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ISPE Blend and Content Uniformity Guidance
ISPE Blend and Content Uniformity Guidance
ISPE Blend and Content Uniformity Guidance
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Publication
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modifications to withdrawn FDA draft stratified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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Purpose and Scope
• Purpose: Propose modifications to the withdrawn FDA draft guidance document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) based on FDA concerns
• Provide a framework that allows multiple approaches to assess blend/content
uniformity
– The Group does 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
– All approaches should be science and risk based
• Publication of other statistical approaches and criteria that can be used within the
framework of this paper is welcomed and encouraged
• Group expects regulators will consider all science- and risk-based approaches
when setting guidance for industry
• Focuses on analyses using traditional sampling and analytical techniques
– Modern analytical methods (including process analytical technology (PAT)) to
assess blend and dosage unit uniformity are encouraged, though not discussed in
this paper as they are outside of its intended scope
Background
• FDA withdrew draft guidance document for industry “Powder Blends and Finished
Dosage Units – Stratified In-Process Dosage Unit Sampling and Assessment” on
August 7, 2013 (2)
• Section V (Exhibit/Validation Batch Powder Mix Homogeneity) and Section VII
(Routine Manufacturing Batch Testing Methods) were no longer consistent with
their current thinking (3)
– 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 (4)
• 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
Formation of ISPE BUCU Group
• 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 (5,6)
– 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
Summary of Proposed Modifications
• 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 (8)
• 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.
Framework
• 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> (9, 10, 11)
– 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
Relevant Information From Original Draft
Guidance Document
• 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)
– 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
Flow Diagram for Stage 1 Process Design and
Stage 2 Process Qualification
Blend (Samples): Sample at least 3 replicate samples from at least 10 locations in the blender or drum
Fail Pass
3.1 ≤ SD ≤ 5.0%
Conduct VCA and of Target Dosage Units (Samples): During filling or
investigation. compression, take at least 3 samples from at
Was root cause: least 40 locations across the batch
Product / Analytical/ Blend Uniformity Assay at least 3 dosage units from at least 20
Process Sampling is Acceptable predetermined locations throughout the batch
Assay a total of at least 10 dosage units taken approximately equally across the batch
including at the beginning and end of run
Fail Pass
Assay at least 20 remaining dosage units
Fail
Dosage units and possibly Blend uniformity & content
blend are not uniform uniformity are acceptable
* Acceptance criteria for Stage 3 Continued Process Verification may have reduced assurance
to comply with USP <905> compared to that used for Stage 2 Process Qualification.
**n is the total number of assay results.
Assessment of Blend and Content Uniformity for
Continued Process Verification (3B): Stage 1 Testing