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PQRI
Introduction
Background to the work of the BUWG
Garth Boehm
BUWG Draft Recommendations
Tom Garcia
Data Mining: Challenging the Theory
Tom Garcia
PQRI
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. ……..
(3) Adequacy of mixing to assure uniformity and homogeneity; …...
PQRI
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OGD’s Draft Guidance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
• Must meet mean 90.0% to 110.0% label claim, RSD NMT 5.0%
PQRI
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 Groups to analyze particular areas and make recommendations on future Regulatory Policy.
PQRI
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).
• The group is charged with making scientifically based recommendations on suitable procedures for assuring batch homogeneity.
PQRI
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
PQRI
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 regarding BU sampling and testing
PQRI
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
• Full Survey and Results can be found at www.pqri.org and a summary in August 2001 Pharmaceutical Technology
PQRI
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 methods
• Uses established acceptance criteria
PQRI
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 error
• Have not adopted any ‘new technology’
PQRI
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
PQRI
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
PQRI
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
PQRI
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?
• What new technologies are available to assess blend uniformity?
PQRI
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
PQRI
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 interpret
3. Acceptance criteria should demonstrate when lack of homogeneity is suspected
PQRI
PQRI BUWG Recommendation for the Use of Stratified Sampling to
Demonstrate Blend & Dosage Unit Content Uniformity
PQRI
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.
PQRIScope of Recommendation
Applies to:• Process validation and
marketed batches for solid oral drug products.
• Products where the active ingredients are introduced into the blend.
Does not apply to:• Drug products where
the determination of dosage-form uniformity by weight variation is allowed.
PQRI
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 throughout the compression/filling operation which have a higher risk of producing failing content uniformity results.
PQRI
Stratified Sampling of Dosage Units
Advantages More accurate & relevant Eliminates blend sampling
errors Detects segregation
following blending Eliminates issues related to
blend sampling of toxic or potent drugs (operator safety)
Disadvantages “Too late”
Batch compressed/filled
Not consistent with “quality by design” Parametric release
Note: Control vs. Test BUA is utilized as a test
PQRI
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)
• Recommendation allows blend sample sizes > 1-3X, if they can be scientifically justified
PQRI
Validation Approach
PQRI
Process Validation
Blend: 10 locations 3 samples per locationAssay 1 sample per location
Acceptance Criteria:RSD 5.0%
All individuals within +/- 10% of mean
Assay 2nd and 3rd blend samples from each location
Proceed to Stage 1Dosage Unit Testing
Mixing problemidentified
FailPass
Proceed to Stage 2Dosage Unit Testing
Yes No
Blend is not uniform.Go back to development
Investigation points to sampling bias or some other attributable cause
PQRI
Process Validation
During compression/filling,sample from at least
20 locations, taking at least 7 dosage units per location
Assay at least 3 dosageunits per location
Acceptance Criteria: RSD of all individuals 6.0%Each location mean within 90-110% target potency
All individual within 75-125% target potency
ProcessValidated
Assay at least 4 additional dosage units per location
Acceptance Criteria: RSD of all individuals 6.0%Each location mean within 90-110% target potency
All individual within 75-125% target potency
Fail
Pass
Pass
Fail
Blend is not uniform or post-blendingpractices cause segregation
PQRI
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
component variance analysis to detect the presence of sampling error
PQRI
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
• USP Content Uniformity Test used as a reference for comparison
PQRI
Figure 1 - No Between-Location VariabilityPopulation Mean = 100%, Wt. RSD = 1.5%
Within-Location RSD Varies from 1 - 10%
Total RSD, %
0 1 2 3 4 5 6 7 8 9 10 11 12
Pro
bab
ility
of M
ee
ting
Cri
teria
, %
0
20
40
60
80
100
120
20x3, 7USP
PQRI
Figure 2 - Between Location Variability ExistsPopulation Mean = 100%, Assay RSD = 1.5%, Wt. RSD = 1.5%
Between Location RSD varies from 1 - 10%
Total RSD, %
0 1 2 3 4 5 6 7 8 9 10 11 12
Pro
ba
bili
ty o
f M
ee
ting
Cri
teri
a,
%
0
20
40
60
80
100
120
20x3, 7USP
PQRIJustification 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– Will pick up outliers, such as subpotent or
superpotent (agglomeration) dosage units
PQRIJustification 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
PQRI
Routine Manufacture
PQRI
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 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 of the
corresponding finished dosage units.
PQRI
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
– 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
PQRI
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/locationmean 90-110%, RSD 5.0%
Stage 2: Test 3 samples/locationmean 90-110%, RSD 6.0%
No
Yes Yes
Adequacy of mix demonstrated;perform 2nd calculation to satisfy compendial release requirements
No
Adequacy of mixnot demonstrated
After passing 5Consecutive Batches
Adequacy of mix demonstrated;perform 2nd calculation to satisfy compendial release requirements
Futurelots
PQRI
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– Consistent with FDA Validation Acceptance Criteria
for demonstrating adequacy of mix for powder blends
PQRI
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)
PQRI
Results of PQRI Datamining Effort
PQRI
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 Validation, PDA 25, USP, and modified USP (ICH) acceptance criteria
PQRI
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)
and large (>400 kg)
• 8 companies submitted 149 batches
PQRI
Characteristics of Submitted Data
• Dosage Form– Tablets: 149
– Capsules: 0
• Manufacturing Process– Direct Comp: 12
– Wet Granulation: 67
– Dry Granulation: 70
PQRI
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
• Conclusion: Computer simulations to estimate criteria rejection rates yield slightly smaller values (conservative) than reject rates based on actual data
PQRI
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%
• Blend RSD 3-5%
• Blend RSD > 5%
PQRIComparison of Blend and
Dosage Form RSDs
PQRI
Blend RSD < 3%
PQRI
Blend RSD 3-5%
PQRI
Blend RSD >5%
PQRI
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
• Blend RSD >5%: Blend data is not predictive of content uniformity of the final dosage form
PQRIComparison of Acceptance
Criteria Criteria
PQRI ValidationResults
131/149 (88%)OGDFDA Validation
136/149 (91%)123/149 (83%)
PQRI RoutineUSP
86/88 (98%)85/88 (97%)
Revised USP (ICH)PDA 25
86/88 (98%)62/88 (70%)
PQRI
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
PQRI
Acknowledgements
• Jerry Planchard (Aventis)
• Garth Boehm (Purepac)
• Joep Timmermans (Merck)
• Jerry Mergen (McNeil)
• Fernando Muzzio (Rutgers)
• Jean-Marie Geoffroy (Abbott)
• Jim Prescott (Jenike & Johanson)
• Pedro Jimenez (Lilly)
• John Dietrick (FDA)
• Jon Clark (FDA)
• Neeru Takiar (FDA)
• Muralidhara Gavini (FDA)
• Laura Foust (Lilly)
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