Blend Uniformity: Update

Ajaz S. Hussain, Ph.D.

Background
Issue: Assuring and documenting adequacy of mixing operations
PQRIs Proposal
Stratified sampling of dosage units (during routine production)

ACPS Meeting November 28, 2001 ACPS Meeting May 8, 2002

Proposal presented and discussed General endorsement

FDA Peer Review (August 14, 2002) PQRI Response (October 17, 2002)

FDA Peer Review

Chiu, Famulare, Holcomb, Hussain, Machado, Tsong, and Shen Acceptability of the stratified sampling concept
Science/Engineering of powder blending and compaction/encapsulation Examples of stratified sampling data made available to FDA by individuals PQRI proposed decisions trees and scientific arguments/justification

19 July 2001, ACPS Meeting

A question of representative sample?

PQRI Proposed Stratified Sampling

% Label Claim

Blend Sample Analysis (Thief) %RSD = <1 PASS USP Content Uniformity Stage 1: PASS

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

120 115 110 105 100 95 90 85 0 2 4 6 8 10 12

Drum #

Tablet core potency - blend segregation in the bin

FDA Peer Review

PQRI Datamining and Statistical Efforts
FDA perspective
Supporting data
Statistical simulation and assumption of normality

Different interpretation
Deviations from normality suggestive of potential content uniformity problems

Additional justification needed to support

Sample size during routine production (batch size, ) Categorization - readily and marginally comply Implications 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 proposal
In general, non-normality = lack of homogeneity The type of segregation (start-up or run-out) will not be found by testing powder in the blender Stratified sampling .. Specifically targets locations .. Which have a higher risk of producing failing content uniformity results 20 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 batches
Standard testing for Readily pass
S1, n=10, mean between 90-110% and RSD 5% S2, n=30, mean between 90-110% and RSD 6%

Tightened testing for Marginally pass

n=30, mean between 90-110% and RSD 6% When 5 each of consecutive batches (n=30) meet an RSD 5% then Standard testing

Prop 3 (a) continued Currently in BUWG proposal:

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

Switch to
Standard test

We propose that we add:

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

Switch to
Tightened test

* When RSD is not due to a justified assignable cause

17-Oct-2002 Slide 17

Next Steps
Internal FDA meeting
Define the outline for a new draft guidance based on the PQRI proposal (review and compliance roles) Assess and plan for training needs Assign the responsibility to a small group of individuals to write the guidance

Draft guidance to seek public comments Formal training of FDA staff (if deemed necessary) Final guidance

Other Peer Review Comments

A range of comments, most captured in the FDA review process Except
Implications and perceptions resulting from continued recommendation of blend testing during validation
increased focus on end-product testing to document quality (moving away from building quality in)

New technological solutions ignored

PQRI 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 requirement

Univariate Testing to Document Quality Approach
Traditional test methods At-line test methods On- and/or At-line test methods for all critical components and processes Current PQRI proposal and draft Guidance Draft Guidance may include information on the use of NIR methods Proposed PAT Guidance Incentive? Higher efficiency Lower risk leading to lower regulatory concern

Multivariate Quality-by Design Approach

New Technological Solutions and PAT

Draft Guidance may include information on the use of NIR methods
PQRI BU/NT proposal on NIR (USP PF article) Other excellent monographs on NIR validation FDAs own laboratory experience with NIR and NIRimaging methods

The 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

19 July 2001, ACPS Meeting

Non-homogeneous distribution of magnesium stearate: Dissolution

100
%Dissolution

75 50 25 0 0

8 60

65

70

75

80

85

Box Number

Global Manufacturing Services

Process Analytical Support Group

Understanding Dissolution

Control Blend
l l l

Problem Blend

Control Blend had normal dissolution. Poor Blend had slower dissolution. Matrix Level difference relates to distribution and particle size of disintegrant within the blend.

Just FYI -

USP Weight Variation or the Content Uniformity

Compressed tablets
Content uniformity not required for products containing 50 mg or more of an active comprising 50% or more, by weight

S1, n=10, range 85-115% and RSD 6%

If 1 unit is outside 85-115% and no unit is outside 75125% or if RSD is >6%, or both conditions prevail, test 20 additional units

S2, n=30, no unit is outside 75-125% and RSD 7.8%