Recommendations for the Assessment of Blend and Content Uniformity: Modern

Approaches to Sampling and Testing

James K. Drennen, III drennen@duq.edu

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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Draft Guidance for industry, “Powder Blends and Finished Dosage Units- Stratified In-Process Dosage Unit Sampling and Assessment.”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Health and Human Services, Food and Drug Administration, Center for Drug Evaluation and Research (CDER), October 2003; withdrawn.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withdrawn guidance document nor the use of USP 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Modifications to the withdrawn draft stratified sampling guidance document are proposed by the ISPE Blend Uniformity and Content Uniformity Group To assess “adequacy of mixing to assure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“Recommendations for the Assessment of Blend and Content Uniformity: Modifications to Withdrawn FDA Draft Stratified Sampling Guidance” J. Pharm.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“Recommendations for the Assessment of Blend and Content Uniformity: Modifications to Withdrawn FDA Draft Stratified Sampling Guidance” Recommends approach… Provide increased confidence that future samples drawn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!