Recommendations for the Assessment of Blend and Content Uniformity: Modern Approaches to Sampling and Testing James K. Drennen, III [email protected]
Recommendations for the Assessment of Blend and Content Uniformity: Modern
Approaches to Sampling and Testing
James K. Drennen, III [email protected]
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Unprecedented Change
Technology Philosophy/Regulatory Methodology
QbD approach Risk Assessment Design Space
Efficient Calibration Calibration Management Automation and Control
Performance based (“clinically relevant”) quality specifications and Quality Metrics
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Regulatory
Draft Guidance for industry, “Powder Blends and Finished Dosage Units- Stratified In-Process Dosage Unit Sampling and Assessment.”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Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), October 2003; withdrawn.
United States Pharmacopeial Convention, USP 37
NF 32, USP General Chapter <905> Uniformity of dosage units, general notices and requirements, Section 3.10, Applicability of Standards.
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Blend Uniformity- Content Uniformity
USP <905> does not use a statistical sampling plan, therefore the results provide limited statistical assurance that future samples from the batch would meet acceptance criteria. FDA no longer supports the approach stated in the
withdrawn guidance document nor the use of USP <905> for batch release
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A Proposed Solution
Modifications to the withdrawn draft stratified sampling guidance document are proposed by the ISPE Blend Uniformity and Content Uniformity Group To assess “adequacy of mixing to assure
uniformity and homogeneity” of the finished product in accordance with cGMPs Method accommodates… Various statistical approaches PAT methods
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Manufacturing Process
PAT PAT
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ISPE Recommendations
“Recommendations for the Assessment of Blend and Content Uniformity: Modifications to Withdrawn FDA Draft Stratified Sampling Guidance” J. Pharm. Innov. (2015) 10:76-83
“Assessment of Blend and Content Uniformity.
Technical Discussion of Sampling Plans and Application of ASTM E2709/E2810” J. Pharm. Innov. (2015) 10:84-97
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ISPE Recommendations
“Recommendations for the Assessment of Blend and Content Uniformity: Modifications to Withdrawn FDA Draft Stratified Sampling Guidance” Recommends approach… Provide increased confidence that future samples drawn
from the batch will comply with USP <905> Link blend and content uniformity
Process design and qualification Continued process verification
J. Pharm. Innov. (2015) 10:76-83
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Modified Approach for Assessment of Blend and Content Uniformity for Process Design and Process Qualification Batches J. Pharm. Innov. (2015) 10:76-83
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Modified Approach for Assessment of Blend and Content Uniformity for Continued Process Verification J. Pharm. Innov. (2015) 10:76-83
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Implementation Notes
BU analysis performed during manufacture of process design and process qualification batches
Adjust sampling plans to batch size Dosage unit samples collected over entire
compression/filling run Use weight correction for dosage unit CU as surrogate for
blend testing Use no weight correction for dosage unit test to be used for
product release
J. Pharm. Innov. (2015) 10:76-83
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Sampling Plan and Application of ASTM Methods
“Assessment of Blend and Content Uniformity. Technical Discussion of Sampling Plans and Application of ASTM E2709/E2810”
Simple random sampling, Stratified sampling, and
Systematic sampling
ASTM method and tolerance interval approach provides a level of confidence (e.g., 90%) and coverage ( eg., 95% of future samples) that additional samples taken from the batch will meet USP <905> criteria
J. Pharm. Innov. (2015) 10:84-97
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PAT METHODS FOR BLEND AND TABLET UNIFORMITY TESTING
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Tablet vs. Blend
270 sec 180 sec
30 sec 90 sec
Ph.D. Dissertation; Sameer Talwar, 2015.
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API Content Uniformity – Tablet Quality
Pred
icte
d C
once
ntra
tion
(% w
/w)
Tablet Sampling Time (Minutes)
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Batch N/3 – 90 seconds – 3 Tablets out of Spec (APAP)
0.105 0.11 0.115 0.12 0.125 0.13 0.135 0.14 0.1450
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40
60
80
100
120
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Batch N/9 – 30 seconds – 486 Tablets out of Spec (APAP)
0.06 0.08 0.1 0.12 0.14 0.16 0.18 0.20
20
40
60
80
100
120
140
160
180Tablet Batch N/9
Predicted Concentration (% w/w)
Freq
uenc
y
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Achievable Level of Uniformity
Complete Random Mixture (CRM) profile for 25 min. mixing time in APAP, Lactose, MCC mixture.
Ph.D. Dissertation; Sameer Talwar, 2015.
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CRM Profile of Homogenous System
Ph.D. Dissertation; Sameer Talwar, 2015.
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Blend vs. Tablet Uniformity
Blend
Tablet
Ph.D. Dissertation; Sameer Talwar, 2015.
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Content Uniformity
Ph.D. Dissertation; Sameer Talwar, 2015.
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Excipient Uniformity – Tablet Quality
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Conclusions
ISPE BU/CU Group has proposed a useful framework for BU/CU testing
PAT methods offer value Product Quality and Process Understanding Facilitate appropriate sampling
Enhance Statistical Confidence
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Thank You!