Product quality attributes

Figure 26, shown earlier, is a simple form of input mapping called table lookup. A more complicated inference mechanism is illustrated in Fig. 30. Here we see a simple example from a fluidized catalytic cracking unit in which multiple product quality attributes can be explained by multiple operating parameters (Ramesh et al., 1992).

Product release Determination of final product 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 normal operation or control of the parameter has a direct impact on product quality attributes. 

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. 

Product Quality Attributes Maintained Over Time... 

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... 

Unit Operation Variables Product Quality Attributes... 

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 ... 

Spray-dried lactose in the formulation may be replaced by spray-dried mannitol such as Pearlitol SD100. Also, the ratio of the lactose to Avicel PH 102 should be optimized for required product quality attributes including blending uniformity, content uniformity, potency, drug release, and breaking strength. 

Today, there is more emphasis on quality of excipients. For example, some inherent quality variability may occur in the natural products magnesium stearate and sodium starch glycolate. What is the impact of the variability of these excipients on product quality attributes Also, excipient viscosity, molecular weight, and particle size relative to API particle size could be critical factors to some formulations. An optimal dissolution method can only be developed on the basis of knowledge of the dmg product. 

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