1. Blend Uniformity - PQRI Research
Ajaz S. Hussain, Ph.D.
Deputy Director
Office of Pharmaceutical Science
CDER, FDA

2. Background Blend uniformity analysis (BUA)
S. Sonja Sekulic
Pfizer Groton Laboratories
Background
Blend uniformity analysis (BUA)
a in-process test
Subject of intense debate (~10 years)
Sample size (1-3x,..), sampling errors, segregation following blending, lack of correlation with content uniformity,….
CGMP issue vs. review issue
Inconsistent enforcement
Draft ANDA Guidance - August 1999
PQRI BUA Project

3. Draft Blend Uniformity Guidance ‘99
Motivation
Inconsistency with respect to supplements for deleting BUA
Concern regarding drug content uniformity
Insufficient information to ensure that “quality was by design”
Blender type, capacity, operating speed and blending time (generally same for pilot and proposed commercial batch)
Recommendations
Scope - for products which require USP content uniformity testing
For complex dosage forms - consult the review div.
Not to submit a supplement to delete BUA when it is also used for compliance with CGMP
Sampling size and procedure
Acceptance criteria and analytical procedure

4. Unconfined yield stress
Performance of a Solids Processing Units AIChE Journal 47: (2001)
Performance
of a Unit
Bulk Mechanical
Properties
Angle of repose
Unconfined yield stress
Forces Acting
on Particles
Adhesion forces
Impact forces
Material
Characteristics
Hamaker constant
Dielectric constant
Young’s modulus
Particle
Attributes
PSD
Shape
Composition
Equipment
Design
Geometry
Constituent parts
Material properties
Operating
Conditions
Speed of moving parts
Temperature
Humidity

5. Today Trial-Error is the Norm Do SOP’s reflect established Heuristic rules?
Segregation is not a serious problem if all the particles are smaller than 30 um or if they are slightly moist
Establish acceptance criteria for
particle size distribution
of excipients
Avoid bulk solids transfer
where particles slide down a
long, inclined chute
Segregation due to percolation is likely to be a concern if the particles of different density or size are poured into a heap or let slide on an inclined chute
The tendency of segregation of binary mixtures due to percolation decreases substantially if the ratio of particle diameters is lower than 1.3
Segregation during emptying of a storage unit is accentuated when funnel flow occurs
Ensure mass flow in hoppers
AIChE Journal 47: (2001)

6. USP Content Uniformity
A question of “representative sample”?
PQRI Proposed
Stratified Sampling
Blend Sample Analysis
(Thief)
%RSD = <1 PASS
USP Content Uniformity
Stage 1: PASS

7. Questions
Is the current PQRI proposal appropriate for inclusion in a planned revised guidance?
If no, please suggest modifications or improvements.
If yes, should the proposed stratified sampling and analysis plan be applicable only for the bioequivalence batch and validation batches?

8. Question (Contd.)
If the proposed stratified sampling and analysis plan is limited only to bioequivalence and validation batches, how should adequacy of mix be ensured for routine production batches?