EMERGING ISSUES AND CONSIDERATIONS IN MANUFACTURING QUALITY CONTROL AND ASSURANCE OF DRUG PRODUCTS

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EMERGING ISSUES AND CONSIDERATIONS IN
MANUFACTURING QUALITY CONTROL AND ASSURANCE OF
DRUG PRODUCTS

• Yi Tsong, Ph.D., Acting Deputy Director
• Quantitative Methods and Research Staff
• OB, OPaSS, CDER, FDA

This presentation does not necessarily represent
the official position of FDA
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Three Dimensions of the Critical Path

• Assessment of Safety how to predict if a
  potential product will be harmful?
• Proof of Efficacy -- how to determine if a
  potential product will have medical benefit?
• Industrialization how to manufacture a product
  at commercial scale with consistently high
  quality?

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Working in Three Dimensions on the Critical Path
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Statistical Chemical Manufacturing Control and
Assurance Programs
Shelf Life Determination Stability
Acceptance Tests of Finished Product
PAT (Process Analytical Technology)
In Vitro Equivalence Tests
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I. Shelf Life Determination Stability

• Pre-Marketing Shelf Life Determination
• Single factor design ? Multiple Factor Design
• ICH Guidance (2001)
• Optimal matrix design (Lin Chen, JBS 2003)
• Significance level (Chen Tsong, JBS, 2003)
• Shelf life determination of multi-factor design
  (Tsong Chen, JBS, 2003)
• Equivalence approach (Tsong, Chen, Lin Chen,
  JBS, 2003)
• General Issues
• Statistical Methods in Pharmaceutical Industry,
  3rd edition, 2004
• Encyclopedia of Biopharmaceutical Stat. 2004
• Encyclopedia of Clinical trials, 2005)

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Shelf Life Determination Stability (2)

• Postmarketing stability
• Scale up
• Mixed effect design (batch is random)
• Nested factor design (specific levels of factors
  within a batch)
• Compliance of stability batches
• Web tool
• User friendly stability analysis tool for FDA
  reviewers

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II. Acceptance Tests of Finished Product

• For general tablets
• Blend uniformity
• Dose content uniformity
• Dissolution test
• Purity test
• For inhaler/unit dose delivery system
• Delivery dose uniformity test
• Single dose system
• Multiple dose system
• Almost all tests are established at 2nd WW
• Without batch specification
• Sample size restricted
• Lack of inference consideration

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USPXXIII 3-stage Dissolution Test Acceptance Rule
Step 1, 6 tablets
No
Step 2, additional 6 tablets
Yes
No
Accept
Step 3, additional 12 tablets
Yes
Accept
No
Reject
Yes
Accept
Tsong, Shen, Shah, JBS, 2004
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Japan 2-Stage Dissolution Test Rule
Step 1, 6 tablets
No
Step 2, additional 6 tablets
Yes
No
Accept
Reject
Yes
Accept
Tsong, Shen, Shah, JBS, 2004
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Tsong, Shen, Shah, JBS, 2004
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3-Stage Dissolution Acceptance TestBased on
Sequential Tolerance Interval
Step 1, 6 tablets
No
Step 2, additional 6 tablets
Yes
Accept
Step 3, additional 12 tablets
Yes
Accept
No
Reject
Yes
Accept
Tsong, Shen, Shah, JBS, 2004
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Tsong, Shen, Shah, JBS, 2004
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Tsong, Shen, Shah, JBS, 2004
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Tsong, Shen, Shah, JBS, 2004
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Tsong, Shen, Shah, JBS, 2004
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Tsong, Shen, Shah, JBS, 2004
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FDA 2-Stage Delivery Dose Uniformity Acceptance
Test
Tsong Shen, 2004
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USP lt905gt, Content Uniformity Test (n 30 units)
Step 1, 10 tablets
No
All 10 within 85-115 RSD ? 6
NMT 1 outside 85-115 All 10 within 75-125
Yes
Yes
Step 2, additional 20 tablets
No
Accept
Reject
NMT 1 outside 85-115 All 30 within 75-125 RSD
? 7.8
No
Reject
Yes
Accept
Tsong, Shen, JBS, 2006
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Researches in Acceptance Tests of Finished Product

• Parametric Tolerance Interval Approach
• Adjusted for sequential tests
• Unified OC curve against coverage
• Various sample sizes
• Small sample acceptance test
• Large sample compliance study
• Very large sample size process monitoring
• Delivery Dose uniformity Test
• Collaborating with IPAC
• Dose Content Uniformity Test
• Multivariate adjustment
• Repeated test adjustment Process control chart

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Hierarchy of Process Understanding
III. Process Analysis Technology
Current State

• Trial-n-Error
• Batch Processes
• silo conditions
• black-box controls
• Quality-by-Inspection

Ajaz Hussain, AAPS 39th Pharm. Technologies
Conf., Jan. 2004
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Hierarchy of Process Understanding
Desired State

• 1st Principles Understanding
• Robust Processes
• Total Quality Control

Ajaz Hussain, AAPS 39th Pharm. Technologies
Conf., Jan. 2004
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Hierarchy of Process Understanding
Intermediate State

• DOE Optimization
• Mechanistic Understanding
• Process Analytical Technology (PAT)
• Feed-forward control
• Real-Time-Release (RTR)
• Quality-by-Design

Ajaz Hussain, AAPS 39th Pharm. Technologies
Conf., Jan. 2004
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Typical Solid Dosage Process
Wet Granulation
Milling/ Sizing
Inspection Release
Blending
Coating
Tablet Press
Cogdill, et al, Fall Tech. Conf., 2004
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Fluidized Bed Drying

• Input factors
• Input air volume, humidity, temperature
• Product moisture content
• Material properties
• Loading
• Output factors
• Drying time
• Material properties
• Used for other operations such as coating and
  granulation

Cogdill, et al, Fall Tech. Conf., 2004
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Wet Granulation

• Input factors
• Rotational speed
• Process scale
• Product moisture content
• Binder fluid application
• Material properties
• Output factors
• Granulation time
• Particle size distribution
• Material properties
• Tablet performance

Cogdill, et al, Fall Tech. Conf., 2004
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Powder Blending

• Factors varied
• Drug concentration
• Rotational speed
• Humidity
• Factors held constant
• Material properties
• Temperature
• Fill level
• Loading scheme

Cogdill, et al, Fall Tech. Conf., 2004
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Tablet Compression

• Input factors
• Compression force
• Dwell time
• Tablet size shape
• Material properties
• Output factors
• Tablet hardness
• Friability
• Tablet performance
• Uniformity

Cogdill, et al, Fall Tech. Conf., 2004
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Blend Uniformity PAT
Traditional test methods
Current PQRI proposal and draft Guidance
Univariate Testing to Document Quality Approach
Draft Guidance may include information on the
use of NIR methods
At-line test methods
On- and/or At-line test methods for all
critical components and processes
Proposed PAT Guidance Incentive? Higher
efficiency Lower risk leading to lower
regulatory concern
Multivariate Quality-by Design Approach
Ajaz Hussain, AAPS 39th Pharm. Technologies
Conf., Jan. 2004
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Powder Blending

• 8-qt plastic V-blender (Patterson-Kelly)
• Blend composition
• Salicyclic acid (SA), 30.5 mm particle size
• Lactose, 115.5 mm particle size
• Input factor levels
• Relative humidity 20, 60
• SA concentration 3, 7, 11
• Rotation speed 12.8, 20.3 rpm

Cogdill, et al, Fall Tech. Conf., 2004
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Powder Blending

• Sampling method
• Blend process monitored for 50 minutes
• Stopped at pre-determined time intervals for
  sampling with thief probe and NIR analysis
• Thief samples analyzed via UV spectroscopy (296.9
  nm)

Cogdill, et al, Fall Tech. Conf., 2004
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Powder Blending

• Typical powder blend profiles

Cogdill, et al, Fall Tech. Conf., 2004
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D-Optimal Design of Experiment

• 3 Factors
• Humidity
• Blender speed
• Salicylic acid Concentration
• Experimental design generated using JMP
• ND 16 experiments

Cogdill, et al, Fall Tech. Conf., 2004
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Cogdill, et al, Fall Tech. Conf., 2004
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Thief-Sample Position Dependency

• Outliers were flagged during UV analysis as
  samples exceeding 1.5x IQR

Cogdill, et al, Fall Tech. Conf., 2004
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Results
P 0.0002
P 0.002
P 0.0331
Cogdill, et al, Fall Tech. Conf., 2004
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PAT (Process Analytical Technology)

• Optimal Design of Experiment
• Collect Data to Establish Control Chart
• Univariate
• Multivariate
• PCA
• Profile
• Application of Multi-level Control
• Specification
• Trend
• Statistical Monitoring and Feedback System
• Similar concepts are applicable also to
  batch-to-batch control of finished products

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IV. In Vitro Equivalence Tests

• Generic Product Requirement
• SUPAC (Scale-up and Post Approval Changes)
  Requirement
• Biowaiver
• Comparability of new suppliers
• Formulation change
• Manufacturer site Change

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In Vitro Equivalence Tests

• Dissolution Profile Similarity Test
• Particle Size Distribution Profile Equivalence
• Pharmaceutical Equivalence

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Dissolution Profile Similarity
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Dissolution Profile Similarity

• The U.S. FDA Guidance, (SUPAC IR), 1997
• The U.S. FDA Guidance, (SUPAC MR), 1997
• The U.S. FDA Guidance, (SUPAC ER), 1997
• Sathe, Tsong, Shah, In Vitro-In Vivo Correlation,
  ed. Young D., Devane J.D., and Butler J., Plenum
  Publishing Corp., 1996.
• Tsong, Hammerstrom, Sathe, Shah. Proceedings of
  the Biopharmaceutical Section of ASA, pp.
  129-134, 1996.
• Tsong, Hammerstrom, Sathe, Shah. DIJ, 30
  1105-1112, 1996.
• Shah, Tsong, Sathe, Liu. Pharmaceutical Research,
  15 889-896, 1998.
• Ma, Wang, Liu, Tsong. JBS, 10(2)229-249, 2000.

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Particle Size Distribution Profile Equivalence
Test of Inhaler Products
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Particle Size Distribution Profile Equivalence
Test of Inhaler Products
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Particle Size Distribution Profile Equivalence
Test of Inhaler Products
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Challenges and Opportunities in CMC

• Shelf Life and Stability
• Pooling batches by equivalence
• Pre-marketing to Scale-up, postmarketing
• Measurements difference between stability and
  compliance
• Quality of finished products
• WWII compendia to modern inference
• From mean and STD to tolerance interval
• Multiple and repeated tests
• Restricted sample size to unrestricted sample
  size
• Batch test versus test during process

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Challenges and Opportunities in CMC

• PAT
• From acceptance test to quality by design
• To identify, manage, monitor, and control
  critical variables of the manufacturing process
• Statistical expertise in process control
• In-vitro equivalence
• Variation between laboratories, technicians, and
  environmental conditions
• No conventional statistics and critical values

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Thank You For Your Interest!!!