office of new drug chemistry, ops, cder, food and drug administration establishing dissolution...
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Office of New Drug Chemistry, OPS, CDER, Food and Drug Administration
Establishing Dissolution Specification
Current CMC Practice
Vibhakar Shah, Ph.D.Office of New Drug Chemistry
Office of Pharmaceutical ScienceCenter for Drug Evaluation and Research, FDA
Advisory Committee for pharmaceutical ScienceMay 3-4, 2005
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Outline:
Overview of Current Practice CMC Assessment
ICH Q6A Principles
Case Study Example Extended-Release Oral Suspension
Original Drug Development strategy Dissolution Results Critical Issues Recommendations Improvements Dissolution Results: Post-Improvements
Concluding Remarks
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Current Practice:
Establishing dissolution specification(s) is a shared responsibility between the Office of New Drug Chemistry (ONDC) and the Office of Clinical Pharmacology and Biopharmaceutics (OCPB)
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
CMC Assessment:Scientific Analysis and Assessment:
Physico-chemical properties of the formulation components: drug substance(s) and excipients Solubility pKa particle size distribution Polymorphic forms Others
Impact of these physico-chemical properties on Processibility of the formulation components Safety, efficacy, (BA/BE, dissolution), and stability of the
drug product Manufacturing processes, especially those having
potential to influence the release profile of the drug substance Control strategy of critical process parameters In-process testing
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
CMC Assessment: Relationship of in-process testing to critical quality
attributes (e.g., dissolution) of the drug product: Particle size distribution Release rate Compression force, tablet hardness, friability etc.
Development and validation aspects of the proposed in-vitro dissolution method (e.g., UV, HPLC etc.): Chromatographic parameters Specificity, linearity, accuracy, precision, ruggedness,
etc. Release time point intervals
Available in-vitro dissolution data from development, clinical, bio-, and primary stability batches for a discerning trend on storage
The proposed shelf-life of the drug product on the basis of the stability data analysis of dissolution as well as other DP attributes
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
CMC Assessment:
In coordination with OCPB,
appropriate dissolution specifications
(test method and acceptance criteria)
that are reflective of the dissolution
data from various batches (clinical,
bio-, stability) of the drug product are
recommended.
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
ICH Q6A Principles:Quality Attributes with potential relevance
to dissolution within ICH Q6A: Particle size (DS): Decision Tree #3 Polymorphic content (DS): Decision Tree #4 Polymorphic change (DP): Decision Tree #4
From the forgoing discussion (CMC assessment) it should be apparent that ICH Q6A principles for setting specifications (e.g., dissolution) are well integrated in the quality assessment of the drug product
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
ICH Q6A
Decision Tree #3
Drug Substance
Particle Size Distribution
Acceptance Criteria
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
ICH Q6A
Decision Tree #4
Drug Substance
Polymorphic Content
Acceptance
Criteria
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
ICH Q6A
Decision Tree #4
Drug Product
Polymorphic Change
Acceptance Criteria
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Case Study Example
Extended-Release Oral Suspension
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Extended-Release (ER) Oral Suspension: 505(b)(2) application:
Safety and efficacy of the proposed active ingredients for the proposed indication established through immediate release products available under the Tentative OTC Monograph for the same indication
Therefore, no clinical trials requiredProposed Dose:
Single dose (Q12h) to patients 6 years of age or older
Equivalent to the nominal OTC monograph doses, given Q6h X 2
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Drug Product Formulation:
Two different active ingredients: DS1 and DS2 DS1 is anchored to a drug carrier support and
coated separately with semipermeable polymer to prevent dose dumping and to impart extended release (ER) profile
DS2 binds to the drug carrier support in-situ during the manufacturing process, but it is not coated
Both active ingredients along with other excipients are suspended in aqueous based solution
Concerns: Safety implications due to potential dose dumping Efficacy implications due to insufficient rate and extent of
release of the actives
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Drug Development Strategy: Demonstrate bioavailability of the drug product
formulation (6% coating of DS1) to a reference drug, an immediate-release (IR) Solution, containing the same two active ingredients
Formulate three experimental drug product formulations, each differing only by the coating level of semipermeable polymer on DS1: Low (2% w/w): Fast release formulation Medium (5.5% w/w): Intermediate release
formulation High (9% w/w): Slow release formulation
Establish IVIVC for each active among these three experimental formulations
Establish dissolution specifications for both actives based on generated dissolution profiles from the slow and fast release drug product formulations
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
NDA Submission Data:
Manufactured five formulations of the DP containing DS1 coated with varying levels of semipermeable polymer: 2% (low), 5.5% (medium), 9% (high) as well as 6% and 10%
Performed following PK studies: Multi dose bioavailability (BA) study with IR
solution and Single dose food effect study DP Formulation containing DS1 with 6% polymer
coating Single dose IVIVC study:
DP Formulations containing DS1 with 2%, 5.5% and 9% polymer coating
In-vivo results from 4 Batches (PK studies) and in-vitro dissolution data from nine batches (4 PK and 5 stability)
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Applicant’s Claims: Level A IVIVC established for both the actives of the
ER suspension
The mean and individual Level A IVIVC models for DS2 met the FDA validation criteria and can be used for setting dissolution specifications and biowaivers
The mean and individual Level A IVIVC models for DS1 failed the FDA validation criteria in that the predicted values had a larger error than recommended
However, if the dissolution criteria remain within the dissolution profiles tested in IVIVC study, the DS1 results can serve as a mapping study for the formulation
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Agency’s Findings of PK Results: BA and Food Effect Studies: (6% coating of DS1):
Systemic exposures of both actives were favorable between the ER suspension and multiple dose of reference IR solution
Observed no food effect for both actives
IVIVC Study: (2%, 5.5% and 9% coating of DS1): DS1:
Failed to establish in-vivo in-vitro correlation (IVIVC) Observed more than 20 % of difference in Cmax for
formulations of fast and slow dissolution profile DS2:
Level “A” IVIVC established, but failed to validate the IVIVC The formulations used in IVIVC study were found bio-
inequivalent, i.e., Cmax of the formulations used in the IVIVC study were different by more than 20%
The proposed dissolution specification and the approach to set a dissolution specification based on IVIVC by mapping was found unacceptable
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Stability Results Analysis:
Contradictory release profiles observed between drug product formulations containing 6% and 9% coated DS1
DS2 showed more decrease in dissolution than DS1
Observed substantial (up to 20%) decrease in dissolution (% release) at 1 hr, 3 hr, and 6 hr time points for both actives from their corresponding initial values among bio- and primary stability batches at all storage conditions
The decrease in dissolution was most notable at 3 hr and 6 hr time points
The decrease in dissolutions is minimum at 12 hr time point
The decrease in dissolution for both actives levels off by nine months on storage
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Dissolution Results of DS1
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%M
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DS
1 R
lzd
0 3 6 9 12 18 0 3 6 9 12 18 0 3 6 9 12 18 0 3 6 9 12 18
1 3 6 12
Months within RlzTime
Y
B21A9%_IVIVC
B34A5.5%_IVIVC
B35A2%_IVIVC
B47A6%_BA
6%
9%5.5%
2%
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Dissolution Results of DS2
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DS
2 R
lzd
0 3 6 9 12 18 0 3 6 9 12 18 0 3 6 9 12 18 0 3 6 9 12 18
1 3 6 12
Months within RlzTime
Y
B21A9%_IVIVC
B34A5.5%_IVIVC
B35A2%_IVIVC
B47A6%_BA
6%
9%
5.5%
2%
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Potential Critical Issues:
Raw materials Controls (including excipients): Particle size distribution control of drug carrier support Particle size distribution control of excipients
Manufacturing Process & In-process controls: Binding of DS1 to drug carrier support Coating level and coating process for DS1 Other manufacturing Processes Particle size distribution of coated DS1 Release profile of DS1
Controls: Particle size distribution (PSD)
Criteria (drug carrier support, coated drug bound carrier support)
Method (e.g., sieving vs. laser diffraction) Dissolution method
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Revised Drug Development Strategy:
Abandon IVIVC approach to set dissolution acceptance criteria
Conduct PK studies (BA/BE) on commercial scale bio-batch containing DS1 at the specified target coating level (rather than a range) and compare it to the reference IR solution
Manufacture additional three pilot scale primary stability batches of the drug product containing DS1 at the specified target coating level
Propose dissolution acceptance criteria based on in-vitro dissolution profiles obtained for both actives from the bio-batch
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Applicant’s Improvements:
Process Improvements: Specified the target coating level of semipermeable
polymer within X±1% for the DS1 Revised coating and subsequent manufacturing
processes Instituted appropriate process controls to stabilize
binding of both actives to the drug carrier support in the suspension
Manufactured 1 commercial scale bio- and 3 pilot scale stability batches
Controls: Instituted appropriate particle size measurement
method (e.g., laser diffraction) for drug carrier support, and coated drug (DS1) bound carrier particles
Revised PSD acceptance criteria for drug carrier support, coated drug (DS1) bound carrier support particles and suspension stabilizing excipients
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Agency’s Findings of PK Results: Post-Improvement
Three PK Studies conducted utilizing DP formulation containing X±1% coating of DS1: BA/BE assessment PK at steady state Food effect study
Results: The PK profiles of DS1 and DS2 from test ER
suspension were found similar/comparable to the reference IR solution following single and multiple dose administration
Food had no effect on bioavailability of both actives
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Post Improvement Stability Results Analysis:
Observed stable and consistent release profiles (1hr, 3hr, 6hr and 12hr time points) for both DS1 and DS2 on storage within each of the bio- and three primary stability batches
Observed no discernible trend in release profiles of DS1 and DS2 among bio- and primary stability batches at all storage conditions
Comparable release profiles for both DS1 and DS2 among bio- and three primary stability batches
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Post-Improvement Dissolution Results of DS1
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DS
1 R
lzd
(Pos
t Mfg
Pro
cess
Impr
ovem
ents
)
0 3 6 7 9 12 0 3 6 7 9 12 0 3 6 7 9 12 0 3 6 7 9 12
1 3 6 12
Months within RlzTime(hr)
Y
S15A(x%)
S89A(x%)
S90A(x%)
Bio23A(x%)
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Post-Improvement Dissolution Results of DS2
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DS
2 R
lzd
(Pos
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Pro
cess
Impr
ovem
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)
0 3 6 7 9 12 0 3 6 7 9 12 0 3 6 7 9 12 0 3 6 7 9 12
1 3 6 12
Months within RlzTime(hr)
Y
S15A(x%)
S89A(x%)
S90A(x%)
Bio23A(x%)
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Concluding Remarks:
Identified probable causes of discrepant and inconsistent dissolution results for DS1 and DS2
Recommended corrective measures to address the issues
End results: Consistent manufacturing process Acceptable BA/BE results Stable and consistent release profiles without
any discernible trend on storage for both drug substances DS1 and DS2
Dissolution criteria better reflective of the data Improvement in the quality of the drug product Improvement in assurance against the safety
and efficacy concerns
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Concluding Remarks:
The case study example highlighted:Lack of/poor understanding of the raw
material properties and manufacturing processes that were critical to be controlled for consistent quality and thereby desired performance (e.g., extended-release/dissolution) of the drug product
Inadequate efforts invested by the applicant during the drug development to understand the causal links of dissolution failures
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Concluding Remarks:
The case study example stresses a dire need for improvement to the existing drug development efforts to understand: The relationship between the raw material
properties of formulation components and critical quality attributes of the drug product (which and how)
The effect of raw material properties of formulation components on their processibility for selected manufacturing processes
The effect of manufacturing processes and associated critical process parameters on the critical quality attributes of the drug product
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Advisory Committee for pharmaceutical Science, May 3-4, 2005
Concluding Remarks:
There is no substitute to a
systematic and scientific
approach to a drug
development for a safe,
efficacious and quality drug
product.