This presentation summarizes recommendations from an ISPE working group for assessing blend and content uniformity. The group proposed modifications to address issues with the withdrawn 2002 FDA guidance. Key recommendations include a two-stage blend testing approach using statistical analysis and flexibility in selecting sampling plans, acceptance criteria, and confidence/coverage levels using a risk-based approach.

1. This presentation is compiled by “ Drug Regulations”
a non profit organization which provides free online
resource to the Pharmaceutical Professional.
Visit http://www.drugregulations.org for latest
information from the world of Pharmaceuticals.

2. This presentation is compiled from freely available resource like
the website of FDA & ISPE specifically a paper of ISPE
titled
“Paper published Garcia, Thomas et.al., Recommendations for the
assessment of blend and content uniformity: modifications to withdrawn
FDA draft stratified sampling guidance, J Pharm Innov, 2014, (DOI)
10.1007/s12247-014-9207-0.”
“Drug Regulations” is a non profit organization which provides free
online resource to the Pharmaceutical Professional.
Visit Our Website GMP Training
for latest information from the world of Pharmaceuticals.
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3.  This presentation highlights
◦ The reasons which lead to the withdrawal
of the 2002 Guidance of the FDA
◦ The current Industry Consensus as
represented by the ISPE BUCU group
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4.  This presentation is based on following
paper published by the ISPE BUCU group
◦ “Garcia, Thomas et.al., Recommendations for the
assessment of blend and content uniformity:
modifications to withdrawn FDA draft stratified
sampling guidance, J Pharm Innov, 2014, (DOI)
10.1007/s12247-014-9207-0.”
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5.  FDA withdrew draft guidance
◦ “Powder Blends and Finished Dosage Units – Stratified In-
Process Dosage Unit Sampling and Assessment” on August
7, 2013
 Following Sections were no longer consistent with
current FDA Thinking
◦ Section V (Exhibit/Validation Batch Powder Mix
Homogeneity) and
◦ Section VII (Routine Manufacturing Batch Testing Methods)
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6.  Section V recommended that 3 replicate blend samples be taken
from at least 10 locations, but no requirement to test all replicates
 Preference to test all replicate samples to allow variance component
analysis of the data
 High between location variability implies the blend is not
homogenous
 Acceptance criteria Section VII were based on limits stated in USP
General Chapter
◦ <905> Uniformity of Dosage Units
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7.  USP <905> does not use a statistical sampling plan
 Results provide limited statistical assurance that future
samples from the batch would pass
 FDA no longer supports the approach stated in the withdrawn
guidance document, nor the use of USP <905> for batch
release
 Created a gap for manufacturers & products that use
traditional blend & dosage unit uniformity approaches for
process validation & commercial batch release
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8.  Formed in August 2013 to discuss approaches to assess blend
and content uniformity
 Sponsored by the International Society for Pharmaceutical
Engineering (ISPE)
 Session at ISPE Annual Meeting (November 6, 2013) covering the
current issues associated with blend and content uniformity
analysis
◦ FDA concerns with current practices
◦ Importance of using statistically sound sampling plans and acceptance criteria
 Consider the impact that therapeutic properties of the drug can
have on content uniformity acceptance criteria
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10.  Modifications are proposed by the Group to assess “adequacy of mixing to
assure uniformity and homogeneity” of the finished product in accordance
with CGMP requirement 21 CFR 211.110 (7)
 Blend sampling and testing plans are revised to be more explicit
 Statistical approaches and sampling plans provide more confidence that
future samples from the batch will comply with USP <905>.
 Flexible risk based approach to define the number of dosage units to be
tested during routine manufacture
◦ Balance consumer’s risk and producer s risk
◦ Approach can be applied to all stages of process validation
 Can use for various dosage forms for which USP <905> applies
◦ Tablets, capsules (all types), sachets, powder filled bottles and in some instances semisolids,
regardless of drug loading.
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11.  Satisfies CGMP and application review requirements for in- process and
release testing to demonstrate adequacy of the powder mix and uniform
content of the dosage units
 Multiple approaches, sampling plans and acceptance criteria can be used
to assess blend and/or dosage unit uniformity, including:
 Various statistical approaches that use confidence intervals and/or
tolerance intervals that provide assurance of complying with USP <905>
 The application of PAT sensors to determine uniformity of powder mix
and blending end points
 The application of PAT and large n acceptance criteria to demonstrate
uniformity of dosage units
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12.  Retains the use in-process dosage unit data as a surrogate measure
for blend uniformity and release testing of the drug product during
commercial production
 The identification of blending parameters and assessment of blend
homogeneity throughout the blender and/or intermediate bulk
containers using appropriate sampling plans
 Sampling Technique and procedure:
 Assess impact of blend sample size (e.g., 1-10X dosage unit range;
sizes > 3X can be used with adequate justification)
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13.  Sampling errors should be identified, which may be negated by the use
of in- situ analytical techniques using real-time sampling and analysis
 Design sampling plans and evaluate the data using appropriate
statistical analysis, such as variance component analysis to measure
variability present in the results
 Include significant events (start-up, end of run, bin change-over
samples)
 Low dose / high potency drugs may require more rigorous sampling
plans
 Compare blend, in-process dosage units, and finished product data to
justify the use of in-process dosage units to demonstrate blend and
content uniformity for finished product release
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15.  [Example Sampling Plan]
 Take at least 3 blend samples from at least 10 locations in the
blender
 Stage 1 Blend Testing:
◦ Assay 1 sample from each location and calculate the standard deviation (SD) for the
samples
 SD ≤ 3.0% of target, blend uniformity is acceptable; proceed to
Stage 1 dosage unit testing
 SD is >3.0% of target, proceed to Stage 2 blend testing
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16.  Stage 2 Blend Testing:
◦ Assay the replicate blend samples from each location and calculate the SD for the samples
 SD ≤ 3.0%, blend uniformity is acceptable; proceed to Stage 1 dosage
unit testing. VCA not required
 SD 3.1% - 5.0% (inclusive), blend uniformity is acceptable; proceed to
Stage 2 dosage unit testing; recommend performing VCA for the blend
and dosage unit data
 SD > 5.0%, conduct an investigation, including VCA
 If the high SD is attributed to a sampling/assay error, proceed to Stage 2
dosage unit testing
 If the high SD is attributed to a product/process related cause, the blend
uniformity is unacceptable
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17.  [Example Sampling Plan]
 Sample at least 3 in-process dosage units from at least 40 approximately equally
spaced predetermined locations throughout the batch (including the beginning
and end of the run)
 2. Assay at least 3 dosage units per location from at least 20 (of the 40)
predetermined locations (including the beginning and end of the run); values
should not be weight corrected
 3. Determine if:
◦ All individual values between 75.0-125.0% (non-weight corrected)
◦ Data complies with the acceptance criteria for the statistical approach, sample size and confidence
& coverage selected
◦ If the results comply with, blend and dosage unit uniformity is demonstrated
◦ If either of the above acceptance criteria are not met, proceed to Stage 2 testing
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18.  Assay at least 3 dosage units per location from the remaining 20 locations
that were not tested during Stage 1
 Determine if the data comply with the acceptance criteria:
◦ All individual values between 75.0-125.0% (non-weight corrected)
◦ Data complies with the acceptance criteria for the statistical approach, sample size and confidence
& coverage selected
◦ If data complies with above, blend & dosage unit uniformity is demonstrated
◦ If not, the blend and/or dosage units are not uniform
 For products requiring Stage 2 testing, consider performing VCA on the
combined (Stage 1 and Stage 2) dosage unit data to identify potential
sources of variability that can lead to process improvements
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19.  Manufacturer decides what statistical approach, sampling
plan, acceptance criteria and levels of confidence and
coverage to use during Continued Process Verification to
provide assurance in passing USP <905>
◦ Based on the levels of producer and consumer risks they are willing to
accept
◦ If the in-process dosage unit data is used as a surrogate test for blend
uniformity and batch release (non-weight corrected data), a systematic
sampling plan should be used to identify the position of sampling
locations
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21.  Sample one in-process dosage unit from 30 locations
throughout the compression or filling process including
beginning and end of run samples
 Locations must be across the entire batch, including
beginning and end (i.e. not just a random sample)
 Stage 1 Testing: Assay 1 dosage unit from at least 10 of the
30 sampling locations
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22.  Determine if acceptance criteria are met
◦ All individual values between 75.0-125.0% (non-weight corrected)
◦ If the results comply with the acceptance criteria for the statistical
approach, sample size and levels of confidence & coverage selected.
◦ If the results comply, blend and dosage unit uniformity is demonstrated
◦ If either of the above acceptance criteria are not met, proceed to Stage 2
testing
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23.  Test the remaining 20 dosage units Determine is acceptance
criteria are met
◦ All individual values should be between 75.0-125.0% (non-weight
corrected)
◦ The data complies with the acceptance criteria for the statistical approach,
sample size and levels of confidence & coverage selected
◦ If the data comply, blend and dosage unit uniformity is demonstrated
◦ If the data does not comply, the dosage units and possibly the blend are
not uniform
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24.  For products with blend SDs 3.1-5.0% and/or required Stage 2
dosage unit testing during Process Qualification:
◦ Additional samples may be needed during Continued Process Verification (Stage
3A)
◦ Number of dosage units assayed should be risk based • Higher SDs (4.0-
5.0%) comparable to Process Qualification
 Stage 2 quantities
◦ Moderate SDs (3.1-4.0%) comparable to Process Qualification Stage 2
quantities.
◦ Quantities tested can be reduced if:
◦ Process changes improve blend and/or dosage unit uniformity
◦ A due diligence effort fails to improve the process resulting in high but
consistent (and acceptable) SDs, indicating its the best the process can do
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25.  Blend uniformity analysis should be performed during Process
Design and Process Qualification batches
◦ Do not skip blend uniformity testing and default directly to dosage units
◦ BUA can be performed for any mixing operation, although the final blend
(lubricated) is the best indicator prior to compression or filling
 Fewer sampling locations may be justified for smaller scale
batches (e.g., early Process Design batches; small Process
Qualification and commercial batch sizes)
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26.  Sample at least 3 blend samples and at least 3 dosage units
from each location
 Revised sampling plans must be appropriate for assuring
acceptable blend and dosage unit uniformity
 Acceptance criteria may be adjusted to be phase appropriate
(especially during Process Design)
 Situations may exist where it is not possible to sample blends
◦ e.g., Potent drugs manufactured in high containment equipment
(significant operator safety risks)
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27.  Recommend a 2-stage approach for the assessment of blend
uniformity – Unnecessary to assay blend replicates if SD ≤
3.0% for the first set of samples
 Total SD, between location and within location variance
components would be very small
 If SD > 3.0%, VCA information could identify sources of
variability, and opportunities to improve blend uniformity
◦ Weight correction is justified when using dosage unit content uniformity
as a surrogate test to demonstrate blend uniformity
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28. ◦ In-process dosage units must be sampled over the entire batch to assure
the entire blender is uniform, including beginning and end of run
 Weight correction is not allowed when using dosage unit
content uniformity data for batch release
 If the in-process dosage unit is not the final dosage form
(e.g., tablet core versus film coated tablet) demonstrate
content uniformity is not significantly impacted during
subsequent unit operations (e.g., film coating)
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29.  Blend SD of 3.1 - 5.0%
◦ Blend uniformity is acceptable, but proceed to Stage 2 in-process dosage unit testing
◦ Group recommends performing VCA on the blend and dosage unit data to assess between location
and within location variance components to identify opportunities to improve blend uniformity
 Blend SD >5.0%
◦ Conduct an investigation (including VCA) to determine if the variability was due to a non-blending
issue (e.g., sampling bias, analytical error or other non-formulation/process causes)
◦ Compare blend and dosage unit variance components
◦ If an error can be demonstrated and justified, implement corrective measures and proceed to Stage
2 dosage unit testing
◦ If the high SD is product/process related, then blend uniformity is unacceptable and further
formulation and/or process development is required for the product
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30.  VCA recommended if SD for the blend and/or dosage units is >3%
◦ VCA results for blend and dosage unit data can identify potential opportunities to reduce variability, including if the
source of the variability is due to product/process issues or sampling/assay error
◦ Significant within-location variance in the blend data:
 Variability may be due to poor micro-mixing and/or agglomeration
◦ Can carry over to the dosage units
 Sampling error
◦ Sampling errors of the blend will not carry over to the dosage units
◦ Significant between-location variance
◦ Non-uniformity throughout the blender – Blending operation is not optimized
◦ Segregation has occurred
◦ Plot the data to help diagnose the problem
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31.  Framework provides flexibility to use the preferred
statistical approach and acceptance criteria when
assessing content uniformity of the dosage units,
with justification
◦ Applicant must demonstrate why the sampling plan, statistical
approach and acceptance criteria selected are appropriate for
ensuring drug product content uniformity, and future samples
taken from the batch will have a high probability of passing USP
<905>
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32.  Confidence and coverage levels should be selected
using a risk based approach
◦ Balance consumer’s and producer’s risks
◦ Consider other factors such as the therapeutic index of the
drug – Confidence/coverage levels should be fit for purpose
◦ Especially for Stage 1 Process Design; many statistical
approaches may be too discriminating for drug products in
development
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33.  Consider Pharmacokinetic characteristics of the drug when
defining acceptance criteria for dosage unit uniformity
 Drugs with high potency and/or narrow therapeutic indices
may require tighter acceptance criteria to reduce consumer
risk
 Drugs with wide therapeutic indices can tolerate broader
acceptance criteria and minimize producer’s risk
 An assessment of in vivo impact of the dosing unit precision
can be obtained by conducting pharmacokinetic simulations
employing a target potency distribution as an input (6, 12)
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34.  Multiple statistical approaches, sampling plans and
acceptance criteria can be inserted within the framework to
provide confidence in passing USP <905>
 Modifications to the original draft stratified sampling
guidance document (based on the framework) can fill the void
created by its withdrawal
 The approach is scientifically justified, especially for products
that use traditional analytical techniques to assess adequacy
of powder mix and dosage unit uniformity
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35. This presentation is compiled from freely available resource like
the website of FDA & ISPE specifically a paper of ISPE
titled
“Paper published Garcia, Thomas et.al., Recommendations for the
assessment of blend and content uniformity: modifications to withdrawn
FDA draft stratified sampling guidance, J Pharm Innov, 2014, (DOI)
10.1007/s12247-014-9207-0.”
“Drug Regulations” is a non profit organization which provides free
online resource to the Pharmaceutical Professional.
Visit Our Website GMP Training
for latest information from the world of Pharmaceuticals.
02-09-2016 35
Visit Our WEBSITE GMP Training
http://fdagmp.blogspot.in/