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Blend Uniformity: Update Ajaz S. Hussain, Ph.D.

Blend Uniformity

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A brief in validation of blend in manufacturing process validation

Text of Blend Uniformity

  • Blend Uniformity: UpdateAjaz S. Hussain, Ph.D.

  • BackgroundIssue: Assuring and documenting adequacy of mixing operationsPQRIs Proposal Stratified sampling of dosage units (during routine production)ACPS Meeting November 28, 2001 ACPS Meeting May 8, 2002Proposal presented and discussedGeneral endorsementFDA Peer Review (August 14, 2002)PQRI Response (October 17, 2002)

  • FDA Peer ReviewChiu, Famulare, Holcomb, Hussain, Machado, Tsong, and ShenAcceptability of the stratified sampling conceptScience/Engineering of powder blending and compaction/encapsulationExamples of stratified sampling data made available to FDA by individualsPQRI proposed decisions trees and scientific arguments/justification

  • Tablet core potency - blend segregation in the bin


  • Blend Sample Analysis


    %RSD =

  • FDA Peer ReviewPQRI Datamining and Statistical EffortsFDA perspectiveSupporting dataStatistical simulation and assumption of normalityDifferent interpretationDeviations from normality suggestive of potential content uniformity problemsAdditional justification needed to support Sample size during routine production (batch size, ) Categorization - readily and marginally complyImplications of of finding high RSD values during routine production

  • PQRI Response (10/17/02)The following points made by PQRI were instrumental in the FDAs decision to accept the proposalIn general, non-normality = lack of homogeneityThe type of segregation (start-up or run-out) will not be found by testing powder in the blenderStratified sampling .. Specifically targets locations .. Which have a higher risk of producing failing content uniformity results20 locations represent every 5% of the batch. More sample locations would not change this substantially..Sampling theory is dependent upon sample being representative of the population

  • PQRI Response (10/17/02)Implications of of finding high RSD values for routine production batchesStandard testing for Readily passS1, n=10, mean between 90-110% and RSD 5%S2, n=30, mean between 90-110% and RSD 6%Tightened testing for Marginally passn=30, mean between 90-110% and RSD 6%When 5 each of consecutive batches (n=30) meet an RSD 5% then Standard testing

  • Slide *


    Prop 3 (a) continued

    Currently in BUWG proposal:

    We propose that we add:

    * When RSD is not due to a justified assignable cause

    When performing

    Switch to

    Tightened testing, when 5 each of consecutive batches (n=30) meet an RSD ( 5.0% then

    Standard test

    When performing

    Switch to

    Standard testing, when the RSD of 1 batch following Stage 2 testing (n=30) is >5.0% then*

    Tightened test

  • Next StepsInternal FDA meeting Define the outline for a new draft guidance based on the PQRI proposal (review and compliance roles)Assess and plan for training needsAssign the responsibility to a small group of individuals to write the guidanceDraft guidance to seek public commentsFormal training of FDA staff (if deemed necessary)Final guidance

  • Other Peer Review CommentsA range of comments, most captured in the FDA review processExcept Implications and perceptions resulting from continued recommendation of blend testing during validationincreased focus on end-product testing to document quality (moving away from building quality in)New technological solutions ignoredPQRI WG was asked to focus on the existing problem within the confines of the draft ANDA guidance

  • PAT: Higher level of quality & efficiency not a requirementUnivariateTesting toDocumentQualityApproachMultivariateQuality-byDesignApproachTraditional testmethodsAt-linetest methodsOn- and/or At-linetest methodsfor all criticalcomponents andprocessesCurrent PQRI proposal and draft GuidanceDraft Guidance may include information onthe use of NIR methodsProposed PAT GuidanceIncentive?Higher efficiencyLower risk leading to lower regulatory concern

  • New Technological Solutions and PATDraft Guidance may include information on the use of NIR methodsPQRI BU/NT proposal on NIR (USP PF article)Other excellent monographs on NIR validationFDAs own laboratory experience with NIR and NIR-imaging methodsThe proposed PAT guidance will further elaborate how to introduce new technologies to improve process understanding and efficiency

  • Lyon, et al. Near-Infrared Spectral Imaging for Quality Assurance of Pharmaceutical Products: Analysis of Tablets to Assess Powder Blend Homogeneity AAPS PharmSciTech 2002; 3 (3) article 17

  • Non-homogeneous distribution of magnesium stearate: Dissolution19 July 2001, ACPS Meeting

  • Global Manufacturing Services

    Process Analytical Support Group

    Understanding Dissolution

    Control Blend had normal dissolution.

    Poor Blend had slower dissolution.

    Matrix Level difference relates to distribution and particle size of disintegrant within the blend.

  • USP Weight Variation or the Content UniformityCompressed tablets Content uniformity not required for products containing 50 mg or more of an active comprising 50% or more, by weightS1, n=10, range 85-115% and RSD 6%If 1 unit is outside 85-115% and no unit is outside 75-125% or if RSD is >6%, or both conditions prevail, test 20 additional unitsS2, n=30, no unit is outside 75-125% and RSD 7.8%

    Just FYI -