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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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