Targeting specific patient populations for distinct …targeted release Sustained release LMP...

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Targeting specific patient populations for distinct oral dosing formulation challenges – flexible technology is key

DDF – Berlin (Germany) – March 13, 2019

Univ.-Prof. Dr. Sven Stegemann

Technische Universität Graz

Table of content

▪ Introduction

▪ The regulatory framework FDA & EMA

▪ Disease incidences in the pediatric patient population

▪ Considerations for patient-centric drug product design

▪ Key formulation design targets for pediatric/multimorbid patients

▪ Industrial considerations in patient-centric & pediatric product

▪ Case studies – Melt Spray Congeal (MSC) technology

▪ Conclusion

STE – FDA/PQRI Conference – April 10, 2019

Introduction

▪ Lonza is focusing on Fit-for-Purpose compound & formulation design throughout the

product life-cycle and across all patient populations

▪ This presentation will focus on addressing key formulation challenges for pediatric patients

Custom API Development

• Early Intermediates• GMP Intermediates• HPAPI• Cytotoxic Payloads

Bioavailability Enhancement Drug Delivery

• Extended Release• Osmotics• Multiparticulates• Targeted Delivery• Colonic Delivery

• Micronization• Nanotechnologies• Solid Dispersions• Lipid / Liquid-Based

Formulations

Introduction

Some facts about outcomes of medicines grew the awareness of the patient factor

▪ “Drugs don't work in patients who don't take them” [citation Everett Koop]

▪ Adherence in primary care is about 25-80 % [Gapgemini Report: Estimated annual pharmaceutical revenue loss

due to medication non-adherence (2012)]

▪ In 2000, 44,000 to 98,000 deaths occur yearly due to medical errors, making medical errors

the eighth leading cause of death in the United States [American Hospital Association. Hospital Statistics.

Chicago. 1999]

▪ Therapeutic Failures and adverse drug withdrawal events were associated with 5.9% of

hospitalizations; of these admissions, 90.0% were rated as potentially preventable mostly due

to medication nonadherence and suboptimal prescribing. [Marcum et al (2012) [J Gerontol A Biol Sci Med Sci.

67(8):867–874]

▪ Illusion of Control [Casarett, D. NEJM 374;13:1203 (2016)]

STE – DDF Conference – March 13, 2019

Regulatory framework – FDA & EMA

The past decade patient centric product focus

▪ ICH Q8 (R2) Guideline on pharmaceutical development (2009)

− quality defined as the suitability drug substance/product for intended use

− “in all cases, the product should be designed to meet patients’ needs and intended product

performance”

▪ Pharmacovigilance Module VI (2012)

− This includes adverse reactions which arise from:

• “the use outside the terms of the marketing authorisation, including overdose, off-label use,

misuse, abuse and medication errors”

▪ Guidance for industry (FDA) Safety consideration for product design to minimize medication errors

(April 2016)

− Therefore, the goal is to design a drug product that enables safe and correct use and

eliminates or reduces design elements which could cause use related hazards.

− In order to identify and assess potential medication errors, the product designer must understand

how the drug product will be used, including who will handle or use the product, the chronicity of

use, the environments of use, and how the end users will interact with the drug productSTE – DDF Conference – March 13, 2019


▪ The continuing evolution of patient focused/centric drug development

− Real World Evidence (RWE) and Real World Data (RWD)

− Patient involvement in drug development and the regulatory

decision process

− „intended use“ as one endpoint (Patient centric design)

− „special populations“ with regard to their needs

(pediatrics, geriatrics, frail, …)

− Mandatory requirement to develop a pediatric

formulation/product design



Pediatric regulatory imperatives & trends

▪ Pediatric investigation plan (PIP, EU) or pediatric study plan (PSP, US) are required

during early clinical development of adult products for:− NCE / NME

− Different formulation

− Additional indications

− New dosing regimens

− New route of administration

− Extended release formulations

▪ Regulations are trending toward fewer waivers/exceptions to the development of

pediatric medicines.

− Oncology indications will no longer get a waiver in the US (RACE Act, 2017)

▪ Increase in expedited drug development and review programs (Priority Review (70%),

Breakthrough Therapies (43%) Fast Track (45%)

− Total development time-lines down to 5 years

Disease incidences in the pediatric population

Incidences of disease in children in developed countries


highest

lowest

ranking10

oncology

Neonatal disorders

CNS diseaseInfections

Congenital disorders

Considerations for patient-centric drug products

Pharmaceutical drug product

▪ The comprehensive presentation of the therapeutic entity to the end user (patient/caregiver/ health care

provider) including the type of dosage form; formulation; dose; dosing frequency; primary, secondary, and

tertiary packaging; medical device; dosing devices; instructions for use (as in the SmPC/PIL/ product label);

and other authority-approved patient support tools and programs.

Patient centric pharmaceutical drug product design

▪ The process of identifying the comprehensive needs of individuals or the target patient population and

utilizing the identified needs to design pharmaceutical drug products that provide the best overall benefit to

risk profile for that target patient population over the intended duration of treatment.

Stegemann et al AAPS J 18(5):1047-55 (2016)STE – DDF Conference – March 13, 2019

Considerations for patient-centric drug products

Patient-centric pharmaceutical drug product design elements

▪ Divided into:

− Design Drivers (Characteristics disease/condition, Characteristics drug substance/ physiology,

characteritistics drug therapy, characteristics drug product, patient characteritics, medication

management (adherence and administration), Usability (handling, storage and disposal)

− Design inputs (e.g. specific needs tobe considered)

− Design outputs (e.g. design option to address such needs)

Stegemann et al AAPS J 18(5):1047-55 (2016)STE – DDF Conference – March 13, 2019

Key formulation design targets for pediatric/multimorbid patients

▪ Key formulation „design drivers“

− Swallowing disfunctions (either immature or pathological swallowing physiology)

▪ Key formulation „design inputs“

− Dose adaptation required either by

• Weight

• Body surface

• Kidney cearance

• Pharmacogenomic based

− Excipient safety

• Metabolism limitations

• Dosing escalation (polypharmacy)

▪ Key formulation „design outputs“

− Individual dosing

− Dose swallowability/pallatability/acceptability


Taste Masking

Mini-tablets &

Multiparticulates

Industrial considerations for patient-centric & pediatric products

Target product profile

Performance and Safety

Patient Profile

Dosage Form

Selection

For example:

• Meet target release profile• Provide good, consistent

absorption• Excipient selection and level

For example:

• Taste/odor• Identification• Palatability• Usability• Acceptability

For example:

• Formulation / dosage form compatibility

• Scalability, packaging• Usability, storage, convenience• Facilitates dosing accuracy

Optimal area: High probability that the final

dosage form will meet all needs


▪ Development resource allocation

− Existing expertise and technology availability

− Technology/product flexibility (e.g. drug release, dose strength,etc)

− Timelines and complexity

▪ Commercial viability

− Degree of standardization

− Maximization of scale

− Transferability

− COGS

▪ Market compatability

− Level of patient/user acceptance

− Degree of intuitive perception




▪ Key for delivering Fit-for-Purpose compound & formulation design are Technology Platforms

▪ They need to be flexible with regard to:

− API solubility

− Dose strength

− Release patterns

− Taste masking

− Dosage form

− Dose administration

▪ Multiparticulate design can

provide such features


▪ The multiparticulate formulations are highly flexible & well understood and use established

technology platforms

▪ They are available in-house or through experienced CDMOs (e.g. Lonza)


Sizes1.0 - 3.0 mm

Immediate Modified

Crystalline

AmorphousD

esir

ed D

rug

Form

Desired Release Target

Industrial considerations in patient-centric & pediatric product

▪ The multiparticulate formulations are highly flexible & well understood and use established

technology platform

▪ They are available in-house or through experienced CDMOs (e.g. Lonza)


Sizes1.0 - 3.0 mm

Immediate Modified

Crystalline

AmorphousD

esir

ed D

rug

Form

Desired Release Target



▪ Multiparticulates and Mini-tablets are proven for

their high degree of acceptability for pediatric

patients

▪ They provide

− Ease of administration by care givers

− Flexibility in dosing and dose adjustment

− Safe and easy swallowing

− High swallowed dose accuracy

− Effective taste-masking

− Transportability and storage/stability Acceptability of coated/uncoated minitablets and 15% glucose sirup from 3 performed clinical studies

Case studies – Melt Spray Congeal (MSC) technology

MSC Technology Platform concept


Aqueous Solubility

Compound: Solubilized/crystalline Target Release mechanism: Solubilization, emulsification, digestion

Compound:

Crystalline

Target Release mechanism:

Diffusion

Compound:

Solubilized


Erosion, solubilization

Compound:

Crystalline


Erosion/diffusion

HighLow

Targ

et

Rele

ase R

ate

Slo

wF

ast

BA enhancement Coating may be needed

for taste-masking/

targeted release

Sustained

release

LMP formulations can be readily tailored to fit compound properties and meet required dissolution profiles.

Case studies – Melt Spray Congeal (MSC) technology


either

Extrusion

Melt Tank

Melt Feed

MSC Sieve Fluid Bed Encapsulation

Used during functional coating

(Not required for non-coated LMPs)

AtomizationCongealing

PSD Control is Important for

Coating Uniformity Oral pH

Gastric pH

Coated LMP

Core

http://www.ima-pharma.com/Product/EN/Products-F575/Solid_Dose_Processing_/_Manufacturing-S591/Capsule_filling-T610/Capsule_fillers_for_small_and_medium_production-Q613/Capsule_filler___Zanasi_70C-M31.html

http://www.google.com/url?sa=i&rct=j&q=&esrc=s&source=images&cd=&cad=rja&uact=8&ved=0ahUKEwjvhqyjjeXLAhVHXh4KHRv-DogQjRwIBw&url=http://dir.indiamart.com/impcat/melting-tanks.html&bvm=bv.117868183,d.dmo&psig=AFQjCNGPHHEZgdzQ_D3H4ceE1aV0gFb1Og&ust=1459313664832451

Case study – Melt Spray Congeal (MSC) technology

Development of a high

dosed drug (2 g) MSC

formulation suited for

pediatric patients

▪ Dissolution rate depend

on the formulation

(formation of hydrophilic

pores)

▪ Taste masking by pH

dependent release (e.g.

in acidic media) or

coating

▪ Mouthfeel determined

by the particle size (for

pediatrics target is < 0.4

mm)


5-minute soak (15% released) 10-minute soak (24% released) 15-minute soak (32% released)

30-minute soak (52% released) 60-minute soak (75% released)

All Images 300x magnification.

50 mm 50 mm 50 mm

50 mm 50 mm

Case study 1 – Melt Spray Congeal (MSC) technology

▪ Azithromycin MSC in vitro release confirmed constant (linear) release kinetics through

the formation of hydrophilic pores


0

25

50

75

100

0 10 20 30 40 50 60

% D

isso

lved

Time (min)

Release mechanism: Aqueous

pore diffusion


▪ Formulation optimization to match the optimal therapeutic window for the pediatric

population was achieved through an IVIVC


0.0

2.0

4.0

6.0

8.0

10.0

0 15 30 45 60 75 90 105

In Vitro % Released at 30 min

AU

C(0

-4 h

r) m

cg

.hr/

mL

2% poloxamer

3% poloxamer

4% poloxamer

Immediate release sachet

35 70

Acceptable tolerability demonstrated

Acceptable bioavailability demonstrated

0.0

2.0

4.0

6.0

8.0

10.0

0 15 30 45 60 75 90 105

In Vitro % Released at 30 min

AU

C(0

-4 h

r) m

cg

.hr/

mL

2% poloxamer

3% poloxamer

4% poloxamer

Immediate release sachet

35 70

Acceptable tolerability demonstrated

Acceptable bioavailability demonstrated

Faster in vitro release

Incr

ease

d B

A

In Vitro – In Vivo

Relationship


▪ Comparative in-vivo study confirmed improved safety (absence of initial high plasma

peak and maintenance of the MIC plasma concentration) in pediatric patients


Mean serum azithromycin concentration following administration of 1 x 2 g sustained release

or 2 x 1g commercial sachet azithromycin to health subjects under fasting conditions

Commercial

sachet

LMP particles

consisting of the

compound suspended

in a glyceryl behenate

and poloxamer matrix MSC

formulation


▪ Development of 3 MSC enteric formulations for a phase 1 study with different intestinal

release profiles

Target Product Profile


Goal Deliver 3 MR products to clinic for Ph1 healthy volunteer study & supporting stability

Target Patients Children less than 12 years old

Drug Form Maintain crystalline salt form

Dose 5-25 mgA, Q.D.

Drug Loading Less 10% w/w for uniform dosing and robust capsule filling

Dosage Form Bulk multiparticulate for flexible dosing in the clinic

Release Profile Gastric protection to avoid dose dumping, modified release targeting the upper GI

Particle Size Less than 0.4 mm for mouthfeel and younger patients

Stability Predicted greater 2 years at room temperature


Formulation release kinetics determined and developed based

on predictive models for drug absorption

▪ A drug-containing lipid core was formulated for in vitro release rates

spanning 2-8 hours

▪ A enteric coating was applied for gastric protection of 1 hour


Controlled Release Technology Map

In-Vitro: %Release vs. Time PK: Concentration vs. Time

Stomach→Intestine

3

2

1

3

2

1

100 µm

Conclusion

▪ The inclusion of patients and their needs in drug product development continues to emerge in

regulatory guidelines and outcome based healthcare decisions

▪ The provision of pediatric formulations is already a mandatory regulatory requirement for new

product development programs

▪ Patient centric drug product design using the 505(b)(2) regulatory pathway provides

substantial opportunities for enhanced generic developments serving patient populations with

unmet medical needs

▪ Multiparticulates and mini-tablets are based on established technology platforms, suitable to

deal with multiple drug characteristics and release kinetics while maintaining the flexibility to

serve different dose strength, patient populations and manufacturing efficiency

▪ The Melt Spray Congeal (MSC) technology allows fast screening and tailoring of drug

formuation for special populations like pediatric patients


Univ.-Prof. Dr. Sven Stegemann Lonza Pharma & Biotech

Graz University of Technology Small Molecule Technologies

Inffeldgasse 13

8010 Graz Dr. Eduardo Jule

Austria Director Business Development - Europe

e-mail: [email protected] e-mail: [email protected]

Phone: +43 316 873 0422

Mobile: +49 172 6054869 Mobile: +34 679 380 580

Fax: +43 (316) 873 - 1030422


mailto:[email protected]

Targeting specific patient populations for distinct …targeted release Sustained release LMP...

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