RISK-BASED CHANGE CONTROL - Risk Management Applications in Pharmaceutical and Biopharmaceutical Manufacturing - page 372

level of management. Risk communication should include senior management for
high risk rankings.
13.7 CASE STUDIES
To better illustrate how to integrate QRM in change control using the FMEA
approach, four case studies are presented here. (The final step of evaluating risk
after implementation of mitigation actions is not included in these examples.)
13.7.1 Case Study #1: Changing Magnesium Stearate from Bovine
to Vegetable-Based
13.7.1.1 Change Description The animal grade magnesium stearate used in
the formulation for a tablet is to be replaced by an equivalent vegetable grade
to reduce risk of BSE/TSE contamination. (Magnesium stearate is added to the
tablet's final blend in the manufacturing process to facilitate lubrication during
tablet compression.)
The supplier proposes using an equivalent grade material with comparable
particle size distribution and shape, to minimize the impact of the change. There
is no change to the material release specification, supplier, or manufacturing site.
13.7.1.2 Potentially Impacted Critical Quality Attributes The final blend prop-
erties are sensitive to the hydrophobicity of magnesium stearate. Even though the
material may meet the release specifications, a replacement material with slightly
different hydrophobic properties could potentially impact the tablet's critical qual-
ity attributes, such as appearance, hardness, and dissolution (because of under-
or over-lubrication).
Under-lubrication may cause adhesion of the powder to the punches during
compression, leading to sticking and potential alteration of the embossing used
to identify the tablet and/or the strength. An illegible imprint is considered a
critical defect.
Over-lubrication, a result of excess coating of the granules with hydropho-
bic material, can delay dissolution or alter the cohesion between particles and
adversely affect tablet hardness, producing soft tablets.
13.7.1.3 Calculated Risk The risk analysis (Table 13.5) led to unacceptable
medium level risks and required a mitigation plan. It is assumed here that imple-
mentation of these recommended actions would not create any new risks to be
evaluated.
13.7.1.4 Recommended Actions One verification batch will be produced with
extensive stratified testing for appearance, hardness, and dissolution to ensure
equivalency of the alternative Mg stearate in the formulation. Implementation of
this action would reduce the risk to as low as reasonably practical, by providing