Recommendations for the Assessment of Blend and Content
J Pharm Innov
DOI 10.1007/s12247-014-9207-0
RESEARCH ARTICLE
Recommendations for the Assessment of Blend and Content
Uniformity: Modifications to Withdrawn FDA Draft Stratified
Sampling Guidance
Thomas Garcia & James Bergum & James Prescott & Ravindra Tejwani &
Thomas Parks & Jon Clark & William Brown & Fernando Muzzio &
Samir Patel & Charles Hoiberg
# Springer Science+Business Media New York 2014
Abstract
Introduction The following paper describes the International
Society for Pharmaceutical Engineering (ISPE)-sponsored
Blend Uniformity and Content Uniformity Group’s proposed
modifications to the withdrawn FDA draft guidance document
for industry “Powder Blends and Finished Dosage Units—
Stratified In-Process Dosage Unit Sampling and Assessment.”
The modifications targeted FDA’s primary concerns that led to
the withdrawal of the draft guidance document, which were
insufficient blend uniformity testing and that a one-time passing of the criteria stated in USP General Chapter
Uniformity of Dosage Units testing lacks confidence to ensure
the content uniformity of a batch.
Method The Group’s approach discusses when triplicate
blend samples should be analyzed and the importance of
performing variance component analysis on the data to identify root causes of non-uniformity. The Group recommends
the use of statistically based approaches, acceptance criteria,
and sampling plans for assessing content uniformity for batch
release that provide increased confidence that future samples
drawn from the batch will comply with USP .
Alternative statistical approaches, sampling plans, and acceptance criteria, including modern analytical method (e.g., process analytical technology (PAT)) sampling plans, may be
substituted for those mentioned in this paper, with justification.
This approach also links blend and content uniformity testing to
the three stages of the life cycle process validation approach.
Conclusion A framework for the assessment of blend and
content uniformity that provides greater assurance of passing
USP is presented.
The views presented in this article by the authors do not necessarily reflect
those of their respective companies or organizations.
T. Garcia (*)
Pfizer Worldwide Research and Development, Groton, CT, USA
e-mail: thomas.p.garcia@pfizer.com
S. Patel
Teva Pharmaceuticals, North Wales, PA, USA
e-mail: Samir.Patel@tevapharm.com
J. Bergum
BergumSTATS, Howell, NJ, USA
e-mail: james.bergum@BergumSTATS.com
J. Clark : W. Brown
United States Pharmacopeia-National Formulary, Rockville, MD,
USA
J. Prescott
Jenike and Johanson, Inc., Tyngsboro, MA, USA
e-mail: jkprescott@jenike.com
J. Clark
e-mail: JEC@USP.org
W. Brown
e-mail: WEB@USP.org
R. Tejwani
Bristol-Myers Squibb Company Research and Development, New
Brunswick, NJ, USA
e-mail: ravi.tejwani@bms.com
C. Hoiberg
Pfizer Inc., Silver Springs, MD, USA
e-mail: charles.p.hoiberg@pfizer.com
T. Parks
Eli Lilly and Company, Indianapolis, IN, USA
e-mail: tparks@lilly.com
F. Muzzio
Rutgers University, New Brunswick, NJ, USA
e-mail: fjmuzzio@yahoo.com
J Pharm Innov
Keywords Blend uniformity . Dosage unit uniformity .
Adequacy of mix . USP Uniformity of Dosage Units
Preface
The authors of this paper recommend that any approach used
to demonstrate uniformity of blends and dosage units be
science and risk based and that many approaches could be
used with justification. A framework for the use of multiple
approaches is provided in the following paper, which is
intended to propose modifications to the withdrawn FDA draft
guidance document for industry “Powder Blends and Finished
Dosage Units—Stratified In-Process Dosage Unit Sampling
and Assessment” [1]. This paper provides an approach to
address the void created by the withdrawal of the draft guidance document. The paper focuses on statistical analyses
assuming traditional sampling and analytical techniques. The
authors do not advocate that the sampling plans, statistical
approaches, and acceptance criteria given in this paper be the
only way that blend and content uniformity should be
assessed. To the contrary, the publication of other statistical
approaches that can be used within the framework of this
paper is welcomed and encouraged, and it is expected that
regulators will consider all science- and risk-based approaches
when setting guidance for industry. These other approaches
may include alternative statistical analyses, as well as modern
analytical methods (including process analytical technology
(PAT)) to assess blend and dosage unit uniformity, with justification. However, alternate statistical methods and PAT approaches are not discussed in this paper as they are outside of
its intended scope.
Introduction
The FDA announced the withdrawal of its draft guidance document for industry “Powder Blends and Finished Dosage
Units—Stratified In-Process Dosage Unit Sampling and
Assessment” on August 7, 2013 [2]. The withdrawal of the
document, which was widely used in the pharmaceutical industry, resulted in uncertainty for manufacturers that were currently
applying it to approved products, as well as to those in development. FDA stated that Section V (Exhibit/Validation Batch
Powder Mix Homogeneity) and Section VII (Routine
Manufacturing Batch Testing Methods) of this document were
no longer consistent with their current thinking [3]. Although
Section V recommended that three replicate samples be taken
from at least 10 locations, there was no requirement to test all
replicate samples. FDA prefers that all replicate samples be
tested, which allows statistical analysis of the data. If the
between-location variability is demonstrated to be high, then
the blend is not considered to be homogenous. The acceptance
criteria for the Standard and Marginal Criteria Methods in
Section VII were based on limits stated in USP General
Chapter Uniformity of Dosage Units [4]. However,
USP does not use a statistical sampling plan, and therefore, the results provide limited statistical assurance that future
samples from the batch would meet acceptance criteria. As such,
FDA no longer supports the approach stated in the withdrawn
guidance document nor the use of USP for batch release.
This decision resulted in a gap for manufacturers and products
that rely on traditional blend and dosage unit uniformity approaches for process validation and commercial batch release.
The International Society for Pharmaceutical Engineering
(ISPE) sponsored the Blend Uniformity and Content
Uniformity Group (referred to as Group), which was formed
in August 2013 to discuss approaches to assess blend and
content uniformity. The Group presented a series of talks
during a session at the ISPE Annual Meeting (November 6,
2013) covering the current issues associated with blend and
content uniformity analysis [5, 6]. FDA concerns with current
practices and the importance of using statistically sound sampling plans and acceptance criteria were discussed.
Consideration of the impact that the therapeutic properties of
the drug can have on content uniformity acceptance criteria
was noted. Substrate from this session was considered when
defining the approach presented in this paper.
Modifications to the withdrawn draft stratified sampling
guidance document are proposed by the Group to assess
“adequacy of mixing to assure uniformity and homogeneity”
of the finished product in accordance with Current Good
Manufacturing Practices (CGMP) requirement 21 CFR
211.110 [7]. The approaches described in this paper focus on
traditional sampling and analytical techniques used in the
pharmaceutical industry for the assessment of blend and dosage unit uniformity. Blend sampling and testing plans are
revised to be more explicit (for example, when replicate blend
samples should be assayed), and statistical approaches are
used for the analysis of dosage form uniformity to provide
more confidence that future samples from the batch will
comply with USP . For routine manufacture, the proposal allows a flexible risk-based approach to define the
number of dosage units to be tested. The number selected
should balance process capability, consumer’s risk, and producer’s risk. The approach can be applied to all stages of
process validation1 [8]. It can be used for various types of
dosage forms for which USP applies, including tablets,
capsules (all types), sachets, powder-filled bottles, and in
some instances semisolids, regardless of drug loading.
1
To avoid confusion with stage 1 and stage 2 testing for blend and dosage
units described in the proposed approach, this paper will refer to the three
stages of validation simply as “process design” (for stage 1 validation),
“process qualification” (for stage 2 validation), and “continued process
verification,” (for stage 3 validation).
J Pharm Innov
The Group believes that the framework described in this
paper 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 within this framework to assess blend and/or dosage unit
uniformity, with justification. This includes the following:
&
&
&
Various statistical approaches that use confidence intervals
and/or tolerance intervals that provide assurance of complying with USP [9–11]
The application of process analytical technology (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
&
run, bin change-over samples) though in relative proportion to the overall size of the batch. Drugs that have low
dose and/or high potency may require more rigorous
sampling plans.
A recommendation to compare the powder mix uniformity with the in-process dosage unit and finished product
content uniformity. If in-process dosage unit uniformity
data is used for product release, data analysis should
demonstrate that it provides assurance of the content uniformity of the finished product. Any discrepancies observed during process scale-up should be investigated.
Corrective actions to improve the formulation or
manufacturing process may be necessary.
Blend Sampling and Assessment During Process Design2 and
Process Qualification Batches
Modified Approach for the Assessment of Blend
and Content Uniformity for Process Design and Process
Qualification Batches
Relevant Information from Original Draft Guidance
Document
Information contained in Section IV of the original draft
stratified sampling guidance document is still applicable to
the modified approach. This includes the following:
&
&
&
&
&
The ability to use in-process dosage unit data as a surrogate measure of blend uniformity during commercial production (continued process verification).
The use of in-process dosage unit data obtained during the
compression/filling process for the release testing of the
finished product.
The identification of blending parameters and assessment
of blend homogeneity throughout the blender and/or intermediate bulk containers using appropriate sampling
plans.
A recommendation to assess the effects of powder sampling size (e.g., 1–10× dosage unit range; sizes >3× can be
used with adequate justification) when developing a blend
sampling technique and procedure that is capable of measuring the true uniformity of the blend. Sampling errors
should be identified, which may be negated by the use of
in situ analytical techniques using real-time sampling and
analysis.
A recommendation to design blend and dosage unit sampling plans and evaluate the data using appropriate statistical analysis, such as variance component analysis (VCA)
to measure variability present in the results. Sampling
plans should include significant events (start-up, end of
Figure 1 contains a flow diagram for the assessment of the
adequacy of powder mix and dosage unit uniformity during
the manufacture of process design and process qualification
batches, based on modifications to the withdrawn draft stratified sampling guidance document.
1. At least 3 blend samples should be taken from at least 10
locations in the blender according to the sampling
protocol.3
2. Stage 1 blend testing: Assay one sample from each location. Calculate the standard deviation (SD) for the
samples.
(a) If the SD≤3.0 % of target, proceed to stage 1 dosage
unit testing. VCA is generally not required.
(b) If the SD is >3.0 % of target, proceed to stage 2 blend
testing.
3. Stage 2 blend testing: Assay the replicate blend samples
from each location. Calculate the SD for the samples.
(a) If the SD≤3.0 % of target, proceed to stage 1 dosage
unit testing (assay at least 3 dosage units from at least
20 locations).
(b) If the SD is >5.0 % of target, conduct an investigation, including VCA, to determine if the variability
was due to a product/process issue or sampling/assay
error. Part of this investigation may include a
2
Although the strategy described in this section can be applied to batches
manufactured during stage 1 process design, the sampling plans, statistical approach, and acceptance criteria may be modified to be phase
appropriate.
3
Fewer locations may be sampled for the assessment of smaller batches,
with justification.
J Pharm Innov
Fig. 1 Process flow diagram for
assessment of blend and content
uniformity for process design and
process qualification batches
Blend (Samples): Sample at least 3 replicate samples from at least 10 locaons in the blender or drum
Assay 1 sample per locaon
Blend Uniformity Acceptance Criteria – Stage 1: SD ≤ 3.0% of target
Pass
Fail
Assay samples 2 & 3 per locaon
SD > 5.0% of Target
BU Stage 2
3.1 ≤ SD ≤ 5.0%
of Target
Conduct VCA and
invesgaon.
Was root cause:
Product /
Process
SD ≤ 3.0% of Target
Analycal/
Sampling
Blend Uniformity
is Acceptable
Dosage Units (Samples): During
filling or compression, take at
least 3 samples from at least 40
locaons across the batch
Assay at least 3 dosage units from
at least 40 predetermined
locaons throughout the batch
Blend Uniformity is Acceptable
Dosage Units (Samples): During filling or
compression, take at least 3 samples from at
least 40 locaons across the batch
Assay at least 3 dosage units from at least 20
predetermined locaons throughout the batch
Acceptance Criteria – Stage 1
All individual values within 75.0-125.0% and,
Complies with stascal test to provide an
appropriate level of assurance to comply with
USP for n*
Pass
Fail
Assay at least 3 dosage units from the remaining 20 locaons not tested in Stage 1.
Acceptance Criteria – Stage 2
All individual values within 75.0-125.0% and,
Complies with stascal test to provide an appropriate level of assurance to
comply with USP for n*
Pass
Fail
Blend is not uniform
Dosage Units are not uniform
Blend & content uniformity are acceptable
*n is the total number of assay results.
performed for the blend data to identify potential variability reduction and blend improvement opportunities.4
comparison of the blend VCA components with
those calculated for the subsequent dosage forms.
i. If the high SD is attributed to a sampling/assay error,
proceed to stage 2 dosage unit testing (assay at least 3
dosage units from at least 40 locations).
ii. If the high SD is attributed to a product/process-related
cause, the blend uniformity is unacceptable.
(c) If the SD is between 3.1 and 5.0 % of target (inclusive),
blend uniformity is acceptable. However, dosage unit
testing should be conducted at the stage 2 level to provide
increased assurance that the blend produces acceptable
dosage forms. It is also recommended that a VCA be
4
Variance component analysis is recommended if the standard deviation
for the blend and/or dosage units is >3 %. After performing the VCA,
attribute the variability to either variation in the uniformity of the blend
and/or other causes depending on if one or both of the variance components (between and within location) are significant. Significant withinlocation variance (above that of the analytical method) in the blend data
can be an indication of one factor or a combination of factors such as
variation of the blend mix, sampling error, or agglomeration. Sampling
errors of the blend will not carry over to the dosage units, while variation
of the mix at the within-location scale, and/or agglomeration, can carry
over to the dosage units. Significant between-location variance (above
that of analytical method) in the blend data can indicate that the blending
operation is not optimized or that segregation has occurred.
J Pharm Innov
In-Process Dosage Unit Sampling for Process Design5
and Process Qualification Batches6
1. Sample at least 3 in-process dosage units from at least
40 approximately equally spaced predetermined locations7 throughout the batch (including the beginning
and end of the run8; values should not be weight
corrected.
2. Stage 1 dosage unit testing: 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).
(a) Determine if the data comply with the acceptance criteria for the statistical approach, sample
size, and levels of confidence and coverage
selected.
(b) All individual values should be between 75.0 and
125.0 % (non-weight corrected).
(c) If either of the above acceptance criteria is not met,
proceed to stage 2 testing,
3. Stage 2 dosage unit testing: Assay at least 3 dosage units
per location from the remaining 20 locations that were not
tested during stage 1.
(a) Determine if the data comply with the acceptance criteria for the statistical approach, sample
size, and levels of confidence and coverage
selected.
(b) All individual values should be between 75.0 and
125.0 % (non-weight corrected).
(c) If the results comply with the acceptance criteria,
dosage unit uniformity is demonstrated. If not, the
dosage units are not uniform.
(d) 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.
Modified Approach for the Assessment of Blend
and Content Uniformity for Continued Process
Verification
Figure 2 contains a flow diagram for the assessment of blend
and dosage unit uniformity during continued process verification (stage 3b) of commercial batches. The manufacturer
decides what statistical approach, sampling plan, acceptance
criteria, and levels of confidence and coverage to use to
provide assurance in passing USP . This particular
example, which is for demonstration purposes only, uses a
sampling plan where one dosage unit is tested from 30 locations throughout the compression or filling process. Other
sample plans using different quantities of dosage units may
be used, with justification.9 Because the in-process dosage
unit data can also be used as a surrogate test for both batch
release (non-weight-corrected data) and blend uniformity, a
systematic sampling plan should be used to identify the position of sampling locations and ensure samples are taken
throughout the entire batch (including beginning and end of
run locations).
Procedure for Assessing Blend and Content Uniformity
During Continued Process Verification (Stage 3b)
1. Sample 1 in-process dosage unit from 30 locations
throughout the compression or filling process including
the beginning and end of the run.
2. Stage 1 testing: Assay 1 dosage unit from at least 10 of the
30 sampling locations. (The 10 locations need to be
identified in the sampling plan and are from across the
entire batch, including beginning and end (i.e., not just a
random sample from the 30 locations).
(a) Determine if the data comply with the acceptance
criteria for the statistical approach, sample size, and
levels of confidence and coverage selected.
(b) All individual values should be between 75.0 and
125.0 % (non-weight corrected).
(c) If the results comply with the acceptance criteria,
blend and dosage unit uniformity is demonstrated.
If either of the above acceptance criteria is not met,
proceed to stage 2 testing.
5
Although the strategy described in this section can be applied to batches
manufactured during stage 1 process design, the sampling plans, statistical approach and acceptance criteria may be modified to be phase
appropriate.
6
This example of a sampling plan was designed to provide appropriate
data for estimating between-location and within-location variance components to meet FDA expectations [3].
7
Fewer locations may be sampled for the assessment of smaller batches,
with justification.
8
Initial locations to be tested are identified prior to batch manufacture,
and must be representative of the entire batch.
3. Stage 2 testing: Test the remaining 20 dosage units and
determine if the results comply with
9
The manufacturer determines the number of dosage units to analyze
during continued process verification, based on the results of process
design and process qualification batch data, as well as the levels of
producer and consumer risks they are willing to accept.
J Pharm Innov
Fig. 2 Process flow diagram for
assessment of blend and content
uniformity for continued process
verification (stage 3b) batches
b
Dosage Units (Samples)
During filling or compression, take at least 1 dosage unit from at least 30 locaons spread
approximately equally across the batch including at the beginning and end of run
Assay a total of at least 10 dosage units taken approximately equally across the batch
including at the beginning and end of run
Acceptance Criteria – Stage 1*
All individual values within 75.0-125.0% and,
Complies with stascal test to provide an appropriate level of assurance to comply with USP
for n**
Fail
Pass
Assay at least 20 remaining dosage units
Acceptance Criteria – Stage 2*
All individual values within 75.0-125.0% and,
Complies with stascal test to provide an
appropriate level of assurance to comply with USP
for n**
Pass
Fail
Dosage units and possibly
blend are not uniform
Blend uniformity & content
uniformity are acceptable
* Acceptance criteria for Stage 3 Connued Process Verificaon may have reduced assurance
to comply with USP compared to that used for Stage 2 Process Qualificaon.
**n is the total number of assay results.
(a) The acceptance criteria for the statistical approach,
sample size, and levels of confidence and coverage
selected.
(b) All individual values should be between 75.0 and
125.0 % (non-weight corrected).
(c) If the results comply with the acceptance criteria,
blend and dosage unit uniformity is demonstrated.
If not, the dosage units and possibly the blend are not
uniform.
Continued Process Verification (Stage 3a)
If a product had blend standard deviations in the 3.1–
5.0 % of target range and/or it required stage 2 testing
for the dosage units during process qualification, additional samples may need to be analyzed during continued
process verification (stage 3a). The number of dosage
units that should be assayed depends on the magnitude
of the risks associated with the process. If a product has
standard deviations for the blend and/or dosage units in
the 4.0–5.0 % of target range, a greater number of dosage
units may be required to demonstrate adequacy of powder
mix and dosage unit uniformity (perhaps comparable to
stage 2 dosage unit testing quantities) during continued
process verification (stage 3a). For products with blend
and/or dosage unit standard deviations in the 3.1–4.0
range, stage 1 dosage unit testing may suffice. The number of samples tested could be reduced if process changes
are implemented that demonstrate an improvement in
blend and/or dosage unit uniformity. Testing may also
be reduced after a due diligence effort to improve the
process still results in high but consistent (and acceptable)
standard deviations for the blend and/or dosage unit data,
indicating this is the best uniformity that the process can
achieve.
Process Life Cycle
One element of continued process verification is to monitor process performance across batches. Standard deviations, acceptance values (AV), or other metrics for dosage
unit uniformity could be monitored across batches, to
J Pharm Innov
detect any trends or shifts in the manufacturing process
over the product’s life cycle.
Comments Regarding Implementation of the Approach
Blend and Dosage Unit Uniformity Analysis
Blend uniformity analysis should be performed during the
manufacture of process design and process qualification
batches. Manufacturers should not skip blend uniformity testing and default directly to dosage unit uniformity analysis
during the manufacture of process qualification batches.
Although an assessment of blend uniformity can be performed
for any mixing operation in the manufacturing process, the
final blend (lubricated) is the best indicator of the uniformity
of the blend prior to compression or filling operations.
Fewer sampling locations may be justified for smaller-scale
batches (e.g., early process design batches; small process
qualification and commercial batch sizes), and acceptance
criteria may be adjusted to be phase appropriate. However,
at least 3 blend samples and at least 3 dosage units should be
taken from each location. Revised sampling plans for smaller
batch sizes must be appropriate for assuring acceptable blend
and dosage unit uniformity. The Group recognizes that situations may exist where it is not possible to sample blends. For
example, for potent drugs manufactured in high-containment
equipment, blend sampling may not be possible and/or would
expose the operators to significant safety risks.
The Group recommends a 2-stage approach for the assessment of blend uniformity. It is not necessary to assay replicates
from each blender location if the standard deviation for the
first set of samples is ≤3.0 % of target because the total
standard deviation and the between- and within-location variance components would be very small. However, if the
standard deviation is >3.0 % of target, information obtained
from VCA after testing the remaining samples could be of
value in identifying potential product/process-related variability resulting in opportunities to improve the uniformity of the
blend.
Weight correction is justified when using dosage unit content uniformity as a surrogate test to demonstrate the adequacy
of the powder mix during routine commercial manufacture.
Performing a weight-corrected analysis can be helpful in
identifying if a failure to meet routine CU release criteria is
due to a blend or post-blend issue. Dosage unit samples must
be taken over the entire compression or filling run, to ensure
the data is representative of all areas in the blender. However,
because weight variation is an error component impacting the
dose that the consumer receives, it is necessary to use the nonweight-corrected results if the in-process dosage unit data is to
be used for product release. If the in-process dosage unit is not
the final dosage form (e.g., tablet core versus film-coated
tablet), an assessment should be conducted that demonstrates
content uniformity is not significantly impacted during subsequent unit operations (e.g., film coating).
Investigations
When the blend standard deviation is between 3.1 and 5.0 %
of target, the blend uniformity is acceptable and one can
proceed to in-process dosage unit sampling. However, the
group recommends that VCA be performed on the blend data
to assess between-location and within-location variance components which may be used to identify opportunities to improve blend uniformity for future batches.
If the standard deviation is >5.0 % of target, conduct an
investigation (including VCA) to determine if the variability
was due to a non-blending issue that resulted in an erroneous
assessment of the true uniformity of the blend (such as sampling bias, analytical error, or other non-formulation/process
causes). If the presence of such an error can be demonstrated
and justified, then corrective measures should be implemented
and the batch can proceed to stage 2 dosage unit testing. If,
instead, the high standard deviation is attributed to a product/
process-related cause, then blend uniformity is unacceptable
and further formulation and/or process development is required for the product.
Whenever stage 2 dosage unit testing is required, VCA of
the data is recommended to determine if location-to-location
issues exist over the course of the compression or filling run. It
is valuable to compare the results of VCA performed on
dosage units to those obtained for the blend. The knowledge
gained from these comparisons may provide insight into blend
and content uniformity improvements.
Acceptance Criteria
The statistical approaches and acceptance criteria, including
the level of confidence and coverage associated with the
method, for dosage units have intentionally been omitted in
Figs. 1 and 2. This provides the manufacturer the flexibility to
use the preferred statistical approach and acceptance criteria
when assessing content uniformity of the dosage units, with
justification. Confidence and coverage levels should be selected using a risk-based approach that balances consumer’s
and producer’s risks, and other factors such as the therapeutic
index of the drug. The selected statistical approach should
provide sufficient confidence that the drug product is of acceptable content uniformity and future samples taken from the
batch (if tested) will have a high probability of passing USP
. The selected statistical approach, sampling plans, and
confidence/coverage levels should also be fit for the purpose,
especially during stage 1 process design where many
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statistical approaches may be too discriminating for nonoptimized drug products in early development.
Two statistical approaches that may be used are the ASTM
E2709/E2810 method and tolerance interval (TI) approach.
The ASTM method provides a level of confidence (for example, 90 %) and coverage (for example, 95 % of future samples)
that additional samples take from the batch will meet USP
criteria. The TI test provides a level of confidence (for
example, 95 %) that some percentage (for example 95 %) of
the dosage units will fall within a range (for example, 85.0–
115.0 %). An alternative analysis of the TI data can also
predict the probability that future batches will pass USP
, providing a comparison to the ASTM method. Both
approaches provide increased confidence that future samples
taken from the batch will pass USP criteria.
For some products, the pharmacokinetic characteristics of
the drug may need to be considered when defining acceptance
criteria for dosage unit uniformity. For example, drugs with
high potency and/or narrow therapeutic indices may require
tighter acceptance criteria to reduce consumer risk (i.e., the
risk of releasing an unacceptable batch to treat a condition).
Conversely, drugs with wide therapeutic indices can tolerate
broader acceptance criteria and minimize producer’s risk (i.e.,
the risk of failing an acceptable batch). 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. The control parameters
used in the proposed flow charts (Figs. 1 and 2) represent the
target potency distribution for the dosing units. Example
methods of such simulations have been discussed elsewhere
[6, 12].
The framework defined in Figs. 1 and 2 has the flexibility
to accommodate different statistical approaches, sampling
plans, and acceptance criteria, simply by inserting them into
the appropriate boxes in the flow diagrams [9–11]. Regardless
of which approach is selected, it is up to the applicant to
demonstrate why the sampling plan, statistical approach, and
acceptance criteria selected are appropriate for ensuring the
content uniformity of the product.
Summary
The Group has proposed modifications to the original draft
stratified sampling guidance document [1], which could fill
the void resulting from its withdrawal. The approach is scientifically justified, especially for products that use traditional
analytical techniques to assess the adequacy of the powder
mix and dosage unit uniformity. This paper contains a framework into which statistical approaches, sampling plans, and
acceptance criteria can be inserted to demonstrate blend and
dosage unit uniformity. The authors acknowledged that alternate acceptable approaches exist and others are being developed, which can also be used within the framework defined in
this paper to assure compliance with USP .
References
1. Guidance for industry, “Powder Blends and Finished Dosage Units—
Stratified In-Process Dosage Unit Sampling and Assessment”. U.S.
Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER),
October 2003, Pharmaceutical CGMPs.
2. Federal Register / Vol. 78, No. 152, p. 48175-48176, August 7,
2013/Notices.
3. Questions and answers on current good manufacturing practices,
good guidance practices, level 2 guidance—production and process
controls. CDER/OC Office of Manufacturing and Product Quality:
CGMP Subject Matter Contacts, 6 August 2013. http://www.fda.gov/
Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
ucm124782.htm.
4. United States Pharmacopeia Convention, USP 37 NF 32, USP
General Chapter Uniformity of dosage units, general notices
and requirements, Section 3.10, Applicability of standards.
5. “Stratified sampling” presented at 2013 ISPE Annual Meeting,
Washington Marriott Wardman Park, Washington, DC, 3-6
November 2013
6. Bergum J. Current events in blend and content uniformity. Pharm
Eng. 2014;34(2):1–10.
7. CFR 211.110, Code of Federal Regulations, Title 21, Volume 4,
Revised as of April 1, 2014.
8. Guidance for industry, “Process Validation: General Principles and
Practices,” U.S. Department of Health and Human Services, Food
and Drug Administration, Center for Drug Evaluation and Research
(CDER), Center for Biologics Evaluation and Research (CBER),
Center for Veterinary Medicine (CVM), January 2011, Current
Good Manufacturing Practices, Revision 1
9. Bergum J, Parks T, et.al. Assessment of blend and content uniformity: technical discussion of sampling plans and application of ASTM
E2709/E2810, accepted for publication in J. Pharm. Innov.,
December, 2014
10. Bergum J., Tolerance interval alternative to ASTM E2709/E2810
methodology to provide assurance of passing the USP uniformity
of dosage unit (UDU) test , submitted to Pharmaceutical
Engineering, October, 2014
11. De los Santos P, Liu J, Pfahler L, Harrington B, Vukovinsky K,
“Performance characteristics and alternative approaches for the
ASTM E2709/2810 (CUDAL) method for ensuring that a product
meets USP uniformity of dosage units”, Submitted to
Pharmaceutical Engineering, October 2014
12. Tejwani R. “Relating blend uniformity specification to the finished
product” presented at 2013 ISPE Annual Meeting, Washington
Marriott Wardman Park, Washington, DC, November 6, 2013
DOI 10.1007/s12247-014-9207-0
RESEARCH ARTICLE
Recommendations for the Assessment of Blend and Content
Uniformity: Modifications to Withdrawn FDA Draft Stratified
Sampling Guidance
Thomas Garcia & James Bergum & James Prescott & Ravindra Tejwani &
Thomas Parks & Jon Clark & William Brown & Fernando Muzzio &
Samir Patel & Charles Hoiberg
# Springer Science+Business Media New York 2014
Abstract
Introduction The following paper describes the International
Society for Pharmaceutical Engineering (ISPE)-sponsored
Blend Uniformity and Content Uniformity Group’s proposed
modifications to the withdrawn FDA draft guidance document
for industry “Powder Blends and Finished Dosage Units—
Stratified In-Process Dosage Unit Sampling and Assessment.”
The modifications targeted FDA’s primary concerns that led to
the withdrawal of the draft guidance document, which were
insufficient blend uniformity testing and that a one-time passing of the criteria stated in USP General Chapter
Uniformity of Dosage Units testing lacks confidence to ensure
the content uniformity of a batch.
Method The Group’s approach discusses when triplicate
blend samples should be analyzed and the importance of
performing variance component analysis on the data to identify root causes of non-uniformity. The Group recommends
the use of statistically based approaches, acceptance criteria,
and sampling plans for assessing content uniformity for batch
release that provide increased confidence that future samples
drawn from the batch will comply with USP .
Alternative statistical approaches, sampling plans, and acceptance criteria, including modern analytical method (e.g., process analytical technology (PAT)) sampling plans, may be
substituted for those mentioned in this paper, with justification.
This approach also links blend and content uniformity testing to
the three stages of the life cycle process validation approach.
Conclusion A framework for the assessment of blend and
content uniformity that provides greater assurance of passing
USP is presented.
The views presented in this article by the authors do not necessarily reflect
those of their respective companies or organizations.
T. Garcia (*)
Pfizer Worldwide Research and Development, Groton, CT, USA
e-mail: thomas.p.garcia@pfizer.com
S. Patel
Teva Pharmaceuticals, North Wales, PA, USA
e-mail: Samir.Patel@tevapharm.com
J. Bergum
BergumSTATS, Howell, NJ, USA
e-mail: james.bergum@BergumSTATS.com
J. Clark : W. Brown
United States Pharmacopeia-National Formulary, Rockville, MD,
USA
J. Prescott
Jenike and Johanson, Inc., Tyngsboro, MA, USA
e-mail: jkprescott@jenike.com
J. Clark
e-mail: JEC@USP.org
W. Brown
e-mail: WEB@USP.org
R. Tejwani
Bristol-Myers Squibb Company Research and Development, New
Brunswick, NJ, USA
e-mail: ravi.tejwani@bms.com
C. Hoiberg
Pfizer Inc., Silver Springs, MD, USA
e-mail: charles.p.hoiberg@pfizer.com
T. Parks
Eli Lilly and Company, Indianapolis, IN, USA
e-mail: tparks@lilly.com
F. Muzzio
Rutgers University, New Brunswick, NJ, USA
e-mail: fjmuzzio@yahoo.com
J Pharm Innov
Keywords Blend uniformity . Dosage unit uniformity .
Adequacy of mix . USP Uniformity of Dosage Units
Preface
The authors of this paper recommend that any approach used
to demonstrate uniformity of blends and dosage units be
science and risk based and that many approaches could be
used with justification. A framework for the use of multiple
approaches is provided in the following paper, which is
intended to propose modifications to the withdrawn FDA draft
guidance document for industry “Powder Blends and Finished
Dosage Units—Stratified In-Process Dosage Unit Sampling
and Assessment” [1]. This paper provides an approach to
address the void created by the withdrawal of the draft guidance document. The paper focuses on statistical analyses
assuming traditional sampling and analytical techniques. The
authors do not advocate that the sampling plans, statistical
approaches, and acceptance criteria given in this paper be the
only way that blend and content uniformity should be
assessed. To the contrary, the publication of other statistical
approaches that can be used within the framework of this
paper is welcomed and encouraged, and it is expected that
regulators will consider all science- and risk-based approaches
when setting guidance for industry. These other approaches
may include alternative statistical analyses, as well as modern
analytical methods (including process analytical technology
(PAT)) to assess blend and dosage unit uniformity, with justification. However, alternate statistical methods and PAT approaches are not discussed in this paper as they are outside of
its intended scope.
Introduction
The FDA announced the withdrawal of its draft guidance document for industry “Powder Blends and Finished Dosage
Units—Stratified In-Process Dosage Unit Sampling and
Assessment” on August 7, 2013 [2]. The withdrawal of the
document, which was widely used in the pharmaceutical industry, resulted in uncertainty for manufacturers that were currently
applying it to approved products, as well as to those in development. FDA stated that Section V (Exhibit/Validation Batch
Powder Mix Homogeneity) and Section VII (Routine
Manufacturing Batch Testing Methods) of this document were
no longer consistent with their current thinking [3]. Although
Section V recommended that three replicate samples be taken
from at least 10 locations, there was no requirement to test all
replicate samples. FDA prefers that all replicate samples be
tested, which allows statistical analysis of the data. If the
between-location variability is demonstrated to be high, then
the blend is not considered to be homogenous. The acceptance
criteria for the Standard and Marginal Criteria Methods in
Section VII were based on limits stated in USP General
Chapter Uniformity of Dosage Units [4]. However,
USP does not use a statistical sampling plan, and therefore, the results provide limited statistical assurance that future
samples from the batch would meet acceptance criteria. As such,
FDA no longer supports the approach stated in the withdrawn
guidance document nor the use of USP for batch release.
This decision resulted in a gap for manufacturers and products
that rely on traditional blend and dosage unit uniformity approaches for process validation and commercial batch release.
The International Society for Pharmaceutical Engineering
(ISPE) sponsored the Blend Uniformity and Content
Uniformity Group (referred to as Group), which was formed
in August 2013 to discuss approaches to assess blend and
content uniformity. The Group presented a series of talks
during a session at the ISPE Annual Meeting (November 6,
2013) covering the current issues associated with blend and
content uniformity analysis [5, 6]. FDA concerns with current
practices and the importance of using statistically sound sampling plans and acceptance criteria were discussed.
Consideration of the impact that the therapeutic properties of
the drug can have on content uniformity acceptance criteria
was noted. Substrate from this session was considered when
defining the approach presented in this paper.
Modifications to the withdrawn draft stratified sampling
guidance document are proposed by the Group to assess
“adequacy of mixing to assure uniformity and homogeneity”
of the finished product in accordance with Current Good
Manufacturing Practices (CGMP) requirement 21 CFR
211.110 [7]. The approaches described in this paper focus on
traditional sampling and analytical techniques used in the
pharmaceutical industry for the assessment of blend and dosage unit uniformity. Blend sampling and testing plans are
revised to be more explicit (for example, when replicate blend
samples should be assayed), and statistical approaches are
used for the analysis of dosage form uniformity to provide
more confidence that future samples from the batch will
comply with USP . For routine manufacture, the proposal allows a flexible risk-based approach to define the
number of dosage units to be tested. The number selected
should balance process capability, consumer’s risk, and producer’s risk. The approach can be applied to all stages of
process validation1 [8]. It can be used for various types of
dosage forms for which USP applies, including tablets,
capsules (all types), sachets, powder-filled bottles, and in
some instances semisolids, regardless of drug loading.
1
To avoid confusion with stage 1 and stage 2 testing for blend and dosage
units described in the proposed approach, this paper will refer to the three
stages of validation simply as “process design” (for stage 1 validation),
“process qualification” (for stage 2 validation), and “continued process
verification,” (for stage 3 validation).
J Pharm Innov
The Group believes that the framework described in this
paper 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 within this framework to assess blend and/or dosage unit
uniformity, with justification. This includes the following:
&
&
&
Various statistical approaches that use confidence intervals
and/or tolerance intervals that provide assurance of complying with USP [9–11]
The application of process analytical technology (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
&
run, bin change-over samples) though in relative proportion to the overall size of the batch. Drugs that have low
dose and/or high potency may require more rigorous
sampling plans.
A recommendation to compare the powder mix uniformity with the in-process dosage unit and finished product
content uniformity. If in-process dosage unit uniformity
data is used for product release, data analysis should
demonstrate that it provides assurance of the content uniformity of the finished product. Any discrepancies observed during process scale-up should be investigated.
Corrective actions to improve the formulation or
manufacturing process may be necessary.
Blend Sampling and Assessment During Process Design2 and
Process Qualification Batches
Modified Approach for the Assessment of Blend
and Content Uniformity for Process Design and Process
Qualification Batches
Relevant Information from Original Draft Guidance
Document
Information contained in Section IV of the original draft
stratified sampling guidance document is still applicable to
the modified approach. This includes the following:
&
&
&
&
&
The ability to use in-process dosage unit data as a surrogate measure of blend uniformity during commercial production (continued process verification).
The use of in-process dosage unit data obtained during the
compression/filling process for the release testing of the
finished product.
The identification of blending parameters and assessment
of blend homogeneity throughout the blender and/or intermediate bulk containers using appropriate sampling
plans.
A recommendation to assess the effects of powder sampling size (e.g., 1–10× dosage unit range; sizes >3× can be
used with adequate justification) when developing a blend
sampling technique and procedure that is capable of measuring the true uniformity of the blend. Sampling errors
should be identified, which may be negated by the use of
in situ analytical techniques using real-time sampling and
analysis.
A recommendation to design blend and dosage unit sampling plans and evaluate the data using appropriate statistical analysis, such as variance component analysis (VCA)
to measure variability present in the results. Sampling
plans should include significant events (start-up, end of
Figure 1 contains a flow diagram for the assessment of the
adequacy of powder mix and dosage unit uniformity during
the manufacture of process design and process qualification
batches, based on modifications to the withdrawn draft stratified sampling guidance document.
1. At least 3 blend samples should be taken from at least 10
locations in the blender according to the sampling
protocol.3
2. Stage 1 blend testing: Assay one sample from each location. Calculate the standard deviation (SD) for the
samples.
(a) If the SD≤3.0 % of target, proceed to stage 1 dosage
unit testing. VCA is generally not required.
(b) If the SD is >3.0 % of target, proceed to stage 2 blend
testing.
3. Stage 2 blend testing: Assay the replicate blend samples
from each location. Calculate the SD for the samples.
(a) If the SD≤3.0 % of target, proceed to stage 1 dosage
unit testing (assay at least 3 dosage units from at least
20 locations).
(b) If the SD is >5.0 % of target, conduct an investigation, including VCA, to determine if the variability
was due to a product/process issue or sampling/assay
error. Part of this investigation may include a
2
Although the strategy described in this section can be applied to batches
manufactured during stage 1 process design, the sampling plans, statistical approach, and acceptance criteria may be modified to be phase
appropriate.
3
Fewer locations may be sampled for the assessment of smaller batches,
with justification.
J Pharm Innov
Fig. 1 Process flow diagram for
assessment of blend and content
uniformity for process design and
process qualification batches
Blend (Samples): Sample at least 3 replicate samples from at least 10 locaons in the blender or drum
Assay 1 sample per locaon
Blend Uniformity Acceptance Criteria – Stage 1: SD ≤ 3.0% of target
Pass
Fail
Assay samples 2 & 3 per locaon
SD > 5.0% of Target
BU Stage 2
3.1 ≤ SD ≤ 5.0%
of Target
Conduct VCA and
invesgaon.
Was root cause:
Product /
Process
SD ≤ 3.0% of Target
Analycal/
Sampling
Blend Uniformity
is Acceptable
Dosage Units (Samples): During
filling or compression, take at
least 3 samples from at least 40
locaons across the batch
Assay at least 3 dosage units from
at least 40 predetermined
locaons throughout the batch
Blend Uniformity is Acceptable
Dosage Units (Samples): During filling or
compression, take at least 3 samples from at
least 40 locaons across the batch
Assay at least 3 dosage units from at least 20
predetermined locaons throughout the batch
Acceptance Criteria – Stage 1
All individual values within 75.0-125.0% and,
Complies with stascal test to provide an
appropriate level of assurance to comply with
USP for n*
Pass
Fail
Assay at least 3 dosage units from the remaining 20 locaons not tested in Stage 1.
Acceptance Criteria – Stage 2
All individual values within 75.0-125.0% and,
Complies with stascal test to provide an appropriate level of assurance to
comply with USP for n*
Pass
Fail
Blend is not uniform
Dosage Units are not uniform
Blend & content uniformity are acceptable
*n is the total number of assay results.
performed for the blend data to identify potential variability reduction and blend improvement opportunities.4
comparison of the blend VCA components with
those calculated for the subsequent dosage forms.
i. If the high SD is attributed to a sampling/assay error,
proceed to stage 2 dosage unit testing (assay at least 3
dosage units from at least 40 locations).
ii. If the high SD is attributed to a product/process-related
cause, the blend uniformity is unacceptable.
(c) If the SD is between 3.1 and 5.0 % of target (inclusive),
blend uniformity is acceptable. However, dosage unit
testing should be conducted at the stage 2 level to provide
increased assurance that the blend produces acceptable
dosage forms. It is also recommended that a VCA be
4
Variance component analysis is recommended if the standard deviation
for the blend and/or dosage units is >3 %. After performing the VCA,
attribute the variability to either variation in the uniformity of the blend
and/or other causes depending on if one or both of the variance components (between and within location) are significant. Significant withinlocation variance (above that of the analytical method) in the blend data
can be an indication of one factor or a combination of factors such as
variation of the blend mix, sampling error, or agglomeration. Sampling
errors of the blend will not carry over to the dosage units, while variation
of the mix at the within-location scale, and/or agglomeration, can carry
over to the dosage units. Significant between-location variance (above
that of analytical method) in the blend data can indicate that the blending
operation is not optimized or that segregation has occurred.
J Pharm Innov
In-Process Dosage Unit Sampling for Process Design5
and Process Qualification Batches6
1. Sample at least 3 in-process dosage units from at least
40 approximately equally spaced predetermined locations7 throughout the batch (including the beginning
and end of the run8; values should not be weight
corrected.
2. Stage 1 dosage unit testing: 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).
(a) Determine if the data comply with the acceptance criteria for the statistical approach, sample
size, and levels of confidence and coverage
selected.
(b) All individual values should be between 75.0 and
125.0 % (non-weight corrected).
(c) If either of the above acceptance criteria is not met,
proceed to stage 2 testing,
3. Stage 2 dosage unit testing: Assay at least 3 dosage units
per location from the remaining 20 locations that were not
tested during stage 1.
(a) Determine if the data comply with the acceptance criteria for the statistical approach, sample
size, and levels of confidence and coverage
selected.
(b) All individual values should be between 75.0 and
125.0 % (non-weight corrected).
(c) If the results comply with the acceptance criteria,
dosage unit uniformity is demonstrated. If not, the
dosage units are not uniform.
(d) 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.
Modified Approach for the Assessment of Blend
and Content Uniformity for Continued Process
Verification
Figure 2 contains a flow diagram for the assessment of blend
and dosage unit uniformity during continued process verification (stage 3b) of commercial batches. The manufacturer
decides what statistical approach, sampling plan, acceptance
criteria, and levels of confidence and coverage to use to
provide assurance in passing USP . This particular
example, which is for demonstration purposes only, uses a
sampling plan where one dosage unit is tested from 30 locations throughout the compression or filling process. Other
sample plans using different quantities of dosage units may
be used, with justification.9 Because the in-process dosage
unit data can also be used as a surrogate test for both batch
release (non-weight-corrected data) and blend uniformity, a
systematic sampling plan should be used to identify the position of sampling locations and ensure samples are taken
throughout the entire batch (including beginning and end of
run locations).
Procedure for Assessing Blend and Content Uniformity
During Continued Process Verification (Stage 3b)
1. Sample 1 in-process dosage unit from 30 locations
throughout the compression or filling process including
the beginning and end of the run.
2. Stage 1 testing: Assay 1 dosage unit from at least 10 of the
30 sampling locations. (The 10 locations need to be
identified in the sampling plan and are from across the
entire batch, including beginning and end (i.e., not just a
random sample from the 30 locations).
(a) Determine if the data comply with the acceptance
criteria for the statistical approach, sample size, and
levels of confidence and coverage selected.
(b) All individual values should be between 75.0 and
125.0 % (non-weight corrected).
(c) If the results comply with the acceptance criteria,
blend and dosage unit uniformity is demonstrated.
If either of the above acceptance criteria is not met,
proceed to stage 2 testing.
5
Although the strategy described in this section can be applied to batches
manufactured during stage 1 process design, the sampling plans, statistical approach and acceptance criteria may be modified to be phase
appropriate.
6
This example of a sampling plan was designed to provide appropriate
data for estimating between-location and within-location variance components to meet FDA expectations [3].
7
Fewer locations may be sampled for the assessment of smaller batches,
with justification.
8
Initial locations to be tested are identified prior to batch manufacture,
and must be representative of the entire batch.
3. Stage 2 testing: Test the remaining 20 dosage units and
determine if the results comply with
9
The manufacturer determines the number of dosage units to analyze
during continued process verification, based on the results of process
design and process qualification batch data, as well as the levels of
producer and consumer risks they are willing to accept.
J Pharm Innov
Fig. 2 Process flow diagram for
assessment of blend and content
uniformity for continued process
verification (stage 3b) batches
b
Dosage Units (Samples)
During filling or compression, take at least 1 dosage unit from at least 30 locaons spread
approximately equally across the batch including at the beginning and end of run
Assay a total of at least 10 dosage units taken approximately equally across the batch
including at the beginning and end of run
Acceptance Criteria – Stage 1*
All individual values within 75.0-125.0% and,
Complies with stascal test to provide an appropriate level of assurance to comply with USP
for n**
Fail
Pass
Assay at least 20 remaining dosage units
Acceptance Criteria – Stage 2*
All individual values within 75.0-125.0% and,
Complies with stascal test to provide an
appropriate level of assurance to comply with USP
for n**
Pass
Fail
Dosage units and possibly
blend are not uniform
Blend uniformity & content
uniformity are acceptable
* Acceptance criteria for Stage 3 Connued Process Verificaon may have reduced assurance
to comply with USP compared to that used for Stage 2 Process Qualificaon.
**n is the total number of assay results.
(a) The acceptance criteria for the statistical approach,
sample size, and levels of confidence and coverage
selected.
(b) All individual values should be between 75.0 and
125.0 % (non-weight corrected).
(c) If the results comply with the acceptance criteria,
blend and dosage unit uniformity is demonstrated.
If not, the dosage units and possibly the blend are not
uniform.
Continued Process Verification (Stage 3a)
If a product had blend standard deviations in the 3.1–
5.0 % of target range and/or it required stage 2 testing
for the dosage units during process qualification, additional samples may need to be analyzed during continued
process verification (stage 3a). The number of dosage
units that should be assayed depends on the magnitude
of the risks associated with the process. If a product has
standard deviations for the blend and/or dosage units in
the 4.0–5.0 % of target range, a greater number of dosage
units may be required to demonstrate adequacy of powder
mix and dosage unit uniformity (perhaps comparable to
stage 2 dosage unit testing quantities) during continued
process verification (stage 3a). For products with blend
and/or dosage unit standard deviations in the 3.1–4.0
range, stage 1 dosage unit testing may suffice. The number of samples tested could be reduced if process changes
are implemented that demonstrate an improvement in
blend and/or dosage unit uniformity. Testing may also
be reduced after a due diligence effort to improve the
process still results in high but consistent (and acceptable)
standard deviations for the blend and/or dosage unit data,
indicating this is the best uniformity that the process can
achieve.
Process Life Cycle
One element of continued process verification is to monitor process performance across batches. Standard deviations, acceptance values (AV), or other metrics for dosage
unit uniformity could be monitored across batches, to
J Pharm Innov
detect any trends or shifts in the manufacturing process
over the product’s life cycle.
Comments Regarding Implementation of the Approach
Blend and Dosage Unit Uniformity Analysis
Blend uniformity analysis should be performed during the
manufacture of process design and process qualification
batches. Manufacturers should not skip blend uniformity testing and default directly to dosage unit uniformity analysis
during the manufacture of process qualification batches.
Although an assessment of blend uniformity can be performed
for any mixing operation in the manufacturing process, the
final blend (lubricated) is the best indicator of the uniformity
of the blend prior to compression or filling operations.
Fewer sampling locations may be justified for smaller-scale
batches (e.g., early process design batches; small process
qualification and commercial batch sizes), and acceptance
criteria may be adjusted to be phase appropriate. However,
at least 3 blend samples and at least 3 dosage units should be
taken from each location. Revised sampling plans for smaller
batch sizes must be appropriate for assuring acceptable blend
and dosage unit uniformity. The Group recognizes that situations may exist where it is not possible to sample blends. For
example, for potent drugs manufactured in high-containment
equipment, blend sampling may not be possible and/or would
expose the operators to significant safety risks.
The Group recommends a 2-stage approach for the assessment of blend uniformity. It is not necessary to assay replicates
from each blender location if the standard deviation for the
first set of samples is ≤3.0 % of target because the total
standard deviation and the between- and within-location variance components would be very small. However, if the
standard deviation is >3.0 % of target, information obtained
from VCA after testing the remaining samples could be of
value in identifying potential product/process-related variability resulting in opportunities to improve the uniformity of the
blend.
Weight correction is justified when using dosage unit content uniformity as a surrogate test to demonstrate the adequacy
of the powder mix during routine commercial manufacture.
Performing a weight-corrected analysis can be helpful in
identifying if a failure to meet routine CU release criteria is
due to a blend or post-blend issue. Dosage unit samples must
be taken over the entire compression or filling run, to ensure
the data is representative of all areas in the blender. However,
because weight variation is an error component impacting the
dose that the consumer receives, it is necessary to use the nonweight-corrected results if the in-process dosage unit data is to
be used for product release. If the in-process dosage unit is not
the final dosage form (e.g., tablet core versus film-coated
tablet), an assessment should be conducted that demonstrates
content uniformity is not significantly impacted during subsequent unit operations (e.g., film coating).
Investigations
When the blend standard deviation is between 3.1 and 5.0 %
of target, the blend uniformity is acceptable and one can
proceed to in-process dosage unit sampling. However, the
group recommends that VCA be performed on the blend data
to assess between-location and within-location variance components which may be used to identify opportunities to improve blend uniformity for future batches.
If the standard deviation is >5.0 % of target, conduct an
investigation (including VCA) to determine if the variability
was due to a non-blending issue that resulted in an erroneous
assessment of the true uniformity of the blend (such as sampling bias, analytical error, or other non-formulation/process
causes). If the presence of such an error can be demonstrated
and justified, then corrective measures should be implemented
and the batch can proceed to stage 2 dosage unit testing. If,
instead, the high standard deviation is attributed to a product/
process-related cause, then blend uniformity is unacceptable
and further formulation and/or process development is required for the product.
Whenever stage 2 dosage unit testing is required, VCA of
the data is recommended to determine if location-to-location
issues exist over the course of the compression or filling run. It
is valuable to compare the results of VCA performed on
dosage units to those obtained for the blend. The knowledge
gained from these comparisons may provide insight into blend
and content uniformity improvements.
Acceptance Criteria
The statistical approaches and acceptance criteria, including
the level of confidence and coverage associated with the
method, for dosage units have intentionally been omitted in
Figs. 1 and 2. This provides the manufacturer the flexibility to
use the preferred statistical approach and acceptance criteria
when assessing content uniformity of the dosage units, with
justification. Confidence and coverage levels should be selected using a risk-based approach that balances consumer’s
and producer’s risks, and other factors such as the therapeutic
index of the drug. The selected statistical approach should
provide sufficient confidence that the drug product is of acceptable content uniformity and future samples taken from the
batch (if tested) will have a high probability of passing USP
. The selected statistical approach, sampling plans, and
confidence/coverage levels should also be fit for the purpose,
especially during stage 1 process design where many
J Pharm Innov
statistical approaches may be too discriminating for nonoptimized drug products in early development.
Two statistical approaches that may be used are the ASTM
E2709/E2810 method and tolerance interval (TI) approach.
The ASTM method provides a level of confidence (for example, 90 %) and coverage (for example, 95 % of future samples)
that additional samples take from the batch will meet USP
criteria. The TI test provides a level of confidence (for
example, 95 %) that some percentage (for example 95 %) of
the dosage units will fall within a range (for example, 85.0–
115.0 %). An alternative analysis of the TI data can also
predict the probability that future batches will pass USP
, providing a comparison to the ASTM method. Both
approaches provide increased confidence that future samples
taken from the batch will pass USP criteria.
For some products, the pharmacokinetic characteristics of
the drug may need to be considered when defining acceptance
criteria for dosage unit uniformity. For example, drugs with
high potency and/or narrow therapeutic indices may require
tighter acceptance criteria to reduce consumer risk (i.e., the
risk of releasing an unacceptable batch to treat a condition).
Conversely, drugs with wide therapeutic indices can tolerate
broader acceptance criteria and minimize producer’s risk (i.e.,
the risk of failing an acceptable batch). 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. The control parameters
used in the proposed flow charts (Figs. 1 and 2) represent the
target potency distribution for the dosing units. Example
methods of such simulations have been discussed elsewhere
[6, 12].
The framework defined in Figs. 1 and 2 has the flexibility
to accommodate different statistical approaches, sampling
plans, and acceptance criteria, simply by inserting them into
the appropriate boxes in the flow diagrams [9–11]. Regardless
of which approach is selected, it is up to the applicant to
demonstrate why the sampling plan, statistical approach, and
acceptance criteria selected are appropriate for ensuring the
content uniformity of the product.
Summary
The Group has proposed modifications to the original draft
stratified sampling guidance document [1], which could fill
the void resulting from its withdrawal. The approach is scientifically justified, especially for products that use traditional
analytical techniques to assess the adequacy of the powder
mix and dosage unit uniformity. This paper contains a framework into which statistical approaches, sampling plans, and
acceptance criteria can be inserted to demonstrate blend and
dosage unit uniformity. The authors acknowledged that alternate acceptable approaches exist and others are being developed, which can also be used within the framework defined in
this paper to assure compliance with USP .
References
1. Guidance for industry, “Powder Blends and Finished Dosage Units—
Stratified In-Process Dosage Unit Sampling and Assessment”. U.S.
Department of Health and Human Services, Food and Drug
Administration, Center for Drug Evaluation and Research (CDER),
October 2003, Pharmaceutical CGMPs.
2. Federal Register / Vol. 78, No. 152, p. 48175-48176, August 7,
2013/Notices.
3. Questions and answers on current good manufacturing practices,
good guidance practices, level 2 guidance—production and process
controls. CDER/OC Office of Manufacturing and Product Quality:
CGMP Subject Matter Contacts, 6 August 2013. http://www.fda.gov/
Drugs/GuidanceComplianceRegulatoryInformation/Guidances/
ucm124782.htm.
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