BASS XIBASS XI 11
EMERGING ISSUES AND CONSIDERATIONS IN
MANUFACTURING QUALITY CONTROL AND ASSURANCE OF
DRUG PRODUCTSYi 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
BASS XIBASS XI 22
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?
BASS XIBASS XI 33
Working in Three Dimensions on the Working in Three Dimensions on the Critical PathCritical Path
BASS XIBASS XI 44
Statistical Chemical Manufacturing Control and Assurance Programs
Shelf Life Determination
& Stability
Acceptance Tests of Finished Product
PAT (Process Analytical
Technology)
In Vitro Equivalence
Tests
BASS XIBASS XI 55
• 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)
I. Shelf Life Determination & Stability
BASS XIBASS XI 66
• 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
Shelf Life Determination & Stability (2)
BASS XIBASS XI 77
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
BASS XIBASS XI 88
USPXXIII 3-stage Dissolution Test Acceptance Rule
Step 1, 6 tablets
%5)( QXMinNo
Accept
Yes
Step 2, additional 6 tablets
Yes
No
Step 3, additional 12 tablets
Yes
No Reject
%15)(
QXMin
QX
5%-Q tablets2 than more No
%15)( ,
QXMinQX
Accept
Accept
Tsong, Shen, Shah, JBS, 2004
BASS XIBASS XI 99
Japan 2-Stage Dissolution Test RuleJapan 2-Stage Dissolution Test Rule
Step 1, 6 tablets
10%-QMin(X)
Q*8226.0
sXNo
Accept
YesStep 2, additional 6 tablets
Yes
Accept
No Reject10%-QMin(X)
Q*5184.0
sX
Tsong, Shen, Shah, JBS, 2004
BASS XIBASS XI 1010
Dissolution Test Acceptance Rule based on Sequential Tolerance Interval Approach
H0: Pr(X Q) P vs. Ha: Pr(X Q) > P
X – tablet dissolution at T, X N(, )
Acceptance if H0 is rejected (i.e. more than 100P% of the tablets dissolved more than Q at time T).
e.g. P = .90
Tsong, Shen, Shah, JBS, 2004
BASS XIBASS XI 1111
3-Stage Dissolution Acceptance Test3-Stage Dissolution Acceptance TestBased on Sequential Tolerance Interval Based on Sequential Tolerance Interval
Step 1, 6 tablets
1 1 AQX No
Accept
Yes
Step 2, additional 6 tablets
Yes
Accept
Step 3, additional 12 tablets
Yes
NoReject
Accept
2 2 AQX
3 3 AQX
Tsong, Shen, Shah, JBS, 2004
BASS XIBASS XI 1212
0 10 20 30 40 50 60 70 80 90RSD
0.0
0.2
0.4
0.6
0.8
1.0
Pro
ba
bili
ty o
f acc
ep
tan
ce
USPXXIIIJPProposed, 80% coverageProposed, 90% coverage
Figure 4 OC curves of acceptance rules for dissolution testing. Mean=Q+10%
Tsong, Shen, Shah, JBS, 2004
BASS XIBASS XI 1313
0.0 0.1 0.2 0.3 0.4Proportion (<Q)
0.0
0.2
0.4
0.6
0.8
1.0
Pro
babili
ty o
f acc
epta
nce
USPXXIIIJPProposed, 90% coverageProposed, 80% coverage
Figure 8 OC curves of acceptance rules for dissolution testing. Mean=Q+2%
Tsong, Shen, Shah, JBS, 2004
BASS XIBASS XI 1414
0.0 0.1 0.2 0.3 0.4
Proportion (<Q)
0.0
0.2
0.4
0.6
0.8
1.0
Pro
ba
bili
ty o
f acc
ep
tan
ce
USPXXIIIJPProposed, 90% coverageProposed, 80% coverage
Figure 10 OC curves of acceptance rules for dissolution testing. Mean=Q+10%
Tsong, Shen, Shah, JBS, 2004
BASS XIBASS XI 1515
0.1 0.2 0.3 0.4Proportion (>Q)
0.000
0.005
0.010
0.015
0.020
0.025
Pro
babili
ty o
f acc
epta
nce
USPXXIIIJPProposed
Figure 6 OC curves of acceptance rules for dissolution testing. Mean=Q-5%
Tsong, Shen, Shah, JBS, 2004
BASS XIBASS XI 1616
0.0 0.1 0.2 0.3 0.4
Proportion (<Q)
0.0
0.2
0.4
0.6
0.8
1.0
Pro
ba
bili
ty o
f a
cce
pta
nce
Figure 12 The influence of sampling size on OC curves of acceptance rules
N.6.6.12, coverage=0.9N.12.12.24, coverage=0.9N.18.18.36, coverage=0.9N.6.6.12, Coverage=0.8N.12.12.24, coverage=0.8N.18.18.36, coverage=0.8
Tsong, Shen, Shah, JBS, 2004
BASS XIBASS XI 1717
Acceptance Probability by Stage FDA Test MD 10/10/30/30
0
0.1
0.2
0.3
0.4
0.5
0.6
0.7
0.8
0.9
1
4 5 6 7 8 9 10 11 12 13 14 15 16 17 18 19 20STD
Acc
epta
nce
Pro
babi
lity
1sr and 2nd Tiers Combined
First Tier Only
2nd Tier Only
FDA 2-Stage Delivery Dose Uniformity Acceptance Test
Tsong & Shen, 2004
BASS XIBASS XI 1818
Step 1, 10 tablets
No
Accept
Yes
NMT 1 outside 85-115% All 10 within 75-125% Yes
Reject
No Step 2, additional 20 tablets
NMT 1 outside 85-115%All 30 within 75-125%
RSD 7.8%
Yes RejectAccept
All 10 within 85-115% RSD 6%
No
USP <905>, Content Uniformity Test (n = 30 units)
Tsong, Shen, JBS, 2006
BASS XIBASS XI 1919
• 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
Researches in Acceptance Tests of Finished Product
BASS XIBASS XI 2020
Ajaz Hussain, AAPS 39th Pharm. Technologies Conf., Jan. 2004
Hierarchy of Process UnderstandingHierarchy of Process Understanding
Current State:
• “Trial-n-Error”• Batch Processes
• ‘silo’ conditions• ‘black-box’ controls
• Quality-by-Inspection
III. Process Analysis Technology
BASS XIBASS XI 2121
Ajaz Hussain, AAPS 39th Pharm. Technologies Conf., Jan. 2004
Hierarchy of Process Understanding
Desired State:
• 1st Principles Understanding • Robust Processes• Total Quality Control
BASS XIBASS XI 2222
Ajaz Hussain, AAPS 39th Pharm. Technologies Conf., Jan. 2004
Hierarchy of Process Understanding
•DOE Optimization•Mechanistic Understanding•Process Analytical Technology (PAT)
•Feed-forward control•Real-Time-Release (RTR)•Quality-by-Design
Intermediate State:
BASS XIBASS XI 2323
Typical Solid Dosage Process
FBDrier
Wet Granulation
Dispensory
Milling/Sizing
Blending
TabletPress
CoatingInspection &
Release
PAT PAT PAT PAT
PAT PAT PAT
Cogdill, et al, Fall Tech. Conf., 2004
BASS XIBASS XI 2424
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
BASS XIBASS XI 2525
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
BASS XIBASS XI 2626
• Factors varied:– Drug concentration– Rotational speed– Humidity
• Factors held constant– Material properties– Temperature– Fill level– Loading scheme
Powder Blending
Cogdill, et al, Fall Tech. Conf., 2004
BASS XIBASS XI 2727
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
BASS XIBASS XI 2828
Blend Uniformity & PATBlend Uniformity & PAT
UnivariateTesting toDocument
QualityApproach
MultivariateQuality-by
DesignApproach
Traditional testmethods
At-linetest methods
On- and/or At-linetest methodsfor all critical
components andprocesses
Current PQRI proposal and draft Guidance
Draft Guidance may include information onthe use of NIR methods
Proposed PAT GuidanceIncentive?
Higher efficiencyLower “risk” leading to lower regulatory concern
Ajaz Hussain, AAPS 39th Pharm. Technologies Conf., Jan. 2004
BASS XIBASS XI 2929
• 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
Powder BlendingPowder Blending
Cogdill, et al, Fall Tech. Conf., 2004
BASS XIBASS XI 3030
• 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)
Powder Blending
Cogdill, et al, Fall Tech. Conf., 2004
BASS XIBASS XI 3131
Powder Blending
0
10
20
30
40
50
60
70
80
0 5 10 15 20 25 30 35 40 45 50
Time (min)
%R
elat
ive
Stan
dard
Dev
iati
on
Left shell
Right shell
Top
Middle
Bottom
•Typical powder blend profiles
Cogdill, et al, Fall Tech. Conf., 2004
BASS XIBASS XI 3232
•3 Factors– Humidity– Blender speed– Salicylic acid Concentration
•Experimental design generated using JMP
•ND = 16 experiments
D-Optimal Design of Experiment
Cogdill, et al, Fall Tech. Conf., 2004
BASS XIBASS XI 3333
Order
Experimental Conditions
HumiditySalicylic acid
ConcentrationBlender Speed *
I 20% 3% 12.8
II 20% 11% 12.8
III 20% 3% 20.3
IV 20% 7% 12.8
V 20% 7% 20.3
VI 20% 11% 20.3
VII 20% 11% 12.8
VIII 60% 3% 20.3
IX 60% 11% 20.3
X 60% 7% 12.8
XI 60% 7% 20.3
XII 60% 7% 20.3
XIII 60% 11% 12.8
XIV 60% 3% 20.3
XV 60% 7% 12.8
XVI 60% 3% 12.8
* Blender speed measured in rpm
Cogdill, et al, Fall Tech. Conf., 2004
BASS XIBASS XI 3434
Thief-Sample Position Dependency
RL
1 2
3 4
5
0
5
10
15
20
25
30
35
40
1 2 3 4 5
Location
% O
utli
ers
BA
• Outliers were flagged during UV analysis as samples exceeding 1.5x IQR
Cogdill, et al, Fall Tech. Conf., 2004
BASS XIBASS XI 3535
Results
00.1
0.20.30.40.5
0.60.70.80.9
1
Blender Speed Humidity Concentration
P = 0.0002
P = 0.002
P = 0.0331
Cogdill, et al, Fall Tech. Conf., 2004
BASS XIBASS XI 3636
• 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
PAT (Process Analytical Technology)
BASS XIBASS XI 3737
•Generic Product Requirement
•SUPAC (Scale-up and Post Approval Changes) Requirement– Biowaiver– Comparability of new suppliers– Formulation change– Manufacturer site Change
IV. In Vitro Equivalence Tests
BASS XIBASS XI 3838
•Dissolution Profile Similarity Test
•Particle Size Distribution Profile Equivalence
•Pharmaceutical Equivalence
In Vitro Equivalence Tests
BASS XIBASS XI 3939
Dissolution Profile Similarity
3
3
3
3
3
J
J
J
J
J
H
H
H
H
H
F
F
F
F
F
B
B
B
B
B
E
E
E
E
E
0 30 60 90 120 150 1800
20
40
60
80
100
120
Time in Minutes
Reference Batch
Test Batch 1
Test Batch 2
Test Batch 3
Test Batch 4
Test Batch 5
% Dissolved
Sample Mean Dissolution Data
BASS XIBASS XI 4040
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.
BASS XIBASS XI 4141
Particle Size Distribution Profile Equivalence Test of Inhaler Products
BASS XIBASS XI 4242
EXAMPLE OF PARTICLE SIZE % DISTRIBUTION OF SINGLE SPRAY OF ONE TEST CANISTER AND TWO REFERENCE CANISTERS
Product ST & ACT
Throat ST0 ST1 ST2 ST3 ST4 ST5 ST6 ST7 Filter
Test 14.28 38.26 1.83 2.06 2.24 7.56 17.97 13.11 1.59 0.51 0.57 Ref #1 18.56 46.32 2.15 0.43 0.92 9.11 12.00 7.11 2.44 0.82 0.14 Ref #2 19.22 47.51 2.03 0.82 0.83 9.06 10.21 7.15 2.01 0.94 0.20
Weighted Ratio of Chi-square distances s Wsχ
2[test: (Ref1+Ref2)/2] ------------------------------------ s Wsχ
2[Ref1:Ref2)] Proposed by Tsong et al in 2001, (Tsong, Shen, Adam, JBS, 2006)
Currently under evaluation by Pharmaceutical Quality Research Institute
Particle Size Distribution Profile Equivalence Test of Inhaler Products
BASS XIBASS XI 4343
PARTICLE SIZE DISTRIBUTION OF TEST AND TWO REFERENCE CANISTERS
0.00
5.00
10.00
15.00
20.00
25.00
30.00
35.00
40.00
45.00
50.00
STAGE OF THE CASCADE IMPACTOR
% O
F P
AR
TIC
LE
S
Test Ref #1 Ref #2
Particle Size Distribution Profile Equivalence Test of Inhaler Products
BASS XIBASS XI 4444
Challenges and Opportunities in CMCChallenges 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
BASS XIBASS XI 4545
• 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
Challenges and Opportunities in CMCChallenges and Opportunities in CMC
BASS XIBASS XI 4646
Thank You For Your Interest!!!