Criticality Management of a Drug Product and its Manufacturing Process - Pharmaceutical Technology

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Criticality Management of a Drug Product and its Manufacturing Process
Criticality management combines pharmaceutical product, process, and material knowledge and risk management in one approach, which is reflected in a single document.


Pharmaceutical Technology
Volume 9, Issue 32, pp. 6680

Risk analysis to define the intrinsic criticality of process parameters or material attributes


Figure 4 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
In the fourth step of criticality management (see Figure 2), one evaluates the intrinsic criticality of each influential process para-meter or material attribute. A risk analysis is performed to check and control whether the variation of influential parameters or material attributes can jeopardize an end product's CQA, stability, or manufacturability. The risk analysis is performed for each individual influential parameter or material attribute to determine its effect on individual end-product CQAs while still taking into account the interactions with other parameters or material attributes. Figure 4 shows the overall risk process.

There has been much debate about the definition of critical parameters and attributes. Not every influential parameter or attribute should be called critical. A distinction should be made between the vitally important process parameters or material attributes and those with minor, though statistically significant effects.

A critical parameter or attribute has a strong relationship with the CQAs of the end product. Furthermore, the quality of the end product is likely to be affected if the variability of this process parameter or material attribute is not tightly controlled.


Figure 5 (ALL FIGURES ARE COURTESY OF THE AUTHORS.)
The starting point in the risk analysis is that the product quality and its manufacturability are considered acceptable when the process parameters operate within the design space. If they operate outside the design space, the quality or manufacturability might be affected. However, the design space is not necessarily set at the edge of failure. One must determine what the risk is that an individual process parameter or material attribute will drift outside the design space and lead to a defective product if no specific controls are applied. The higher this risk, the higher the intrinsic criticality of the process parameter or material attribute. This intrinsic criticality is defined based on severity and probability. When robust model equations are in place, quantitative risk approaches might be used. It is also possible to use qualitative approaches to identify the critical parameters or material attributes that need tight controls. The severity (i.e., high, medium, or low) defines the potential magnitude of the effect on the end product CQAs when a process parameter or material attribute moves outside its design space. The magnitude in effect has to do with the strength of the relationship between the process parameter or material attribute and the end-product CQA—or with the closeness of the design space to the edge of failure. Probability (i.e., high, medium, or low) defines the likelihood that the process parameter or material attribute will move outside its design space when no special controls are applied. This likelihood has to do with the mean and variation of the process parameter or material attribute versus the design space or with the location of the normal operating ranges versus the design space. Probability should be rated without the controls to accurately evaluate the intrinsic risk in a process parameter or material attribute. Reference tables can be used to define low, medium, and high. Based on the severity and probability scores, an intrinsic criticality rating (1 to 5) is attributed to each influential process parameter or material attribute (see Figure 5) and filled out in the parameter table (see Table IV).

Process parameters or material attributes with a high intrinsic criticality are designated as critical and need tighter controls such as higher sampling frequency and advanced control systems. It should be noted that the detectability score of an FMEA should not yet be used to define the intrinsic criticality because otherwise no parameter or material attribute will be called critical if good controls are in place. Indeed, a control strategy does not make a process parameter or material attribute less critical, it simply controls the parameter or attribute.


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