Analytical methods.
The model and worst-case compound evaluation did not replace any analytical-method validation activities. Analytical recovery
must be established for each compound in the portfolio, but not on all surfaces. If multiple limits are to be considered,
or if a range of reporting is required, the lowest limit may be evaluated, and that recovery can be applied to all acceptance
limits as a conservative estimate. In the analytical method, three recovery factors were presented: Group 1, Group 2, and
Group 3. Methods could be validated for any surface within a group and could be considered representative. The authors chose
stainless steel 316L because it is the most prevalent, and cast iron because it is a common material on a tablet press. Type
III hard anodized aluminum is the only surface in Group 3. This strategy did not ignore any uncommon surfaces. It grouped
them appropriately, swabbed them, and applied a representative recovery factor.
Variability.
Method variability was evaluated by performing a control sample (Compound A, 6 replicates, 0.5-μg swab, stainless steel 316L,
Ra = 3.5) each day. The mean recovery of the entire experiment was 52%. These data suggested that the swabbing ability of
the analyst did not change over time. The standard deviation within a day typically was less than 6. The pooled-within-run
standard deviation was 3.99 over the course of the experiments. This value was used as a criterion for grouping new surfaces.
The day-to-day standard deviation was 15.34.
Figure 5
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Incorporating new materials of construction into the grouping strategy.
Periodically, new equipment will be introduced into the CTM area that incorporates a product-contact surface made of a material
of construction that is not listed in Table II. This problem is often caused by alloys of metals that have already been evaluated
and by polymers of proprietary composition. Because surface recovery must be evaluated, personnel need a way to incorporate
new surfaces into the groupings outlined in Table II. When a new piece of equipment is purchased, CTM-engineering employees
prepare the needed documentation to evaluate the equipment with regard to the cleaning program before use. If an identified
sampling location is made of a new material of construction, the engineer asks the person responsible for the cleaning program
and analytical development to perform the next steps, which are shown in Figure 5.
Suppose that new equipment incorporated three new materials: a crystalline thermoplastic polyester marketed under the trade
name of Ertalyte (Quadrant Engineering, Reading, PA), stainless steel 420, and stainless steel 630. Without the grouping strategy
in place, method revalidation would have to occur for all compounds handled by this piece of equipment. With the strategy
in place, these surfaces are placed into groups based on model-compound recovery. No method revisions are required.
The analytical recovery of Compound A was evaluated for Ertalyte, stainless steel 420, and stainless steel 630 at the 5.0-μg/in.2 level. The authors used the validated method to evaluate the recovery of the three new surfaces compared with a representative
surface from Group 1 (i.e., stainless steel 316L), Group 2 (i.e., cast iron), and Group 3 (Type III hard anodized aluminum).
Recovery was evaluated for both the group representative and the new surfaces on the same two days with three replicates on
each day. As an alternative, six replicates may be performed on the same day as the controls because the comparison of recovery
is relative.
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The new surfaces are placed in one of the three groups or define a new lower group, based on how close their average is to
that of the group control. The authors obtained a cutoff value of 3.0% in the following manner. Based upon the data for the
control, the within-day standard deviation was calculated to be 3.99 and was used in Equation 1. A series of one-sided hypothesis
tests with an error rate of α = 0.10 were performed to assess whether the new surface mean was less than a specified control-surface
mean. The confidence limit half-width for the difference between the means of two surfaces was computed using the within-day
standard deviation because the replicates for each surface had to be run on the same two days, with each day treated as a
block. For these calculations, it was assumed that this standard deviation was known. The lower one-sided confidence limit
for the difference in means was derived using the following steps:
This calculation did not indicate a difference between a control surface and the new surface under evaluation if the recovery
differed by less than 3.0%. This approach was conservative because Eq. 1 categorized a new surface into Group 2 if it differed
from stainless steel by more than 3.0%, which could be viewed as a strict criterion. Because the results were obtained on
the same days and runs, the authors believed that this approach was reasonable. When evaluating the recovery of a new surface,
this strategy helps personnel to place each material into the appropriate group. The grouping starts with a comparison of
the new surface average to that of Group 1 (stainless steel 316L) and continues sequentially. If the new surface recovery
(NSR) is more than 3.0% less than that of the group reference, it is compared with the reference surface in the next lower
group until a group is found with which it does not differ by more than 3.0%. If no such group is found, then the new surface
forms a new, lower group. The procedure is as follows:
- If the NSR > mean stainless-steel recovery – 3.0%, the new surface belongs in Group 1.
- If the NSR > mean cast-iron recovery – 3.0%, the new surface belongs in Group 2.
- If the NSR > mean Type III anodized aluminum recovery – 3.0%, the new surface belongs in Group 3.
- If the NSR < mean Type III anodized aluminum recovery – 3.0%, the new surface becomes a new group or becomes the worst-case
surface for Group 3 and is used in all future method validations.
Table III: Swab recovery of three new materials of construction compared with controls from each representative group.
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The data for the three new surfaces are outlined in Table III. Based on this approach, Ertalyte was placed into Group 1 because
the difference between its recovery and that of stainless steel 316L (i.e., Group 1) was less than 3.0% (i.e., 2.48%). The
recovery from stainless steel 420 and stainless steel 630 was more than 3.0% less than that from stainless steel 316L, but
greater than that from cast iron. The authors placed stainless steel 420 and stainless steel 630 into Group 2.
The placement of these two grades of stainless steel into Group 2 highlighted the conservative nature of this approach because
their recoveries were only 4% and 8% less than that from stainless steel 316L. The recoveries were 12% and 9% greater than
that from cast iron for stainless steel 630 and 420, respectively. Table II was updated to reflect this placement. Because
the grouping strategy was conservative, it prevented the underestimation of recovery factors when assay values were reported
and prevented the formation of additional groups for method validation unless the recovery value for a new surface is sufficiently
low to warrant such an addition.
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