3980 s1 10_gardner

Designing quality in

Colin R Gardner,

Currently: CSO, Transform Pharmaceuticals Inc

Lexington, MA, 02421

Formerly: VP Global Pharmaceutical R&D

Merck & Co Inc.

Acknowledgement for useful discussions:

Dr. Scott Reynolds,

Executive Director, Pharmaceutical Development,

Merck and Co Inc.

www.transformpharma.com

Presentation to Manufacturing Subcommittee of the FDA Advisory Committee for Pharmaceutical Science.

Sept 17 , 2003

Summary

• Continuum of process development activities from NCE selection through manufacturing

• Fundamental NCE characterization and process development leads to meaningful control points

• Success of the scale up exercise is judged by rational comparison of meaningful process and product parameters

• Fingerprint parameters are identified to monitor process robustness and used to flag issues before control is lost

Issues within the industry

Lifecycle Management

Development

0.5 - 2 yrs 1 - 2 yrs 1.5 - 3.5 yrs 2.5 - 4 yrs 0.5-2 yrs

R&D takes6.5 - 13.5 yearsUp to $800MM

Discovery

Drug Discovery / Development / Marketing

Market

2-5 yrs

Submission&Approval

10-20 yrs

Source: PRTM

Phase 3 Phase 2a/bPhase 1Pre-

clinicalDevelopment

TargetsHits

LeadsCandidate

Challenges: - Find safe and effective drugs - Speed to market

Drug company products

• Approved label claim used to position product in the market

•The marketed dosage form(s)

•The API

Drug company products

• Approved label claim used to position product in the market

•The marketed dosage form(s)

•The API

Intra-company Consequences

• R&D heads focus on potency, selectivity, safety and clinical response

• do not uniformly recognize the importance of investment in process chemistry and formulation development

• Inexperienced clinical staff often set timelines and targets independent of product development capabilities

• The goals and rewards of Discovery, Development and Manufacturing staffs are often not aligned

• CEO’s have not regarded manufacturing excellence as a competitive advantage

Issues created by the regulatory agencies

• Depth of understanding of process engineering

•Timeframe to review and understand the regulatory filing

•Training of compliance inspectors – especially for PAI’s

PAI examples

Scaling up a suspension formulation

Batch size Biobatch 10 liters

Commercial batch 100 liters

Mixing time

15 mins 45 mins

drug excipients drug excipients

FDA inspector conclusion: “The processes are different”

Preparation tank

Filling tank

Filling points

Re-circulating filling line

Pump

Suspension formulation preparation and filling

FDA inspector conclusion:

“Any stoppage of the filing process > 15 mins should result in destruction of the entire batch

Preservative adsorption to tubing

What can we do about this situation?

Manufacturing processes start with the choice of the NCE, its form and formulation

We must link discovery, early development, process scale-up and manufacturing

• Develop methodologies to improve:

• Candidate selection

• Form selection and Formulation design

• Process development and optimization

• Process control

• Scale-up and tech transfer

• Process validation

• Process monitoring and continuous improvement

• Demonstrate reduced risk to regulatory agencies

• Obtain regulatory relief

• Demonstrate value to company management

Industry role

HOW?

Building in “developability”

1. Picking better development candidates:

Discovery Development

Target

HTS

SyntheticchemistryScale up

100-500mg

Animal modelProbe Tox,

PK, met

Pre-clinical Research & Early Development Process

2-4 cmpds

GLPTox

F & F

Process chemistry

Sample collection

in vitro selectivity

in vitro metabolism

in vitro Tox

Animal modelefficacy

Earl

y D

iscovery

Lead

op

tim

izati

on

Pharm. Sci.

Ph I

Genomics Libraries

Hits to Leads

Lead optimization

New R&D Challenges

DrugDiscovery

Preclinicaldevelopment

Clinical development

Resourceconstraints

Timeconstraints

Discoveryrevolution

Pharmaceutical Development

Discovery Development

Target

HTS

SyntheticchemistryScale up

100-500mg

Animal modelProbe Tox,

PK, met

2-4 cmpds

GLPTox

F & F

Process chemistry

Sample collection

in vitro selectivity

in vitro metabolism

in vitro Tox

Animal modelefficacy

Earl

y D

iscovery

Lead

op

tim

izati

on

Pharm. Sci.

Ph I

Genomics Libraries

Hits to Leads

Lead optimization

Pre-clinical Research & Early Development Process

Candidate selection:Building in “Developability”

Lead (active molecule)

MetabolismSelectivity

Potency

LO (optimized molecule)

Physical properties

Potency

Selectivity

Metabolism

Best leadsPhysical / chemical

propertiesBiopharmaceutics

2. Form and formulation selection

Product Development Timeline

DevelopSynthetic

Route

FirstSupplies

Non GLPProbes

IND/PhaseI/II Safety

Drug Substance Transfer toManufacturing

Validation

Safety Assessment

• Extended Safety Studies• Degradate Qualification

Carcinogenicity

PAI

LaunchQuantities

Product Development• Preformulation Studies• Biopharm Evaluation

• Formulation Design

• Phase I/IIA Formulations• Analytical Methods

• Composition & Process Defined• Probe Stability

$5-10MM

• Process Development and Scale Up• Biobatch• Specifications• MCSS

Transfer to Manufacturing

First inMan

PhaseIIB

Approval

• Develop Process and Scale-up• Establish Specifications

• Phase I/IIA• Wide Dose Range• Multiple Formulations

• Phase IIB Dose Range

•Phase III•Final process•>1/10 scale

PAI

Dis

cove

ry

Lau

nchValidation

LaunchQuantities

Clinical Program

PhaseIII

$250-800MM

3-10 years 4-8 years

FileNDAWMA

crg development timeline

Exploration of solid forms

solvent

process impurityor degradate

process (t,T)

Traditional

process (t,T)

process impurityor degradate

solvent

High throughput

Crystalline TrihydrateSolubility ~0.73 mg/mL

Weakly Crystalline Anhydrous FormSolubility >100 mg/mL

Ritonavir: HIV protease inhibitor

ONH

HN

NH

N

CH3

O

OHO

CH3H3C

O

N

SS

NH3C

H3C

ABT-538 discovered Launch of semi-solid capsule/polymorph I Polymorph II appears, <50% solubility

Product pulled from the market Massive effort to reformulate the product Reformulated softgel capsule launched

Case history:

199219961998

1998 - 19991999

Summary of Ritonavir Crystal Forms

IV

mp 122 °C mp 125 °C mp 80 °C mp 97 °C mp 116 °C

Launch in 1996

Summer of 1998

TransForm 2002 – 6 week effort

Launch in 1996

Summer of 1998 Morissette et al. PNAS 100, (2003).

2002 5 forms found

TPI 745: New salt form with improved solubility

So

lub

ility

New TPI Form Has Faster Onset

Salt form with “solubility modifier”

30 mpk P.O.

0

5000

1 104

1.5 104

2 104

0 2 4 6 8

TPI-745A

TPI-745B

time, hours

Cmax Tmax AUCTPI-A 23.2±6.2 1.3±1.0* 139±26

TPI-B 19.6±4.6 2.1±1.1 135±24

T-745 21.4±4.0 2.8±1.6 150±43

Parent

0

10

20

30

0 5 10

TPI-336

Marketed capsule

Neat chemical in capsule

Solution in 2:1 PEG/water

Dose, mg/kg

Faster Onset, Increased Bioavailability and Linear Dose Response

New form & formulation combination significantly improves dissolution, resulting in better onset and bioavailability

The current norm

The future

environmental

raw material properties

process conditions

environmental

raw material properties

process conditions

3. Process development

Pharmaceutical Process Development:Objectives

• Provide a continuous link from early phase characterization to final manufacturing process

• Define process based on unit operations approach

• Provide a road map for tracking success of scale up activities and technology transfer

• Enable effective process monitoring and improvements

Pharmaceutical Process Development: Initial Design

• Identify parts of process which are most susceptible to failure upon scale-up

• Conceptual “scale down” of the final manufacturing process into the pilot plant and the lab

Process Understanding

• Determine fundamental process constraints– Where appropriate, utilize unit operations

which are most forgiving – lower risk

• Identify underlying principles which control process– Avoid “black box” analysis– Identify appropriate process parameters to

monitor and control - value of PAT - provides confidence about process robustness

Pharmaceutical Process Development: Optimization

environmental

raw material properties

process conditions

environmental

raw material properties

process conditions

• Optimization Studies– Find regions of process parameters where

performance is most stable– Design process to operate within this region.

Process optimization

Region where process is unstable

Process most stableTarget values

environmental

raw material properties

process conditions

Pharmaceutical Process Development: Optimization

environmental

raw material properties

process conditions

• Optimization Studies– Find regions of process parameters where

performance is most stable– Design process to operate within this region.

•Process Robustness–Stress ranges of variables–Include ranges in materials, environmental conditions, process parameters

Region where process is robust

Region where process is unstable

Process most stableTarget values

Process optimization

Pharmaceutical Process Development: Process Control

• Define process through measurable, quantitative endpoints – PAT?

• Eliminate dependence upon qualitative endpoints

• Evaluate how process can respond to variations in process equipment performance and/or raw materials characteristics

• Provide continuous fingerprint of process performance – NOT regulatory specifications

Pharmaceutical Process Development: Continuous Improvement

• “Hooks” for future process improvement.– Plan into development program collection of

“fingerprint” data for future comparisons– Design validation protocols to collect similar

“fingerprints”– Use in manufacturing to continuously

monitor process operation and status

Process optimization

Region where process is unstable

Process most stableTarget values

Region where process is robust

Fingerprint region to monitor process robustness and prospectively identify drifts

Summary

• Continuum of process development activities from NCE selection through manufacturing

• Fundamental NCE characterization and process development leads to meaningful control points

• Success of the scale up exercise is judged by rational comparison of meaningful process and product parameters

• Fingerprint parameters are identified to monitor process robustness and used to flag issues before control is lost