Blend Uniformity - PQRI Research

Ajaz S. Hussain, Ph.D.

Deputy Director

Office of Pharmaceutical Science

CDER, FDA

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

S. Sonja SekulicPfizer Groton Laboratories

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

Performance of a Solids Processing Units AIChE Journal 47: 107-125 (2001)

MaterialCharacteristics

Hamaker constantDielectric constantYoung’s modulus

ParticleAttributes

PSDShape

Composition

EquipmentDesignGeometry

Constituent partsMaterial properties

OperatingConditions

Speed of moving partsTemperature

Humidity

Bulk MechanicalPropertiesAngle of repose

Unconfined yield stress

Forces Actingon Particles

Adhesion forcesImpact forces

Performanceof a Unit

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 moistSegregation 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 occursAIChE Journal 47: 107-125 (2001)

Ensure mass flow in hoppers

Avoid bulk solids transferwhere particles slide down a

long, inclined chute

Establish acceptance criteria forparticle size distribution

of excipients

Content Uniformity Data on Tablets (Prod. D, Comp. X)

Drum #

0 2 4 6 8 10 12

% L

abel

Cla

im

85

90

95

100

105

110

115

120Blend Sample Analysis

(Thief)%RSD = <1 PASS

USP Content UniformityStage 1: PASS

A question of “representative sample”?

PQRI Proposed Stratified Sampling

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?

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?