Introduction
Background to the work of the BUWG
Garth Boehm
BUWG Draft Recommendations
Tom Garcia
Data Mining: Challenging the Theory
Tom Garcia
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BUWG Actions
Conducted Industry Practices Survey
Published Uniformity Troubleshooting Guide
Held Public Workshop on BU testing issues
Held several Working Group meetings
Written Draft Proposal for use of Stratified Testing of
Dosage Units
Sought data to challenge proposed method
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Troubleshooting Guide
Early in the BUWG discussions it became apparent
that no concise guide was available for diagnosing
blend or dosage unit uniformity problems
Jim Prescott and Tom Garcia took on the task of
writing the guide and designing a companion chart
Published in March 2001 Pharmaceutical
Technology
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Public Workshop
Based around the theme Is BU Testing a Value
Added Test?
Held September 2000, about 200 people attended
Several formal presentations on aspects of blending,
blend sampling, acceptance criteria, new
technology, BUWG progress
Summary published in September 2001 Pharm Tech
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Public Workshop
Presentations based around the following:
Blending of solids is a poorly understood process
Very difficult to sample powder bed with
conventional sampling thieves
Sampling errors are common & occur both ways
Post-blending segregation can be a serious problem
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Public Workshop
Major part involved break-out sessions to
elicit feedback from attendees.
Is Blend Uniformity Testing on every batch a valueadded test?
How do you validate a process when you have a
sampling problem?
What new technologies are available to assess blend
uniformity?
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Public Workshop
Conclusions
Blend Uniformity Testing on every batch is not a
value-added test
Appropriate and meaningful BU testing should be
conducted during development and validation
Higher costs are acceptable if they yield meaningful
data
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Scope of Recommendation
Applies to:
Process validation and
marketed batches for
solid oral drug
products.
Products where the
active ingredients are
introduced into the
blend.
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Stratified Sampling
The process of selecting units deliberately from
various locations within a lot or batch or from
various phases or periods of a process to obtain a
sample. [Glossary and Tables for Statistical Quality Control
, ASQC Quality Press, copyright 1983.]
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Disadvantages
Too late
Batch compressed/filled
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Process Development
Stratified sampling plan is not a substitution for
poor process development
Sampling technique should be defined during
process development
Determine appropriate sampling device
Identify an acceptable sampling plan (for both blend and
dosage units)
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Validation Approach
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Process Validation
Blend: 10 locations 3 samples per location
Assay 1 sample per location
Acceptance Criteria:
RSD 5.0%
All individuals within +/- 10% of mean
Fail
Pass
Proceed to Stage 1
Dosage Unit Testing
Mixing problem
identified
Yes
Blend is not uniform.
Go back to development
No
Investigation points to sampling
bias or some other attributable cause
Proceed to Stage 2
Dosage Unit Testing
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Process Validation
During compression/filling,
sample from at least
20 locations, taking at least
7 dosage units per location
Pass
Process
Validated
Fail
Assay at least 4 additional dosage units per location
Pass
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Weight variability
Assay variability
Between location error
Within location error
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Routine Manufacture
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Routine Manufacture
For ANDA exhibit and/or validation batches:
RSD 4.0%, all mean results
90-110%, all values between 75-125%
Yes [Readily Complies]
No
Yes
Yes
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After passing 5
Consecutive Batches
No
Adequacy of mix
not demonstrated
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Alternative Approaches
BUWG recommendation is one approach for
evaluation of adequacy of mix
The cGMP requirements are open to other
approaches
On-line monitoring techniques such as NIR
PDA 25 approach
Traditional methods (direct sampling/analysis of
blend sample)
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149
0
Manufacturing Process
Direct Comp:
Wet Granulation:
Dry Granulation:
12
67
70
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Comparison of Acceptance
Criteria
Criteria
Results
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131/149 (88%)
OGD
136/149 (91%)
FDA Validation
123/149 (83%)
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86/88 (98%)
USP
85/88 (97%)
Revised USP (ICH) 86/88 (98%)
PDA 25
62/88 (70%)
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Datamining Results:
Readily vs. Marginally Comply
83/88 (94%) passed PQRI Validation
acceptance criteria
Of the batches that met PQRI Validation
acceptance criteria
Readily Comply: 79/83
Marginally Comply: 4/83
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Acknowledgements