Biomedical Engineering Reference
In-Depth Information
TABL E 10.3. Some Aspects of Product Development and Manufacture
Where FMEA can be Applied
Formulation Design
Filling (Machine, Process)
Excipients
Container/closure and machinability
Formulated bulk
Stopper and capping
Storage
Visual inspection
Filter selection
Secondary packaging
Sterile filtration
Cleaning validation
impact on the product (e.g., through aggregation or oxidation). To address this failure
mode, two studies were designed. The first examined the impact of storage conditions on
the quality parameter of excipient 1; most expected to have an impact on product quality.
In this case, it was taken to be the oxidation status of the excipient, as measured by the
peroxide number. It was determined that the facility where the excipient is used obtains it
in 3 kg bottles. Each run uses 0.5 kg of excipient 1 and a campaign usually consisted of
4-6 runs. A small DOE study was conducted to determine the impact of storage
temperature (refrigerated versus room temperature) and air head-space (low, high) on
the rate of oxidation of the excipient. While the generally accepted practice is to store the
excipient under refrigerated conditions, a drawback is the possibility of moisture
absorption due to repeated opening and closing of the bottle when cold. Similarly,
while layering with nitrogen is the accepted practice, the quality of the nitrogen layering
in a manufacturing environment in actual practice may be questionablewhen there are no
controls placed on the process and the quality of the layering is up to the thoroughness of
the operator. The study provided a correlation between change in oxidation status of the
surfactant with time as a function of the storage temperature and headspace volume. This
was followed by another simple DOE inwhich the product was formulatedwith excipient
of varying levels of oxidation, the range of which was determined in the previous study.
These formulation compositions were then placed on long-term and accelerated stability
and a correlation created between the product quality parameters and the surfactant
quality and thereby to the storage condition of the rawmaterial. The outcome was a limit
on the acceptable oxidation number of the excipient and a recommendation to the
handling of an opened excipient bottle in the plant (a hold-time operational range)—
“Use within 30 days of opening. Discard bottle if not used within 30 days.”
An example of an FMEA applied to a portion of the fill/finish process is provided in
Table 10.5. To address this failure mode, sorption studies for both excipient 1 and protein
were performed on the filter to ensure the filter is appropriate (Fig. 10.7). Another study
was done to assess impact of filtration/fill stop on the material when the solution is
stationary in the filter (Table 10.6). These laboratory studies confirmed that the filters
were appropriate and the degree of sorption was measurable. Other experiments showed
that degree of sorption was dependent on flow rate and filter size, leading to a decision to
study these phenomena at scale. Experiments at scale confirmed that the sorption over the
range of process flow rates was acceptable and the surfactant concentrations obtained fell
in the range that had been defined acceptable in the formulation composition robustness
study. The machine stop study allowed a process parameter range to be set for this
