Quality Standards for Medicines, Supplements, and Food Ingredients throughout the World

PQRI

December 17, 2009

Rockville MD

Closing Remarks

Roger WilliamsUSP

Topics

• The Past

• The Present (Current Meeting)

• The Partners (Competitors)

• The Future

Acceptance Criteria

Process Variability

Analytical Measurement and

Uncertainty

Certified Reference Material

Release Specifications

Realms of Specifications & Measurements

Measurement

“Trueness”

Manufacturing

1974 Drug Bioequivalence Panel/OTA

Members

• Berliner

• Cluff

• Doluisio

• Melmon

• Nadas

• Oates

• Riegelman

• Shideman

• Zelen

• Robbins

Conclusions

• No BE standards

• BA causes therapeutic failures

• Procedures available

• BA critical for some drugs/not all

• GMPs and compendial standards

inadequate

• New standards needed

• Research needed, including

in vitro/animal models

• Strengthen current standards/submit

studies

• Eliminate exemptions

• New organization

FDA BA/BE Guidances

• BA/BE Studies for Orally Administered Drug Products

• Statistical Approaches to Establishing BE

• Bioanalytical Method Validation

• Waiver of In Vivo BA/BE Studies for IR Solid Oral Dosage Forms Based on a BSC Classification System

• Food-Effect BA and Fed BE Studies

• Extended Release Oral Dosage Forms: Development, Evaluation, and Application of In Vitro/In Vivo Correlations

• Dissolution Testing of Immediate Release Solid Oral Dosage Forms

• BA/BE for Nasal Aerosols/Nasal Sprays for Local Action

• Metaproterenol Sulfate and Albuterol MDIs In Vitro (General Missing)

• Corticosteroids, Dermatologic (Topical) In Vivo (General Missing)

Topics

• The Past

• The Present (Current Meeting)

• The Partners (Competitors)

• The Future

FDA’s Laws, Regulations, and

Guidances on Equivalence: 3:

Guidances

Complex Drug Substances, Excipients,

and Reagents Coordinating Committee

Co-Chair: Roger Williams

Co-Chair: Yuan-Yuan Chiu

Executive Secretary: June Cory

Botanicals Technical Committee

Chair:

Complex ExcipientsTechnical Committee

Chair:

Protein Products Technical Committee

Chair: D. Wu

rDMA Reagents Technical Committee

Chair:

Synthetic Peptides Technical Committee

Co-Chair: C. Niu (CDER)

Co-Chair: I. Berkower (CBER)

Bovine Spongiform

Encephalopathy WG

Chair: Y. Chiu

Comparability Protocol WG

(CBER/CDER)

Chair: S. Moore/B. Yetter

Botanicals CMC WG

Chair: Y. Chiu

Vice Chair: C. Chen

Liposomes WG

Chair: L. Zhou

Cyclodextrins WG

Chair: D. Koble

Glycosylated Proteins WG*

Chair: Non-glycosylated Proteins WG

Chair: D. Wu

Monoclonal Antibodies WG

Chair: E. Nashed

rDNA Enzymes WG

Chair: S. Moore

CTD-Biotechnology WG

(CBER/CDER)

Chair: N. Goldman/D. Wu

Natural and Synthetic

Conjugated Estrogens WG

Facilitator: Y. Chiu

Chair: W. Adams/T. Layloff

Exec. Sec: D. Moore

Oligonucleotide WG*

Chair: R. Kambhampati

rDNA Derived Cell

Metabolites WG (CDER/CVM)

Chair: D. Wu

Antibiotic WG

Chair: Richard Adams*Completed Guidances: Q6B, March 1999June 29, 1999

Overarching Guideline (CHMP/437/04).

“Guideline on Similar Biological Medicinal Products”

Biotechnology- derived proteins

IFN-Epoetin LMMH

Quality

Non-

clinical

Clinical

Non-

clinical

Clinical

Non-

clinical

Clinical

Annex guidelines -

specific data

requirements

EMEA Biosimilar Guidelines (2009)

filgrastim

Non-

clinical

Clinical

Non-

clinical

Clinical

Non-

clinical

Clinical

Somatropin

General guidelines

Defines philosophy

and principles

Non-

clinical

Clinical

Insulin

Under review

Under Development

From John Purves & Peter Richardson, EMEA

Topics

• The Past

• The Present (Current Meeting)

• The Partners (Competitors)

• The Future

Research Consortia

• Program on the Pharmaceutical Industry/MIT

• National Institute for Pharmaceutical Technology and Education

• Center for Biomedical Innovation (CBI)

• Center for Process Analytical Chemistry (CPAC)/University of Washington

• European Federation for Pharmaceutical Sciences

• Center for Pharmaceutical Processing Research/Purdue

• Consortium for the Advancement of Manufacturing of Pharmaceuticals (CAMP), Pharmaceutical Manufacturing Initiative/MIT

• Product Quality Research Institute

• New Jersey Institute of Technology

• Center for Advanced Research in Biotechnology

• Critical Path

• Reagan-Udall

• Innovative Medicines Initiative

COUNTERFEIT DRUGS

Manufacture

Wholesale

Pharmacy

Demand Quality

Needle in a Haystack

How did

you find it?

How will you

find another

one?

How will you

prevent it from

happening

again?

Topics

• The Past

• The Present (Current Meeting)

• The Competitors

• The Future

Identity Confirmation

Every pharmaceutical ingredient, formulated product, together with its

packaging materials has unique characteristics or “fingerprints” that can

be probed using various regions of the electromagnetic spectrum.

Spectroscopic Methods of Counterfeit Detection

TruScan System Logic

NO YES

determine if aspects of

measurement statistically

contradict reference model

Suspect(Raman evidence of

discrepancy)

PASS(no Raman evidence to

believe otherwise)

measurement reference

(library)

• The Science of Measurement embraces both experimental and

theoretical determinations at any level of uncertainty in any field

of Science and Technology.

– Fundamental metrology includes the establishment of

measurement units, new measurement methods, realization

of measurement standards and the transfer of traceability.

– Applied metrology concerns the application of measurement

science to manufacturing, ensuring the suitability of

measurement instruments, their calibration and quality

control of measurements.

– Legal metrology concerns regulatory requirements of

measurements and measuring instruments.

Metrology

The Food and Drugs Landscape: White Papers

Standards/Conformity Assessments

• Conformity assessment:Demonstration that specified requirements (standards) relating

to a product (medicine/ingredient), process/system (GxPs), person/body

are fulfilled (professional)

• Conformity assessment includes:Sampling and testing, inspection, supplier’s declaration of conformity,

certification, and management system assessment and registration

• It also includes:Accreditation of the competence of those activities by a third party

and recognition (usually by a government agency) of an

accreditation programs

• PartiesFirst parties (sellers); second parties (buyers); third parties

(individual group independent of buyers and sellers)

India Expansion: View-01

USP Convention Headquarters

Quality Standards for Medicines, Supplements, and Food Ingredients throughout the World

Thank You

Research to Policy

PQRI as a Collaborative Vision for the Future

Product Quality Research Initiative

Initial Meeting

February 10-11, 1998

JW Marriott Hotel

Washington, DC

ROGER L. WILLIAMS, M.D.DEPUTY CENTER DIRECTOR FOR PHARMACEUTICAL SCIENCE

CENTER FOR DRUG EVALUATION AND RESEARCHFOOD AND DRUG ADMINISTRATION

TOPICS

.Themes

.Structures

.The Collaboration: PQRI

.The Future

PQRI

INDUSTRY

FDA ACADEMIA

And More

• Critical Path

• Reagan-Udall

• Innovative Medicines Initiative

REVIEWR

ES

EA

RC

H

POLICY

FDA Industry

Academia

Research Policy Review

WHO Bilaterals/Trilaterals ICH Industry

ICH: Common Technical Document Information

Technology

FDA Industry

Academia

Good Review

Practices

PQRI

(Quality)

Review

Management

CDDI

(Safety /Efficacy)

1. Clinical

2. Clinical

Pharmacology

3. Pharmacology/

Toxicology

4. Biopharmaceutics

5. Chemistry

Manufacturing

Controls

6. Microbiology

7. Environmental

Assessments

TRACKS

1.

2.

3.

4.

5.

6.

7.

Medical Policy

Coordinating Committee

Pharmacology/

Toxicology

Coordinating Committee

Biopharmaceutics

Coordinating Committee

Chemistry Manufacturing

Controls Coordinating

Committee

USP

EURO

SEARO

WEPRO

AFRO

PAHO

EMRO

Overview

TOPICS

.Themes

.Structures

.The Collaboration: PQRI

.The Future

Food and Drug Administration

Commissioner

Deputy Commissioner/Senior Advisor

Special Assistant for Investigations

Executive Assistant

Chief Mediator and Ombudsman

Senior Advisor for Science

Office of Executive

Operations

Office of the

Administrative

Law Judge

Office of Equal

Employment Opportunity

and Civi l Rights

Office of the

Chief Counsel

Office of Internal

Affairs

Deputy Commissioner

for OperationsDeputy Commissioner

for PolicyDeputy Commissioner

for External Affairs

Deputy Commissioner

for Management and

Systems

Office of Planning and Evaluation

Office of Management

Office of Information Resources Management

Office of Health Affairs

Office of International Affairs

Office of Legislative Affairs

Office of Consumer Affairs

Office of Public Affairs

Office of AIDS and SpecialHealth Issues

Office of Women's Health

Regulations Policy andManagement Staff

Policy Development andCoordination Staff

Policy Research Staff

International Policy Staff

Office of Regulatory Affairs

Center for Biologics Evaluation and Research

Center for Drug Evaluation and Research

Center for Devices andRadiological Health

Center for Food Safety andApplied Nutrition

Center for VeterinaryMedicine

Office of Orphan ProductsDevelopment

National Center forToxicological Research

Office of Science

OTR Organization

OFFICE OF

TESTING AND RESEARCH

OTR

J. MacGregor

Regulatory Research

and Analysis Staff

RRAS

JF Contrera

Laboratory of

Clinical Pharmacology

LCP

JM Collins

DIVISION of

Product Quality

Research

DPQR

KP Flora

DIVISION of

Applied

Pharmacology Research

DAPR

FD Sistare

DIVISION of

Testing and Applied

Analytical Development

DTAAD

TP Layloff

TOPICS

.Themes

.Structures

.The Collaboration: PQRI

.The Future

PQRI

l A process for industry, academia and the FDA to collaborate on focused research projects designed to meet the challenges associated with product quality aspects of drug development and evaluation

Definition of Research

• Retrospective Investigations

• Workshop Seminars

• Prospective Studies

• Literature Searches

• Other

AA

PS

Work

shops

Tra

nsd

erm

al W

ork

shop (

144)

1986

Tar

get

ed D

rug D

eliv

er S

yst

ems

(67)

1987

In V

itro

and I

n V

ivo T

esti

ng a

nd

Corr

elat

ion f

or

Ora

l C

ontr

oll

ed/M

odif

ied

Rel

ease

Dosa

ge

Form

s (4

14)

1988

In V

ivo P

ercu

taneo

us

Pen

etra

tion/A

bso

rpti

on (

389)

1989

Sta

bil

ity G

uid

elin

es f

or

Tes

ting P

har

mac

euti

cals

Pro

duct

s (3

83)

1989

Topic

al T

her

apeu

tic

Pro

duct

s (2

75)

1990

Anal

yti

cal

Met

hods

Val

idat

ion (

495)

1990

Inte

gra

tion o

f P

har

mac

od

yn

amic

s, P

har

mac

okin

etic

s an

d

Tox

icokin

etic

s in

Rat

ional

Dru

g D

evel

opm

ent

(673)

1991

Der

mat

olo

gic

al T

her

apeu

tics

Pro

duct

s II

(244)

1994

Sca

le-u

p o

f O

ral

Soli

d D

osa

ge

Form

s (2

48)

1991

Dev

elopm

ent

of

Sta

ndar

ds

and S

pec

ific

atio

ns

in t

he

1990s

(186)

1992

Inte

rnat

ional

Chem

ical

and P

har

mac

euti

cal

(160)

1992

Sca

le-u

p o

f O

ral

Ex

tended

Rel

ease

Dosa

ge

Form

s (2

48)

1992

Work

shop o

n P

har

mac

euti

cal

Pac

kag

e(9

9)

1993

The

Role

of

Dru

g S

olu

bil

ity i

n F

orm

ula

tion D

evel

opm

ent

(43)

1993

Sca

le-u

p o

f L

iquid

and S

emis

oli

d D

isper

se S

yst

ems

(169)

1993

Chem

istr

y a

nd P

har

mac

y c

onsi

der

atio

n D

uri

ng t

he

Dru

g D

evel

opm

ent

and R

evie

w P

roce

ss (

184)

1993

Sta

bil

ity G

uid

elin

es f

or

test

ing P

har

mac

euti

cal

Pro

duct

s (3

75)

1994

Work

shop o

n M

anufa

cturi

ng S

ite

Chan

ges

(239)

1994

Wo

rksh

op o

n E

val

uat

ion o

f O

rall

y A

dm

inis

tere

d

Hig

hly

Var

iable

Dru

gs

and D

rug F

orm

ula

tions

(371)

1995

Work

shop o

n I

mpuri

ties

in D

rug S

ubst

ance

s an

d P

roduct

s (3

80)

1995

AA

PS

Work

shop o

n D

esig

nin

g t

he

Glo

bal

Chem

istr

y, M

anufa

cturi

ng

and c

ontr

ols

(C

MC

) D

oss

ier

(304)

1995

Dis

solu

tion C

alib

rati

on a

nd T

esti

ng (

266)

1995

AA

PS

/FD

A W

ork

shop o

n P

oly

morp

his

m o

f D

rug S

ubst

ance

s (2

77)

1996

The

Impac

t of

Tec

hnolo

gy C

han

ges

on R

egula

tory

Met

hods

for

Phar

mac

euti

cals

(156)

1996

Sca

le-U

p o

f A

dhes

ive

Tra

nsd

erm

al D

rug D

eliv

ery S

yst

ems

(200)

1996

Bio

equ

ival

ence

of

Topic

al D

erm

atolo

gic

al D

osa

ge

Form

s

Met

hods

for

Eval

uat

ion o

f B

ioeq

uiv

alen

ce (

263)

1996

AA

PS

work

shop o

n c

GM

P a

nd V

alid

atio

n I

ssues

in

the

Anal

yti

cal

Lab

ora

tory

(255)

1997

AA

PS

/FD

A W

ork

shop o

n D

rug S

ubst

ance

Man

ufa

cturi

ng C

han

ges

(465)

1997

AA

PS

/CR

S/F

DA

Work

shop o

n S

cien

tifi

c F

oundat

ion a

nd A

ppli

cati

ons

for

Bio

phar

mac

euti

cs C

lass

ific

atio

n S

yst

em a

nd

In V

itro

-In V

ivo C

orr

elat

ions

(334)

1997

AA

PS

Work

shop o

n A

sses

smen

t of

Val

ue

and A

ppli

cati

ons

of

In-V

itro

Tes

ting o

f T

opic

al D

erm

atolo

gic

al D

rug P

roduct

s1997

AA

PS

Wo

rksh

op o

n C

MC

in t

he

Dev

elopm

ent

of

Dru

gs

Incl

udin

g B

iote

chnolo

gy-D

eriv

ed P

roduct

s1997

Collaborating Organizations

CDER/FDA Center for Drug Evaluation and Research

AAPS American Association of Pharmaceutical Scientists

GPIA Generic Pharmaceutical Industry Association

NAPM National Association of Pharmaceutical Manufacturers

NDMA Nonprescription Drug Manufacturers Association

NPA National Pharmaceutical Alliance

PDA Parenteral Drug Association

PhRMA Pharmaceutical Research and Manufacturers of America

PQRI Development Efforts

January 11, 1996March 5, 1996April 18, 1996September 30, 1996December 16, 1996July 1, 1997September 11, 1997December 16, 1997

PQRI Workshop (Proposal Draft 15)

Planning Meetings (Proposal Draft 1.0)

PQRI Proposed Structure

l Responsible for developing the specific mission and operating policies of the Initiative.

l Review research outcomes and assess the overall impact of Initiative activities

Steering Committee

l FDA

– Director OPS, Chair CMC CC, and Chair B CC

l One member and an observer from:

n AAPS

n GPIA

n NAPM

n NDMA

n NPA

n PDA

n PhRMA

Steering Committee:

Membership

l FDA

– Review representatives from CMCCC, and BCC

– Research representatives from OTR

l Other members nominated by the collaborating organizations and nominated by the Steering Committee

Technical Committee:

Membership

l Establish a general program in the topic area

l Define specific research projects

l Establish priorities

l Evaluate research proposals

l Select working group members

l Review research outcomes

l Evaluate regulatory impact of research and policy recommendations

Technical Committee: Function

l Design research studies

l Supervise research projects

l Summarize and report research results

l Develop recommendations reflecting the research for transmission to the Technical Committees for further consideration and endorsement

Working Groups: Function

Drug Substance Technical

Committee: Umbrella Hypothesis

l Adherence to cGMP’s and a sufficient number of critical physical and chemical drug substance specifications will be adequate to show unchanged identity, strength, quality, purity, and potency of a drug substance in the presence of pre- and post approval changes in: 1) manufacturing: scale, site, equipment, controls and process; 2) routes of synthesis; 3) packaging; 4) suppliers of drug substance.

Drug Product Technical

Committee: Umbrella Hypothesis

l Adherence to cGMP’s and a sufficient number of established product specifications will be adequate to show unchanged product quality and performance of drug products that undergo any pre- and post approval changes in: 1) components and composition; 2) manufacturing scale; 3) site of manufacture; 4) equipment and process; and 5) packaging.

Biopharmaceutics Technical

Committee: Umbrella Hypothesis

l In vitro and physico-chemical product tests can be developed to assure equivalent bioavailability of many pharmaceutical dosage forms.

Science Management Technical

Committee

l The goal of this technical committee will to develop strategies that maximize the efficiency of the processes that produce an optimally performing drug product that meets public health objectives for identity, strength, quality, purity, and potency.

FDA-AAPS: CRADA Objectives

l AAPS provides a “neutral” environment for collecting and disseminating PQRI generated information

l AAPS and FDA provide scientific expertise for PQRI programs

l AAPS and FDA administer PQRI activities and programs

Next Steps/Issues

l MOU with AAPS

l CRADA with AAPS

l Steering Committee/Technical Committees

– Incorporate Public Comments

l Technical Committees

– Finalize Programs and Projects

– Prioritize/Start Project(s)

l Resource/Other Issues

TOPICS

.Themes

.Structures

.The Collaboration: PQRI

.The Future

FDA Industry

Academia

Research Policy Review

WHO Bilaterals/Trilaterals ICH Industry

ICH: Common Technical Document Information

Technology

FDA Industry

Academia

Good Review

Practices

PQRI

(Quality)

Review

Management

CDDI

(Safety /Efficacy)

1. Clinical

2. Clinical

Pharmacology

3. Pharmacology/

Toxicology

4. Biopharmaceutics

5. Chemistry

Manufacturing

Controls

6. Microbiology

7. Environmental

Assessments

TRACKS

1.

2.

3.

4.

5.

6.

7.

Medical Policy

Coordinating Committee

Pharmacology/

Toxicology

Coordinating Committee

Biopharmaceutics

Coordinating Committee

Chemistry Manufacturing

Controls Coordinating

Committee

USP

EURO

SEARO

WEPRO

AFRO

PAHO

EMRO

Overview

PQRI Conference

Day 1:

1. Introduce the PQRI Initiative

2. Results from FDA-Sponsored Research Activities

Day 2:

1. Input to Steering Committee

2. Input to Technical Committees

Day 3:

Role of AAPS

Summaries from Breakout Session

Close