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 Robin H. Bogner, R.Ph., Ph.D. Associate
Professor of Pharmaceutics, Department
of Pharmaceutical Science, University of
Connecticut in Storrs, CT
 John Groskoph, Senior Director, New
Products CMC, Department of Global
Chemistry Manufacturing & Controls,
Pfizer Inc.
 Do you find that current quality and
continuous improvement initiatives (such as
science of scale, Quality by Design, Right
first time, Six Sigma, Design of Experiments
(are adapted to your needs (such as providing
quicker development cycle, facilitate filling,
and providing robust manufacturing
processes).

--Yes
--No
Innovations are Demanded by the Market

Patients Prefer “Pills”

Easy to Easy to Acceptable

administer identify taste*

* Relative to oral liquids

 Emerging Promising

Orally Disintegrating
Tablets
External Lubrication Continuous processing

Controlled release
combination technologies Nanoparticulates
Ink-jet printing
Amorphous forms
Electrospray powder
deposition
SEDDS
 Started with
• Disintegrates on the tongue
within seconds to minutes

• Requires taste-masking

• Rapidly dissolving porous matrix

• Specially processed sugars
• Effervescence

Expanded to other therapeutic areas • Compressed or lyophilized

in particular
psychiatric drugs • Develop in-house or outsource to
migraine drugs specialty companies

Bogner, Wilkocz, “Fast-Dissolving Tablets: New Dosage Convenience for Patients” US Pharmacist 27(3):34-43 (2002)
Habib, Khankari, Hontz, “Fast-Dissolve Drug Delivery Systems” Crit Rev Ther Drug Carrier Syst 17:61-72 (2000)
Chang, Guo, Burnside, Couch, “Fast-Dissolving Tablets” Pharm Technol 24(6): 52-58 (2000)
Lialda
• lipophilic matrix core
• surrounded by hydrophilic matrix
• surrounded by enteric coating

Equetro
Capsule containing
• 25% IR beads
• 35% enteric-release beads
• 40% hydrophilic polymer
coated beads
Dilacor XR
Capsule contains
• 2-4 triple layer tablets depending on dose
• each tablets 60 mg
• inner hydrophilic layer sandwiched by
hydrophobic out layers
 Self-
Emulsifying Spray Drying
Drug Delivery
Systems

Hot Melt Emerging

Extrusion Technologies
Improve
Dissolution

* Thayer, “Finding Solutions: Custom Manufacturers Take on Drug Solubility Issues to Help
Pharmaceutical Firms Move Products Through Development” C&E News 88(22):13-18 (2010)
 Many of the emerging technologies to improve solubility
reduce crystalline order  amorphous or solution

Amorph/Cryst
Drug Solubility

Indomethacin 7  Disordered
6
Iopanoic acid
 Higher free energy
11
Glipizide
than xstal
Glybenclamide 17
34
 Higher mobility than
Hydrochlorothiazide
13
xstal
Terfenadine

Griseofulvin 29  Not a single

Spironolactone 110 definable state like a
Danazol 27 xstal

Murdande, Pikal, Shanker, Bogner, “Solubility Advantage of Pharmaceuticals: II. Application of Quantitative
Thermodynamic Relationships for Prediction of Solubility Enhancement in Structurally Diverse Insoluble
Pharmaceuticals” Pharm Res 27(12): 2704-2714 (2010)
 Hot Melt Extrusion
Disperse/dissolve drug in softened/molten polymer-based matrix

Kaletra Meltrex

Crowley et al. , “Pharmaceutical Applications of Hot-Melt Extrusion: Part 1”

Drug Dev Ind Pharm 33:909-926 (2007)

Andrews, et al.“Hot-melt extrusion: an emerging drug delivery technology” Pharmaceutical Technology Europe 21(1): (2009)
 Self-Emulsifying Drug Delivery Systems

Drug is dissolved in an oil-based formulation contained in capsules (softgels)

designed to emulsify spontaneously to produce fine oil-in-water

emulsions when introduced into an aqueous phase under gentle agitation.

Drug is highly soluble in emulsified droplets

 Spray Drying
Emerging Technologies
Spray drying produces a
flowable powder

Often amorphous depending on

formulation and processing

Journal of Pharmaceutical Sciences

http://www.bendres.com/drug-delivery-manuf.shtml
• Deposition of precise amounts of small
quantities of drug on a matrix (e.g. placebo
tablet)

• Envisioned for customized dosing for the

advent of individualized medicine
 Emerging Promising

Orally Disintegrating
Tablets
External Lubrication Continuous processing

Controlled release
combination technologies Nanoparticulates
Ink-jet printing
Amorphous forms
Electrospray powder
deposition
SEDDS

Remon, Vervaet Continuous Processing of Pharmaceuticals Encyclopedia of Pharmaceutical

Technology: 3rd Edition (2006)

Peltonen, Hirvonen, Pharmaceutical Nanocrystals by Nanomilling: Critical Process Parameters,

Particle Fracturing and Stabilization Methods, Journal of Pharmacy and Pharmacology
62(11):1569-1579 (2010)
 Does your company outsource the
manufacture of tablets and capsules
because you lack the expertise the task
requires
--Yes
--No
Future of Quality by
Design
Future of QbD - Where have we been?
 FDA (ONDQA) Pilot Program for Quality by Design
 Built on the concepts articulated in ICH Q8, 9 and 10.
 Considerable focus on understanding multi-factorial
relationships between parameters and attributes to
establish a design space (Q8)
 Use of formal risk assessments to determine criticality
(Q8 and Q9)
 Evaluation of quality systems ability to accommodate
pharmaceutical products developed via Quality by
Design approaches (Q10)
 Control strategies were fairly traditional (end-product
testing)
Future of QbD - where we are going?
 FDA (CBER) Pilot Program for QbD submissions for
Bios products
 Approach is the same for small molecules
 Significantly larger number of parameters to evaluate and
potentially control
 Control Strategies may be more demanding

 EMA PAT Team has a worksharing pilot for QbD

submissions (national licenses)

 Additional recently announced joint FDA/EMA pilot

program for small molecule QbD submissions
Future of QbD
 Real Time Release testing
 Shift of analytical control strategy from an off-line,
post-manufacturing approach to an approach where
data is generated during the manufacture of the
batch.
 RTRt does not mean less testing, in fact it often
means more analytical data is generated!
 Provides for control closer to the source of variability
in the process
 Allows for Real Time Release of the batch
 Regulators have already demonstrated their
willingness to review and approve RTRt submissions
 Example of RTRt
API & Excipients
Mag
Stearate

ID test

Dispensing Blend Sieving Blend Granulation

Weight, Hardness,
Moisture, Assay, UdU
Mag
Stearate
Disintegration

Coating Tabletting Blend

Future of QbD
 Use of Large Sample Sizes (Large N)
 New control strategies allow for significantly larger
sample sizes than traditional compendial testing
 Modified approaches are required to treat this data,
especially for uniformity testing
 zero tolerance criteria no longer make sense
 Pharma paper in 2006 (Sandell, et. al.)
 FDA and EDQM teams continue discussions
Future of QbD
 Continuous Quality Verification
 Shiftin validation approach from “3 batches”
to continuous monitoring
 Regulatory agencies have already indicated
acceptance of CQV concept
 Challenge is how to present validation reports
to GMP inspectors
 Elements of CQV
1. Process Understanding
CPP/CQA’s
Risk Assessment Review
Process Knowledge Report
2. Continuous
4. Continuous
Quality
Process
Monitoring
Improvement
and Feedback
Change Product Process Control
Management Quality Strategy
Documentation
Batch Record
Data
Specifications
3. Process Analysis
Initial Process Performance
Evaluation
Acceptance & Release
Ongoing Process Monitoring
CpK Statistics Database
Annual Product Review
Future of QbD
 Analytical QbD
 An analytical method can be viewed in the same way
as a manufacturing process
 Relationships can be established between method
variables and method outputs
 A “design space” can be identified within which a
method can be run and robust results can be
generated, i.e. more robust methods
 Can provide flexibility to reduce the burden of post-
approval method changes as long as we operate
within the methods design space
 A QbD is still an area requiring more discussion within
the regulatory community
Future of QbD
 Application of QbD principles to existing
products
 Process redesign
 Partial design spaces
 Enhanced control strategies (including RTRt)
 Enhanced process understanding
 New technologies such as continuous
manufacturing
Continuous Direct Compression
 Continuous Dry Granulation
1 Excipients Lubricant

Metering
Feeders API

2
In-Line Blender

SCADA
3
Roller Compactor
4 Lube Metering
Mill Feeder

In-Line Blender 5
1. Raw Material
2. Blend Uniformity
3. Compacts
4. Particle Size
5. Blend Uniformity 6, 7
6. Content Uniformity
7. Assay
Continuous Wet Granulation
Thank You
 Does your company outsource the
manufacture of tablets and capsules
because you lack the equipment the task
requires?

--Yes
--No
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