IBC Found Course in Pharma Analysis In-Process Sampling 1

Joint CVG/Therapeutic Products Directorate

Convention Risk Based Decision Making in
Pharmaceutical Validation
Geoff Carr
Oct 06, 2005
Doubletree International Plaza Hotel, Toronto, Canada
http://www.patheon.com geoff.carr@patheon.com
Applications of Stratified Sampling to In-
Process Controls and Blend Uniformity
Testing for Solid Oral Dosage Forms
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Introduction
Very important to have good assurances that manufacture
processes are performing satisfactorily during pharmaceutical
production
Process Validation is conducted to ensure that a particular process
is inherently sound
In-process controls are designed to challenge the process on a
batch by batch basis and demonstrate that each batch manufacture
ran satisfactorily
Analogous to conducting validation studies on analytical
procedures and then applying system suitability tests each time
the method is applied to demonstrate that it performed correctly
and results are valid
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Introduction
In-process controls represent a good example of practical
applications of analytical science
This topic will be concerned with the demonstration of the
adequacy of powder mixing as an in-process control
Important in the manufacture of solid oral dosage forms eg tablets
and capsules
Requirement during development, CTM manufacture, registration
batches, process validation and commercial manufacture
Specific FDA requirement that we can demonstrate adequate
mixing of powder blends during manufacture
This presentation will deal with issues associated with Blend
Uniformity (BU) testing
IBC Found Course in Pharma Analysis In-Process Sampling 4
Menu
Introduction
Background to Blend Uniformity Testing
What is PQRI
FDA Guidance on Stratified Sampling
Case Study
Conclusions
IBC Found Course in Pharma Analysis In-Process Sampling 5
Menu
Introduction
Introduction
Introduction
Background to Blend Uniformity Testing
What is PQRI
What is PQRI
What is PQRI
FDA Guidance on Stratified Sampling
FDA Guidance on Stratified Sampling
FDA Guidance on Stratified Sampling
Case Study
Case Study
Case Study
Conclusions
Conclusions
Conclusions
IBC Found Course in Pharma Analysis In-Process Sampling 6
Background
Blend uniformity testing has been considered the most
appropriate way of demonstrating that powders were adequately
mixed prior to compression into tablets or filling of capsules
Logically this would seem to be a very appropriate approach
FDA issued a DRAFT Guidance in Aug 1999
FDA Guidance proposed that the mean value for BU samples
should be within 90.0 to 110.0% label claim and RSD 5.0%
Limits may seem to be very tight in view of typical 85.0 to
115.0% Stage 1 limits for Content Uniformity (CU) but note that
CU limits are designed to cope with additional tablet compression
or capsule fill variabilities
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Background
BU testing typically conducted on sample sizes equivalent to 2 to
3 dosage units
Samples taken from blender as Top, Middle, Bottom samples
using a sample thief
Generally about 12 locations sampled in a blender
Our Manufacturing Batch Records (MBRs) include a sampling
plan for the blender being used
This all looks very straightforward and should not create any
issues
BUT
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Background
When sample thief is inserted into blend it can be very disruptive
Local segregation
Selective adsorption
Electrostatic effects
etc
To get samples from 12 locations requires x4 insertions of thief
into blend and MBR Sampling Plan indicates locations
We then typically take 2 or even 3 sets of samples
Set 1 - For analysis
Set 2 - Spare set
Set 3 - QC retain set
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Background
We have had clients that insisted on BU testing with even very
small batches
Under these circumstances we get occasional rogue results that
then can create big problems
You cannot conduct a complete Out of Specification (OOS)
investigation so difficult to confirm/overcome OOS value
Sampling artefacts are well known with standard thieves and so
alternative designs are available to offer alternatives eg
compaction thieves
Very thin thieves
Even so, problems still continue which led to so much negative
response from industry to the FDA DRAFT Guidance that they
withdrew it in May 2002
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Background
You cant overcome a blend uniformity failure by just meeting
Content Uniformity (CU) Test requirements
A typical commercial scale batch could consist of 1 million
tablet/capsule units
CU testing requires that just 10 units be tested at Stage 1
Could increase to 30 units if Stage 2 testing required
Either way, sample size is extremely small and it is dubious
whether this could be considered representative
Therefore not surprising that Reg Agencies such as FDA insist
that we apply in-process controls and in this case can demonstrate
satisfactory blend uniformity
IBC Found Course in Pharma Analysis In-Process Sampling 11
Menu
Introduction
Introduction
Introduction
Background to Blend Uniformity Testing
Background to Blend Uniformity Testing
Background to Blend Uniformity Testing
What is PQRI
FDA Guidance on Stratified Sampling
FDA Guidance on Stratified Sampling
FDA Guidance on Stratified Sampling
Case Study
Case Study
Case Study
Conclusions
Conclusions
Conclusions
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What is PQRI?
PQRI is the Product Quality Research Institute
Created in Jan 1996
Collaborative body that involves FDA Centre for Drug
EvaluationResearch (CDER) , N American Pharmaceutical
Institutes and academia
Mission To generate scientific information in support of
regulatory policies through research
For more info, visit www.pqri.org
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What is PQRI?
PQRI Member Organisations include:
AAPS = American Association of Pharmaceutical Scientists
CHPA = Consumer Healthcare Products Association
PDA = Parenteral Drug Association
USP = United States Pharmacopeia
PhRMA = Pharmaceutical Research and Manufacturers of
America
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What is PQRI?
PQRI sets up Working Groups to deal with various subject areas
Blend Uniformity Working Group (BUWG) was actioned to
propose suitable in-process control systems for powder blends
PQRI proposal was issued in March 2002
The Use of Stratified Sampling of Blend and Dosage Units to
Demonstrate Adequacy of Mix for Powder Blends
Much of the content of this paper has then been taken into a new
FDA DRAFT Guidance for Industry
Powder Blends and Finished Dosage Units Stratified In-
Process Dosage Unit Sampling and Assessment
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Menu
Introduction
Introduction
Introduction
Background to Blend Uniformity Testing
Background to Blend Uniformity Testing
Background to Blend Uniformity Testing
What is PQRI
What is PQRI
What is PQRI
FDA Guidance on Stratified Sampling
Case Study
Case Study
Case Study
Conclusions
Conclusions
Conclusions
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FDA Guidance
Essentially based on principles of stratified sampling as described
in PQRI recommendations but more details of how to apply them
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FDA Guidance Scope
Stratified Sampling
Process by which samples of dosage units are taken at
predefined intervals and collecting samples from specifically
targeted locations during compression/filling operation
Targeted locations supposed to have the greatest potential of
demonstrating extreme high or low results
Guidance does not restrict us to this procedure and recognises that
traditional BU/CU sampling are still acceptable
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FDA Guidance Applications
Guidance recognises different phases of applications and
generally as:
Process Development Phase
Exhibit/Validation Batch Phase
Verification of Manufacturing Criteria Phase
Routine Manufacturing Phase
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FDA Guidance Applications
Process Development Phase
Correlation of In-Process Stratified Sampling with Powder Mix
and Finished Product
Document recommends that procedures recommended in this
section be completed if intended to apply stratified sampling at
later stages of development etc
3 phases to this section:
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FDA Guidance Applications
Process Development Phase
Correlation of In-Process Stratified Sampling with Powder Mix
and Finished Product
A. Assessment of Powder Mix Uniformity
Conduct blend analysis by extensively sampling from blender
and/or intermediate bulk containers (IBCs)
Identify
Optimum processing conditions
Blending time
Speed range
Dead spots in blenders
Locations for segregations in IBCs
Sampling errors
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FDA Guidance Applications
Process Development Phase
Correlation of In-Process Stratified Sampling with Powder Mix
and Finished Product
A. Assessment of Powder Mix Uniformity contd
Define sample sizes and develop a reliable method for measuring
true uniformity of the blend
Recognises sample sizes could be from 1 to 10x dosage unit
but requires justifications for sample sizes greater than 3x
dosage units
Design blend sampling plan and evaluate by appropriate
statistical analysis
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FDA Guidance Applications
Process Development Phase
Correlation of In-Process Stratified Sampling with Powder Mix and
Finished Product
A. Assessment of Powder Mix Uniformity contd
Investigate any variabilities within sample sets ie is it attributable to
Lack of blend uniformity?
Sampling error?
Within location variability could be
Inadequacy of mixing
Sampling error
Agglomeration
1 or more of the above
Between location variability could be:
Inadequate blending operation
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FDA Guidance Applications
Process Development Phase
Correlation of In-Process Stratified Sampling with Powder Mix and
Finished Product
B Correlation of Powder Mix Uniformity with Stratified In-Process
Dosage Unit Data
Conduct periodic sampling and testing of dosage units at defined
intervals/locations during compression/filling
Minimum of 20 appropriately spaced sampling points
At least 7 units at each point
Total minimum of 140 samples
Take additional samples of 7s from additional locations to assess
significant events
Filling/emptying hoppers/IBCs
Start/end of compression/filling
Equipment shutdown
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FDA Guidance Applications
Process Development Phase
Correlation of In-Process Stratified Sampling with Powder Mix
and Finished Product
B Correlation of Powder Mix Uniformity with Stratified In-
Process Dosage Unit Data
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FDA Guidance Applications
Process Development Phase
Correlation of In-Process Stratified Sampling with Powder Mix
and Finished Product
B Correlation of Powder Mix Uniformity with Stratified In-
Process Dosage Unit Data
Recommended that summary of this data will be required in NDA
submission!!!
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FDA Guidance Applications
Process Development Phase
Correlation of In-Process Stratified Sampling with Powder Mix and
Finished Product
B Correlation of Powder Mix Uniformity with Stratified In-Process
Dosage Unit Data
Compare BU with CU values
Investigate discrepancies
Plenty of literature references provided that may help
Suggests correction of discrepancies could involve
Back to drawing board on product development
Process optimisation
Sampling issues to be corrected using state-of-the-art methods for
real time sampling and analysis
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FDA Guidance Applications
Process Development Phase
Correlation of In-Process Stratified Sampling with Powder Mix
and Finished Product
C. Correlation of Stratified In-Process Samples with Finished
Product
Conduct CU test on finished product
Compare results with those obtained from stratified in-process
dosage units without weight correction
Prepare Table to show that data demonstrates that stratified in-
process sampling provides assurances of CU in finished product
Recommends that this is included in NDA
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FDA Guidance Applications
Exhibit/Validation Batch Phase Phase
Note that Exhibit Batch means any batch submitted in support of
an NDA or ANDA
Includes bioequivalence, test and commercial production
batches!!!!
Recommends independent assessment of
Uniformity of powder blend
In-process dosage unit content uniformity
Finished product content uniformity
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FDA Guidance Applications
Exhibit/Validation Batch Phase
Powder Mix Homogeneity
Identify at least 10 sampling locations in blender
Should represent potential areas of poor blending
For tumbling blenders eg V-blenders, take samples from at
least 2 depths along the axis of the blender
For convective blenders eg ribbon blender concentrate on on
corners and discharge areas
Recommends at least 20 locations for convective blenders
Take at least 3 replicate samples from each selected location
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FDA Guidance Applications
Exhibit/Validation Batch Phase
Powder Mix Homogeneity
The following criteria proposed:
Assay 1 sample per location ie
n 10 for tumbler blenders
n 20 for covective blenders
RSD of all individual results 5.0%
All individual results 10.0% (absolute) of mean value
ie if mean = 95.0%, 10.0% (absolute) of mean value = 85.0
to 105.0% and not 9.5%
If criteria satisfied, proceed to next phase
If criteria not satisfied, investigate (as shown later) and do not
proceed further
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FDA Guidance Applications
Exhibit/Validation Batch Phase
Powder Mix Homogeneity
Guidance recognises that sampling errors can occur
Recommends use of in-process dosage unit data in conjunction
with blend sample data to evaluate blend uniformity
This is in effect exactly the recommendation that originally came
from PQRI
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FDA Guidance Applications
Exhibit/Validation Batch Phase
Stratified In-Process Dosage Unit Sampling
Using the stratified sampling approach previously developed,
determine RSD values
(Assess normality)
Test results then classified according to RSD as follows:
Readily passes RSD 4.0%
Marginally passes RSD 6.0%
Inappropriate (to demonstrate batch homogeneity) > 6.0%
So thats the objective, this is how we are recommended to
proceed:
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FDA Guidance Applications
Exhibit/Validation Batch Phase
A Sampling and Analysis
Select locations during compression/filling for taking samples
Include significant process event locations as previously defined
Specifically tells us to take beginning and end samples from units
that would normally be included in the batch
Take from at least 20 locations with 7 units each to give a
minimum total of 140 units
Assay at least 3 units from the sets of 7 and weight correct the
values
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FDA Guidance Applications
Exhibit/Validation Batch Phase
A Sampling and Analysis contd
Analyse the data to demonstrate
Normal distribution of API content
Investigate any trends
Bimodal distributions
Any distribution other than normal
Prepare a summary report and include in NDA
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FDA Guidance Applications
Exhibit/Validation Batch Phase
B Criteria for Readily Pass Category
RSD of individual results 4.0% (n 60)
Each location mean is 90.0 to 110.0% of label claim (n 3)
Each individual value is 75.0 to 125.0% of label claim
If all criteria satisfied, we are ready to go to routine batch testing
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FDA Guidance Applications
Exhibit/Validation Batch Phase
C Criteria for Marginally Pass Category
Assay the remaining units from the sets of 7
Check results against following criteria:
RSD of individual results 6.0% (n 140)
Each location mean is 90.0 to 110% of label claim (n = 7)
Each individual value is 75.0 to 125.0% of label claim
Guidance not clear on how to proceed if we satisfy these criteria.
I assume we just proceed as for Readily Pass
If we dont satisfy 1 or more of the above, investigate, establish
cause(s), take corrective actions and repeat
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FDA Guidance Applications
Exhibit/Validation Batch Phase
D Sample Locations for Routine Manufacture
Using data collected above, select stratified sampling locations
Take into account significant process events
Identify at least 10 sampling locations
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FDA Guidance Applications Routine
Manufacture Phase
Recommends evaluation against the following criteria:
Standard Criteria Method (SCM)
Marginal Criteria Method (MCM)
Depending on data obtained from validation batch stage
Decision tree provided to show how criteria can switch between
SCM and MCM
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FDA Guidance Reporting Use of
Stratified Sampling
New Applications
Recommends the following information be provided in
Manufacturing Process and Process Controls section (CTD
3.2.P.3.3)
Statements that this Guidance was used or description of
alternative methods
Summary of data analysis from powder mix assessment and
stratified sample testing
Summary of In-Process dosage unit stratified sampling data
that shows normal distribution of API in product
Summary of powder mix sampling data analysis
demonstrating it meets acceptance criteria for validation and
establishing initial criteria
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FDA Guidance Reporting Use of
Stratified Sampling
New Applications contd
Product specification (CTD 3.2.P.4.1) should include statement
that methods of this Guidance were used to demonstrate finished
product content uniformity or a description of alternative methods
Recommends that information provided in Pharmaceutical
Development Information section (CTD 3.2.P.2.2)
Summary of data analysis that correlates in-process dosage
unit stratified sampling with finished product content
uniformity
Summary of data analysis for correlation of blend uniformity
with in-process dosage unit stratified sampling
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FDA Guidance Reporting Use of
Stratified Sampling
Post Approval Changes
To change from an existing approach to the procedures in this
Guidance, considered a minor change that should be noted in the
next annual report together with the information as defined for
NDA above
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Menu
Introduction
Introduction
Introduction
Background to Blend Uniformity Testing
Background to Blend Uniformity Testing
Background to Blend Uniformity Testing
What is PQRI
What is PQRI
What is PQRI
FDA Guidance on Stratified Sampling
FDA Guidance on Stratified Sampling
FDA Guidance on Stratified Sampling
Case Study
Conclusions
Conclusions
Conclusions
IBC Found Course in Pharma Analysis In-Process Sampling 43
Case Study
Dosage form tablets in 2 strengths
0.5mg
1mg
Stage of development Phase II
Case involves the first batches of each strength for an early
Phase II study
Scale of manufacture about 100,000 tablets of each strength
Equivalent to about 26Kg of blend
BU problems had been observed in a feasibility batch of the
0.5mg strength but the 1mg strength seemed to be OK
For the Phase II CTM batch we encountered problems with 1mg
tablets
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Case Study
In-process results for blend uniformity:
IBC Found Course in Pharma Analysis In-Process Sampling 45
Case Study
To summarise BU results
Acceptance criteria:
Mean value 90.0 to 110.0% label claim
RSD 5.0%
Results obtained
Mean value 94.8% of lc
Max 103.6%
Min 85.2%
RSD 6.6%
IBC Found Course in Pharma Analysis In-Process Sampling 46
Case Study
An OOS investigation was initiated and as part of this Sample
Sets 2 and 3 were tested and previous results were supported
Powder blend was held in a single drum and so this was also
sampled with following results
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Case Study
Mean value (n = 9) 97.3% lc
Max 115.8%
Min 75.4%
RSD 12.2%
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Case Study
Blend batch was given Conditional Release to compression and
stratified sampling conducted during compression with following
results
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Case Study
In-process results for weight corrected content uniformity:
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Case Study
To summarise CU results with weight correction
Overall mean value (n=154) 96.3% of lc
Max 110.9%
Min 91.4%
Overall RSD 3.0%
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Case Study
In-process results for content uniformity without weight
correction:
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Case Study
To summarise CU results without weight correction
Overall mean value (n=154) 96.3% of lc
Max 111.4%
Min 90.5%
Overall RSD 3.3%
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Case Study
Other analytical data for this batch
Content uniformity (n=10)
Mean 97.9% of lc
Max 100.4%
Min 94.6%
RSD 2.2%
Potency assay
99.1%
100.9%
Dissolution (n = 6)
Mean 100%
Max 101%
Min 98%
RSD 1.4%
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Case Study
Stratified sample data quite clearly indicated that the blend
homogeneity data was misleading
Content uniformity, potency assay and dissolution data showed
reasonable agreements with the stratified sample data
IBC Found Course in Pharma Analysis In-Process Sampling 55
Menu
Introduction
Introduction
Introduction
Background to Blend Uniformity Testing
Background to Blend Uniformity Testing
Background to Blend Uniformity Testing
What is PQRI
What is PQRI
What is PQRI
FDA Guidance on Stratified Sampling
FDA Guidance on Stratified Sampling
FDA Guidance on Stratified Sampling
Case Study
Case Study
Case Study
Conclusions
IBC Found Course in Pharma Analysis In-Process Sampling 56
Conclusions
Stratified sampling is an FDA recommended approach of
overcoming difficulties of in-process blend homogeneity testing
To follow these principles will generate a considerable amount of
analytical samples
Interpretation of results will require very close collaborations
between Analytical and Manufacturing Groups
It may be acceptable to FDA but how will other ICH territories
react to this?
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Conclusions
More details of PQRI and FDA Guidance documents are
available from their respective websites which are available at:
PQRI - http://www.pqri.org/
FDA - http://www.fda.gov/ - Section, CGMPs DRAFT