Quality Target Product Profile:
Integrating Product in vivo
Performance with Product Design
Arzu Selen, Ph.D.
Biopharmaceutics Research Lead
Office of New Drug Quality Assessment/CDER/FDA
CRS-AAPS Joint workshop: Using Novel Methods
(Including Population Pharmacokinetics) to support the
Development of Clinically Relevant Product Specification
November 13, 2010
Morial Convention Center
New Orleans, Louisiana
Expectations
• Dialog on Quality Target Product Profile (QTPP)
and effective integration of biopharmaceutics
and QbD principles leading to “novel” methods
for optimizing patient/consumer benefit
• What may QTPP driven “clinically relevant”
dissolution/release specifications look like?
• Identify opportunities for advancing our
understanding and tools/enablers (multidimensional collaborations)
2
Outline
• Background
– Integration of QbD and biopharmaceutics
• Key Considerations:
– Driven by Quality Target Product Profile
– Clinically relevant specification setting and
QTPP (Novel Approach?)
• Examples for discussion
• Summary and What’s Ahead
3
QbD Brings in “Seamlessness”:
Key Considerations for Quality
(Patient Benefit)
Product:
– Designed to meet its intended use
– Consistently delivers the desired/intended dose
Manufacturing Process:
– Designed to consistently meet product critical quality
attributes
– Suitable for continuous monitoring and updates and
allows for consistent quality over time (life cycle)
Understanding the Main Sources of Variability:
– Due to starting materials and process
– Due to Methodology and assumptions
– Due to product-patient interface and the patient
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QbD and QTPP
• Facilitates identification of what’s needed/critical
for the patient/consumer in the Quality Target
Product Profile (such as Critical Quality
Attributes, CQAs)
• Identifies risks and best approaches to manage
• Uses tools/enablers in an optimized fashion
(such as integration of QbD and
biopharmaceutics)
• Generates and enables knowledge sharing
• An iterative, learning, life-cycle process for
optimizing decision-making and the therapeutic
outcomes for the patient benefit.
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“The End” or “The Beginning”
A drug product designed, developed and
manufactured according to Quality Target
Product Profile with specification (such
as dissolution/release acceptance criteria)
consistent with the desired in vivo
performance of the product.
(Linking process, product and patient for
patient benefit.)
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Tracing back….
Evolution of some of the thinking:
Integration of Biopharmaceutics and QbD
2009 QbD and Biopharmaceutics Workshop
in Rockville, MD.
Identification of the nine synergistic
areas
7
Integration of QbD and Biopharmaceutics
Critical factors
for product
performance
Building and
sharing knowledge
The AAPS Journal, Vol. 12, No. 3, 465-472, 2010
(the June 2009 Workshop and article)
Patient
Benefit
QTPP driven
specification
Biopharmaceutics
Risk Assessment
Road Map
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The Synergistic Nine Areas
Center around patient benefit
• QTPP driven specification (context specific
specification)
•Biopharmaceutics Risk Assessment Road Map
•Advancing and leveraging contributing factors
–Mechanistic understanding,
–Modern manufacturing and controls
–In silico (computational) tools
–Statistical approaches
•Building and sharing Knowledge
–Knowledge sharing and database and glossary
–Multidimensional Collaboration
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Product, process
and manufacturing
knowledge
The nine areas
Desired in vivo
performance
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Possible Approaches for Clinically
Relevant specification for drug
dissolution/release
Based on assuring
bioequivalence to
the clinical trial batch
Hybrids
and other (?)
methods
QTPP-driven: Product characteristics critical for
therapeutic benefit identified in QTPP, guide selection
of appropriate drug product and process design and
development. Careful characterization of CQA’s
and critical process parameters with appropriate
biopharmaceutics studies, result in desired
In vivo performance, and thereby, enable linking product,
process, and patient (desired therapeutic outcomes).
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Characteristics of Dissolution/Release
Specification Setting with QbD
Implementation
• Enriched with knowledge on product,
process and desired in vivo performance
(biopharmaceutics)
• Enables development of a specification
range based on critical product quality
attributes for supporting desired in vivo
performance of the product for patient
benefit.
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Critical Success Factors for the
QTPP-driven Approach?
• Understanding/characterizing sources of
variability and reducing impact of variability.
• Understanding/characterizing Critical Quality
Attributes (CQAs) that can lead to desired
therapeutic outcomes.
• Pharmacokinetic study and the long-term
clinical study, with critical endpoints, are
designed cohesively to enrich the collected
data and enable its broader application.
13
A possible QbD Approach Linking
in vitro and in vivo Data?
1) Determine target (including desired in vivo performance)
2) Develop a “suitable (predictive)” dissolution/release method
3) Estimate therapeutic range and “maximum” acceptable variability
(considering patient and product and interaction between both)
4) Continue to refine the in vitro method during clinical
development (before NDA submission) linking product quality
attributes and performance
5) Optimize the in vitro dissolution/release method and link the
release test to the clinically meaningful dissolution test that can
be used subsequently to quantify changes.
6) Establish meaningful dissolution/release specification
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Additional Considerations
• Is the selected dosage form suitable given the
PK, biopharmaceutics and target patient
population?
• Are there subsets of patients in the study? Are
they adequately represented?
• Are the selected PK parameters meaningful
(could correlate with clinical effect?)
• Can we estimate likely outcomes and impact?
• Can alternate study designs, specific for the
question at hand be developed and tested out?
• And others?
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What would/could QTPP driven
specification look like?
Some potential/hypothetical QTPP Approaches
and semi-modified examples.
The provided examples are for generating discussion, and the
views expressed are those of the author and do not reflect the
official views of the FDA.
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What may be QTPP
Considerations/Questions?
Some basic leading questions for identifying product
characteristics suitable to link to desired therapeutic
effect and for identifying potential product, process, and
biopharmaceutics parameters for ensuring product
quality (that/those may also be used for specification
setting).
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Example 1:
Potential QTPP Considerations and Knowns
• Indication and usage:
Rapid dissolving, acute analgesic
• Patient population: general (adequately characterized)
• Product and process
– Key/critical product characteristics and process
parameters
• Suitability of dosage form: Oral dosage form
• Rate controlling CQA: Particle size
• Methods in place to ensure particle size is maintained
for product quality: Yes
• Rapid disintegration in less than 2 minutes
– And ?
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Example 1 (Continued)
• Drug PK and biopharmaceutics considerations
– Adequately and rapidly absorbed, PK adequately
characterized
– Dosage form suitable to deliver the intended dose for
the desired effect: Yes.
• Method issues:
– Choice of PK parameters, analytical considerations,
study design (suitability): Acceptable for intended
purposes.
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Example 1 (Continued)
• Clinical assessment:
– Study designs consistent with the study objectives and
suitable to detect drug product performance (i.e.
appropriate critical clinical measurements are included in a
manner that may correlate with the intended drug product
effectiveness and safety)
• Big picture issues are identified and addressed (or being
addressed, depending on the stage of development)
• CQA ensuring product quality and acceptable ranges are
identified and appropriate
• Key parameter linking process, product and in vivo
performance is identified
– “tmax less than 0.5 hrs in 80% of the subjects is
ensured if particle size is less than X and
disintegration is complete in less than 2 minutes”
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Imagine this was the available data, and
also predicted/confirmed by in silico, in vitro and in vivo
approaches
Solid line: un-milled drug
Dotted line: once-milled drug
Dashed line: twice milled drug
In the reference publication: Computer
simulations based on a theoretical
dissolution model and a pharmacokinetic
model to explore effect of particle size
distribution on dissolution rate and oral
absorption
R.J. Hintz and K. C. Johnson. Int. J. Pharm., 51, 9-17, 1989
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Example 1
Possible QTPP driven specification?
(Working Example for Discussion)
“tmax (maximum plasma drug
concentration) less than 0.5 hrs in
majority (80%?) of the subjects is
ensured if particle size is less than
“X” and disintegration is complete in
less than 2 minutes.”
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Example 2:
Potential QTPP Considerations and Knowns
• Indication and usage:
Chronic, for cardio-protective effect, drug release profile is
developed to ensure desired chronotherapeutic effect.
• Patient population: adequately characterized
• Product and process
– Key/critical product characteristics and process parameters
• Suitability of dosage form: Oral dosage form
• Rate controlling CQA: Drug release is controlled by
release from a “multilayer dosage form” (hypothetical
example)
• Methods in place to ensure that the CQA’s are
maintained for product quality: Yes
• Drug release profile
– And ?
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Example 2 (Continued)
• Drug PK and biopharmaceutics considerations?
– Adequately and rapidly absorbed, PK adequately
characterized
– Dosage form suitable to deliver the intended dose
according to the desired effect: Yes. In vitro drug release
information can predict of in vivo performance. (Acceptable
PK model)
• Method issues:
– Choice of PK parameters, analytical considerations, study
design (suitability): Acceptable for intended purposes.
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Example 2 (Continued)
• Clinical assessment:
• Study designs consistent with the study objectives
• Study design is suitable to detect drug product
performance (i.e. appropriate critical clinical
measurements are included in a manner that may
correlate with the intended drug product effectiveness
and safety)
• Big picture issues are identified and addressed
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Example 2 (Continued)
• CQAs ensuring product quality and acceptable ranges are
identified and are appropriate
• Key parameter linking process, product and in vivo
performance is identified
– Process and product attributes that enable
consistent drug release pattern from the multilayer
tablets yield AUC(6-18) values that are equal or
greater than 1000 ng.h/mL and correlate with the
desired in vivo performance (decreased incidence
of tachycardia), linking therapeutic efficacy, product
design, and product performance. As such,
associated specifications and controls are identified
as clinically relevant.
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Imagine this is the Data from Example 2
Test Formula 1
Test
TestFormula
Formula22
D.Sica et al. AJH, 16 (5), 128A and 129A, May 2003
27
Example 2
Possible QTPP driven specification?
(working example for discussion)
“AUC (6-18) for drug X equal to or greater
than 1000 ng.h/mL, associated with
therapeutic benefit, is achieved in majority
(80%?) of the subjects if manufacturing
controls (a, b, and c) are in place and drug
release of 50% is achieved within x
minutes using the established dissolution
method.”
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Example 3:
Potential QTPP Considerations and Knowns
• Indication and usage:
Chronic, sustained drug release profile is needed for the
intended hypotensive effect.
• Patient population: adequately characterized
• Product and process
– Key/critical product characteristics and process parameters
• Suitability of dosage form: Oral dosage form
• Rate controlling CQA: Needs additional product
development work to achieve sustained plateau
concentrations, early work is from an IR tablet
formulation.
• Methods in place to ensure that the CQA’s are
maintained for product quality: Yes
• Sustained drug release is critical for therapeutic benefit
– And ?
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Example 3 (Continued)
• Drug PK and biopharmaceutics considerations?
– Adequately and rapidly absorbed, has short elimination
half-life (approx. 1-1.5 hrs)
F. Langenbucher and J.Mysicka, br. J. Clin. Pharmac.19, 151S-162S, 1985
30
Example 3 (Continued)
• Drug PK and biopharmaceutics considerations?
– As identified, an alternate dosage form will be explored for
the desired effect: Need additional work
(in fact, in the publication, authors worked on OROS
dosage forms to achieve sustained concentrations)
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Example 3 (Continued)
F. Langenbucher and J.Mysicka, br. J. Clin. Pharmac.19, 151S-162S, 1985
32
Example 3 (Continued)
• Method issues:
– Choice of PK parameters, analytical considerations, study
design (suitability): Acceptable for intended purposes. CQA
ensuring product quality and acceptable ranges are identified
and appropriate (assuming this information becomes available
and is acceptable)
• Key parameter linking process, product and in vivo
performance is identified
– OROS product with identified characteristics (such as
pore size, and film coat thickness) (hypothetical for
our purposes) ensures in vivo delivery of the desired
sustained concentrations over the dosing interval and
this correlates with the identified therapeutic window
(efficacy and safety). Release rate identified in this
manner, x ng/mL/unit time is achieved when the
identified controls for the product are kept within the
acceptable range.
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Example 3
Possible QTPP driven specification?
(working example for discussion)
“Delivery/release rate of drug X within a range of
“a to b” is achieved in majority (80%?) of the
subjects if manufacturing controls (as identified)
are in place. Desired therapeutic effect is
obtained if the drug release continues for “12”
hrs in vivo. Corresponding in vitro release test
shows that in vitro drug release rate should be
maintained at “c”, over the defined period using
the established dissolution method.”
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Example 4:
Potential QTPP Considerations and Knowns
• Indication and usage:
For treating a metabolic disorder, chronic use, need to give
large doses to pediatric patients
• Patient population: pediatric population, unique dosage form
considerations (including taste, mouth feel, and administration
of dose in soft foods)
• Product and process
– Key/critical product characteristics and process parameters
• Suitability of dosage form: Oral dosage form
• Rate controlling CQA: Drug release controlled by
excipient and a suitable manufacturing process
• Methods in place to ensure that the CQA’s are
maintained for product quality: Yes
• Drug release profile critical for in vivo performance
– And ?
35
Example 4 (Continued)
• Drug PK and biopharmaceutics considerations?
– Adequately and rapidly absorbed
– Dosage form suitable to deliver the intended dose
according to the desired effect.
– Dose: 250-700 mg/day per kg body weight (i.e. Six times
1 g per day for a 2 year old infant)
– Desired Formulation: Oral multiparticulate dosage form
– Taste masked (and negligible amounts released in buccal
cavity)
– Should dissolve in acidic gastric fluid and release dose
rapidly and completely
– The selected manufacturing process should use excipients
suitable for the pediatric population and for the intended
delivery pattern/characteristics
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Example 4 (Continued)
Identifying a more suitable manufacturing process for
desired drug release profile
First approach
Second approach
J. Breitkreutz, M. Bornhöft, F. Wöll, and P. Kleinebudde, Eur. J. Pharm. Biopharm. 56,
247–253, 2003
J. Breitkreutz, F. El-Saleh, C. Kiera et al., Eur. J. Pharm. Biopharm. 56, 255-260, 2003
37
Example 4 (Continued)
• Method issues:
– Choice of PK parameters, analytical considerations, study
design (suitability): Acceptable for intended purposes.
– Clinical assessment:
• Study designs consistent with the study objectives
• Study design is suitable to detect drug product
performance (i.e. appropriate critical clinical
measurements are included in a manner that may
correlate with the intended drug product effectiveness
and safety)
– In vitro drug release information may be predictive of in
vivo performance (bioavailability).
• Big picture issues are identified and addressed
38
Example 4 (Continued)
• Taste-masked for 5 min in buccal cavity
• Mixing coated granules with milk, jelly, pudding directly
on a spoon facilitates swallowing
• Dissolution test shows 70% released after 5 min
• CQA (dissolution) ensuring product quality and acceptable
ranges are identified and appropriate
• Key parameter linking process, product and in vivo
performance is identified
– Process and product attributes that predict in vivo
performance/availability correlate with dissolution
profile of no more than 60% in 20 min. according to
the established dissolution method.
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Example 4
Possible QTPP driven specification?
(working example for discussion)
– Process related and product attributes, including
taste-masking for 5 min in buccal cavity,
acceptable mouth feel, and acceptable stability of
granules in the recommended soft foods (when
prepared as directed) constitute the critical
quality attributes for this product. Desired in
vivo performance/availability of the API correlate
with dissolution profile of the drug product such
that no more than 60% should dissolve in 20 min.
using the established dissolution method.
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Summary and What’s Ahead?
• Effective integration of QbD and biopharmaceutics is leading
to innovative approaches linking product/process knowledge
and understanding (CQAs) to patient benefit.
• Quality Target Product Profile driven specifications need
further discussion and development.
• Quality Target Product Profile not only identifies, product
characteristics, it also facilitates, cohesive decision-making
and describes optimal use of the product, identifies the
necessary controls and ensures product quality.
• Collaboration and innovation are key for moving forward with
science and risk-based approaches and for ensuring patient
health benefit. Need your ideas and input!!
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One step closer?
YES
NO
DEPENDS
42
Wright Brothers Flight # 41, Huffman
Prairie, Dayton, Ohio, 1905.
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Acknowledgements
•
•
•
•
•
•
Moheb Nasr, Ph.D.
Christine Moore, Ph.D.
ONDQA Biopharmaceutics Team:
Angelica Dorantes, Ph.D., Houda Mahayni, Ph.D.,
Sandra Suarez Sharp, Ph.D., Kareen Riviere, Ph.D.,
Tapash Ghosh, Ph.D., Albert Chen, Ph.D.,
John Duan, Ph.D. and Patrick Marroum, Ph.D.
Office of New Drug Quality Assessment
AAPS QbD and Product Performance Focus Group
Authors of the references and their publications are gratefully
acknowledged.
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