start smart, move faster. · late stage discovery pre-clinical phase i drug development has many...

start smart, move faster.

OptiForm® solution suite as your early development toolkit to improve the odds of success

JULIEN MEISSONNIER

VICE PRESIDENT, SCIENCE & TECHNOLOGY

OCTOBER 25, 2017

©2017 Catalent Pharma Solutions. All rights reserved.

LATE STAGE DISCOVERY PHASE IPRE-CLINICAL

Drug development has many pitfalls which can stall, stop, or require you to rework your program

1 Drug Solubility: Importance and Enhancement Techniques, ISRN Pharmaceutics, Ketan T. Savjani, Anuradha K. Gajjar, and Jignasa K. Savjani, Published online 2012 Jul 5. doi: 10.5402/2012/1957272 Alavijeh, Mohammad S., Palmer, Alan M.; The Pivotal Role Of Drug Metabolism And Pharmacokinetics In The Discovery And Development Of New Medicines, Drugs: the investigational drugs journal 7(8):755-63 · September 20043 R. Lipp; The Innovator Pipeline: Bioavailability Challenges and Advanced Oral Drug Delivery Opportunities, Am. Pharm. Rev., 20134 “Clinical Development Success Rates 2006-2015” BIO; June 2016

Molecule’s Solubility>40% of NCE developed are insoluble in water1

Understanding of DMPK and ADME40% of drugs fail due to not having a good DMPK model2

Bioavailability ChallengesOnly 1 in 10 new molecules in active clinical development are readily bioavailable3

High rate of attritionAn estimated 34% of drugs fail between first toxicity study and Phase I

Likelihood of Approval:

$9.6%4

2© Catalent, Inc. 2017. All rights reserved.

High attrition rates may mask root cause

Select, assess, enhance and deliver the right drug candidate in early development

LATE STAGE DISCOVERY PHASE IPRE-CLINICAL

A partner offering early development, bioavailability enhancement and GLP / GMP formulation can put

your molecule on the FAST TRACK to clinic.

What is the right molecule?Assess molecule developability leveraging DPMK toolkit

What is the right molecule form?Expertise in solid state characterization and salt selection

What is the right formulation?Broadest selection of proven technologies to overcome challenges

What is the right dosage form?For conventional and enhanced dose forms, formulations designed for success


Optiform® Solution Suite Now Brings All These Services Into One Efficient Streamlined Offering

Phase 1 Dose FormsEnabled Formulations & First-in-Human Strategies

GMP Manufacturing

Release & Stability

Phase 1Candidate selection

Pre-formulation

Formulation Selection

OptiForm

Select

DMPK Modeling

Rapid Parallel Screen

GLP Studies

Enhanced or Conventional Formulations

Maximize Exposure while Maintaining Safety

Right Dosage Form

Right MoleculeRight Molecule

FormRight Formulation

Right GLP Formulation

Solid State Selection

Molecule Characterization

Particle Size Reduction

Lipid Formulation

Solid Dispersion

Conventional

DELIVERABLES


Working with Catalent gives your molecule the best chance at success, early

OptiForm® Solution Suite offers a full range of integrated pre-formulation services that helps you start early and start smart

• Rapid and efficient solubility testing with OptiForm® Select

• In-silico DMPK modeling

• Optimization through salt and polymorph screening with OptiForm® API

• Dedicated Scientific Advisorprovides insights and recommendations for preclinical and clinical development design

Phase 1Candidate Selection Pre-FormulationFormulation

SelectionGLP Studies

What is the right molecule to make a drug candidate ?

Assess molecule developability leveraging DMPK models

Assume we have 5 molecules with the following in vitro efficacy:

Compound 1 Compound 3 Compound 5 Compound 2 Compound 4

6

WHICH MOLECULE IS THE BEST?

We know which one is the most potent, but which one makes the best drug?


DCS = Developability Classification System

Efficacy: 1 is best, 5 is worst

SLAD: solubility- limited absorbable dose

DCS classification indicates that all molecules need formulation support, except compound 5…


Molecule Efficacy ranking

DCS class SLAD (mg)

Compound 1 5 IV 63

Compound 2 2 IIb 25

Compound 3 4 IIb 14

Compound 4 1 IIa 545

Compound 5 3 I 4000

Next, rank molecules by effect (efficacy) and look at developability (DCS Class and SLAD)


Powerful PBPK modeling software helps predict a successful pathway

GastroPlus™ can predict each molecule’s fraction absorbed (Fa) based on physicochemical properties:

Fa 500 mg = fraction of dose that is absorbed assuming a dose of 500 mg


8

Molecule Fa 500 mg(%)

Dose absorbed (mg)

Compound 1 31 155

Compound 2 38 190

Compound 3 39 195

Compound 4 19 95

Compound 5 100 500

GastroPlusTM is a trademark of Simulations Plus

© Catalent, Inc. 2017. All rights reserved.

1. DMPK properties

2. Developability (formulation)

3. Effect (efficacy)


Molecule Efficacy DCS class Fa 500 mg(%)

F(%)

Compound 1 5 IV 31 13

Compound 2 2 IIb 38 31

Compound 3 4 IIb 39 0,3

Compound 4 1 IIa 19 15

Compound 5 3 I 100 36

9

F only if clearance

is provided

This process allows a data-driven decision to be made on the ideal candidate using multiple inputs


Formulation Selection

Accelerate Using Proven High Throughput Screening Tools

We utilize unique solid state screening services to improve stability and solubility• OptiForm® API high-throughput salt form

screening platform• Polymorph screening

A best practice for candidates which provides data on:• Solubility / stability in relevant media (e.g.,

FaSSIF and FeSSIF)• Permeability• Photo and thermal stability• Particle state properties (size, density, flow)• Hygroscopicity

The Better You Know Your Molecule The More Effectively Its Challenges Can Be Solved

Reach critical decision points on formulation strategy sooner with OptiForm® Solution Suite

Phase 1Candidate Selection Pre-Formulation GLP Studies

Characterization

What is the right formulation?Selecting drug delivery technologies to overcome challenges



12

… how can it help us select a suitable formulation?

Avoid the Last Judgement for your molecule!We all know the BCS, but…

http://goo.gl/3v6GCq; https://goo.gl/DG0knr; https://goo.gl/6UaB59; https://goo.gl/D14HTV

Gordon’s Real BCS

SolubilityHigh Low

Perm

eability

Hig

hLow

Formulation Purgatory

Bioavailability Limbo


http://goo.gl/3v6GCq

https://goo.gl/DG0knr

https://goo.gl/6UaB59

https://goo.gl/D14HTV

Developing a modified classification system to assist in formulation

Biopharmaceutics Classification System (BCS) –regulatory tool

• Conservative, efficacy and patient safety in mind

— When is there no bio-inequivalence risk?

• Useful in late development and post-launch

Developability Classification System (DCS) –developability tool

• Aim: realistic, product development issues in mind

— What factors are likely to control the extent of oral absorption?

• Permeability, solubility/dose, dissolution rate

• Particularly useful in evaluating potential new drug candidates

Butler & Dressman 2010 J. Pharm. Sci. 99 (12) 4940–495413


14

The Developability Classification System (DCS) goes a needed step beyond BCS for formulation


BCS Classification

PE

RM

EA

BIL

ITY

H

L

SOLUBILITYH L

Source: Butler, J. The optimal use of biorelevant media & simple modeling for the prediction of in-vivo oral behaviour(http://www.apsgb.co.uk/Events/PastEvents/20110609/James%20Butler.pdf)

I

III IV

Good solubility and permeability

Good solubility Poor permeability

Poor solubility and permeability

IIa

IIbSolubility limited

Dissolution rate limited

Poor solubility Good permeability

II

DCS (Developability) vs. BCS Classification

Source: Dr. S. Page, Roche, CRS Meeting July 12-16, 2008, NY

http://www.apsgb.co.uk/Events/PastEvents/20110609/James Butler.pdf

Catalent’s data-driven approach helps you determine the most successful formulation strategy

&

1 CHARACTERIZE 2 FORMULATION STRATEGY

High throughput molecule

characterization

Physiochemical Properties

DCS Classification Technology Fit DMPK Modeling

DCS I No Issues

DCS IIaDissolution IssuesParticle engineering• Micronization• Co-micronization• Salt form

DCS IIbSolubility Issues• Lipid formulation• Solid dispersion

• Spray Drying• Hot Melt Extrusion

1

2

3

Abbreviated Approaches

1&2

API/Powder in Bottle

API/Powder in Capsule

Solution in PEG

Enabling Technology 3

Amorphous Dispersion

Lipid Formulation


?

Catalent’s data-driven approach helps you determine the most successful formulation strategy

&

1 CHARACTERIZE 2 FORMULATION STRATEGY

High throughput molecule

characterization

Physiochemical Properties

DCS Classification Technology Fit DMPK Modeling

DCS I No Issues

DCS IIaDissolution IssuesParticle engineering• Micronization• Co-micronization• Salt form

DCS IIbSolubility Issues• Lipid formulation• Solid dispersion

• Spray Drying• Hot Melt Extrusion

1

2

3

Abbreviated Approaches

1&2

API/Powder in Bottle

API/Powder in Capsule

Solution in PEG

Enabling Technology 3

Amorphous Dispersion

Lipid Formulation


Closing the gap between in vitro results and in vivo testing during formulation selection

17

in-vitro in-vivo


Formulation development > in-vitro dissolution > in-vivo testing

Formulation development

In-vitro dissolution

PBPK modeling

In-vivo testing

> > >


18

Dose XXX mgFasted

Ref #1 Ref #2 Ideal* 60% dissolved

30% dissolved

Fa (%) 67 42 88 83 78

F (%) 41 25 54 50 46

Cmax measured (ng/ml) 1490 781 nd nd nd

Cmax predicted (ng/ml) 1080 735 1535 1500 1410

• 100% of the dose immediately dissolved (ideal case) and no precipitationRef #1: milled drug substanceRef #2: coarse drug substance

• Borderline DCS IIa/IIb molecule

• High drug load targeted

• Concentration (Cmax) rather than AUC dependent activity

• PBPK model established correlation with fed and fasted conditions



19

• Parallel screening approach of various solubility enhancing technologies

Formulation Technology

Stability Drug Load(%)

Solubility Inc.(%)

Cmax Increase (fold)

Lipid DDS + 17 95 1.43

Hot Melt Extrusion - 30 10 nd

Spray Drying + 35 50 1.35

Micronization* + 80 35 1.28


Comprehensive Strategies for Soluble & Poorly Soluble Molecules to Move Quickly into GLP and Clinical Studies

FAST and COMPREHENSIVEtransition to IND Enabling GLP & Phase I:

• GLP study materials based on intended route of administration (oral and IV)

• Enhanced & Abbreviated Strategies for first-in-human clinical studies

• API–in Capsule/Bottle

• Liquid in Bottle

• Simple Blend Capsules

• Direct Compression Tablets

• Micronization

• Softgel

• Amorphous: Spray Dry & HME

Phase 1Candidate Selection Pre-Formulation GLP StudiesFormulation

Selection

NEW OptiForm® Solution Suite: Fastest & Most Efficient Path From Candidate Selection To Phase I

FasterAll the solutions you need seamlessly integrated in one program with a single point of contact to advance your molecule quickly

FlexibleTailored to meet your goals and needs of your molecule while conserving API

Fact-basedData-driven approach improves confidence in next steps guided by recommendations from dedicated scientific advisors

Provided by the experts in drug development with 80+ years of experience and over 500 completed development programs




Acknowledgments

Jan Neelissen, Scientific Adviser for PK/PD modeling, Catalent Pharma Solutions


Upcoming Webinar:

Integrating PK modelling and in vivo studies

to guide early phase development

November 28, 2017

Visit www.catalent.com for more information

Catalyst + Talent.Our name combines these ideas.

[email protected]+1 888 SOLUTION (765-8846)00800 88 55 6178 EUROPE

23©2016 Catalent Pharma Solutions. All rights reserved

THANK YOU FOR YOUR

ATTENTION!

better treatments by design™satisfying the needs of patients, prescribers and payers with your dose form strategy

DAN PEIZER

STRATEGIC MARKETING DIRECTORCATALENT PHARMA SOLUTIONS

Successful early formulation is only half the battle…

Most new drugs launch into well-established disease areas, and according to McKinsey, 67% of all drug launches fail to meet expectations1

25

1Ahlawat, H. Chierchia, G., van Arkel, P. “The Secret of Successful Drug Launches” https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/the-secret-of-successful-drug-launches, March 2014

Drug archetypes:

Strong differentiation,high patient burden

Low differentiation,established standards

Unmet need

Over 50% of launches require innovative approaches meeting stakeholder needs to be successful vs. competitors

Considering the enormous time and effort spent on drug development and launches, how can this be changed?


https://www.mckinsey.com/industries/pharmaceuticals-and-medical-products/our-insights/the-secret-of-successful-drug-launches

A deep understanding of the stakeholders in success and their needs is the first step

© Catalent, Inc. 2017. All rights reserved. 26

• COMPLIANCE: Dose burden / frequency, food effects

• RESOLUTION: Patient variables, side effects

• CLINICAL OUTCOMES: performance vs. standard of care

• ECONOMIC OUTCOMES: cost, symptom control / resolution

• EASE OF USE: Tailored to patient group considerations

• EXPERIENCE: Easy to consistently remain on therapy

• TIME LINES: CMC, stability, scale-up

• SAFETY & EFFICACY: Optimized bioavailability

• DIFFERENTIATION: Efficacy and compliance improvements

Patients are the most critical stakeholder in dose design

60%of NMEs approved

since 2009 were not outcomes-

optimized

API-Wasting Formula (cost)

Potential to Self-

Administer

Increased Regimen

Complexity

Complex Handling/

Distribution

© Catalent, Inc. 2017. All rights reserved.27

Therapeutic adherence is a way to assess real world patient considerations

28

For every 100 prescriptions written for a chronic outpatient drug…

… up to 16 never even reach the pharmacy…

… an additional 20% are poor responders…

… and 40% are non-adherent after six months.


As a result, 70% are non-adherent after 12 months…

Only

1 in 4 receive

expected clinical benefit

Therapies FAIL if patients don’t get the drug!


What are the significant drug development challenges?

Safety (75%)

Achieving target profile (53%)

Solubility (42%)

Permeability (34%)

Targeted delivery (31%)

Cost (30%)

Patient dosing convenience (29%)

Patient adherence (28%)

Half life (25%)

Impact on patient’s drug regimen (24%)


When do patient factors lead to changes in dose design?


Never

Rarely

Occasionally

Frequently

Preclin Phase I Phase II Phase III

31

Improving outcomes: patient-focused design

Absorption rate kinetics (first/zero order)

Active/passive transport

Age-specific differences (ADME)

Aging-related receptor performance differences (PD)

Binding saturation

Bioavailability (AUC)

Cmax/Tmax/Half-life

Compactibility

Compliance-enhancing pakaging

CYP450 interactions

Defined Daily Dose

Device – ease of use

Dissolution rate

Dose dumping

Dose form color

Dose form diameter

Dose form length

Dosing frequency

Dysphagia

Molecule & polymorph properties

PK & PD properties

Patient-observed properties

Product Design Factors Linked to Impaired Outcomes 1

1 Catalent/Catalent Institute analysis of >2,000 clinical studies indexed in PubMed32


First pass effect

Food co-administration instructions

Food effect (labeling)

Formulation stability

Gastric/intestinal degradation

Handling, flow, blending

Hygrosopicity

Luminal pH differences

Molecular stability

Multi-lingual packaging

Particle shape

Particle size

Patient insert design

Perceived dose adequacy (MDIs)

Permeability

Primary package design

Secondary package design

Product Design Factors Linked to Impaired Outcomes 1

1 Catalent/Catalent Institute analysis of >2,000 clinical studies indexed in PubMed



PK & PD properties



Difficult to take or administer

Regimen complexity

Side effects

Low perceived efficacy

CostDifficult to supply

or distribute


PK & PD properties




Catalent helps you design a solution for any oral drug development challenge

Catalent has the broadest array of technologies to provide formulations that optimize bioavailability, stability and manufacturability.


Real-world success of your therapy requires that your stakeholder’s needs are both understood and met

A Patient First Perspective to Dose Design Can Make All the Difference

A drug treating chronic psychiatric conditions in patients known to have therapeutic compliance issues

A dose form preventing cheeking or spitting and improving dose

experience

A modified release profile to avoid food effects; A way to minimize

unintentional exposure

36

ZYDIS® ODTFAST DISSOLVE TABLETS

OPTISHELL®

NON-GELATIN CAPSULES

A dose form with taste masking and flavor options retaining dose loading

and therapeutic properties FLEXDOSESM

SERVICES© Catalent, Inc. 2017. All rights reserved.

A chemotherapeutic with narrow therapeutic index for which plasma peak concentrations could significantly impact safety and efficacy

An over the counter treatment for children with a bitter API traditionally in a hard tablet dose

Catalent brings it together with Better Treatments By Design™

Optimizing your molecule and overcoming formulation challenges are critical to success – but are not the final step!

A comprehensive approach to development is key:


Select & Optimize

API

Overcome formulation challenges

Assess stakeholder

needs

Select optimal dose

form

Robust CMC & scale-up

With extensive development, formulation, and drug delivery technologies and expertise, Catalent is uniquely capable of

offering this holistic approach to improving outcomes

When should dose design begin?

While there are reasons not to optimize dose form for Phase I…

• Time and expense

• Relatively high chance of failure (~30%)2

• Reduced dose for safety and flexibility in dose escalation

38

…BEWARE of ignoring dose design going into Phase II!

• Number of participants increases 2-5 times

• Patients with disease / condition

• Assessment for efficacy and side effects

• Chance of failure more than DOUBLES to ~67% 2

2 https://www.fda.gov/forpatients/approvals/drugs/ucm405622.htm


Intelligent dose design decisions made EARLY may improve both clinical outcomes and save time and expense of

reformulation later

In summary, better therapies start with a comprehensive approach and strategy

Get the right stakeholder insights!

Get the right molecule!

Get the FORM of the molecule right

Get the FORMULATION right

Get the DOSE FORM / DEVICE right

Get the PACKAGING & LABELING right





THANK YOU FOR YOUR

ATTENTION!

tipping the scales in your favorimportance of building scalability and manufacturability into your development program

MICHAEL J VALAZZA, R.PH.

VP, BUSINESS DEVELOPMENT

CATALENT PHARMA SOLUTIONS

You’ve selected a finished dose formulation –NOW WHAT??

Scale-up can be a major challenge, especially those requiring complex formulations

Some questions that need to be addressed include:

If successful at bench scale, can it be scaled to commercial?

Will quality and stability targets be achieved?

Is the batch size and process economically feasible?

Can my manufacturing partner handle the process and scale needed and supply where I need it?

The average technical transfer to a suitable site can take 12-18 months and cost up to $1,500,000 (depending on formulation and regulatory requirements). So these are

CRITICAL concerns!


Choose a partner that starts with the end in mind

The benefits achieved in time and cost savings by working with full service development partners who manufacture what they formulate can be SIGNIFICANT

• Seamless transfer from early stage formulations and methods to dose design and scale up

• Availability of proper scale equipment and experience with commercialization

• In-house analytical services for quality and stability testing

Catalent works with the end in mind, helping solidify your CMC section and providing advanced drug delivery

technologies that can achieve optimal real-word results


Seamless transition from development to supply.


Guiding Principles

• A single Development Plan

• This document will cover the full development activities for the project.

• This plan will evolve through the course of development & transfer

• Plan reviewed and endorsed by the team.

• Major changes (timeline, resources, level of risk) to the baseline plan will be reviewed with the team.

Only take a risk to gain a specific reward46


Risk Assessment Tools

• Two Approaches

1. Prospective: At start of project, attempt to characterize and understand risk elements and their impact

2. Continuous: Throughout project, at pre-defined stages

• Several tools and approaches to identify, communicate and mitigate risks.

• The team should conduct these assessments together.


Risk Management vs. Crisis Management

• Crisis Management = reactive

— Historically very good at crisis management – “can-do” attitude

• Risk Management = proactive planning to manage risk

— Historically done sporadically, not systematically

— May have resulted in over-managing some risks while not managing others

• Objective is not to avoid all risks, but to properly manage those where the potential benefit outweighs the costs/impacts


Cultural Fit

• More Products: Do they have a culture of innovation that can benefit the Pharma Co.?

— Lifecycle management options

— Modified Release dosage forms?

— Unique delivery systems

• Better Treatments: Can they improve drug products by using their Drug Delivery Systems?

— Bioavailability Enhancement solutions

• Softgel, Hot Melt Extrusion, Spray Dried Dispersions, Nano-technology

— Oral Disintegrating Tablets, Controlled Release platforms

— Biologics innovations, unique Blow-Fill-Seal unit dose designs

3rd Party Selection Criteria


A full range of solid oral dose forms.Immediate and controlled release.


Versatile delivery technologies leveraging our Softgel manufacturing expertise

Abuse resistance, reducing API recovery


Catalent Announces Agreement to Acquire Cook Pharmica

• On October 23, 2017 Catalent announced the closing of the acquisition of Cook Pharmica

• This acquisition is in response to continued growth in biologics and high demand for drug substance and drug product services across all phases of product development

• Combines Catalent’s rapidly growing Biologics business with Cook Pharmica’s biomanufacturing capacity, deep expertise in liquid and lyophilized sterile formulation, and fill/finish across vials, prefilled syringes, cartridges.

55

+


Operational

• Are they productivity and performance-metric driven?

• Do they practice Lean or Six Sigma to drive out costs?

— How successful has it been?

— Will they provide the statistics?

• Do they have Environmental, Health and Safety rigor?

• Does it appear as if their ability to reliably supply is a foundation of their business?

3rd Party Selection Criteria

Quality Financial

LegalAccount

Management


A global network to supply your product where its needed

Catalent’s 31manufacturing sites spanning 5continents and global team of over 10,000…

• …produce over 7,000 products and ship 70 billion doses in over 240,000shipments annually

• …serve more than 1,000 customers in over 80 countries


Review & Closure

• Be Open & Honest

• Assess exercise

• What went well?

• What didn’t go well?

• Distill learnings and revise process as needed


5959





THANK YOU FOR YOUR

ATTENTION!

start smart, move faster. · late stage discovery pre-clinical phase i drug development has many...

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