usp disso_bazil 2013_spec v6

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


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


• 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


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


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.)


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


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


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)



3: NLT 80% at 9 hours(Full Release of Drug)



USP <711> - ER Dosage Forms, Example: L1



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




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




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%


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


L1 L2L3

USP <711> - Delayed-Release Dosage Forms Acid Stage


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


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


A1: < 10%

A2 & A3: < 25%

B1

B2

B3

[Acid Stage]

B1

B2

B3

B1

B2


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


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


• 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


• 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.)


• 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



An Ideal Approach for Setting CRS



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


Example – Selecting the Appropriate Specifications



Example – Evaluation against Bulk Density and Particle Size


(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)



Example – Impact from Packaging



Example – Impact from Coating


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


SUB-TITLE, DATEBack Up Slides

ICH Q6A, Decision Tree #7-3


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 disso_bazil 2013_spec v6

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