Biomedical Engineering Reference
In-Depth Information
stability under preferred (2-8
C) and accelerated (25
C) storage conditions in the
appropriate container/closure system. The data available after a year were analyzed as
an intermediate point. It was found that at 2-8
C, none of the quality attributes were
impacted, suggesting a robust formulation. A design space for the formulation could
therefore be defined. Under accelerated conditions, the analysis showed impact of pH
and buffer strength on deamidation and oxidation (see Fig. 10.6a and b). The model
dependencies on buffer strength are weak. Impact of pH on deamidation is well
understood, and the finding fits with knowledge of the deamidation mechanism. The
interaction plots confirm that pH 5.5 is optimum with respect to deamidation. Low pH
also favors lower oxidation.
Case Study FMEA: Process Analysis.
FMEA is a tool to analyze a process or
product to determine potential reliability problems through identification and detailing
of a process map that leads to the finished product, what might go wrong at the various
steps in this process, howmight it go wrong, and what would be the impact. An extended
analysis requires an assessment of the (1) S
¼
severity of themode of failure and relates to
the effect on the product safety or efficacy (2) O
¼
probability that the failure mode will
occur, and (3) D
difficulty to detect the mode of failure. The three aspects of the failure
mode are assigned numbers, usually between 1 and 10, with the higher the risk, the
greater the number. These numbers are multiplied to obtain the risk priority number
(RPN
¼
D). Understanding the risk level through the RPN can then help in
prioritizing activities, experiments, and plans for riskmitigation strategies. FMEA can be
applied to all aspects of product development and manufacture (Table 10.3).
An example of such an analysis pertaining to formulation excipients is provided in
Table 10.4. The process of analysis is exemplified here by considering the first failure
mode. Incorrect amounts of charged excipients were identified as a potential mode for
failure under the category excipients. The potential effect of incorrect excipient levels
would be an out of specification (OOS) at release or a stability failure. Of the potential
causes for such a failure, simple incorrect addition was assigned a low RPN. The
probability of occurrence that this would not be detected was considered low due to the
presence of GMP manufacturing controls. The severity was assigned a 5 since the failure
mode could cause a batch failure but was not likely to harm patients. The action required
in this case is to ensure that batch records are correct and the proper controls are in place.
The other potential cause for this mode of failurewas considered to be simply variability/
errors in weighing large amounts of material and liquids as a consequence of accuracy of
balances, and so on in the relevant ranges. The probability that this would occur was
assigned a 6 and the probability that this would not be detectedwas assessed as 8. AnRPN
of 240 implied that some corrective/remedial action would be required—in this case by
identifying the range of excipients level that would be acceptable. From the first row, it is
clear that the variability of the amount of excipients charged amounts to a high RPN. One
of the ways to address this failure mode would be the robustness and formulation design
space experiment shown as Case Study DOE in the previous subsection.
The high RPN number for the second failure mode identified here pertains to the
quality of raw material. Experience and insight suggest that among the formulation
ingredients, excipient 1 is most susceptible to deterioration in quality, which may have an
¼
O
S
