Stratified Sampling Powder Blends and Finished Dosage Units — Stratified In-Process Dosage Unit Sampling and Assessment
Stratified Sampling
Powder Blends and Finished
Dosage Units — Stratified In-Process Dosage Unit Sampling and Assessment
INTRODUCTION
This
guidance is intended to assist manufacturers of human drug products in meeting
the requirements of 21 CFR 211.110 for demonstrating the adequacy of mixing to
ensure uniformity of in-process powder blends and finished dosage units. This guidance describes the procedures for
assessing powder mix adequacy, correlating in-process dosage unit test results
with powder mix test results, and establishing the initial criteria for control
procedures used in routine manufacturing.
FDA's
guidance documents, including this guidance, do not establish legally
enforceable responsibilities. Instead,
guidances describe the Agency's current thinking on a topic and should be
viewed only as recommendations, unless specific regulatory or statutory
requirements are cited. The use of the
word should in Agency guidances means
that something is suggested or recommended, but not required.
Scope
Stratified sampling is the process of sampling
dosage units at predefined intervals and collecting representative samples from
specifically targeted locations in the compression/filling operation that have
the greatest potential to yield extreme highs and lows in test results. These test results are used to monitor the
manufacturing process output that is most responsible for causing finished
product variability. The test results
can be used to develop a single control procedure to ensure adequate powder mix
and uniform content in finished products.
The
methods described in this guidance are not intended to be the only methods for
meeting US-FDA requirements to demonstrate the adequacy of powder mix. Traditional powder blend sampling and
testing, in conjunction with testing for uniformity of content in the finished
product, can be used to comply with current good manufacturing practice
requirements
This
guidance provides recommendations on how to:
·
Conduct
powder blend sampling and analyses.
·
Establish
initial criteria for stratified sampling of in-process dosage units and
evaluation of test results.
·
Analyze
the stratified samples and evaluate data.
·
Correlate
the stratified sample data with the powder blend data.
·
Assess
powder mix uniformity.
- Correlate the stratified sample data with the finished dosage unit data and assess uniformity of content.
·
Test
exhibit and validation batches for adequacy of powder mix.
·
Test
and evaluate routine manufacturing batches.
a.
Assessment of Powder Mix Uniformity
b.
Correlation of Powder Mix Uniformity with StratifiedIn- Process Dosage Unit Data
verification of manufacturing Criteria
You
should complete the assessment of powder mix uniformity and correlation of
stratified in-process dosage unit sampling development procedures before
establishing the criteria and controls for routine manufacturing. We also recommend that you assess the
normality and determine RSD from the results of stratified in-process dosage
unit sampling and testing that were developed.
The RSD value should be used to classify the testing results as either readily pass (RSD £
4.0%), marginally pass (RSD £
6.0%) or inappropriate for
demonstration of batch homogeneity (RSD > 6.0%). The procedures are discussed in the following
sections:
b.
Criteria to Meet the Readily
Pass Classification
For each separate batch, compare the test results to
the following criteria:
·
For
all individual results (for each batch n ³ 60) the RSD £ 4.0
percent.
·
Each
location mean is within 90.0 percent to110.0 percent of target strength.
·
All
individual results are within the range of 75.0 percent to 125.0 percent of
target strength.
If
your test results meet these criteria, they are classified as readily pass and you can start routine
batch testing using the Standard Verification Method (SVM) described below. If your test results fail to meet these
criteria, we recommend that you compare the results with the marginally pass criteria described
below.
c.
Criteria to Meet the Marginally
Pass Classification
If
your dosage unit test results fail to meet the criteria for the readily pass classification, you should
assay the remaining dosage units (all 7 units per location) and compare the
test results to the following criteria:
·
For
all individual results (for one batch n ³ 140) the RSD £ 6.0
percent.
·
Each
location mean is within 90.0 percent to 110.0 percent of target strength.
·
All
individual results are within the range of 75.0 percent to 125.0 percent of
target strength.
If
your test results meet these criteria, results can be classified as marginally pass. If your samples do not meet these criteria,
we recommend that you investigate the failure, find justified and assignable
cause(s), correct the deficiencies, and repeat the powder mix homogeneity
assessment, in-process dosage unit sampling correlation, and initial criteria
establishment procedures. The
disposition of batches that have failed the marginally pass criteria is outside the scope of this guidance.
d.
Sample Locations for Routine Manufacturing
We
recommend that you prepare a summary of the data analysis from the powder mix
assessment and stratified sample testing.
From the data analysis, you should establish the stratified sample
locations for routine manufacturing, taking into account significant process
events and their effect on in-process dosage unit and finished dosage unit
quality attributes. You should identify
at least 10 sampling locations during capsule filling or tablet compression to
represent the entire routine manufacturing batch.
Routine manufacturing batch Testing methods
We
recommend that you evaluate the routine manufacturing batches against the
following criteria after completing the procedures described above to assess
the adequacy of the powder mix and uniform content in finished dosage form.
These
routine manufacturing batch-testing methods include the Standard Criteria
Method (SCM) and the Marginal Criteria Method (MCM). The SCM consists of two stages, each with the
same accept/reject criteria. The second of the two stages recommends using
a larger sample size to meet these criteria.
The MCM uses accept/reject
criteria that are different from the SCM.
If the
batch data fail to conform to the SCM criteria, we recommend continued sampling
and testing to intensified criteria (MCM).
Both verification methods and the procedures for switching from one to
the other are detailed below and in the flow chart in Attachment 2.
A. Standard
Criteria Method (SCM)
We
recommend using the SCM verification method when either of the following
conditions is met:
·
Results
of establishing initial criteria are classified as readily pass.
·
Results
of testing to the MCM pass the criteria for switching to the SCM (see section C
below).
The SCM should meet the same criteria using a
different number of sample test results as described below:
1. Stage 1 Test
To perform the stage 1 test, we recommend that you
(1) collect at least 3 dosage units from each sampling location, (2) assay 1
dosage unit from each location, (3) weight correct the results, and (4) compare
the results with the following criteria:
·
RSD
of all individual results (n ³ 10) £ 5.0
percent.
·
Mean
of all results is 90.0 percent to 110.0 percent of target assay.
If the
results pass these criteria and the adequacy of mix and uniformity of dosage
unit content for the batch are adequate, you can use the SCM for the next
batch. If test results fail stage 1 criteria, you should conduct extended
testing to stage 2 acceptance criteria.
2. Stage 2 Test
To
perform the stage 2 test, we recommend that you assay the remaining two dosage
units (from stage 1) for each sampling location and compute the mean and RSD of
data combined from both stage 1 and stage 2. Compare the results with the following
criteria:
·
For
all individual results (n ³ 30) the RSD £ 5.0
percent.
·
Mean
of all results is 90.0 percent to 110.0 percent of target assay.
If
your results pass these criteria, the adequacy of mix and uniformity of content
for the batch are adequate and you can use stage 1 of SCM for the next
batch. If test results fail the
criteria, use the MCM described in the next section.
B. Marginal
Criteria Method (MCM)
After
powder mix assessment, in-process dosage unit stratified sampling correlation
and initial criteria establishment, we recommend that you use the MCM when either
of the following conditions is met:
·
Results
of initial criteria establishment qualified as marginally pass.
·
Results
of initial criteria establishment qualified as readily pass or a batch was tested according to SCM and the test
results failed both stage 1 and stage 2 criteria.
Then,
we recommend you use the weight-corrected results from the stage 2 SCM analysis and compare this with the MVM criteria:
·
For
all individual results (n ³ 30) the RSD £ 6.0
percent.
·
Mean
of all results is 90.0 percent to 110.0 percent of target assay.
We
recommend that all results from analysis of any remaining location samples be
computed with the stage 2 SCM
data. No test results should be removed
from the analysis. If the test results
pass these criteria, the adequacy of mix and uniformity of content for the
batch are adequate. We recommend that
you continue to test routine manufacturing batches with MCM criteria. If the test results fail the criteria, you
should no longer use the verification testing methods to ensure adequacy of
mixing or uniformity of content until you investigate the failure (per 21 CFR
211.192) to establish justified assignable cause(s), take necessary corrective
actions and repeat the powder mix assessment, stratified sample correlation,
and initial criteria establishment procedures.
C. Switching to Standard Test
Method from Marginal Test Method
It is
appropriate to switch to the SCM when the following criterion is met:
·
Five
consecutive batches pass the MCM criteria and result in RSD £ 5.0
percent
Comments
Post a Comment