Manufacturing QC and QA

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


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


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


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


Yes

Accept


Yes

NoReject

Accept

2 2 AQX

3 3 AQX


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%


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




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




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%


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


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


Hierarchy of Process Understanding

Desired State:

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

BASS XIBASS XI 2222


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


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


BASS XIBASS XI 2626

• Factors varied:– Drug concentration– Rotational speed– Humidity

• Factors held constant– Material properties– Temperature– Fill level– Loading scheme

Powder Blending


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


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


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


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


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


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


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


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


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


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


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


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!!!