Designing Quality into ER Products: Technology Selection 2nd FDA/PQRI Conference on Advancing Product Quality

Dissolution Testing and Specification for Extended Release Products

N. Bethesda, Maryland

Presented By: Al Berchielli October 6th , 2015

Acknowledgements • Pfizer Colleagues

– Formulation Design & Development • • • • • •

Avi Thombre Scott Herbig Sheri Shamblin Mike Roy Alistair Coupe Alan Carmody

– New Haven Clinical Research Unit

• Janyce Rogers, Robert Vitale, and Kennis Kahler

– Biopharmaceutics Group • • • • •

Ravi Shanker Kazuko Sagawa Rong Li Joe Kushner Fady Ibrahim

A. Berchielli – 2nd FDA/PQRI Conference on Advancing Product Quality, N. Bethesda, Maryland, October 6th, 2015

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Outline • ER Technology Selection (thoughts-> models -> feasibility) – Selection Process – Formulation Platform Toolbox

Today’s talk will focus on ER design for PK performance

• ER Formulation Digital Design – Osmotic Bilayer Tablet (example of predictive design tool) – Prototype in-vitro testing (dissolution & stability) Scintigraphy

• Early Clinical Concept Testing (PK)

Matrix In-vivo release rate

– Rapid design & small scale manufacture – Extemporaneous Preparation

PK Profile

• Pharmacy Compounding

– A. Berchielli – 2nd FDA/PQRI Conference on Advancing Product Quality, N. Bethesda, Maryland, October 6th, 2015

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Defining Pharmaceutical Quality • Pharmaceutical Quality:

The suitability of either a drug substance or drug product for its intended use. This term includes such attributes as the identity, strength, and purity. ICH Q6A Guidelines step 4 version 6-OCT-1999, p.19

“Deliver Clinical Performance” “Bioavailability”

Reference: CMC Strategy Forum Europe 2014 , Sarah Kennett, Ph.D.

A. Berchielli – 2nd FDA/PQRI Conference on Advancing Product Quality, N. Bethesda, Maryland, October 6th, 2015

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Defining and Selecting the MR (e.g., ER, DR, CR) Dosage Form

Pfizer Osmotic Digital Design

Note: Process generally takes ~2 weeks, but can be longer if dose changes

(e.g., as clinical study design progresses the formulation dose may change to cover a different range)

A. Berchielli – 2nd FDA/PQRI Conference on Advancing Product Quality, N. Bethesda, Maryland, October 6th, 2015

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MR (e.g., ER, DR, CR) Feasibility Assessment Flowchart Initial "criteria" dose; half-life stability; pH-solubility dose/solubility ratio therapeutic index regional permeability metabolism

Define CR objectives

Confirm initial criteria are met

pH-solubility profile

pH-stability profile

Excipient

Evaluate potential for precipitation in GI tract

Desired PK profile

Evaluate potential for Simulations degradation in GI tract

compatibility

Potential drug release profiles

Regional

permeability

Reference: Assessment of the feasibility of oral CR in an exploratory development setting DDT • Volume 10, Number 17 • September 2005, A. Thombre

Define target dose and release profile

rat/dog/ human

Assess presystemic

metabolism

Caco-2 absorption Predicted or actual human ADME

+ Dose solubility maps

Select technology via decision trees

+ Understand technology attributes + PGS attributes Equipment, expertise, cost, precedence + IP matters & competitive analysis

A. Berchielli – 2nd FDA/PQRI Conference on Advancing Product Quality, N. Bethesda, Maryland, October 6th, 2015

Recommendations  Degree of difficulty & probability of success  Resources/timeline  Solubilization strategies  Recommend excipients  Scale-up plan and and path to commercialization

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Some Key Considerations for Technology Selection • Dose-Solubility Map 1000

Dose (mg)

Solubilization Needed

Multiparticulates

Matrix tablet

Single Layer Osmotic tablet Single Layer Osmotic tablet

100

Bilayer Osmotic tablet Matrix tablet Drug solubility enables range of technologies

10 Multiparticulates

1 0.001

0.01

0.1

1

10

Solubility (mg/mL)

100

1000

• Special Considerations (Patient Demographics) – Children / Pediatrics (i.e., small dosage forms, chewable, multiparticulates, taste masking) – Elderly (e.g., small tablets…easy to swallow, QD dosing, combinations)

A. Berchielli – 2nd FDA/PQRI Conference on Advancing Product Quality, N. Bethesda, Maryland, October 6th, 2015

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Solid Oral ER Formulation Toolbox • Osmotic Tablets

Example Dissolution for Osmotic Tablet

–

Benefits: good IVIVC expected, administration w/food does not affect release rate

–

Limitations: higher dose (>500 mgA) design can be challenging for single unit

• Matrix Tablets –

Benefits: higher doses more feasible, simple manufacturing, highly used in industry, good performance for diffusion based or broad therapeutic index

Some Pfizer Example Products Below:

Procardia XL (Osmotic)

–

Limitations: Erosion based release mechanism challenging due to food effects, longer initial development time needed (multiple steps to refine PK performance), more clinical experience (PK/scintigraphy) helps to better understand performance

• Multiparticulates / Beads

Detrol LA (Beads in Capsule)

–

Benefits: Dose flexibility, more consistent transit

–

Limitations: More complicated processing, no EP currently in Pfizer, but can dose manufactured beads/multiparticulates in early studies

A. Berchielli – 2nd FDA/PQRI Conference on Advancing Product Quality, N. Bethesda, Maryland, October 6th, 2015

Pristiq ER (Matrix)

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Digital Design (Osmotic Design Model Example) • What does the model do?

– Allows for computer design of tablet weight, dimensions, coating components (e.g., different pore formers/permeability enhancers), coating composition, and coating amount to achieve a desired target release rate.

• Why use the model? – Quickly test different scenarios to get the formulation properties ~1 day – Reduces the need to iterate for different tablet sizes and release rates (get the coating composition right first time, saves experimental time, saves weeks) Dissolution ASAP Stability

• What happens next?

– Make small scale lab prototype (generally