Processed products quality attributes

Process Understanding A process is considered to be well understood when all critical sources of variability are identified and explained, variability is managed by the process, and product quality attributes can be accurately and reliably predicted. 

A key component in any quality system is appropriately responding to nonconformities (i.e., deviations from requirements established under the quality system for in-process material or final product quality attributes, process control parameters, records, procedures, etc.). Nonconformities may be detected during any stage of the... 

Product quality attributes can be accurately and reliably predicted over the design space established for materials used, process parameters, manufacturing, environmental, and other conditions. 

Samples are to be taken during and/or after each critical manufacturing step. All control parameters for the manufacturing process have to be monitored and recorded. Each sample analysis will be performed in duplicate using validated or accepted pharmacopeia methods. The sample results will be used to confirm in-process and final product quality attributes as defined by the preestablished specifications. Conformance with specifications will justify the appropriateness of the critical parameters used during the process validation. 

Confirm critical process parameters and determine their effects on product quality attributes. 

The next risk assessment should be undertaken just prior to issuing the URS, when the process and the user requirements for the system are defined, enabling the affect of system failure, malfunction, or misuse on product quality attributes and the safe operation of the system to be evaluated. This assessment can be reported as part of the URS review and should identify system requirements that need to be reconsidered. 

The parameter controls critical process equipment or elements that may impact product quality attributes independent of the computer system. 

The periodic reviews will be event-based or time-based exercises. Event-based reviews will normally be carried out if there is a controlled change made to the computerized operation that is outside the scope of the original validation and could impact on process or product quality attributes. This will normally be conducted in conjunction with the change control procedure (see Sec. IX.C), and should include a review of all relevant validation documentation to determine the extent of revalidation that may be required. 

Does the system control a manufacturing and/or testing process that has a direct impact on product quality Product quality attributes include identity, efficacy, strength, dosage, safety, and purity. ... 

Awareness of how process parameters and product quality attributes are related often results in more rapid investigations into process failures, glitches, and upsets. 

However, some excipients have multiple functions. For example, microcrystalline cellulose can function as a filler, a binder, and a disintegrant. As seen in Table 7.3, a typical low-dose formulation could include more than 85% filler—binders. Thus, physical and chemical properties for these specialty excipients are extremely important in a low-dose formulation for manufacturability, product performance, and longterm stability. Because the poor physicomechanical properties of components are not altered during manufacture as they are in the wet or dry granulation process, critical material properties and their impact on product quality attributes should be well characterized and understood.23 Discussion in this section will focus on fillers-binders. For those requiring more information on excipients, several excellent books and review articles are available in the literature.24-27... 

To ensure that specifications established for critical product quality attributes are met in a large-scale operation, the formulation and manufacturing process developed in the laboratory must be transferred to production and validated. It is necessary to start with a small scale in pharmaceutical research and development. Unfortunately, small-scale mixers necessary during the early development phase will not necessarily have the same characteristics as a commercial-scale mixer. Currently no mathematical techniques exist to predict the blending behavior of multicomponent solid mixtures therefore, experimental work to ensure the proper scale-up and transfer to the production facility is required. Consider the following process parameters for a tumbling blender during scale-up trials ... 

The development of a qualified down-scale model of a process module is integral to the approach of process validation using bench-scale experiments, as described earlier. We have developed down-scale models of process steps ranging from various types of process chromatography for protein purification to separation by precipitation and filtration. These down-scale models have been utilized to evaluate the effects of relevant process parameters on product-quality attributes. The normal logical sequence of process development, of course, is bench scale to pilot scale to full scale. However, for many plasma protein purification processes, a reverse order needs to be followed. As licensed full-scale processes already exist, the full-scale process steps need to be scaled down to construct small process models in order to evaluate the robustness of process parameters on the product without impacting full-scale production. These models can also be utilized to evaluate process changes, improvements, and optimizations easily and economically. 

An input parameter value is directly related to an output parameter or quality attribute specifically, the output parameter of one unit operation often is the input parameter for the subsequent unit operation [32]. Equivalently stated, critical Ys (outputs or responses) from one stage often are inputs for next the stage [37]. Input parameters are assessed as to whether they significantly impact critical output parameters (e.g., product safety, identity, and efficacy), although the definition of significant varies among applications [32]. As all product quality attributes are not routinely measured during process development, some output variables are selected... 

Process validation starts with the identification of product quality attributes and justification of acceptance criteria, followed by a review of the risk analysis, execution of process development runs, and compilation of clinical material manufacturing data to set specifications considering process variability [11]. There is a greater focus on process validation for downstream steps rather than for upstream steps because downstream steps are associated with virus removal. Process validation is just one approach used to control virus contamination, however others include cell bank characterization, in-process testing, inactivation procedures, control of raw materials, containment, and postmarket surveillance [6]. 

Kawas, M.L. and Moreira, R.M. 2001. Characterization of product quality attributes of tortilla chips during the frying process, J. Food Eng., 47 97-107. 

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