This dosage form consists of a solution of active ingredient encased within a
spherical, plasticized gelatin shell. Unlike hard gelatin capsules, for which several
discrete operations are required to produce the final product, the softgel is
formed, filled, and hermetically sealed in one continuous operation [16]. Molten
gelatin mass is formed into two sheets or ribbons, each of which passes over a
die of the desired size and shape. At the point at which the two rotating dies
meet, the hemispheres are sealed and simultaneously filled with the solution of
active ingredient. Next the capsules are cleaned by immersion in an organic
solvent, dried, and inspected. (See Fig. 9.)
According to the process instructions, the active ingredient powder is dissolved
in vegetable oil with the aid of a solubilizer. Blend time is stated as 25
to 30 min. This is an elapsed time. Because a range of time is permitted, this
step is one for which historical data will be sought (Table 5). The bulk solution
is assayed to confirm that the prescribed weight of drug C was charged and
dissolution is complete before capsule filling may proceed. Concentration of the
active ingredient should vary very little from one batch to another with such a
straightforward process. We will want to confirm that this is the case. The purity
of each active ingredient raw material receipt is also of interest for reasons
previously stated.
The instructions for gelatin mass preparation direct that gelatin powder be
blended with water, a plasticizer, and colorant until a uniform consistency is
achieved, then heated until molten. The recommended blend time is 20 min at
a temperature of 60°C ± 5°. The temperature of the molten gelatin just prior to
formation into a ribbon is critical; too high a temperature causes the gelatin to
deteriorate, and a low temperature affects flow rate. Both conditions are to be
avoided for their deleterious effect on capsule formation. For these reasons,gelatin mass temperature is listed in Table 5. Blend time is of interest, too, as a
measure of process and raw material performance.
An important specification for gelatin is bloom strength, a quality of the
raw material that determines whether or not a capsule can be formed and sealed.
As with active ingredient purity, we will want to know this value for each lot
of gelatin used in the validation study.
The rationale of their selection is as follows: die rotation speed controls dwell time. If there is insufficient contact
time, the capsule halves will not properly seal. Subpotent softgels may result
from loss of liquid fill through a poorly developed seam. Gelatin ribbon thickness
determines capsule wall and seam thickness. Insufficient thickness will
contribute to poorly formed capsules and leakers. An overly thick ribbon results
in shell sealing problems. Ribbon condition is influenced by the temperature of
the gelatin mass, as previously noted. Relative humidity in the encapsulation
room is important to efficient drying. Minimally, we will want to know the
room condition during the time in which the 20 batches in this study were manufactured.
It would be best to examine environmental conditions over a longer
time period, say 1 year, to capture seasonal trends should they exist.
The batch record instructs the encapsulation machine operator to measure
and record seam and wall thickness every 45 min. Softgel weight is also checked
periodically by this operator. This information could be useful in demonstrating
process control but to a large extent seam and wall thickness are controlled by
manufacturing conditions for which historical data are already being sought. For
this reason, the results of these in-process monitors need not be pursued initially.
Consistent with the approach taken for other dosage forms previously discussed,
finished softgel weight data can be obtained from quality control reports when
dissolution and assay results are collected.
Sunday, January 31, 2010
Coated Tablet (Drug B)
Let’s now turn our attention to a different dosage form, applying some of the
strategies developed during the examination of drug A. Again we want to identify
the process steps that are responsible for distributing the active ingredient
as well as the tests that measure the effectiveness of those actions. Drug B is a
sugar-coated tablet prepared in the traditional manner; that is, layers are slowly
built up around a core by applying a coat of shellac and then subcoating, gross-
Copyright © 2003 Marcel Dekker, Inc.
ing, and smoothing coats until specifications are met at each stage. In the case
of drug B, the core contains two active ingredients. The coating, on the other
hand, has no medicinal value and is intended solely to enhance the aesthetic
appearance of the product. The manufacturing process is shown in Figure 6.
Table 3 summarizes the selected critical steps for the manufacture of the
core tablet of drug B. The core is prepared by dry-blending the first active
ingredient (i.e., B1) with several excipients. Blend time is of interest for its
impact on the distribution of the therapeutic agent. The premix just prepared is
granulated using an alcohol-binder solution. The process directions allow the
operator some latitude in using additional alcohol to ensure that the batch is
uniformly wet. It will be necessary to know whether or not additional alcohol
is routinely required, and if so, how much is used. Besides measuring operator
technique, the wetting step affects particle size distribution. The oven tray dryer
is identified for drying the wet mix. Granulation drying time is of interest, because
loss on drying is not measured. Once dry, the granulation is milled using
a specified screen size and machine setting. Alternate equipment is not provided
for in the aforementioned steps.
The powder produced in the prior operation is combined with the second
active ingredient (B2), as well as several other excipients in a twin-shell blender
and mixed for several min. For reasons previously discussed, mix time is of
interest, and thus it is listed as a critical process step.
The blend of the two active ingredients (B1 and B2) is slugged and then
the slugs are oscillated. Slugger model and tooling are listed in the batch instructions.
The thickness of the slug is specified, but no information is recorded on
the slugging operation, as control of this procedure is left to the experience of
the press operator. The batch record permits the use of only one screen size.
Since all of the batches have been made in the same manner, this important
process step will not be included as one to be studied.
Next, lubricant and oscillated granulation are blended for several min. The
elapsed mixing time is of interest because of its impact on drug distribution and
the effect of the lubricant on dissolution. During compression, 1000 randomly
selected cores are accumulated for use by quality control.
The ATW, hardness, and disintegration time are determined by the press
operator during compression. As in the case of drug A, we will not rely on these
results for our study, but rather on the test data from quality control.
Following approval of the bulk cores by quality control, they are shellaccoated.
According to the manufacturing directions, one or two coats may be
applied based on the process operator’s judgment. A third coat is permissible
but only in response to directions from the supervisor. In any event, the actual
number of coats applied is recorded in the batch record. Because of its potential
impact on drug availability,Once the shellacking stage has been completed, the cores are built up
through a series of coating operations. The number of applications of coating
solution, the volume of coating solution applied, and the coating environment
can influence product performance and therefore need to be studied.
The quality control tests selected after review of in-process and finishedproduct
specifications are listed in Table 3. The rationale for selection has been
addressed in general terms during the review for drug A. These quality control
tests, while informative, provide no insight into how the shellac coating will
behave a number of years from now. For some perspective, we can examine the
stability profile of commercial batches placed into the stability program. Of
course, the batches considered would have been made by the same process as
the one being validated. Particular attention should be paid to disintegration and
dissolution results.
strategies developed during the examination of drug A. Again we want to identify
the process steps that are responsible for distributing the active ingredient
as well as the tests that measure the effectiveness of those actions. Drug B is a
sugar-coated tablet prepared in the traditional manner; that is, layers are slowly
built up around a core by applying a coat of shellac and then subcoating, gross-
Copyright © 2003 Marcel Dekker, Inc.
ing, and smoothing coats until specifications are met at each stage. In the case
of drug B, the core contains two active ingredients. The coating, on the other
hand, has no medicinal value and is intended solely to enhance the aesthetic
appearance of the product. The manufacturing process is shown in Figure 6.
Table 3 summarizes the selected critical steps for the manufacture of the
core tablet of drug B. The core is prepared by dry-blending the first active
ingredient (i.e., B1) with several excipients. Blend time is of interest for its
impact on the distribution of the therapeutic agent. The premix just prepared is
granulated using an alcohol-binder solution. The process directions allow the
operator some latitude in using additional alcohol to ensure that the batch is
uniformly wet. It will be necessary to know whether or not additional alcohol
is routinely required, and if so, how much is used. Besides measuring operator
technique, the wetting step affects particle size distribution. The oven tray dryer
is identified for drying the wet mix. Granulation drying time is of interest, because
loss on drying is not measured. Once dry, the granulation is milled using
a specified screen size and machine setting. Alternate equipment is not provided
for in the aforementioned steps.
The powder produced in the prior operation is combined with the second
active ingredient (B2), as well as several other excipients in a twin-shell blender
and mixed for several min. For reasons previously discussed, mix time is of
interest, and thus it is listed as a critical process step.
The blend of the two active ingredients (B1 and B2) is slugged and then
the slugs are oscillated. Slugger model and tooling are listed in the batch instructions.
The thickness of the slug is specified, but no information is recorded on
the slugging operation, as control of this procedure is left to the experience of
the press operator. The batch record permits the use of only one screen size.
Since all of the batches have been made in the same manner, this important
process step will not be included as one to be studied.
Next, lubricant and oscillated granulation are blended for several min. The
elapsed mixing time is of interest because of its impact on drug distribution and
the effect of the lubricant on dissolution. During compression, 1000 randomly
selected cores are accumulated for use by quality control.
The ATW, hardness, and disintegration time are determined by the press
operator during compression. As in the case of drug A, we will not rely on these
results for our study, but rather on the test data from quality control.
Following approval of the bulk cores by quality control, they are shellaccoated.
According to the manufacturing directions, one or two coats may be
applied based on the process operator’s judgment. A third coat is permissible
but only in response to directions from the supervisor. In any event, the actual
number of coats applied is recorded in the batch record. Because of its potential
impact on drug availability,Once the shellacking stage has been completed, the cores are built up
through a series of coating operations. The number of applications of coating
solution, the volume of coating solution applied, and the coating environment
can influence product performance and therefore need to be studied.
The quality control tests selected after review of in-process and finishedproduct
specifications are listed in Table 3. The rationale for selection has been
addressed in general terms during the review for drug A. These quality control
tests, while informative, provide no insight into how the shellac coating will
behave a number of years from now. For some perspective, we can examine the
stability profile of commercial batches placed into the stability program. Of
course, the batches considered would have been made by the same process as
the one being validated. Particular attention should be paid to disintegration and
dissolution results.
Evaluation of Historical Data
Earlier in the discussion of process validation strategies, 20 production batches
were suggested as a minimum number upon which to draw conclusions about
the validity of the process. In this particular example, however, two distinct
methods of drying are provided. In order to have sufficient history on each
operation, the number of batches examined was increased to 30.
The batches were selected so that the same number was dried by each
process. For the other critical manufacturing steps and release tests listed in
Table 1, data were collected for all 30 batches.
The first manufacturing step, premix blending time, was consistently reported
as 10 min, but with one exception. In this instance, the powders were
tumbled for 20 min, which is still within the limits (10 to 20 min) prescribed
by the batch record. It would be interesting to know if this source of variability can materially affect attributes of the final product. Unfortunately, having only
one batch produced by the 20-min process does not permit statistically valid
comparisons. At best, test results for the single 20-min batch can be screened
using summary data from the remainder of the study. Under different circumstances,
batches would have been grouped by mixing time and compared by
dosage form attributes. More than likely, subsequent manipulation of the blend
would have negated any contribution, allowing us to conclude that a mixing
time of 10 to 20 min is not unreasonable.
At the wet milling step we encounter a situation similar to preblending;
that is, only two of the 30 study batches are prepared using the no. 5 drilled
screen. The no. 7 is obviously the screen of choice. The purpose of this step is
to produce particles of reasonably uniform size, which in turn will improve
drying. From the records, we also know that the no. 5 screen was used
only with batches that were tray dried. Elapsed drying time and residual
moisture were compared for the two batches from the no. 5 screen process
and the other 13 batches that were tray dried. No important differences were
detected. Still, in light of the limited use of the no. 5 screen, it would not
be inappropriate to recommend this option be eliminated from the processing
instructions.
Mean drying time for the oven tray process is 19.2 hr. All 15 batches
were dried within the specified time of 16 to 20 hr. No seasonal influence was
apparent. The average moisture content of these batches is 1.2%; the standard
deviation is 0.3%. The 15 batches dried using the fluid bed dryer had a residual
moisture of 0.8% (SD = 0.1%). Drying time is mechanically controlled and not
recorded. The statistics favor the fluid bed process; it is more efficient and
uniform. There is nothing in these data to disqualify the oven tray dryer from
further use, however.
Oscillation of the dried granulation and lubricant was accomplished in
every instance using a no. 10 wire screen. Reference to the no. 12 screen, the
alternative method for pulverizing the batch, must be deleted from the manufacturing
instructions for the process to be validated retrospectively.
The final mix blending time was reported as either 10 or 15 min. Twentyone
of the 30 batches were tumbled for 10 min and the remainder were mixed
for 15 min. The mixing time is not mechanically controlled or automatically
recorded; it is left to the operator to interpret elapsed time. Because of the
importance of the step to distribution of the therapeutic agent, a comparison was
made between the distribution of the percentage of relative tablet potency [(tablet
assay/tablet weight) × 100] for the two mixing times. The frequency distributions
of the two populations are shown in Figure 3.
The two histograms are visually different, with the 15-min process exhibiting
more dispersion. Despite this difference both populations are tightly grouped,
which is a reflection of the uniformity of the blend.The processes may be studied quantitatively by comparing the means and
standard deviations of the two populations. The effect of final blend time on
lubricant distribution was examined by comparing disintegration time statistics
for the grouped data. None was noted.
The moisture content of the 15 tray-dried batches following final mix
remained essentially unchanged from the drying step. The batches from the fluid
bed process gained moisture. This is probably attributable to handling very dry
material in a relatively humid environment. Both groups are still below the
target for this step of 1.5 %, however.
Table 2 gives a comparison of the moisture contents following the drying
and tumbling steps. The sizable increase in mean moisture content of the fluid
bed-dried batches deserves further study. To determine whether or not all
batches were uniformly affected, the mean moisture content was plotted in the
order in which the batches were produced. Whereas the plot for the tray-dried
batches is unremarkable, the fluid bed process chart (Fig. 4) depicts an unnatural
pattern. Further investigation discloses that heating, ventilation, and air condition
(HVAC) problems were experienced by the area in which a number of
these batches were blended.
During compression, 1000 tablets were randomly selected for use by quality
control. Inspection of the batch records revealed that all 30 batches were
compressed on the same model press operating at approximately the same speed.
All presses were fed by overhead delivery systems of the same design, thus
tableting equipment will not be a source of variability from batch to batch.
The test for disintegration is performed as described in the USP, and the
results are rounded to the nearest half-min. Disintegration time varied over a
narrow range for all batches studied. The 15-batch average for the tray dryer
process (2.7 min) is well below the specification (10 min) for this test. Hardness
of tablets from the tray dryer process averaged 15 Strong–Cobb units (SCU).
All batches exceeded the minimum specification (9 SCU); there is no upper limit. Hardness and disintegration time are not well correlated, probably due to
rounding of test results and the need to compare averages.
On average, tablets from the fluid bed process were slightly harder. Also,
the individual batches had a greater range of hardness than batches from the
alternative drying process. Disintegration time for the fluid bed process averaged
3.0 min. Individual batches ranged from2.0 to 4.5 min. As with the tray process,
no correlation was found between hardness and disintegration time. In summary,
tablets from the fluid bed dryer process were somewhat harder and took slightly
longer to disintegrate. (See Table 2.) These differences are considered insignificant,
however. If any recommendations were made, it would be to lower the
disintegration time specification or establish an internal action limit closer to
the historical upper range of the process.
Control charts were plotted for hardness and average tablet weight (ATW)
to evaluate process performance over time. Separate charts were prepared for
the tray dryer and fluid bed processes. Hardness values are an average of 10
individual measurements. The ATW subgroups are the result of weighing 20
tablets individually. The control charts were inspected for trends and evidence
of instability using well-established methods [9]. Only the control chart for hardness
of tablets from the fluid bed process responded to one of the tests for
pattern instability (Fig. 5); that is, two of three consecutive points exceeded the
2-sigma limit. From the chart it is obvious the general trend toward greater
tablet hardness (from 11 to 25 SCU) is the underlying cause of the instability.
The trend to greater hardness was subsequently arrested and may have to do with attempts to regulate another tablet variable—thickness, for example—
although the records are vague in this regard.
Water content of the bulk tablets irrespective of the drying process was
higher than at the final mix stage (Table 2). This is probably due to the compression
room environment and the low initial moisture of the powder. Still, the
specification limit of 2% is easily met.
The FDA has recently issued draft guidelines that recommend blend uniformity
analysis for all products for which USP requires content uniformity
analysis [10]. The USP requires this test when the product contains less than 50
mg of the active ingredient per dosage form or when the active ingredient is
less than 50% of the dosage form by weight. The concern FDA has is that if
blend uniformity is not achieved with mixing of the final granulation, then some
dosage units are likely not to be uniform [11]. Blend uniformity is not routinely
determined for drug A, nor is there a requirement because the dosage form is
over 50% active ingredient. In the absence of historical information about uniformity
of the blend, the relationship between tablet weight and potency should
be carefully examined.
Tablet weight should bear a direct relationship to milligrams of active
ingredient available where the final blend is homogeneous. This conclusion assumes
that demixing does not occur as the compound is transferred to intermediate
storage containers or to a tablet press hopper [12]. To measure the likelihood
that controlling tablet weight assures dosage uniformity, 50 tablet assays selected
at random (from 300 tablet assays) were compared to tablet weight using
regression analysis. Because the same model tablet press and blender were employed
for every batch, assay results from all 30 batches were pooled. The mean
purity of the 25 receipts of active ingredients used to manufacture the 30 batches
in the validation study was 99.7%, or 0.3% below target. Individual lots ranged from 98.8–102%. Because of these lot-to-lot differences, active ingredient raw
material potency was also included in the regression analysis.
The general model from the regression analysis is [13]
y = bo + b1X1 + b2Y2
where
y = tablet potency
bo = constant
X1 = raw material purity
X2 = tablet weight
Tablet potency was found to be related to raw material purity and tablet
weight as follows:
y = −414.6 + 6.605OX1 + 0.4303X2
We would expect the regression plane to have a significant positive slope;
that is, as purity of the active ingredient and tablet weight increase, so will
tablet potency, and this was found to be the case. Both slopes are statistically
significantly different from 0 at α = 0.025. When the above equation is used to
predict tablet potency given the ideal tablet weight (600 mg) for the product
and mean raw material purity of 99.7%, the resulting value is only 2.1 mg
different from the theoretical value of 500 mg.
In conclusion, drug A production was shown to be within established
specifications, and there is no reason to believe this will not be the case for
future production as long as all practices are continued in their present form.
Furthermore, there is no significant difference between batches produced by the
tray dryer process and the fluid bed process. A validation report should memorialize
these findings. The report should also recommend eliminating the option
to use a no. 5 screen for the wet milling step and a no. 12 screen to pulverize
the dried granulation. There is no experience or only limited experience with
this equipment that supports its continued availability. In the same vein, the
final blend time should be standardized at 10 min and automatically controlled
by means of a timer.
were suggested as a minimum number upon which to draw conclusions about
the validity of the process. In this particular example, however, two distinct
methods of drying are provided. In order to have sufficient history on each
operation, the number of batches examined was increased to 30.
The batches were selected so that the same number was dried by each
process. For the other critical manufacturing steps and release tests listed in
Table 1, data were collected for all 30 batches.
The first manufacturing step, premix blending time, was consistently reported
as 10 min, but with one exception. In this instance, the powders were
tumbled for 20 min, which is still within the limits (10 to 20 min) prescribed
by the batch record. It would be interesting to know if this source of variability can materially affect attributes of the final product. Unfortunately, having only
one batch produced by the 20-min process does not permit statistically valid
comparisons. At best, test results for the single 20-min batch can be screened
using summary data from the remainder of the study. Under different circumstances,
batches would have been grouped by mixing time and compared by
dosage form attributes. More than likely, subsequent manipulation of the blend
would have negated any contribution, allowing us to conclude that a mixing
time of 10 to 20 min is not unreasonable.
At the wet milling step we encounter a situation similar to preblending;
that is, only two of the 30 study batches are prepared using the no. 5 drilled
screen. The no. 7 is obviously the screen of choice. The purpose of this step is
to produce particles of reasonably uniform size, which in turn will improve
drying. From the records, we also know that the no. 5 screen was used
only with batches that were tray dried. Elapsed drying time and residual
moisture were compared for the two batches from the no. 5 screen process
and the other 13 batches that were tray dried. No important differences were
detected. Still, in light of the limited use of the no. 5 screen, it would not
be inappropriate to recommend this option be eliminated from the processing
instructions.
Mean drying time for the oven tray process is 19.2 hr. All 15 batches
were dried within the specified time of 16 to 20 hr. No seasonal influence was
apparent. The average moisture content of these batches is 1.2%; the standard
deviation is 0.3%. The 15 batches dried using the fluid bed dryer had a residual
moisture of 0.8% (SD = 0.1%). Drying time is mechanically controlled and not
recorded. The statistics favor the fluid bed process; it is more efficient and
uniform. There is nothing in these data to disqualify the oven tray dryer from
further use, however.
Oscillation of the dried granulation and lubricant was accomplished in
every instance using a no. 10 wire screen. Reference to the no. 12 screen, the
alternative method for pulverizing the batch, must be deleted from the manufacturing
instructions for the process to be validated retrospectively.
The final mix blending time was reported as either 10 or 15 min. Twentyone
of the 30 batches were tumbled for 10 min and the remainder were mixed
for 15 min. The mixing time is not mechanically controlled or automatically
recorded; it is left to the operator to interpret elapsed time. Because of the
importance of the step to distribution of the therapeutic agent, a comparison was
made between the distribution of the percentage of relative tablet potency [(tablet
assay/tablet weight) × 100] for the two mixing times. The frequency distributions
of the two populations are shown in Figure 3.
The two histograms are visually different, with the 15-min process exhibiting
more dispersion. Despite this difference both populations are tightly grouped,
which is a reflection of the uniformity of the blend.The processes may be studied quantitatively by comparing the means and
standard deviations of the two populations. The effect of final blend time on
lubricant distribution was examined by comparing disintegration time statistics
for the grouped data. None was noted.
The moisture content of the 15 tray-dried batches following final mix
remained essentially unchanged from the drying step. The batches from the fluid
bed process gained moisture. This is probably attributable to handling very dry
material in a relatively humid environment. Both groups are still below the
target for this step of 1.5 %, however.
Table 2 gives a comparison of the moisture contents following the drying
and tumbling steps. The sizable increase in mean moisture content of the fluid
bed-dried batches deserves further study. To determine whether or not all
batches were uniformly affected, the mean moisture content was plotted in the
order in which the batches were produced. Whereas the plot for the tray-dried
batches is unremarkable, the fluid bed process chart (Fig. 4) depicts an unnatural
pattern. Further investigation discloses that heating, ventilation, and air condition
(HVAC) problems were experienced by the area in which a number of
these batches were blended.
During compression, 1000 tablets were randomly selected for use by quality
control. Inspection of the batch records revealed that all 30 batches were
compressed on the same model press operating at approximately the same speed.
All presses were fed by overhead delivery systems of the same design, thus
tableting equipment will not be a source of variability from batch to batch.
The test for disintegration is performed as described in the USP, and the
results are rounded to the nearest half-min. Disintegration time varied over a
narrow range for all batches studied. The 15-batch average for the tray dryer
process (2.7 min) is well below the specification (10 min) for this test. Hardness
of tablets from the tray dryer process averaged 15 Strong–Cobb units (SCU).
All batches exceeded the minimum specification (9 SCU); there is no upper limit. Hardness and disintegration time are not well correlated, probably due to
rounding of test results and the need to compare averages.
On average, tablets from the fluid bed process were slightly harder. Also,
the individual batches had a greater range of hardness than batches from the
alternative drying process. Disintegration time for the fluid bed process averaged
3.0 min. Individual batches ranged from2.0 to 4.5 min. As with the tray process,
no correlation was found between hardness and disintegration time. In summary,
tablets from the fluid bed dryer process were somewhat harder and took slightly
longer to disintegrate. (See Table 2.) These differences are considered insignificant,
however. If any recommendations were made, it would be to lower the
disintegration time specification or establish an internal action limit closer to
the historical upper range of the process.
Control charts were plotted for hardness and average tablet weight (ATW)
to evaluate process performance over time. Separate charts were prepared for
the tray dryer and fluid bed processes. Hardness values are an average of 10
individual measurements. The ATW subgroups are the result of weighing 20
tablets individually. The control charts were inspected for trends and evidence
of instability using well-established methods [9]. Only the control chart for hardness
of tablets from the fluid bed process responded to one of the tests for
pattern instability (Fig. 5); that is, two of three consecutive points exceeded the
2-sigma limit. From the chart it is obvious the general trend toward greater
tablet hardness (from 11 to 25 SCU) is the underlying cause of the instability.
The trend to greater hardness was subsequently arrested and may have to do with attempts to regulate another tablet variable—thickness, for example—
although the records are vague in this regard.
Water content of the bulk tablets irrespective of the drying process was
higher than at the final mix stage (Table 2). This is probably due to the compression
room environment and the low initial moisture of the powder. Still, the
specification limit of 2% is easily met.
The FDA has recently issued draft guidelines that recommend blend uniformity
analysis for all products for which USP requires content uniformity
analysis [10]. The USP requires this test when the product contains less than 50
mg of the active ingredient per dosage form or when the active ingredient is
less than 50% of the dosage form by weight. The concern FDA has is that if
blend uniformity is not achieved with mixing of the final granulation, then some
dosage units are likely not to be uniform [11]. Blend uniformity is not routinely
determined for drug A, nor is there a requirement because the dosage form is
over 50% active ingredient. In the absence of historical information about uniformity
of the blend, the relationship between tablet weight and potency should
be carefully examined.
Tablet weight should bear a direct relationship to milligrams of active
ingredient available where the final blend is homogeneous. This conclusion assumes
that demixing does not occur as the compound is transferred to intermediate
storage containers or to a tablet press hopper [12]. To measure the likelihood
that controlling tablet weight assures dosage uniformity, 50 tablet assays selected
at random (from 300 tablet assays) were compared to tablet weight using
regression analysis. Because the same model tablet press and blender were employed
for every batch, assay results from all 30 batches were pooled. The mean
purity of the 25 receipts of active ingredients used to manufacture the 30 batches
in the validation study was 99.7%, or 0.3% below target. Individual lots ranged from 98.8–102%. Because of these lot-to-lot differences, active ingredient raw
material potency was also included in the regression analysis.
The general model from the regression analysis is [13]
y = bo + b1X1 + b2Y2
where
y = tablet potency
bo = constant
X1 = raw material purity
X2 = tablet weight
Tablet potency was found to be related to raw material purity and tablet
weight as follows:
y = −414.6 + 6.605OX1 + 0.4303X2
We would expect the regression plane to have a significant positive slope;
that is, as purity of the active ingredient and tablet weight increase, so will
tablet potency, and this was found to be the case. Both slopes are statistically
significantly different from 0 at α = 0.025. When the above equation is used to
predict tablet potency given the ideal tablet weight (600 mg) for the product
and mean raw material purity of 99.7%, the resulting value is only 2.1 mg
different from the theoretical value of 500 mg.
In conclusion, drug A production was shown to be within established
specifications, and there is no reason to believe this will not be the case for
future production as long as all practices are continued in their present form.
Furthermore, there is no significant difference between batches produced by the
tray dryer process and the fluid bed process. A validation report should memorialize
these findings. The report should also recommend eliminating the option
to use a no. 5 screen for the wet milling step and a no. 12 screen to pulverize
the dried granulation. There is no experience or only limited experience with
this equipment that supports its continued availability. In the same vein, the
final blend time should be standardized at 10 min and automatically controlled
by means of a timer.
SELECTION AND EVALUATION OF PROCESSING DATA
Drug A is a compressed tablet containing a single active ingredient. Inspection
of the batch record reveals that the following operations are involved in the
manufacture of the dosage unit. The active ingredient is combined with several
excipients in a twin-shell blender. The premix just prepared is granulated using
a purified water-binder solution. The resulting wet mix is milled using a specified
screen and machine setting, then dried using either an oven tray dryer or a
fluid bed dryer. When dry, the blend is oscillated, combined with previously
sized lubricant, and blended. The granulation is then compressed. See Figure 2
for a flow diagram of the manufacturing process.
At the premix blending step, the batch record provides two pieces of infor-mation: recommended blending time and blender load. The latter will be of little
interest, as only one size batch is produced for this product. Blender speed is
not specified in the batch record because it is fixed. Because mixing time has
been recognized as influencing blend uniformity, this operation will become the
first of the critical process steps for which we will want to collect historical
information [8].
The second major step is granulation. The process is controlled by the
operator, whose judgment is relied on for the appropriate end point. As no
information useful for process validation is available, we will move on to the
next step, comminution.
The batch record calls for passing the wet mix through a comminutor
using a no. 5 or 7 drilled stainless steel screen. Knife position and rotational
speed are two other factors that influence particle size; however, the step instruction
is quite specific about machine setup. Therefore, only screen size is a source
of variability for this step. We will want to know the frequency of use of each
screen.
Next, the granulation is dried to a target moisture of 1%. Either a tray or
fluid bed dryer may be used, at the discretion of area supervision. Regardless
of the method, drying time will be of interest. In addition, the final moisture
content should be ascertained for each batch. The dried granulation and lubricant
are then oscillated using a no. 10 or 12 wire screen. This is the last sizing
operation of the process; it will determine the particle size distribution of the
final blend. Knowing the history of use of each screen size is thus important.
The lubricant and granulation are blended for several minutes. The elapsed
mixing time is of interest because of its impact on drug distribution and the
generally deleterious effect of the lubricant on dissolution.
Because excess moisture is thought to have a negative effect on the dosage
form, loss on drying (LOD) is determined on the final blend.
Blending is followed by tableting. During compression, online measurements
such as tablet weight, hardness, and disintegration are made by the process
operator in order to ensure uniformity of the tablets. The weight of the
tablets is not measured individually; rather, the average weight of 10 tablets is
recorded. Although these data are good indicators of operation and machine
performance, we would prefer to have the more precise picture provided by
individual tablet weight.
Disintegration time and tablet hardness data could be collected from the
manufacturing batch records; however, for ease of administration these figures
will be obtained from the quality control test results, which also contain individual
tablet weighings.
Disintegration time was selected as a critical variable because for a drug
substance to be absorbed it must first disintegrate and then dissolve. The resistance
of a tablet to breakage, chipping, and so forth depends on its hardness.Disintegration, too, can be influenced by hardness of the tablet. For these reasons,
hardness testing results also will be examined.
Specifications used by quality control to release drug A are found in a
laboratory procedure. In addition to the previously discussed hardness and disintegration
time requirements, the procedure calls for determining the average
tablet weight by the United States Pharmacopeia (USP) procedure; that is, 20
individual tablets are weighed.
The control procedure also requires assay of individual tablets. Of all the
information available, these data will be the most useful in reaching an opinion
of the adequacy of the process to distribute the therapeutic agent uniformly.
In addition, the laboratory checks the moisture content of the bulk tablets.
It will be interesting to compare these results to the LOD of the final blend to
measure the contribution of material handling.
of the batch record reveals that the following operations are involved in the
manufacture of the dosage unit. The active ingredient is combined with several
excipients in a twin-shell blender. The premix just prepared is granulated using
a purified water-binder solution. The resulting wet mix is milled using a specified
screen and machine setting, then dried using either an oven tray dryer or a
fluid bed dryer. When dry, the blend is oscillated, combined with previously
sized lubricant, and blended. The granulation is then compressed. See Figure 2
for a flow diagram of the manufacturing process.
At the premix blending step, the batch record provides two pieces of infor-mation: recommended blending time and blender load. The latter will be of little
interest, as only one size batch is produced for this product. Blender speed is
not specified in the batch record because it is fixed. Because mixing time has
been recognized as influencing blend uniformity, this operation will become the
first of the critical process steps for which we will want to collect historical
information [8].
The second major step is granulation. The process is controlled by the
operator, whose judgment is relied on for the appropriate end point. As no
information useful for process validation is available, we will move on to the
next step, comminution.
The batch record calls for passing the wet mix through a comminutor
using a no. 5 or 7 drilled stainless steel screen. Knife position and rotational
speed are two other factors that influence particle size; however, the step instruction
is quite specific about machine setup. Therefore, only screen size is a source
of variability for this step. We will want to know the frequency of use of each
screen.
Next, the granulation is dried to a target moisture of 1%. Either a tray or
fluid bed dryer may be used, at the discretion of area supervision. Regardless
of the method, drying time will be of interest. In addition, the final moisture
content should be ascertained for each batch. The dried granulation and lubricant
are then oscillated using a no. 10 or 12 wire screen. This is the last sizing
operation of the process; it will determine the particle size distribution of the
final blend. Knowing the history of use of each screen size is thus important.
The lubricant and granulation are blended for several minutes. The elapsed
mixing time is of interest because of its impact on drug distribution and the
generally deleterious effect of the lubricant on dissolution.
Because excess moisture is thought to have a negative effect on the dosage
form, loss on drying (LOD) is determined on the final blend.
Blending is followed by tableting. During compression, online measurements
such as tablet weight, hardness, and disintegration are made by the process
operator in order to ensure uniformity of the tablets. The weight of the
tablets is not measured individually; rather, the average weight of 10 tablets is
recorded. Although these data are good indicators of operation and machine
performance, we would prefer to have the more precise picture provided by
individual tablet weight.
Disintegration time and tablet hardness data could be collected from the
manufacturing batch records; however, for ease of administration these figures
will be obtained from the quality control test results, which also contain individual
tablet weighings.
Disintegration time was selected as a critical variable because for a drug
substance to be absorbed it must first disintegrate and then dissolve. The resistance
of a tablet to breakage, chipping, and so forth depends on its hardness.Disintegration, too, can be influenced by hardness of the tablet. For these reasons,
hardness testing results also will be examined.
Specifications used by quality control to release drug A are found in a
laboratory procedure. In addition to the previously discussed hardness and disintegration
time requirements, the procedure calls for determining the average
tablet weight by the United States Pharmacopeia (USP) procedure; that is, 20
individual tablets are weighed.
The control procedure also requires assay of individual tablets. Of all the
information available, these data will be the most useful in reaching an opinion
of the adequacy of the process to distribute the therapeutic agent uniformly.
In addition, the laboratory checks the moisture content of the bulk tablets.
It will be interesting to compare these results to the LOD of the final blend to
measure the contribution of material handling.
Other Considerations
Comprehensive records of complaints received either directly from the customer
or through a drug problem reporting program should be reviewed. Furthermore,
a record of any follow-up investigation of such complaints is mandatory [6] and
should be part of this file. Review of customer complaint records can furnish a
useful overview of process performance and possibly hint at product problems.
Complaint analysis should therefore be viewed as a meaningful adjunct to the
critical process step and control test selection process.
Batch yield reflects efficiency of the operation. Because yield figures are
the sum of numerous interactions, they fail in most cases to provide specific
information about process performance and therefore must be used with caution
in retrospective validation. In any event, this information should be collected,
as it can contribute to further refinement of the yield limits that appear in the
batch record.
Lot-to-lot differences in the purity of the therapeutic agent must be considered
when evaluating in-process and finished-product test results. In addition to
potency such qualities as particle size distribution, bulk density, and source of
the material will be of interest. Such information should be available from the
raw material test reports prepared by the quality control laboratory for each lot
of material received. The physical characteristics of the excipients should not
be overlooked, especially for those materials with inherent variability. Metallic
stearates is a classic example. In such instances, the source of supply is desirable
information to have available.
There is value in examining logs of equipment and physical plant maintenance.
These documents can provide a chronological profile of the operating
environment and reveal recent alterations to the process equipment that may
have enough impact to disqualify the product from retrospective validation consideration.
For this reason, it is always prudent to contemplate equipment status
early in the information-gathering stage. The availability of such information
should be ascertained for yet another reason: rarely is equipment dedicated to
Copyright © 2003 Marcel Dekker, Inc.
one product. More often than not, each blender, comminutor, tablet press, and
so forth is used for several operations. Information gathered initially can therefore
be incorporated into subsequent studies.
Retrospective validation is directed primarily toward examining the records
of past performance, but what if one of these documents is not a true
reflection of the operation performed? Suppose that changes have crept into the
processing operation over time and have gone unreported. This condition would
result in the validation of a process that in reality does not exist. It is therefore
essential to audit the existing operation against the written instructions. There is
obvious advantage to undertaking this audit before commencing data acquisition.
Ideally, the manufacture of more than one batch should be witnessed, especially
where multiple-shift operations are involved. The same logic would apply
to the testing performed in process and at the finished stage. If any deviation
from the written directions is noted, an effort must be made to measure its
impact. In this regard, the previously described validation organization is a logical
forum for discussion and evaluation.
As a rule, batches that are rejected or reworked are not suitable for inclusion
in a retrospective validation study [7]. Indeed, a processing failure that is
not fully explainable should be cause to rethink the application of retrospective
validation. Nonconformance to specification that is attributable to a unique
event–operator error, for example, may be justifiably disregarded. In such cases,
the batch is not considered when the historical data are assembled.
Raw materials, both actives and excipients, can be a source of product
variability. To limit this risk, there should be meaningful acceptance specifications
and periodic confirmation of test results reported on the supplier’s certificate
of analysis. Also, purchases must be limited to previously qualified suppliers.
A determination that such controls are in place should be part of any
retrospective validation effort.
or through a drug problem reporting program should be reviewed. Furthermore,
a record of any follow-up investigation of such complaints is mandatory [6] and
should be part of this file. Review of customer complaint records can furnish a
useful overview of process performance and possibly hint at product problems.
Complaint analysis should therefore be viewed as a meaningful adjunct to the
critical process step and control test selection process.
Batch yield reflects efficiency of the operation. Because yield figures are
the sum of numerous interactions, they fail in most cases to provide specific
information about process performance and therefore must be used with caution
in retrospective validation. In any event, this information should be collected,
as it can contribute to further refinement of the yield limits that appear in the
batch record.
Lot-to-lot differences in the purity of the therapeutic agent must be considered
when evaluating in-process and finished-product test results. In addition to
potency such qualities as particle size distribution, bulk density, and source of
the material will be of interest. Such information should be available from the
raw material test reports prepared by the quality control laboratory for each lot
of material received. The physical characteristics of the excipients should not
be overlooked, especially for those materials with inherent variability. Metallic
stearates is a classic example. In such instances, the source of supply is desirable
information to have available.
There is value in examining logs of equipment and physical plant maintenance.
These documents can provide a chronological profile of the operating
environment and reveal recent alterations to the process equipment that may
have enough impact to disqualify the product from retrospective validation consideration.
For this reason, it is always prudent to contemplate equipment status
early in the information-gathering stage. The availability of such information
should be ascertained for yet another reason: rarely is equipment dedicated to
Copyright © 2003 Marcel Dekker, Inc.
one product. More often than not, each blender, comminutor, tablet press, and
so forth is used for several operations. Information gathered initially can therefore
be incorporated into subsequent studies.
Retrospective validation is directed primarily toward examining the records
of past performance, but what if one of these documents is not a true
reflection of the operation performed? Suppose that changes have crept into the
processing operation over time and have gone unreported. This condition would
result in the validation of a process that in reality does not exist. It is therefore
essential to audit the existing operation against the written instructions. There is
obvious advantage to undertaking this audit before commencing data acquisition.
Ideally, the manufacture of more than one batch should be witnessed, especially
where multiple-shift operations are involved. The same logic would apply
to the testing performed in process and at the finished stage. If any deviation
from the written directions is noted, an effort must be made to measure its
impact. In this regard, the previously described validation organization is a logical
forum for discussion and evaluation.
As a rule, batches that are rejected or reworked are not suitable for inclusion
in a retrospective validation study [7]. Indeed, a processing failure that is
not fully explainable should be cause to rethink the application of retrospective
validation. Nonconformance to specification that is attributable to a unique
event–operator error, for example, may be justifiably disregarded. In such cases,
the batch is not considered when the historical data are assembled.
Raw materials, both actives and excipients, can be a source of product
variability. To limit this risk, there should be meaningful acceptance specifications
and periodic confirmation of test results reported on the supplier’s certificate
of analysis. Also, purchases must be limited to previously qualified suppliers.
A determination that such controls are in place should be part of any
retrospective validation effort.
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