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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 administer
Easy to identify
Acceptable taste*
* Relative to oral liquids
Emerging Promising
Orally Disintegrating Tablets
External Lubrication
Controlled release combination technologies
Amorphous forms
SEDDS
Nanoparticulates
Continuous processing
Ink-jet printing
Electrospray powder deposition
Started with• Disintegrates on the tongue
within seconds to minutes
• Requires taste-masking
• Rapidly dissolving porous matrix • Specially processed sugars• Effervescence
• Compressed or lyophilized
• Develop in-house or outsource to specialty companies
Expanded to other therapeutic areasin particular
psychiatric drugsmigraine drugs
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
EquetroCapsule containing• 25% IR beads• 35% enteric-release beads• 40% hydrophilic polymer
coated beadsDilacor XRCapsule contains• 2-4 triple layer tablets depending on dose• each tablets 60 mg• inner hydrophilic layer sandwiched by
hydrophobic out layers
* 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)
Improve Dissolution
Hot Melt Extrusion
Self-Emulsifying
Drug Delivery Systems
Spray Drying
Emerging Technologies
Many of the emerging technologies to improve solubilityreduce crystalline order amorphous or solution
Disordered
Higher free energy than xstal
Higher mobility than xstal
Not a single definable state like a xstal
DrugAmorph/Cryst
Solubility
Indomethacin 7
Iopanoic acid 6
Glipizide 11
Glybenclamide 17
Hydrochlorothiazide 34
Terfenadine 13
Griseofulvin 29
Spironolactone 110
Danazol 27
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
Andrews, et al.“Hot-melt extrusion: an emerging drug delivery technology” Pharmaceutical Technology Europe 21(1): (2009)
Kaletra Meltrex
Crowley et al. , “Pharmaceutical Applications of Hot-Melt Extrusion: Part 1” Drug Dev Ind Pharm 33:909-926 (2007)
Disperse/dissolve drug in softened/molten polymer-based matrix
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
http://www.bendres.com/drug-delivery-manuf.shtml
Spray drying produces a flowable powder
Often amorphous depending on formulation and processing
Journal of Pharmaceutical Sciences
• 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
Controlled release combination technologies
Amorphous forms
SEDDS
Nanoparticulates
Continuous processing
Ink-jet printing
Electrospray powder deposition
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
API & Excipients
Dispensing Blend BlendSieving Granulation
Mag
Stearate
Mag
Stearate
BlendTablettingCoating
ID test
Weight, Hardness,
Assay, UdUMoisture,
Disintegration
Example of RTRt
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
Shift in 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
Product
Quality
1. Process Understanding
CPP/CQA’s
Risk Assessment Review
Process Knowledge Report
2. Continuous
Quality
Monitoring
and Feedback
Process Control
Strategy
Batch Record
Data
Specifications
3. Process AnalysisInitial Process Performance
Evaluation
Acceptance & Release
Ongoing Process Monitoring
CpK Statistics Database
Annual Product Review
4. Continuous
Process
Improvement
Change
Management
Documentation
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
Metering
Feeders
In-Line Blender
Roller Compactor
In-Line Blender
Metering
Feeder
SCADA
Lube
1. Raw Material
2. Blend Uniformity
3. Compacts
4. Particle Size
5. Blend Uniformity
6. Content Uniformity
7. Assay
2
3
4
5
6, 7
Mill
API
Excipients Lubricant1
Continuous Wet Granulation
Thank You
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