Post on 11-Apr-2017
Jian-Hwa HanUSP Dissolution Workshop
Rio de Janeiro - BrazilMay 20-21, 2013
Knowing Your Dissolution Specifications
SUB-TITLE, DATE
• Purpose of Specification
• Dissolution: Regulatory NDA Filing Support• Specifications for Different Dosage Forms • Dissolution Criteria for Stage Testing – USP <711> • Justification of Specifications
• Scientific Assessment
• Clinically Relevant Dissolution Methods and Specificationso An Ideal Approach for Setting CRSo IVIVC Model
• Examples
• Conclusions
Presentation Outline
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 2
• The quality of drug products is determined by their design, development, in-process controls, GMP controls, and process validation, and by specifications applied to the product throughout development and manufacture
• Specifications are chosen to confirm the quality of the drug products, i.e. ensure the Safety and Efficacy of drug products
• Assure manufacture consistency for the quality of product
Purpose of Specifications
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 3
An Overview from NDA Filing Preparation: (Dissolution Focused)• 3.2.P.2 Pharmaceutical Development
• 3.2.P.2.2 Drug Product
• 3.2.P.5 Controls of Drug Product• 3.2.P.5.1 Specifications• 3.2.P.5.2 Analytical Procedures• 3.2.P.5.3 Validation of Analytical Procedures• 3.2.P.5.6 Justification of Specifications
• 3.2.P.8 Stability
Dissolution: Regulatory NDA Filing Supports
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 4
• Immediate-Release Dosage Forms• Delayed-Release Dosage Forms• Extended-Release Dosage Forms without IVIVC
• Minimum of 3 points required• Last time point should be the time where 80% of label claimed amount
is dissolved• Specifications set to pass at Stage 2 level of testing of the USP
acceptance criteria
• Extended-Release Dosage Forms with IVIVC (ICH Q6A, Decision Tree #7-3)
Specifications for Different Dosage Forms
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 5
3. What are appropriate acceptance ranges? [extended release]
YES
NO
NO
YES
YES
NO
YES
NO
Are bioavailabilitydata available for batches
with different drug release rates?Is drug release independent of
in vitro test conditions?
Can an in vitro / in vivorelationship be established?
(Modify in vitro test conditionsif appropriate.)
Use all available stability, clinical, andbioavailability data to establish appropriate acceptance ranges.
Use the in vitro / in vivocorrelation, along with
appropriate batch data, to establish acceptance ranges.
Are acceptanceranges >20% of the
labeled content?
Provide appropriatebioavailability data
to validate theacceptance ranges.
Finalize acceptance ranges.
USP <711> - Immediate-Release Dosage Forms
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 6
StageNumberTested Acceptance Criteria
S1 6 Each unit is not less than Q + 5%.
S2 6 Average of 12 units (S1 + S2) is equal to or greater than Q, and no unit is less than Q - 15%.
S3 12 Average of 24 units (S1 + S2 +S3) is equal to or greater than Q, not more than 2 units are less than Q - 15%, and no unit is less than Q - 25%.
USP <711> - Immediate-Release Dosage Forms (cont.)
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 7
IR - Q: NLT 80% at 30 minutes
30
40
50
60
70
80
90
100
110
0 10 20 30 40 50 60
Time, minutes
%LC
S1≥85%
Individuals only
S2: N = 12, Mean ≥ 80%; Individuals ≥ 65%
S3: N = 24, Mean ≥ 80%; Individuals ≥ 55%; NMT 2 units are < 65%
Individuals only
USP <711> - Extended-Release Dosage Forms
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 8
StageNumberTested Acceptance Criteria
L1 6 No individual value lies outside each of the stated ranges and no individual value is less than the stated amount at the final test time.
L2 6 The average value of the 12 units (L1 + L2) lies within each of the stated ranges and is not less than the stated amount at the final test time; none is more than 10% of labeled content outside each of the stated ranges; and none is more than 10% of labeled content below the stated amount at the final test time.
L3 12 The average value of the 24 units (L1 + L2 + L3) lies within each of the stated ranges, and is not less than the stated amount at the final test time; not more than 2 of the 24 units are more than 10% of labeled content outside each of the stated ranges; not more than 2 of the 24 units are more than 10% of labeled content below the stated amount at the final test time; and none of the units is more than 20% of labeled content outside each of the stated ranges or more than 20% of labeled content below the stated amount at the final test time.
USP <711> - ER Dosage Forms, Example
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 9
Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10 12 14
Time, minutes
%LC
1: NMT 25% at 2 hours(No Dose Dumping)
2: %LC within 50%~70% at 6 hours(Controlled Release)
3: NLT 80% at 9 hours(Full Release of Drug)
1: NMT 25% at 2 hours(No Dose Dumping)
2: %LC within 50%~70% at 6 hours(Controlled Release)
3: NLT 80% at 9 hours(Full Release of Drug)
1: NMT 25% at 2 hours(No Dose Dumping)
2: %LC within 50%~70% at 6 hours(Controlled Release)
USP <711> - ER Dosage Forms, Example: L1
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 10
Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10 12 14
Time, minutes
%LC
L1: Individuals onlyAll within the stated range 3: NLT 80% at 9 hours
1: NMT 25% at 2 hours
2: %LC within 50%~70% at 6 hours
USP <711> - ER Dosage Forms, Example: L2
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 11
Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10 12 14
Time, minutes
%LC
1: none is > 35% at 2 hours
2: %LC within 40~80% at 6 hours
L2: N = 12 ( 6 + 6 )Averages meet L1 criteria(No one outside the purple circle) 3: none is < 70% at 9 hours
USP <711> - ER Dosage Forms, Example: L3
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 12
Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10 12 14
Time, minutes
%LC
1: none is > 45% at 2 hoursNMT 2 units > 35%
2: %LC within 30~90% at 6 hoursNMT 2 units are between Purple and red circles
L3: N = 24 ( 6 + 6 + 12 )Averages meet L1 criteria(No one outside the Red circle)
3: NLT 60% at 9 hours NMT 2 units < 70%
Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
0 2 4 6 8 10 12
Time, minutes
%LC
USP <711> - ER Dosage Forms, Dissolution Data Space
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 13
L1 L2L3
USP <711> - Delayed-Release Dosage Forms Acid Stage
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 14
ANumberTested Acceptance Criteria
A1 6 No individual value exceeds 10% dissolved.
A2 6 Average of the 12 units (A1 + A2) is not more than 10% dissolved, and no individual unit is greater than 25% dissolved.
A3 12 Average of the 24 units (A1 + A2 + A3) is not more than 10% dissolved, and no individual unit is greater than 25% dissolved.
USP <711> - Delayed-Release Dosage Forms Buffer Stage
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 15
BNumberTested Acceptance Criteria
B1 6 Each unit is not less than Q + 5%
B2 6 Average of the 12 units (B1 + B2) is equal to or greater than Q, and no unit is less than Q - 15%.
B3 12 Average of the 24 units (B1 + B2 + B3) equal to or greater than Q, and not more than 2 units is less than Q - 15%, and no unit is less than Q - 25%.
IR - Q: NLT 80% at 30 minutes
0
10
20
30
40
50
60
70
80
90
100
110
-10 0 10 20 30 40 50 60
Time, minutes
%LC
USP <711> - DR + IR Dosage Forms, Example
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 16
A1: < 10%
A2 & A3: < 25%
B1
B2
B3
[Acid Stage]
B1
B2
B3
B1
B2
Extended-Release Dosage Form - Multi-point Specs
0
10
20
30
40
50
60
70
80
90
100
110
-2 0 2 4 6 8 10 12 14
Time, minutes
%LC
USP <711> - DR + ER Dosage Forms, Example
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 17
A1: < 10%
A2 & A3: < 25%
[Acid Stage]
B3
B1
B2
• Relevant Development Data • Dissolution Method Development/Validation• Formulation/Process Development
• Dissolution Test Results for Scale-up/Validation Batches
• Stability Data of Registration Batches at all conditions and packaging
• Dissolution Data of Batches used in Pivotal Clinical Trials and/or in Confirmatory Bioavailability Studies
Justification of Specifications
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 18
• Physico-chemical properties of the drug substance(s): (such as) o Solubility & pH-dependencyo pKao particle size distributiono Polymorphic formso Others
• Impacts from formulation: o Formulation design and operating principles (e.g., disso mechanism)o Excipient properties and functionso Stability of the drug producto Efficacy (BA/BE) vs. Dissolution
• Proposed in-vitro dissolution method:o Media selectiono Apparatus typeo RPM, DPM, Flow rateo Time points for data collection
Scientific Assessment – Factors may Affect Dissolution Behavior and Product Performance
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 19
• Identify critical factors could impact drug release of the product: (such as)o Formulation compositionso Particle size distributiono Moistureo Compression force, tablet hardness, friability etc.
• Manufacturing processes, especially those having potential to influence the release profile of the drug
o E.g., process-induced phase transformation ….o Control strategy of critical process parameters (CPP’s)
• Available in-vitro dissolution data from development, clinical, bio-availability, and primary stability batches for a discerning trend on long term storage(i.e. real time stability data are generated for these lots. Ability to predict long term stability depends on formulation design, release mechanism….)
• The proposed shelf-life of the drug product based on the stability data as well as other drug product attributes
Scientific Assessment (cont.)
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 20
• Clinical Relevant Specifications (CRS) are those specifications that help to establish consistent in vivo performance as proven by their ability to reject batches with inadequate in vivo performance
• Clinical Relevant Dissolution Methodso Can be use to define the Design Space for formulation and
processo Products can be approved based only on the comparability
of their dissolution profiles without having to conduct in vivo studies
(Reference: FDA’s Presentation by Dr. Sandra Suarez Sharp, 2011 AAPS Annual Meeting, Washington, DC, October 23, 2011)
Clinical Relevant Dissolution Methods and Specifications
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 21
(Reference: FDA’s Presentation by Dr. Sandra Suarez Sharp, 2011 AAPS Annual Meeting, Washington, DC, October 23, 2011)
An Ideal Approach for Setting CRS
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 22
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 23
Illustration: Level A IVIVC (2009 LOL conference)
Deconvolution
Observed or predicted Cp profilesIn vitro drug release
Estimated in vivo input
Disposition FunctionIV or IR Cp profiles
IVIVC model
Biostudy
In vivo
-
0.200
0.400
0.600
0.800
1.000
0 5 10 15 20Time (hr)%
Rel
ease
d
A
B
C
Modeling relationship
0.0
20.0
40.0
60.0
80.0
100.0
120.0
0 5 10 15 20 25T(hr)
% R
elea
sed
A
B
C
Convolution
C(t) = f(t)*C(t)
(1) Validation(2) Prediction
IVIVC plot
0.010.0
20.030.040.0
50.060.0
70.080.090.0
100.0110.0
0.0 10.0 20.0 30.0 40.0 50.0In vitro
In v
ivo A
B
C
0
0.2
0.4
0.6
0.8
1
1.2
1.4
0 4 8 12 16 20 24Time (hr)
Plas
ma
Con
c.
IRIV
Y. Qiu. In: Developing Oral Dosage Forms: Pharmaceutical Theory and Practice. Edited by Y. Qiu et al.. Academic Press, San Diego, CA. 2009. pp-379-408
(Reference: FDA’s Presentation by Dr. Sandra Suarez Sharp, 2011 AAPS Annual Meeting, Washington, DC, October 23, 2011)
Example – Selecting the Appropriate Specifications
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 24
(Reference: FDA’s Presentation by Dr. Sandra Suarez Sharp, 2011 AAPS Annual Meeting, Washington, DC, October 23, 2011)
Example – Evaluation against Bulk Density and Particle Size
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 25
(Reference: “Setting Specifications for Dissolution Testing of NR Formulations”, Presentation by Dr. Alexander Pontius, EUFEPS, Barcelona, Feb. 23-24, 2011)
Example – +/- 10% of bio-lot per Specifications for ER/MR (At least 3 Spec time points)
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 26
(Reference: “Setting Specifications for Dissolution Testing of NR Formulations”, Presentation by Dr. Alexander Pontius, EUFEPS, Barcelona, Feb. 23-24, 2011)
Example – Impact from Packaging
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 27
(Reference: “Setting Specifications for Dissolution Testing of NR Formulations”, Presentation by Dr. Alexander Pontius, EUFEPS, Barcelona, Feb. 23-24, 2011)
Example – Impact from Coating
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 28
Conclusions – • The dissolution specifications are established through the
collaborations among Analytical, Formulation, PK and regulatory functions, and the CMC team
• Start accumulating the knowledge and collecting the data from Day 1 of development
• Dissolution method needs to be (i) discriminatory and (ii) bio-relevant if achievable
• Establishing the appropriate dissolution specifications will assure:o Manufacture of the dosage form is consistent o Consistent throughout the product’s life cycle o Each dosage unit within a batch will have the same
pharmaceutical qualities o To show an adequate safety and efficacy* profile [* disso
alone can’t really reflect efficacy without IVIVC/IVIVR]
29USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013
• Dr. Jian-Hwa Han is employed at Abbvie • Ms. Susan George, Dr. Yihong Qiu and Dr. Paul D.
Curry, Jr. are employed at Abbvie who have contributed for scientific discussions and reviewing the presentation materials
• Abbvie fully supports USP’s activities and events• USP provides the traveling fund for this presentation
Disclosures
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 30
Q&A
SUB-TITLE, DATEBack Up Slides
ICH Q6A, Decision Tree #7-3
USP Dissolution Workshop, Rio de Janeiro-Brazil, 2013 33
3. What are appropriate acceptance ranges? [extended release]
YES
NO
NO
YES
YES
NO
YES
NO
Are bioavailabilitydata available for batches
with different drug release rates?Is drug release independent of
in vitro test conditions?
Can an in vitro / in vivorelationship be established?
(Modify in vitro test conditionsif appropriate.)
Use all available stability, clinical, andbioavailability data to establish appropriate acceptance ranges.
Use the in vitro / in vivocorrelation, along with
appropriate batch data, to establish acceptance ranges.
Are acceptanceranges >20% of the
labeled content?
Provide appropriatebioavailability data
to validate theacceptance ranges.
Finalize acceptance ranges.