PQRI

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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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; ...

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Why Test Blend Uniformity?

OGDs Draft Guidance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.
PQRIs mission is to provide a scientific basis for
developing Regulatory Policy.
One of PQRIs initiatives is to set up expert Working
Groups to analyze particular areas and make
recommendations on future Regulatory Policy.

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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.

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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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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

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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

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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

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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

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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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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.

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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.

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

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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)

Recommendation allows blend sample sizes

1-3X, if they can be scientifically justified

>

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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

Assay 2nd and 3rd blend samples

from each location

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

PQRI

Process Validation
During compression/filling,
sample from at least
20 locations, taking at least
7 dosage units per location

Assay at least 3 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

Pass

Process
Validated

Fail
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
Blend is not uniform or post-blending
practices cause segregation

Pass

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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

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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

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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

Will pick up outliers, such as subpotent or
superpotent (agglomeration) dosage units

PQRI

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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Routine Manufacture

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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

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

mean 90-110%, RSD 5.0%

No

Yes

Yes

Adequacy of mix demonstrated;

perform 2nd calculation to satisfy Future
compendial release requirements
lots

PQRI

Stage 2: Test 3 samples/location

mean 90-110%, RSD 6.0%

Adequacy of mix demonstrated;

perform 2nd calculation to satisfy
compendial release requirements

After passing 5
Consecutive Batches

No
Adequacy of mix
not demonstrated

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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)

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Results of PQRI Datamining

Effort

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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

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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

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Characteristics of Submitted Data

Dosage Form
Tablets:
Capsules:

149
0

Manufacturing Process
Direct Comp:
Wet Granulation:
Dry Granulation:

12
67
70

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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%

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Comparison of Blend and

Dosage Form RSDs

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Blend RSD < 3%

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Blend RSD 3-5%

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Blend RSD >5%

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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

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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%)
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

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)