BASS XI BASS XI 1 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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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
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• 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