analysis. Within th( framework of scale-space filtering we can then elucidate the notions o episode, scale, local filtering, structure of scale, distinguishec features, and others. 

Similar considerations were taken into account throughout the process of designing the study and committing the design to a protocol. In addition to analytical quality specifications, decisions were made regarding definitions of limits of detection and quantitation, levels of apparent residues at which confirmation was required, and how such confirmation would be achieved. All of these decisions were based on fulfilling the objectives of the study while operating within unavoidable time and resource constraints. 

The chemical world is often divided into measurers and makers of molecules. This division has deep historic roots, but it artificially impedes taking advantage of both aspects of the chemical sciences. Of key importance to all forms of chemistry are instruments and techniques that allow examination, in space and in time, of the composition and characterization of a chemical system under study. To achieve this end in a practical manner, these instruments will need to multiplex several analytical methods. They will need to meet one or more of the requirements for characterization of the products of combinatorial chemical synthesis, correlation of molecular structure with dynamic processes, high-resolution definition of three-dimensional structures and the dynamics of then-formation, and remote detection and telemetry. 

Water and hydrocarbons occurring together, in shallow aquifer systems, may be considered immiscible for flow calculation purposes however, each is somewhat soluble in the other. Since groundwater cleanup is the purpose behind restorations, it receives greater attention. Definition of water quality based on samples retrieved from monitoring wells relies heavily upon the concentration of individual chemical components found dissolved in those samples. An understanding of the processes that cause concentration gradients is important for the proper interpretation of analytical results. 

Validation is the process of proving that a method is acceptable for its intended purpose. It is important to note that it is the method not the results that is validated. The most important aspect of any analytical method is the quality of the data it ultimately produces. The development and validation of a new analytical method may therefore be an iterative process. Results of validation studies may indicate that a change in the procedure is necessary, which may then require revalidation. Before a method is routinely used, it must be validated. There are a number of criteria for validating an analytical method, as different performance characteristics will require different validation criteria. Therefore, it is necessary to understand what the general definitions and schemes mean in the case of the validation of CE methods (Table 1). Validation in CE has been reviewed in references 1 and 2. The validation of calibrations for analytical separation techniques in general has been outlined in reference 3. The approach to the validation of CE method is similar to that employed for HPLC methods. Individual differences will be discussed under each validation characteristic. 

While throughout this chapter various challenges and pitfalls have already been discussed, this section provides the additional common difficulties in realizing a PA solution within routine production. In general PA requirements far exceed laboratory-based analytical methods, even for the simplest of applications. That is, a successfully implemented process analytical solution provides reliable quality data while withstanding the routine factory operational conditions (enviromnental, work practices, etc.). It also functions with negligible operator and expert intervention. Based on this definition a PA solution necessitates ... 

A small but diverse team of personnel is typically involved in the activities of the Project Identification and Definition Stage (refer to Figure 2.1). Representatives from groups such as process analytics, process control, project management, central engineering and production operations should populate the team in the first stage. The size and diversity of the team should grow from the identification step to the definition step as resources are allocated and plans developed. 

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