Background to the work of the BUWG Garth Boehm BUWG Draft Recommendations Tom Garcia Data Mining: Challenging the Theory Tom Garcia

1. Introduction
Background to the work of the BUWG
Garth Boehm
BUWG Draft Recommendations
Tom Garcia
Data Mining: Challenging the Theory
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Tom Garcia
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2. Why Test Blend Uniformity?
21CFR211.110
(a) To assure batch uniformity and integrity of drug
products, written procedures shall be established and
followed that describe the in-process controls, tests, or
examinations to be conducted on appropriate samples of
in-process materials of each batch. ……..
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(3) Adequacy of mixing to assure uniformity and
homogeneity; …...
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3. Why Test Blend Uniformity?
OGD’s Draft Guidance
• All Solid Dosage forms <50% active or <50 mg require
routine BUA
• Use 6 to 10 samples, 1 - 3 unit weights
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• Must meet mean 90.0% to 110.0% label claim,
RSD NMT 5.0%
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4. Product Quality Research Institute
• PQRI (www.pqri.org) is a collaborative effort between
FDA, Industry, and Academia.
• PQRI’s mission is to provide a scientific basis for
developing Regulatory Policy.
• One of PQRI’s initiatives is to set up ‘expert’ Working
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Groups to analyze particular areas and make
recommendations on future Regulatory Policy.
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5. Blend Uniformity Working Group
• The Blend Uniformity Working Group was established
in late 1999
• The group is chaired by Tom Garcia and has members
from academia, FDA (CDER and DMPQ), and industry
(innovator and generic).
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• The group is charged with making scientifically based
recommendations on suitable procedures for assuring
batch homogeneity.
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6. 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
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• Sought data to challenge proposed method
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7. Industry Practices Survey
• Survey was blinded to assure confidentiality
• Sent to all solid dose sponsors with at least one
approved NDA or ANDA that could be located
• Designed to elicit information on general practices
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regarding BU sampling and testing
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8. Industry Practices Survey
• 28 of 134 replied (20%), mostly large
manufacturers
• Survey asked questions on Demographics,
Sampling, Routine Testing, Validation Testing,
Cause of Failure, Cost, & New Technology
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• Full Survey and Results can be found at
www.pqri.org and a summary in August 2001
Pharmaceutical Technology
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9. Industry Practices Survey
• The picture that emerged was of a conservative
industry that:
• Samples with conventional sampling thieves taking
1 - 3 unit dose sample sizes
• Tests samples with conventional ‘wet’ analytical
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methods
• Uses established acceptance criteria
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10. Industry Practices Survey
• About 2/3 for routine batches and 1/2 for validation
batches are prepared to defeat failing BU results
with enhanced testing
• Have trouble with 10% to 20% of products
• Think failures are due to sampling or analytical
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error
• Have not adopted any ‘new technology’
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11. 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
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• Published in March 2001 Pharmaceutical
Technology
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12. 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
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technology, BUWG progress
• Summary published in September 2001 Pharm Tech
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13. 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
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• Post-blending segregation can be a serious problem
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14. Public Workshop
Major part involved break-out sessions to
elicit feedback from attendees.
• Is Blend Uniformity Testing on every batch a value-
added test?
• How do you validate a process when you have a
sampling problem?
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• What new technologies are available to assess blend
uniformity?
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15. 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
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• Higher costs are acceptable if they yield meaningful
data
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16. Desired Attributes of a BUWG
Recommendation
BUWG Draft Proposal
“The Use of Stratified Testing of Blend and Dosage Units
to demonstrate Adequacy of Mix for Powder Blends”
1. The test should be simple to perform, maximizing the
use of data
2. Acceptance criteria should be easy to evaluate and
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interpret
3. Acceptance criteria should demonstrate when lack of
homogeneity is suspected
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17. PQRI BUWG Recommendation for the
Use of Stratified Sampling to
Demonstrate Blend & Dosage Unit
Content Uniformity
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18. PQRI BUWG Recommendation
• Utilizes stratified sampling
• Collectively considers the uniformity of the
powder blends and dosage units.
• Acknowledges that the best way to assess
blend uniformity may be indirectly by
measuring the uniformity of the dosage units.
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19. Scope of Recommendation
Applies to: Does not apply to:
• Process validation and • Drug products where
marketed batches for the determination of
solid oral drug dosage-form
products. uniformity by weight
• Products where the variation is allowed.
active ingredients are
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introduced into the
blend.
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20. 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.]
• Stratified sampling of the blend and dosage units
specifically targets locations either in the blender or
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throughout the compression/filling operation which
have a higher risk of producing failing content
uniformity results.
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21. Stratified Sampling of Dosage Units
Advantages Disadvantages
• More accurate & relevant • “Too late”
• Eliminates blend sampling • Batch compressed/filled
errors • Not consistent with
• Detects segregation “quality by design”
following blending • Parametric release
• Eliminates issues related to • Note: Control vs. Test
blend sampling of toxic or • BUA is utilized as a test
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potent drugs (operator
safety)
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22. 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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• Recommendation allows blend sample sizes >
1-3X, if they can be scientifically justified
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23. Validation Approach
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24. 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
Assay 2nd and 3rd blend samples
from each location
Proceed to Stage 1
Dosage Unit Testing
Mixing problem
identified
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Yes No
Blend is not uniform. Investigation points to sampling Proceed to Stage 2
Go back to development bias or some other attributable cause Dosage Unit Testing
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25. Process Validation
During compression/filling,
sample from at least Assay at least 3 dosage
20 locations, taking at least units per location
7 dosage units per location
Acceptance Criteria: RSD of all individuals ≤ 6.0% Pass Process
Each location mean within 90-110% target potency
Validated
All individual within 75-125% target potency
Fail
Assay at least 4 additional dosage units per location
Pass
Acceptance Criteria: RSD of all individuals ≤ 6.0%
Each location mean within 90-110% target potency
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All individual within 75-125% target potency
Fail
Blend is not uniform or post-blending
practices cause segregation
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26. Justification of Blend Sample Sizes
and Acceptance Criteria
• Number of Sampling Locations
– At least 10 locations should be used for tumbling
mixers to adequately map blender
– At least 20 locations should be used for convection
mixers, which are more likely to have dead spots
• Replicates Per Location
– At least 3 samples/location required to perform
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component variance analysis to detect the presence
of sampling error
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27. Justification of Dosage Unit Sample
Sizes and Acceptance Criteria
• Number of dosage unit samples and sample size
through the use of OC curves, considering:
– Weight variability
– Assay variability
– Between location error
– Within location error
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• USP Content Uniformity Test used as a
reference for comparison
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28. PQR
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29. PQR
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30. Justification of Dosage Unit
Acceptance Criteria
• RSD ≤ 6.0%
– Consistent with Stage 1 USP Test
• All location means 90-110% target potency
– Detects drifting/segregation or non-uniform spots in
the blend
• All individuals within 75-125% target potency
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– Will pick up outliers, such as subpotent or
superpotent (agglomeration) dosage units
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31. Justification of Dosage Unit
Acceptance Criteria
• Two stage test is consistent with USP
Content Uniformity Test
– Stage 1 and Stage 2 criteria are the same
– Stage 2 test offers a second opportunity to
comply with acceptance criteria, for those
batches which barely fail Stage 1 testing
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32. Routine Manufacture
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33. Merging the cGMP Requirement with
Compendial Release Testing
• Dosage units to be tested are in-process samples
• Perform two calculations on a single set of data
– cGMP Compliance - Normalize for weight
– Compendial Testing - No weight correction
• Acceptance criteria the same as that described in the
USP Content Uniformity Test
• If the in-process sample is not the finished dosage form, you
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must demonstrate during validation that the in-process
results provide the same or better control as the content
uniformity data generated during compendial release testing
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of the corresponding finished dosage units.

34. Definition of “Readily Complies” and
Impact on Degree of Testing Required
• “Readily Comply” is demonstrated if for each
ANDA exhibit and/or validation batch:
– RSD ≤ 4.0%, all mean results within 90.0 – 110.0%, all
individual results between 75.0 – 125.0%
– Stage 1 testing allowed (10 dosage units)
• Testing for products that do not “readily comply”
– Stage 2 testing (30 dosage units) for at least 5 batches
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– If after testing 5 consecutive batches, the criteria for the
mean is met and the RSD routinely is ≤ 5.0%, then Stage
1 testing is allowed
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35. 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 [Does not “Readily Comply”]
Stage 1: Test 1 sample/location No Stage 2: Test 3 samples/location
mean 90-110%, RSD ≤ 5.0% mean 90-110%, RSD ≤ 6.0%
Yes Yes No
Adequacy of mix demonstrated; Adequacy of mix demonstrated; Adequacy of mix
perform 2nd calculation to satisfy Future perform 2nd calculation to satisfy not demonstrated
compendial release requirements lots compendial release requirements
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After passing 5
Consecutive Batches
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36. Justification of cGMP Compliance
Sample Sizes and Acceptance Criteria
• Sample Size: At least 10 locations, 3 dosage
units per location
– Consistent with the USP Content Uniformity Test
• cGMP Acceptance Criteria: RSD ≤ 5.0% and
mean of all samples between 90-110% target
potency
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– Consistent with FDA Validation Acceptance Criteria
for demonstrating adequacy of mix for powder
blends
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37. 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
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– Traditional methods (direct sampling/analysis of
blend sample)
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38. Results of PQRI Datamining
Effort
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39. Objectives of Datamining Effort
• Test the hypothesis “blend uniformity is not
value added testing”
• Test the assumption that means are normally
distributed
– Validate the use of computer simulated data
• Subject batches to PQRI, OGD, FDA
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Validation, PDA 25, USP, and modified USP
(ICH) acceptance criteria
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40. Summary of Data Analyzed
• Desired Categories of Data
• Active ingredient < 5% and between 15-25%
• Product made using direct compression and
granulation processes (either wet or dry)
• Data for tablets and capsules
• Commercial batches both small (50-100 kg)
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and large (>400 kg)
• 8 companies submitted 149 batches
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41. Characteristics of Submitted Data
• Dosage Form
– Tablets: 149
– Capsules: 0
• Manufacturing Process
– Direct Comp: 12
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– Wet Granulation: 67
– Dry Granulation: 70
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42. Test for Normality of Means
• Tested both location and within location means for
normality using the Wilk-Shapiro test for normality
– Location: ~ 11% of batches had at least 1 value that
was statistically different
• Most were at beginning/end of run
– Within Location: ~15% of batches had at least 1
value that was statistically different
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• Conclusion: Computer simulations to estimate
criteria rejection rates yield slightly smaller values
(conservative) than reject rates based on actual data
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43. Comparison of Blend and Dosage
Unit Content Uniformity Data
• Primary means to test they hypothesis “blend
uniformity testing is not value added”
• Plots prepared comparing dosage unit RSD
as a function of blend RSD
– Break the curve down into 3 zones:
• Blend RSD <3%
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• Blend RSD 3-5%
• Blend RSD > 5%
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44. Comparison of Blend and
Dosage Form RSDs
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45. Blend RSD < 3%
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46. Blend RSD 3-5%
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47. Blend RSD >5%
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48. Correlation Between Blend and
Dosage Unit RSD
• Blend RSD < 3%: Blend data is predictive of
final dosage form uniformity
– Dosage form RSD often higher (weight variability,
segregation?)
• Blend RSD 3-5%: Diminished correlation
between blend data & dosage form uniformity
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• Blend RSD >5%: Blend data is not predictive of
content uniformity of the final dosage form
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49. Comparison of Acceptance
Criteria
Criteria Results
PQRI Validation 131/149 (88%)
OGD 136/149 (91%)
FDA Validation 123/149 (83%)
PQRI Routine 86/88 (98%)
USP 85/88 (97%)
Revised USP (ICH) 86/88 (98%)
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PDA 25 62/88 (70%)
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50. 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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51. Acknowledgements
• Jerry Planchard (Aventis) • Jim Prescott (Jenike &
• Garth Boehm (Purepac) Johanson)
• Joep Timmermans (Merck) • Pedro Jimenez (Lilly)
• Jerry Mergen (McNeil) • John Dietrick (FDA)
• Fernando Muzzio (Rutgers) • Jon Clark (FDA)
• Jean-Marie Geoffroy • Neeru Takiar (FDA)
(Abbott) • Muralidhara Gavini (FDA)
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• Laura Foust (Lilly)
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