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Blend Uniformity

This document summarizes discussions around assuring adequate mixing of pharmaceutical powders. It discusses the Pharmaceutical Quality Research Institute's (PQRI) proposal for using stratified sampling of dosage units during production to test for content uniformity. The proposal was presented to the FDA and generally endorsed. At an FDA peer review, the stratified sampling concept was found acceptable. However, the FDA requested additional justification around sample sizes, categorization of results, and implications of high variability values during production. The PQRI provided further arguments addressing these points, which helped gain FDA acceptance of the proposal. Next steps discussed implementing the proposal in a new FDA guidance.

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Sagi Nguyen
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255 views16 pages

Blend Uniformity

This document summarizes discussions around assuring adequate mixing of pharmaceutical powders. It discusses the Pharmaceutical Quality Research Institute's (PQRI) proposal for using stratified sampling of dosage units during production to test for content uniformity. The proposal was presented to the FDA and generally endorsed. At an FDA peer review, the stratified sampling concept was found acceptable. However, the FDA requested additional justification around sample sizes, categorization of results, and implications of high variability values during production. The PQRI provided further arguments addressing these points, which helped gain FDA acceptance of the proposal. Next steps discussed implementing the proposal in a new FDA guidance.

Uploaded by

Sagi Nguyen
Copyright
© © All Rights Reserved
We take content rights seriously. If you suspect this is your content, claim it here.
Available Formats
Download as PPT, PDF, TXT or read online on Scribd
You are on page 1/ 16

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

USP Content Uniformity


Stage 1: PASS

120
115

% Label Claim

Blend Sample Analysis


(Thief)
%RSD = <1 PASS

Content Uniformity Data


on Tablets (Prod. D, Comp. X)

110
105
100
95
90
85
0

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

Switch to

Tightened testing, when 5 each of consecutive


batches (n=30) meet an RSD 5.0% then

Standard test

We propose that we add:


When performing

Switch to

Standard testing, when the RSD of 1 batch


following Stage 2 testing (n=30) is > 5.0% then*

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

Multivariate
Quality-by
Design
Approach

Traditional test
methods

Current PQRI proposal


and draft Guidance

At-line
test methods

Draft Guidance may


include information on
the use of NIR methods

On- and/or At-line


test methods
for all critical
components and
processes

Proposed PAT Guidance


Incentive?
Higher efficiency
Lower risk leading to
lower regulatory concern

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

% D is s o lu t io n

100
75
50
25
0
0

8 60

65

70

Box Number

75

80

85

Global Manufacturing Services

Process Analytical Support Group

Understanding Dissolution

Control Blend

Control Blend had normal dissolution.

Poor Blend had slower dissolution.

Problem Blend

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%

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