Blend Uniformity - PQRI Research

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Presentation transcript:

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

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

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

Unconfined yield stress Performance of a Solids Processing Units AIChE Journal 47: 107-125 (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

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: 107-125 (2001)

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

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?