fundamentals of internationa regulatory affairs, first edition comparative matrix

Copyright © 2010 by the Regulatory Affairs Professionals Society.All rights reserved.

ISBN: 0-9787006-5-1Every precaution is taken to ensure accuracy of content; however, the publisher cannot accept responsibility for the correctness of the information supplied.

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Regulatory Affairs Professionals Society iii

Foreword

The global regulatory environment is changing at an ever-increasing speed to address scientific and technological developments. Competent Authorities are struggling to keep pace with the continually changing demands of the life sciences industry. At the same time, numerous efforts have been made to deregulate, streamline and harmonize regula-tory processes across regions as the industry continues to move toward globalization.

Varying registration regulations mean duplication of effort for each country or region to obtain marketing approval that is time-consuming and expensive. According to the International Conference of Harmonisation (ICH), the move to rationalize and harmonize regulations has been driven by concerns over rising costs of healthcare and R&D, the need to meet public expectations and the push to have life-saving medicines reach patients with minimum delay. Other international initiatives include the Global Harmonization Task Force (GHTF) for medical device regulations, the Pharmaceutical Inspection Convention and Pharmaceutical Inspection Cooperation Scheme (jointly referred to as PIC/S) for Good Manufacturing Practice compliance, the International Organization for Standardization (ISO) and the International Cooperation on Harmonisation of Technical Requirements for Registration of Veterinary Medicinal Products (VICH).

This trend makes now the right time to explore the international dimension to regulatory affairs. This book discusses regulatory topics related to human and veterinary medicinal products, medical devices, food supplements and cosmetics. In addition, it reviews specific selected topics such as generic medicinal products and biosimilars, biotech products, orphan drugs, advertising and promotion and enforcement.

Although regulations are enacted at the national or regional level, companies working in a fast-moving global environment may find this book a good source of information that highlights harmonization efforts and provides useful information about specific regulatory requirements.

Chapter content is complemented by a comparative matrix of guidelines and regulations, a glossary and a compre-hensive index. I hope this will be an excellent reference book for regulatory professionals working in multiple markets and a useful study tool for the Regulatory Affairs Certification General Scope exam.

I would like to extend special thanks to the Regulatory Affairs Professionals Society (RAPS) for its excellent work in helping and guiding the regulatory profession and for giving me the opportunity to write this book. In addition I would like to thank all contributing authors for their time and effort.

Salma Michor, MBA, PhD, CMgr, RACPrincipal Author and EditorMichor Consulting e.U.Vienna, Austria

iv Regulatory Affairs Professionals Society

Acknowledgements

Principal Author and Editor

Salma Michor, MBA, PhD, CMgr, RACMichor Consulting e.U.Vienna, Austria

Contributing Authors

Matthias Dormeyer, PhDMDC RegAfffairs GmbHCologne, Germany

Heidi Feik, MSc, RACBaxter Innovations GmbHVienne, Austria

Ulrich Granzer, PhDGranzer Regulatory Consulting & ServicesMunich, Germany

Walter Simanko, PhD, RACIntercell AGVienna, Austria

The Regulatory Affairs Professionals Society expresses its gratitude to the volunteers who devoted their time and professional expertise to advance the regulatory profession by contributing to this essential reference text for regula-tory professionals.

Regulatory Affairs Professionals Society v

Table of ContentsChapter 1: Introduction to Regulatory Affairs ............................................................................................................. 1Chapter 2: Premarket Requirements/Dossier Requirements......................................................................................... 7Chapter 3: Authorization Procedures for Medicinal Products .....................................................................................15Chapter 4: Quality Systems and Inspectorate Process—Pharmaceuticals ....................................................................31Chapter 5: Pharmaceutical Postmarketing and Compliance ........................................................................................43Chapter 6: High-Risk Products Derived From Biotechnology ....................................................................................55Chapter 7: Generic Drug Products and Biosimilars ....................................................................................................69Chapter 8: Principles of Orphan Drugs ......................................................................................................................81

Chapter 9: Food Supplements and Cosmetic Products ...............................................................................................87Chapter 10: Veterinary Medicinal Products ..................................................................................................................97Chapter 11: Over-the-Counter Products (OTCs) .......................................................................................................111Chapter 12: Medical Device Premarket Requirements ................................................................................................117Chapter 13: Technical and Regulatory Requirements for Medical Devices .................................................................137Chapter 14: Postmarket Requirements for Medical Devices........................................................................................147Chapter 15: In Vitro Diagnostic Medical Devices ......................................................................................................153Chapter 16: Advertising and Promotion .....................................................................................................................161Chapter 17: Compliance and Enforcement ................................................................................................................167

Figures and TablesFigure 2-1. Diagrammatic Representation of the Organization of the ICH CTD ........................................................ 9Figure 3-1. Overview of a Typical Quality Risk Management Process .........................................................................20Figure 3-2. Procedure for Drug Registration ...............................................................................................................25Figure 3-3. Mutual Recognition Procedure in the EU .................................................................................................25Figure 3-4. Decentralised Procedure (DP) in the EU ..................................................................................................26

Figure 3-5. Centralised Procedure (CP) in the EU ......................................................................................................27Table 4-1. Application of ICH Q7 to API Manufacturing .........................................................................................36Table 5-1. Application of Process Performance and Product Quality Monitoring System Throughout the Product Lifecycle ...................................................................................................................................................45Table 5-2. Application of a CAPA System Throughout the Product Lifecycle ............................................................46Table 5-3. Application of Change Management System Throughout the Product Lifecycle .......................................47Table 5-4. Application of a Management Review of Process Performance and Product Quality Throughout the ........ Product Lifecycle ......................................................................................................................................48Table 5-5. Differences Between Old and New EU Variations Regulations .................................................................50Table 5-6. FDA Postapproval Change Reporting .......................................................................................................51Table 5-7. Summary of Australian Guidelines on Drug Sponsor Reporting of Adverse Drug Reactions .....................52Table 7-1. Biosimilars Authorized for Marketing by the European Commission ........................................................75Table 7-2. Some FOBs Approved by FDA as §505(b)(2) Generic Drugs ...................................................................76Table 8-1. Epidemiologic Thresholds of Orphan Diseases in Various Countries/Regions ...........................................84Table 8-2. Overview of Different Orphan Drug Legislation ......................................................................................85Table 9-1. RDAs of Vitamins and Minerals ...............................................................................................................89

vi Regulatory Affairs Professionals Society

Table 9-2. Dietary Reference Intakes (DRIs): Recommended Intakes for Individual, Vitamins ..................................90Table 9-3. Dietary Reference Intakes (DRIs): Recommended Intakes for Individuals, Elements ................................91Table 9-4. Dietary Reference Intakes (DRIs): Tolerable Upper Intake Levels (UL) Vitamins ......................................92Table 9-5. Dietary Reference Intakes (DRIs): Tolerable Upper Intake Levels (UL), Elements ....................................93Figure 10-1. VICH Steering Committee .....................................................................................................................101Figure 10-2. Information Flow in the Pharmacovigilance System ................................................................................106Table 12-1. Class A Device ........................................................................................................................................121Table 12-2. Class B Device ........................................................................................................................................122

Table 12-3. Class C Device ........................................................................................................................................122Table 12-4. Class D Device .......................................................................................................................................123Table 12-5. Noninvasive Devices ...............................................................................................................................124Table 12-6. Invasive Devices ......................................................................................................................................126Table 12-7. Active Devices ........................................................................................................................................128Table 12-8. Additional Rules .....................................................................................................................................130Figure 12-1. Decision Tree Noninvasive Devices .........................................................................................................131Figure 12-2. Decision Tree Invasive Devices ................................................................................................................132Figure 12-3. Decision Tree Invasive Devices ................................................................................................................133Figure 12-4. Decision Tree Active Devices ...................................................................................................................134Figure 12-5. Decision Tree Active Devices ...................................................................................................................135Figure 12-6. Decision Tree Additional Rules................................................................................................................136Figure 13-1. Premarket Use of the STED ....................................................................................................................139Figure 13-2. Postmarket Use of the STED ..................................................................................................................141Figure 13-3. Postmarket Use of the STED ..................................................................................................................143Figure 13-4. Key Activities for Supplier Control ..........................................................................................................144

Figure 14-1. CAs Reporting Flowchart .......................................................................................................................149Figure 15-1. General GHTF Classification System for IVD Medical Devices .............................................................154Figure 15-2. Regulatory Requirements Related to the Device Risk Class .....................................................................154Table 15-1. Classification Rules for IVDs ..................................................................................................................155Table 15-2. Classification Rules for IVD ...................................................................................................................156Table 15-3. Class A Device ........................................................................................................................................157Table 15-4. Class B Device .......................................................................................................................................158Table 15-5. Class C Device .......................................................................................................................................158Table 15-6. Class D Device .......................................................................................................................................159Figure 17-1. Flow Chart—Overview of Typical Audit Process .....................................................................................173

Regulatory Affairs Professionals Society 177

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Con

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178 Regulatory Affairs Professionals Society

Comparative Matrix of the Regulations Across Product Lines

Intr

oduc

tion

to

Reg

ulat

ory

Aff

airs

Dru

gs a

nd D

evic

es

Regu

latio

ns a

nd G

uide

lines

Dev

ices

GH

TF •

SG2-

N54

R8:

2006

, Med

ical

Dev

ices

Pos

t Mar

ket S

urve

illan

ce: G

loba

l Gui

danc

e fo

r A

dver

se E

vent

Rep

ortin

g fo

r M

edic

al D

evic

es, 1

8 D

ecem

ber

2006

•SG

5-N

2R8:

2007

, 29

May

200

7E

C•

ME

DD

EV

2.1

2-1

rev

6, G

uide

lines

on

a m

edic

al d

evic

e vi

gila

nce

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m, D

ecem

ber

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Dru

gsU

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ral F

ood,

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g, a

nd C

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of 1

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as

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tion

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lic L

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Com

mis

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Dir

ecti

ve 2

003/

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trod

ucin

g de

taile

d sp

ecifi

cati

ons

as r

egar

ds th

e re

quir

emen

ts la

id d

own

in C

ounc

il D

irec

tive

93/

42/E

EC

w

ith

resp

ect t

o m

edic

al d

evic

es m

anuf

actu

red

utili

sing

tiss

ues

of a

nim

al o

rigi

n•

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ulat

ion

(EC

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of t

he E

urop

ean

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iam

ent a

nd o

f the

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ncil

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ptem

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on

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tica

lly m

odifi

ed fo

od a

nd fe

edIC

H•

Phar

mac

ovig

ilanc

e Pl

anni

ng E

2E (

Cur

rent

Ste

p 4

vers

ion,

Nov

embe

r 20

04)

Cha

pter

1

Mai

n To

pics

The

mai

n ai

m o

f dru

g re

gula

tion

is to

kee

p un

safe

pro

duct

s of

f the

mar

ket.

It m

ust b

e st

ress

ed, h

owev

er, t

hat n

o m

edic

inal

pro

duct

is 1

00%

saf

e.

Test

s ca

rrie

d ou

t on

a po

pula

tion

of l

imit

ed s

ize,

und

er c

ontr

olle

d co

ndit

ions

, dur

ing

clin

ical

tria

ls m

ay fa

il to

cat

ch c

riti

cal i

ssue

s an

d ad

vers

e ev

ents

. O

nce

a pr

oduc

t is

on th

e m

arke

t, un

expe

cted

adv

erse

rea

ctio

ns m

ay o

ccur

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cted

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erse

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may

occ

ur a

t a h

ighe

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nce

than

exp

ecte

d.

Hen

ce, d

rug

regu

lati

ons

call

for

drug

mon

itor

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in th

e po

stau

thor

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ion

and

post

mar

ket p

hase

s. M

ost c

ount

ries

hav

e en

acte

d la

ws

to r

egul

ate

med

ical

dev

ices

, foo

d an

d fo

od s

uppl

emen

ts a

nd c

osm

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pro

duct

s in

add

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med

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Non

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requ

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to d

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arm

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HT

F.

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gula

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s fo

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th d

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and

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crea

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in im

port

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nd G

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F ha

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arm

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nce

repo

rtin

g and

post

mar

ket s

urve

illan

ce.



Pre

mar

ket

Req

uire

men

ts (

Dru

gs)

Re

gula

tions

and

Gui

delin

es

Pre

mar

ket

Req

uire

men

ts/

Dos

sier

Req

uire

men

ts

ICH

•O

rgan

izat

ion

of th

e C

TD

for

the

Regi

strat

ion

of P

harm

aceu

tical

s for

Hum

an U

se M

4(R

3) (

Cur

rent

Ste

p 4

vers

ion,

Jan

uary

200

4)•

The

Com

mon

Tec

hnic

al D

ocum

ent f

or th

e Re

gistr

atio

n of

Pha

rmac

eutic

als f

or H

uman

Use

: Qua

lity—

M4Q

(R1)

, Qua

lity

Ove

rall

Sum

mar

y of

Mod

ule

2 M

odul

e 3:

Qua

lity

(Cur

rent

Ste

p 4

vers

ion,

Sep

tem

ber

2002

)•

The

Com

mon

Tec

hnic

al D

ocum

ent f

or th

e Re

gistr

atio

n of

Pha

rmac

eutic

als f

or H

uman

Use

: Saf

ety—

M4S

(R2)

, Non

clin

ical

Ove

rvie

w a

nd N

oncl

inic

al

Sum

mar

ies o

f Mod

ule

2, O

rgan

izat

ion

of M

odul

e 4

(Cur

rent

Ste

p 4

vers

ion,

Dec

embe

r 20

02)

•T

he C

omm

on T

echn

ical

Doc

umen

t for

the

Regi

strat

ion

of P

harm

aceu

tical

s for

Hum

an U

se: E

ffica

cy—

M4E

(R1)

, Clin

ical

Ove

rvie

w a

nd C

linic

al

Sum

mar

ies o

f Mod

ule

2, M

odul

e 5

Clin

ical

Stu

dy R

epor

ts (C

urre

nt S

tep

4 ve

rsio

n, S

epte

mbe

r 20

02)

•T

he C

omm

on T

echn

ical

Doc

umen

t for

the

Regi

strat

ion

of P

harm

aceu

tical

s for

Hum

an U

se: Q

ualit

y—M

4Q(R

1), Q

ualit

y O

vera

ll Su

mm

ary

Mod

ule

2, M

odul

e 3:

Qua

lity

(Cur

rent

Ste

p 4

vers

ion,

Sep

tem

ber

2002

)•

Impu

ritie

s in

New

Dru

g Su

bsta

nces

Q3A

(C

urre

nt S

tep

4 ve

rsio

n, O

ctob

er 2

006)

•Sp

ecifi

catio

ns: T

est P

roce

dure

s and

Acc

epta

nce

Cri

teri

a fo

r N

ew D

rug

Subs

tanc

es a

nd N

ew D

rug

Prod

ucts:

Che

mic

al S

ubsta

nces

Q6A

(in

clud

ing

Dec

ision

Tre

es)

(Cur

rent

Ste

p 4

vers

ion,

Oct

ober

199

9)•

Spec

ifica

tions

: Tes

t Pro

cedu

res a

nd A

ccep

tanc

e C

rite

ria

for

Bio

tech

nolo

gica

l/Bio

logi

cal P

rodu

cts Q

6B, C

urre

nt S

tep

4 ve

rsio

n, 1

0 M

arch

199

9•

Phar

mac

eutic

al D

evel

opm

ent Q

8(R

2) (

Cur

rent

Ste

p 4

vers

ion,

Aug

ust 2

009)

•Sa

fety

Pha

rmac

olog

y St

udie

s for

Hum

an P

harm

aceu

tical

s S7A

(C

urre

nt S

tep

4 ve

rsio

n, N

ovem

ber

2000

)

Cha

pter

2

Mai

n To

pics

Bef

ore

gran

ting

mar

keti

ng a

utho

riza

tion

, the

Com

pete

nt A

utho

rity

eva

luat

es a

tech

nica

l file

(do

ssie

r) th

at c

onta

ins

info

rmat

ion

pert

aini

ng to

the

resu

lts o

f pre

clin

ical

and

clin

ical

test

ing

and

man

ufac

turi

ng. T

he C

omm

on T

echn

ical

Doc

umen

t (C

TD

) pr

ovid

es a

har

mon

ized

dos

sier

str

uctu

re

acce

pted

in th

e E

U, U

S, J

apan

and

man

y ot

her

coun

trie

s. T

he C

TD

has

five

mod

ules

:

M

odul

e 1:

Adm

inis

trat

ive

Info

rmat

ion

(cou

ntry

spe

cific

)

M

odul

e 2:

Hig

h Le

vel W

ritt

en a

nd T

abul

ated

Sum

mar

ies

Mod

ule

3: C

hem

istr

y, M

anuf

actu

ring

and

Con

trol

s (C

MC

)

M

odul

e 4:

Pre

clin

ical

Inf

orm

atio

n

M

odul

e 5:

Clin

ical

Inf

orm

atio

n



Aut

hori

zati

on P

roce

dure

s (D

rugs

)

Regu

latio

ns a

nd G

uide

lines

Aut

hori

zati

on P

roce

dure

s fo

r M

edic

inal

Pro

duct

sIC

H•

Gui

danc

e on

Non

clin

ical

Saf

ety

Stud

ies f

or th

e C

ondu

ct o

f Hum

an C

linic

al T

rial

s and

Mar

ketin

g A

utho

risa

tion

for

Phar

mac

eutic

als M

3(R

2) (

Cur

rent

St

ep 4

ver

sion

, Jun

e 20

09)

•D

etec

tion

of T

oxic

ity to

Rep

rodu

ctio

n fo

r M

edic

inal

Pro

duct

s & T

oxic

ity to

Mal

e Fe

rtili

ty S

5(R

2) (

Cur

rent

Ste

p 4

vers

ion,

Nov

embe

r 20

05)

•G

enot

oxic

ity: A

Sta

ndar

d B

atte

ry fo

r G

enot

oxic

ity T

estin

g of

Pha

rmac

eutic

als S

2B (

Cur

rent

Ste

p 4

vers

ion,

July

199

7)•

Gui

delin

e on

the

Nee

d fo

r C

arci

noge

nici

ty S

tudi

es o

f Pha

rmac

eutic

als S

1A, (

Cur

rent

Ste

p 4

vers

ion,

Nov

embe

r 19

95)

•Sa

fety

Pha

rmac

olog

y St

udie

s for

Hum

an P

harm

aceu

tical

s S7A

, (C

urre

nt S

tep

4 ve

rsio

n, N

ovem

ber

2000

)•

Not

e fo

r G

uida

nce

on T

oxic

okin

etic

s: T

he A

ssessm

ent o

f Sys

tem

ic E

xpos

ure

in T

oxic

ity S

tudi

es S

3A, (

Cur

rent

Ste

p 4

vers

ion,

Oct

ober

199

4)•

Phar

mac

okin

etic

s: G

uida

nce

for

Repe

ated

Dos

e Tiss

ue D

istri

butio

n St

udie

s S3B

, (C

urre

nt S

tep

4 ve

rsio

n, O

ctob

er 1

994)

•St

ruct

ure

and

Con

tent

of C

linic

al S

tudy

Rep

orts

E3, (

Cur

rent

Ste

p 4

vers

ion,

Nov

embe

r 19

95)

•G

uide

line

on G

ood

Clin

ical

Pra

ctic

e E6

(R1)

, (C

urre

nt S

tep

4 ve

rsio

n, Ju

ne 1

996)

•Q

ualit

y R

isk M

anag

emen

t Q9,

(C

urre

nt S

tep

4 ve

rsio

n, N

ovem

ber

2005

)•

Goo

d M

anuf

actu

ring

Pra

ctic

e G

uide

for

Act

ive

Phar

mac

eutic

al In

gred

ient

s Q7,

(C

urre

nt S

tep

4 ve

rsio

n, N

ovem

ber

2000

)O

EC

D •O

EC

D S

erie

s on

Pri

ncip

les

of G

ood

Labo

rato

ry P

ract

ice

and

Com

plia

nce

Mon

itor

ing,

EN

V/M

C/C

HE

M(9

8)17

, 199

8.E

urop

e •R

egul

atio

n (E

C)

No.

726

/200

4 of

the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

31

Mar

ch 2

004

layi

ng d

own

proc

edur

es fo

r th

e au

thor

isat

ion

and

supe

rvis

ion

of m

edic

inal

pro

duct

s fo

r hu

man

and

vet

erin

ary

use

and

esta

blis

hing

a E

urop

ean

Med

icin

es A

genc

y•

Dir

ecti

ve 2

004/

27/E

C o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

31

Mar

ch 2

004

amen

ding

Dir

ecti

ve 2

001/

83/E

C o

n th

e C

omm

unit

y co

de r

elat

ing

to m

edic

inal

pro

duct

s fo

r hu

man

use

•D

irec

tive

200

4/10

/EC

of t

he E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 1

1 Fe

brua

ry 2

004

on th

e ha

rmon

isat

ion

of la

ws,

reg

ulat

ions

and

ad

min

istr

ativ

e pr

ovis

ions

rel

atin

g to

the

appl

icat

ion

of th

e pr

inci

ples

of g

ood

labo

rato

ry p

ract

ice

and

the

veri

ficat

ion

of th

eir

appl

icat

ions

for

test

s on

che

mic

al s

ubst

ance

s•

Dir

ecti

ve 2

004/

9/E

C o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

11

Febr

uary

200

4 on

the

insp

ecti

on a

nd v

erifi

cati

on o

f goo

d la

bora

tory

pr

acti

ce (

GLP

) •

Volu

me

9A, T

he R

ules

Gov

erni

ng M

edic

inal

Pro

duct

s in

the

Euro

pean

Uni

on, G

uide

lines

on

Phar

mac

ovig

ilanc

e fo

r M

edic

inal

Pro

duct

s for

Hum

an

Use

(ve

rsio

n Se

ptem

ber

2008

)U

S•

FDA

, 21

CFR

58

Goo

d La

bora

tory

Pra

ctic

e fo

r N

oncl

inic

al L

abor

ator

y St

udie

s•

FDA

, 21

CFR

314

App

licat

ions

for

FDA

App

rova

l to

Mar

ket a

New

Dru

g



Cha

pter

3

Mai

n To

pics

Mar

keti

ng a

utho

riza

tion

hol

ders

(M

AH

s) h

ave

cert

ain

lega

l res

pons

ibili

ties

. The

follo

win

g lis

t, al

thou

gh n

ot e

xhau

stiv

e, in

clud

es th

e m

ost i

mpo

rtan

t of

thos

e re

spon

sibi

litie

s:•

The

MA

H is

res

pons

ible

for

taki

ng a

ny te

chni

cal a

nd s

cien

tific

pro

gres

s in

to c

onsi

dera

tion

and

upd

atin

g m

anuf

actu

ring

and

con

trol

ope

rati

ons.

•W

hen

anot

her

orga

niza

tion

, par

ticu

larl

y a

cont

ract

com

pany

, is

the

man

ufac

ture

r, th

e M

AH

mus

t ens

ure

that

a w

ritt

en a

gree

men

t is

in p

lace

to

guar

ante

e th

at m

anuf

actu

ring

ope

rati

ons

com

ply

wit

h do

ssie

r ru

les

and

cond

itio

ns a

nd th

at th

e m

anuf

actu

rer

is o

blig

ed to

info

rm th

e M

AH

of

any

chan

ges

befo

re im

plem

enta

tion

.•

If a

ny in

form

atio

n, in

clud

ing

safe

ty is

sues

, whi

ch c

ould

lead

to m

odifi

cati

on o

f the

mar

keti

ng a

utho

riza

tion

dos

sier

or

Sum

mar

y of

Pro

duct

C

hara

cter

isti

cs (

SPC

) is

bro

ught

to th

e at

tent

ion

of th

e M

AH

, the

CA

(s)

mus

t be

info

rmed

imm

edia

tely

•In

mos

t cou

ntri

es, m

arke

ting

aut

hori

zati

ons

are

issu

ed fo

r a

limit

ed ti

me.

The

MA

H is

res

pons

ible

for

rene

win

g th

e lic

ense

bef

ore

the

mar

keti

ng

auth

oriz

atio

n‘s

expi

rati

on d

ate.

The

rul

es g

over

ning

this

var

y fr

om r

egio

n to

reg

ion.

•In

cer

tain

reg

ions

suc

h as

the

EU

, Can

ada,

Sw

itze

rlan

d, A

ustr

alia

, Jap

an a

nd N

ew Z

eala

nd, t

he M

AH

is r

equi

red

to h

ave

a qu

alifi

ed p

erso

n fo

r ba

tch

rele

ase.

•

The

MA

H m

ust h

ave

a qu

alifi

ed p

erso

n in

cha

rge

of p

harm

acov

igila

nce.

•T

he M

AH

mus

t tak

e fu

ll re

spon

sibi

lity

for

med

icin

al p

rodu

ct a

dver

tisi

ng.

•T

he M

AH

mus

t ens

ure

that

all

med

icin

al p

rodu

ct d

ocum

enta

tion

, inc

ludi

ng c

linic

al tr

ial i

nfor

mat

ion,

is r

etai

ned

and

arch

ived

.•

Spec

ial r

equi

rem

ents

may

app

ly to

hig

h-ri

sk p

rodu

cts,

suc

h as

imm

unol

ogic

al m

edic

inal

pro

duct

s an

d m

edic

inal

pro

duct

s de

rive

d fr

om h

uman

bl

ood

or h

uman

pla

sma.

Alth

ough

the

exac

t req

uire

men

ts a

nd p

roce

sses

var

y fr

om c

ount

ry to

cou

ntry

, in

alm

ost a

ll re

gion

s th

e re

quir

emen

ts fo

r ne

w d

rug

appl

icat

ions

req

uire

at

leas

t:•

nonc

linic

al te

stin

g•

appl

icat

ion

to b

egin

clin

ical

tria

ls•

new

dru

g ap

plic

atio

n, in

clud

ing

resu

lts o

f non

clin

ical

and

clin

ical

test

ing

plus

man

ufac

turi

ng in

form

atio

n•

pric

ing

and

reim

burs

emen

t inf

orm

atio

n•

post

mar

ket a

ctiv

itie

s

Thr

ough

out t

his

proc

ess,

app

lican

ts a

re in

freq

uent

con

tact

wit

h th

e C

ompe

tent

Aut

hori

ties

.



Qua

lity

Syst

ems

(Dru

gs)

Re

gula

tions

and

Gui

delin

es

Qua

lity

Syst

ems

and

Insp

ecto

rate

P

roce

ss—

Pha

rmac

euti

cals

ICH

•IC

H, T

he C

omm

on T

echn

ical

Doc

umen

t for

the

Regi

strat

ion

of P

harm

aceu

tical

s for

Hum

an U

se: Q

ualit

y—M

4Q(R

1), Q

ualit

y O

vera

ll Su

mm

ary

of

Mod

ule

2 M

odul

e 3:

Qua

lity,

(C

urre

nt S

tep

4 ve

rsio

n, d

ated

Sep

tem

ber)

•

ICH

, Qua

lity

Risk

Man

agem

ent Q

9, (

Cur

rent

Ste

p 4

vers

ion,

Nov

embe

r 20

05)

•IC

H, P

harm

aceu

tical

Dev

elop

men

t Q8(

R2)

, (C

urre

nt S

tep

4 ve

rsio

n, A

ugus

t 200

9)•

ICH

, Goo

d M

anuf

actu

ring

Pra

ctic

e G

uide

for

Act

ive

Phar

mac

eutic

al In

gred

ient

s Q7,

(C

urre

nt S

tep

4 ve

rsio

n, N

ovem

ber

2000

)W

HO •

WH

O, W

HO

Tec

hnic

al R

epor

t Ser

ies 9

08, 2

003,

Goo

d M

anuf

actu

ring

Pra

ctic

es fo

r ph

arm

aceu

tical

pro

duct

s: m

ain

prin

cipl

esE

U•

Com

mis

sion

Dir

ecti

ve 2

003/

94/E

C o

f 8 O

ctob

er 2

003

layi

ng d

own

the

prin

cipl

es a

nd g

uide

lines

of g

ood

man

ufac

turi

ng p

ract

ice

in r

espe

ct o

f m

edic

inal

pro

duct

s fo

r hu

man

use

and

inve

stig

atio

nal m

edic

inal

pro

duct

s fo

r hu

man

use

•C

omm

issi

on D

irec

tive

91/

412/

EE

C o

f 23

July

199

1 la

ying

dow

n th

e pr

inci

ples

and

gui

delin

es o

f goo

d m

anuf

actu

ring

pra

ctic

e fo

r ve

teri

nary

m

edic

inal

pro

duct

s•

Volu

me

4, T

he R

ules

Gov

erni

ng M

edic

inal

Pro

duct

s in

the

Euro

pean

Uni

on, G

uide

lines

for

good

man

ufac

turi

ng p

ract

ices

for

med

icin

al p

rodu

cts f

or

hum

an a

nd v

eter

inar

y us

e (v

ersi

on F

ebru

ary

2008

)•

Phar

mac

eutic

al In

spec

tion

Con

vent

ion

Gui

de (

publ

ishe

d in

199

7)•

Euro

pean

Fed

erat

ion

of P

harm

aceu

tical

Indu

stry

Asso

ciat

ion’s

Gui

de (

publ

ishe

d in

199

6).

•D

irec

tive

200

1/83

/EC

of t

he E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 6

Nov

embe

r 20

01 o

n th

e C

omm

unit

y co

de r

elat

ing

to m

edic

inal

pr

oduc

ts fo

r hu

man

use

, as

amen

ded

by D

irec

tive

s 20

04/2

7/E

C a

nd R

egul

atio

n (E

C)

No

1901

/200

6•

Dir

ecti

ve 2

001/

82/E

C o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

6 N

ovem

ber

2001

on

the

Com

mun

ity

code

rel

atin

g to

vet

erin

ary

med

icin

al p

rodu

cts,

as

amen

ded

by D

irec

tive

200

4/28

/EC

US

•Fe

dera

l Foo

d, D

rug,

and

Cos

met

ic A

ct (

FD&

C A

ct),

Sec

tion

501

(a)(

2)(b

)•

21 C

FR 2

10 C

urre

nt G

ood

Man

ufac

turi

ng P

ract

ice

in th

e M

anuf

actu

ring

, Pro

cess

ing,

Pac

kagi

ng o

r H

oldi

ng o

f Dru

gs; G

ener

al•

21 C

FR 2

11 C

urre

nt G

ood

Man

ufac

turi

ng P

ract

ice

for

Fini

shed

Pha

rmac

euti

cals

•21

CFR

606

Cur

rent

Goo

d M

anuf

actu

ring

Pra

ctic

e fo

r B

lood

and

Blo

od C

ompo

nent

sC

anad

a •Fo

od a

nd D

rug

Regu

latio

ns, D

ivis

ion

2, P

art C

•G

ood

Man

ufac

turi

ng P

ract

ice

Gui

delin

es, 2

002

Edi

tion

, Ver

sion

2 (

31 D

ecem

ber

2002

)



Cha

pter

4

Mai

n To

pics

Hum

an a

nd v

eter

inar

y dr

ugs

mus

t mee

t min

imum

qua

lity

and

safe

ty r

equi

rem

ents

. Con

cern

s ov

er th

e ri

sing

cos

ts o

f hea

lthca

re a

nd e

scal

atio

n of

the

cost

s of

res

earc

h an

d de

velo

pmen

t (R

&D

), c

oupl

ed w

ith

the

need

to m

eet p

ublic

exp

ecta

tion

s of

saf

e an

d fa

st a

vaila

bilit

y of

new

trea

tmen

ts, p

aved

th

e w

ay fo

r ra

tion

aliz

atio

n an

d ha

rmon

izat

ion.

Wha

t beg

an a

s a

harm

oniz

atio

n of

reg

ulat

ory

requ

irem

ents

for

the

deve

lopm

ent o

f a s

ingl

e m

arke

t for

pha

rmac

euti

cals

in w

hat i

s no

w th

e E

U

beca

me

the

Inte

rnat

iona

l Con

fere

nce

on H

arm

onis

atio

n (I

CH

), a

n in

itia

tive

invo

lvin

g th

ree

regi

ons:

the

EU

, Jap

an a

nd th

e U

S. T

opic

s in

itia

lly

sele

cted

for

harm

oniz

atio

n in

clud

ed s

afet

y, q

ualit

y an

d ef

ficac

y, to

refl

ect t

he th

ree

basi

c cr

iter

ia fo

r ap

prov

ing

and

auth

oriz

ing

new

med

icin

al

prod

ucts

(w

ww

.ich.

org)

. Rec

ent e

mph

asis

on

glob

al c

oope

rati

on h

as h

ighl

ight

ed th

e im

port

ance

of d

isse

min

atin

g in

form

atio

n an

d pr

ovid

ing

inpu

t be

yond

the

ICH

reg

ions

via

inte

rnat

iona

l org

aniz

atio

ns s

uch

as th

e W

orld

Hea

lth O

rgan

izat

ion

(WH

O).

Goo

d M

anuf

actu

ring

Pra

ctic

e (G

MP

)G

MP

can

be d

efine

d as

“T

hat p

art o

f Qua

lity

Ass

uran

ce w

hich

ens

ures

that

pro

duct

s ar

e co

nsis

tent

ly p

rodu

ced

and

cont

rolle

d to

the

qual

ity

stan

dard

s ap

prop

riat

e to

thei

r in

tend

ed u

se.”

Thi

s is

a r

equi

rem

ent f

or b

oth

acti

ve in

gred

ient

s an

d fin

ishe

d ph

arm

aceu

tica

l pro

duct

s.

GM

P as

sum

es th

at li

cens

ed p

harm

aceu

tica

l pro

duct

s ar

e m

anuf

actu

red

by li

cens

ed m

anuf

actu

rers

. To

ensu

re c

ompl

ianc

e, m

anuf

actu

rers

mus

t be

regu

larl

y in

spec

ted

by C

As.

Insp

ecti

ons

Insp

ecti

ons

can

be c

onsi

dere

d pa

rt o

f the

ove

rall

drug

qua

lity

assu

ranc

e sy

stem

. The

y ca

n be

rou

tine

, pre

cise

and

spe

cific

insp

ecti

ons;

follo

w-u

p in

spec

tion

s; o

r qu

alit

y sy

stem

s in

spec

tion

s. T

he o

bjec

tive

of i

nspe

ctin

g ph

arm

aceu

tica

l man

ufac

turi

ng p

lant

s is

to e

nfor

ce G

MP

com

plia

nce

or to

pr

ovid

e au

thor

izat

ion

for

the

man

ufac

ture

of s

peci

fic p

harm

aceu

tica

l pro

duct

s, u

sual

ly in

rel

atio

n to

an

appl

icat

ion

for

mar

keti

ng a

utho

riza

tion

.

Mut

ual R

ecog

niti

on A

gree

men

ts (

MR

As)

MR

As

on G

MP

and

acce

ptan

ce o

f ins

pect

ions

and

qua

lity

syst

ems

amon

g co

untr

ies

impr

ove

the

pace

of g

loba

l tra

de. I

n m

ost c

ases

, eac

h pa

rty

eval

u-at

es th

e ot

her

duri

ng a

tran

siti

onal

ass

essm

ent p

erio

d, w

hich

has

a p

rede

fined

tim

efra

me.

The

ass

essm

ent m

ay in

clud

e an

app

rais

al o

f the

oth

er p

arty

’s ph

arm

aceu

tica

l leg

isla

tion

, gui

danc

es a

nd s

yste

ms;

the

findi

ngs

usua

lly a

re c

onfir

med

dur

ing

com

plia

nce

visi

ts a

nd jo

int i

nspe

ctio

ns. I

f eac

h pa

rty

can

confi

rm th

at th

e ot

her’s

sys

tem

s ar

e eq

uiva

lent

wit

h it

s ow

n, a

n op

erat

iona

l pha

se c

an b

egin

.

Pha

rmac

euti

cal I

nspe

ctio

n C

onve

ntio

nT

he P

harm

aceu

tica

l Ins

pect

ion

Con

vent

ion

and

Phar

mac

euti

cal I

nspe

ctio

n C

oope

rati

on S

chem

e (j

oint

ly r

efer

red

to a

s PI

C/S

) ar

e tw

o in

tern

atio

nal

inst

rum

ents

am

ong

coun

trie

s an

d ph

arm

aceu

tica

l ins

pect

ion

auth

orit

ies

that

toge

ther

pro

vide

act

ive

and

cons

truc

tive

coo

pera

tion

in th

e fie

ld o

f G

MP

(htt

p://

ww

w.p

icsc

hem

e.or

g).



Post

mar

ket

Req

uire

men

ts (

Dru

gs)

Re

gula

tions

and

Gui

delin

esP

harm

aceu

tica

l Po

stm

arke

ting

and

C

ompl

ianc

e

ICH

•Ph

arm

aceu

tical

Qua

lity

Syste

m Q

10, (

Cur

rent

Ste

p 4

vers

ion,

June

200

8)•

Phar

mac

eutic

al D

evel

opm

ent Q

8(R

2), (

Cur

rent

Ste

p 4

vers

ion,

Aug

ust 2

009)

•Q

ualit

y R

isk

Man

agem

ent Q

9, (

Cur

rent

Ste

p 4

vers

ion,

Nov

embe

r 20

05)

•Po

st-A

ppro

val S

afet

y D

ata

Man

agem

ent:

Defi

nitio

ns a

nd S

tand

ards

for

Expe

dite

d Re

port

ing

E2D

, (C

urre

nt S

tep

4 ve

rsio

n, N

ovem

ber

2003

)E

U•

Reg

ulat

ion

(EC

) N

o. 7

26/2

004

of th

e E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 3

1 M

arch

200

4 la

ying

dow

n C

omm

unit

y pr

oced

ures

for

the

auth

oris

atio

n an

d su

perv

isio

n of

med

icin

al p

rodu

cts

for

hum

an a

nd v

eter

inar

y us

e an

d es

tabl

ishi

ng a

Eur

opea

n M

edic

ines

Age

ncy

•D

irec

tive

200

1/83

/EC

of t

he E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 6

Nov

embe

r 20

01 o

n th

e C

omm

unit

y co

de r

elat

ing

to m

edic

inal

pr

oduc

ts fo

r hu

man

use

, as

amen

ded

•C

omm

issi

on R

egul

atio

n (E

EC

) N

o. 1

084/

2003

of 3

June

200

3 co

ncer

ning

the

exam

inat

ion

of v

aria

tion

s to

the

term

s of

a m

arke

ting

au

thor

isat

ion

for

med

icin

al p

rodu

cts

for

hum

an u

se a

nd v

eter

inar

y m

edic

inal

pro

duct

s gr

ante

d by

a c

ompe

tent

aut

hori

ty o

f a M

embe

r St

ate

•C

omm

issi

on R

egul

atio

n (E

EC

) N

o. 1

085/

2003

of 3

June

200

3 co

ncer

ning

the

exam

inat

ion

of v

aria

tion

s to

the

term

s of

a m

arke

ting

au

thor

isat

ion

for

med

icin

al p

rodu

cts

for

hum

an u

se a

nd v

eter

inar

y m

edic

inal

pro

duct

s fa

lling

wit

hin

the

scop

e of

Cou

ncil

Reg

ulat

ion

(EE

C)

No.

230

9/93

•C

omm

issi

on R

egul

atio

n (E

C)

No.

123

4/20

08 o

f 24

Nov

embe

r 20

08 c

once

rnin

g th

e ex

amin

atio

n of

var

iati

ons

to th

e te

rms

of m

arke

ting

au

thor

isat

ions

for

med

icin

al p

rodu

cts

for

hum

an u

se a

nd v

eter

inar

y m

edic

inal

pro

duct

s•

Gui

delin

e on

dos

sier

requ

irem

ents

for T

ype

IA a

nd T

ype

IB n

otifi

catio

ns, R

evis

ion

1 (J

uly

2006

)•

Com

mis

sion

Reg

ulat

ion

(EE

C)

No.

540

/95

of 1

0 M

arch

199

5 la

ying

dow

n th

e ar

rang

emen

ts fo

r re

port

ing

susp

ecte

d un

expe

cted

adv

erse

re

acti

ons

whi

ch a

re n

ot s

erio

us, w

heth

er a

risi

ng in

the

Com

mun

ity

or in

a th

ird

coun

try,

to m

edic

inal

pro

duct

s fo

r hu

man

or

vete

rina

ry u

se

auth

oris

ed in

acc

orda

nce

wit

h th

e pr

ovis

ions

of C

ounc

il R

egul

atio

n (E

EC

) N

o. 2

309/

93

US

•21

CFR

314

.70

Supp

lem

ents

and

oth

er c

hang

es to

an

appr

oved

app

licat

ion

•21

CFR

314

.81

Oth

er p

ostm

arke

ting

rep

orts

•21

CFR

314

.80

Post

mar

keti

ng r

epor

ting

of a

dver

se d

rug

expe

rien

ces

•G

uida

nce

for

Indu

stry:

SU

PAC

-IR

: Im

med

iate

Rel

ease

Sol

id O

ral D

osag

e Fo

rms,

Scal

e-U

p an

d Po

st-ap

prov

al C

hang

es: C

hem

istry

, Man

ufac

turi

ng a

nd

Con

trol

s, In

Vitr

o D

issol

utio

n Te

sting

and

In V

ivo

Bio

equi

vale

nce

Doc

umen

tatio

n, U

S Fo

od a

nd D

rug

Adm

inis

trat

ion

(FD

A),

Cen

ter

for

Dru

g Ev

alua

tion

and

Res

earc

h (C

DE

R)

(Nov

embe

r 19

95)

•G

uida

nce

for

Indu

stry:

SU

PAC

-MR

: Mod

ified

Rel

ease

Sol

id O

ral D

osag

e Fo

rms:

Scal

e-U

p an

d Po

st-A

ppro

val C

hang

es: C

hem

istry

, Man

ufac

turi

ng a

nd

Con

trol

s, In

Vitr

o D

issol

utio

n Te

sting

and

In V

ivo

Bio

equi

vale

nce

Doc

umen

tatio

n, C

DE

R (

Oct

ober

199

7)



•G

uide

lines

for

Repo

rtin

g A

dver

se E

vent

s Asso

ciat

ed w

ith V

acci

ne P

rodu

cts.

Supp

lem

enta

ry G

uide

lines

for

the

Can

adia

n Ph

arm

aceu

tical

Indu

stry,

La

bora

tory

Cen

tre

for

Dis

ease

Con

trol

(Fe

brua

ry 2

000)

•A

nnua

l Dru

g N

otifi

catio

n 20

08 G

uida

nce,

The

rape

utic

Pro

duct

s D

irec

tora

teA

ustr

alia

•A

ustr

alia

n G

uide

line

for

Phar

mac

ovig

ilanc

e Re

spon

sibili

ties o

f Spo

nsor

s of R

egist

ered

Med

icin

es R

egul

ated

by

Dru

g Sa

fety

and

Eva

luat

ion

Bra

nch,

T

hera

peut

ic G

oods

Adm

inis

trat

ion

(TG

A)

(Jul

y 20

03; a

men

ded

31 M

ay 2

005)

•A

ustr

alia

n re

gula

tory

gui

delin

es fo

r pr

escr

iptio

n m

edic

ines

(A

RG

PM),

app

endi

ces

12 a

nd 1

3, T

GA

Cha

pter

5

Mai

n To

pics

Vari

atio

ns a

nd C

hang

es

Am

ong

the

driv

ers

of c

hang

e ar

e in

nova

tion

, con

tinu

al im

prov

emen

t, th

e re

sults

of p

roce

ss p

erfo

rman

ce a

nd p

rodu

ct q

ualit

y m

onit

orin

g, a

nd

corr

ecti

ve a

nd p

reve

ntiv

e ac

tion

s (C

APA

) (I

CH

Pha

rmac

eutic

al Q

ualit

y Sy

stem

Q10

). I

n or

der

to e

valu

ate,

app

rove

and

impl

emen

t the

se c

hang

es

prop

erly

, com

pani

es a

re o

blig

ed to

hav

e an

eff

ecti

ve c

hang

e m

anag

emen

t sys

tem

. In

mos

t ter

rito

ries

, pos

tapp

rova

l cha

nges

mus

t be

reco

rded

and

co

mm

unic

ated

to th

e C

As.

Phar

mac

eutic

al Q

ualit

y Sy

stem

Ele

men

ts So

me

Q10

ele

men

ts m

ay a

lrea

dy b

e in

clud

ed in

reg

iona

l GM

P re

gula

tion

s; h

owev

er, t

he Q

10 m

odel

’s in

tent

is to

enh

ance

thes

e el

emen

ts to

pro

mot

e th

e lif

ecyc

le a

ppro

ach

to p

rodu

ct q

ualit

y.

The

four

bas

ic e

lem

ents

are

: •

proc

ess

perf

orm

ance

and

pro

duct

qua

lity

mon

itor

ing

syst

em•

CA

PA s

yste

m•

chan

ge m

anag

emen

t sys

tem

•m

anag

emen

t rev

iew

of p

roce

ss p

erfo

rman

ce a

nd p

rodu

ct q

ualit

y

Pha

rmac

ovig

ilanc

eM

AH

s m

ust h

ave

a ph

arm

acov

igila

nce

syst

em to

ens

ure

all i

nfor

mat

ion

rele

vant

to a

med

icin

al p

rodu

ct’s

bala

nce

of b

enefi

ts a

nd r

isks

is fu

lly a

nd

prom

ptly

rep

orte

d to

the

CA

s. I

n ad

diti

on, t

he M

AH

gen

eral

ly is

req

uire

d to

hav

e a

qual

ified

per

son

resp

onsi

ble

for

phar

mac

ovig

ilanc

e (Q

PPV

) av

aila

ble

at a

ll ti

mes

.

Sour

ces

of I

ndiv

idua

l Cas

e Sa

fety

Rep

orts

(IC

SR)

•un

solic

ited

sou

rces

•so

licit

ed s

ourc

es•

cont

ract

ual a

gree

men

ts•

regu

lato

ry a

utho

rity

sou

rces

Stan

dard

s fo

r E

xped

ited

Rep

orti

ng

R

epor

ting

of a

ll ca

ses

of a

dver

se d

rug

reac

tion

s (A

DR

s) th

at a

re b

oth

seri

ous

and

unex

pect

ed s

houl

d be

exp

edit

ed.



Min

imum

Cri

teri

a fo

r Re

port

ing

Fo

r th

e pu

rpos

e of

reg

ulat

ory

repo

rtin

g, th

e m

inim

um d

ata

elem

ents

for

an A

DR

cas

e ar

e:

•an

iden

tifia

ble

repo

rter

•an

iden

tifia

ble

pati

ent

•an

adv

erse

rea

ctio

n •

a su

spec

t pro

duct

Repo

rtin

g T

imef

ram

esA

ccor

ding

to I

CH

E2D

, exp

edit

ed r

epor

ting

of s

erio

us a

nd u

nexp

ecte

d A

DR

s is

req

uire

d as

soo

n as

pos

sibl

e, b

ut in

no

case

late

r th

an 1

5 ca

lend

ar

days

of i

niti

al r

ecei

pt o

f the

info

rmat

ion

by th

e M

AH

. The

exa

ct r

epor

ting

tim

e lin

es o

f oth

er s

erio

us r

epor

ts v

ary

amon

g co

untr

ies.

Stan

dard

Ope

rati

ng P

roce

dure

s (S

OPs

)A

ll po

stm

arke

t act

ivit

ies

for

prod

ucts

man

ufac

ture

d in

a G

MP

envi

ronm

ent r

equi

re r

elev

ant S

OPs

. The

SO

Ps m

ust b

e im

plem

ente

d, i.

e., w

ritt

en a

nd

sign

ed o

ff a

nd p

erso

nnel

trai

ned.

Insp

ecti

ons

Ins

pect

ors

may

che

ck th

e av

aila

bilit

y an

d st

atus

of S

OPs

, inc

ludi

ng tr

aini

ng r

ecor

ds. T

he h

andl

ing

of v

aria

tion

s an

d ch

ange

con

trol

is a

typi

cal

ar

ea to

be

targ

eted

dur

ing

rout

ine

insp

ecti

ons.

Ins

pect

ors

will

als

o ch

eck

if so

ftw

are

in u

se h

as b

een

prop

erly

val

idat

ed.



Hig

h-R

isk

Pro

duct

s (D

rugs

)

Re

gula

tions

and

Gui

delin

es

Hig

h-R

isk

Pro

duct

s:

Pro

duct

s D

eriv

ed

From

Bio

tech

nolo

gy

ICH

•V

iral

Saf

ety

Eval

uatio

n of

Bio

tech

nolo

gy P

rodu

cts D

eriv

ed fr

om C

ell L

ines

of H

uman

or

Ani

mal

Ori

gin

Q5A

(R1)

(C

urre

nt S

tep

4 ve

rsio

n, S

epte

mbe

r 19

99)

•Q

ualit

y of

Bio

tech

nolo

gica

l Pro

duct

s: A

naly

sis o

f the

Exp

ressi

on C

onstr

uct i

n C

ells

Use

d fo

r Pr

oduc

tion

of r

-DN

A D

eriv

ed P

rote

in P

rodu

cts Q

5B

(Cur

rent

Ste

p 4

vers

ion,

Nov

embe

r 19

95)

•Q

ualit

y of

Bio

tech

nolo

gica

l Pro

duct

s: St

abili

ty T

estin

g of

Bio

tech

nolo

gica

l/Bio

logi

cal P

rodu

cts Q

5C (

Cur

rent

Ste

p 4

vers

ion,

Nov

embe

r 19

95)

•D

eriv

atio

n an

d C

hara

cter

isatio

n of

Cel

l Sub

strat

es U

sed

for

Prod

uctio

n of

Bio

tech

nolo

gica

l/Bio

logi

cal P

rodu

cts Q

5D (

Cur

rent

Ste

p 4

vers

ion,

July

19

97)

•C

ompa

rabi

lity

of B

iote

chno

logi

cal/B

iolo

gica

l Pro

duct

s Sub

ject

to C

hang

es in

The

ir M

anuf

actu

ring

Pro

cess

Q5E

(C

urre

nt S

tep

4 ve

rsio

n, N

ovem

ber

2004

)•

Spec

ifica

tions

: Tes

t Pro

cedu

res a

nd A

ccep

tanc

e C

rite

ria

for

Bio

tech

nolo

gica

l/Bio

logi

cal P

rodu

cts Q

6B (

Cur

rent

Ste

p 4

vers

ion,

Mar

ch 1

999)

•Pr

eclin

ical

Saf

ety

Eval

uatio

n of

Bio

tech

nolo

gy-D

eriv

ed P

harm

aceu

tical

s S6

(Cur

rent

Ste

p 4

vers

ion,

July

199

7)•

M4:

The

Com

mon

Tec

hnic

al D

ocum

ent

EU

•R

egul

atio

n (E

C)

No.

726

/200

4 of

the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

31

Mar

ch 2

004

layi

ng d

own

Com

mun

ity

proc

edur

es fo

r th

e au

thor

isat

ion

and

supe

rvis

ion

of m

edic

inal

pro

duct

s fo

r hu

man

and

vet

erin

ary

use

and

esta

blis

hing

a E

urop

ean

Med

icin

es A

genc

y•

The

Rul

es G

over

ning

Med

icin

al P

rodu

cts i

n th

e Eu

rope

an U

nion

, Vol

ume

2A, C

hapt

er 4

Pro

cedu

res f

or M

arke

ting

Aut

hori

satio

n, C

entr

alise

d Pr

oced

ure

•E

ME

A/4

10/0

1 R

ev. 2

, Not

e fo

r gu

idan

ce o

n m

inim

ising

the

risk

of t

rans

mitt

ing

anim

al sp

ongi

form

enc

epha

lopa

thy

agen

ts vi

a hu

man

and

vet

erin

ary

med

icin

al p

rodu

cts

•R

egul

atio

n (E

C)

No.

139

4/20

07 o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

13

Nov

embe

r 20

07 o

n ad

vanc

ed th

erap

y m

edic

inal

pr

oduc

ts a

nd a

men

ding

Dir

ecti

ve 2

001/

83/E

C a

nd R

egul

atio

n (E

C)

No.

726

/200

4 •

Dir

ecti

ve 2

001/

83/E

C o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

6 N

ovem

ber

2001

on

the

Com

mun

ity

code

rel

atin

g to

med

icin

al

prod

ucts

for

hum

an u

se, a

s am

ende

d•

Gui

danc

e C

PMP/

QW

P/22

7/02

Rev

. 1, G

uide

line

on A

ctiv

e Su

bsta

nce

Mas

ter

File

Pro

cedu

re (

Febr

uary

200

4)U

S•

21 C

FR, S

ubch

apte

r F

Bio

logi

cs, P

art 6

00 B

iolo

gica

l Pro

duct

s: G

ener

al•

21 C

FR 3

12 I

nves

tiga

tion

al N

ew D

rug

App

licat

ion

•G

uida

nce

for

Indu

stry:

Con

tent

and

For

mat

of I

nves

tigat

iona

l New

Dru

g A

pplic

atio

ns (

IND

s) fo

r Ph

ase

1 St

udie

s of D

rugs

, Inc

ludi

ng W

ell-

Cha

ract

eriz

ed, T

hera

peut

ic, B

iote

chno

logy

-der

ived

Pro

duct

s (N

ovem

ber

1995

)•

New

Dru

g an

d B

iolo

gica

l Dru

g Pr

oduc

ts; E

vide

nce

Nee

ded

to D

emon

strat

e Ef

fect

iven

ess o

f New

Dru

gs W

hen

Hum

an E

ffica

cy S

tudi

es A

re N

ot E

thic

al

or F

easib

le (

Ani

mal

Effi

cacy

Rul

e) (

May

200

2))



Cha

pter

6

Mai

n To

pics

Oft

en, t

he te

rms

“bio

tech

nolo

gy”

and

“bio

logi

cal”

are

use

d sy

nony

mou

sly

or h

ave

over

lapp

ing

defin

itio

ns. F

urth

erm

ore,

defi

niti

ons

and

regu

lato

ry

requ

irem

ents

var

y by

reg

ion.

ICH

ICH

has

issu

ed a

ran

ge o

f gui

delin

es p

erta

inin

g to

bio

logi

cs, w

hich

are

app

licab

le in

the

EU

, US,

Jap

an a

nd o

ther

cou

ntri

es t

hat

reco

gniz

e IC

H (

e.g.

, C

anad

a, A

ustr

alia

, New

Zea

land

).

The

follo

win

g to

pics

are

cov

ered

in th

is c

hapt

er fo

r th

e E

U, U

S, J

apan

, Can

ada,

Asi

a Pa

cific

, Lat

in A

mer

ica,

Afr

ica

and

Rus

sia/

CIS

:•

intr

oduc

tion

and

his

tory

•cu

rren

t pro

cedu

res

and

guid

ance

•do

ssie

r re

quir

emen

ts (

qual

ity,

pre

clin

ical

and

clin

ical

, as

wel

l as

spec

ifics

suc

h as

tran

smis

sibl

e sp

ongi

form

enc

epha

lopa

thie

s TSE

, vir

al c

lear

ance

, et

c.)

•ad

vanc

ed th

erap

y m

edic

inal

pro

duct

s (A

TM

Ps)

•D

rug

Mas

ter

File



Oth

er P

rodu

ct T

ypes

Regu

latio

ns a

nd G

uide

lines

Gen

eric

Dru

g P

rodu

cts

and

Bio

sim

ilars

WH

O •W

HO

Dru

g In

form

atio

n V

ol. 2

2, N

o. 1

, 200

8•

WH

O I

nfor

mal

Con

sulta

tion

on

Inte

rnat

iona

l Non

prop

riet

ary

Nam

es (

INN

) Po

licy

for

Bio

sim

ilar

Prod

ucts

, Gen

eva,

4–5

Sep

tem

ber

2006

EU

•E

urop

ean

Med

icin

es A

genc

y (Q

&A

), D

oc. R

ef. E

ME

A/3

9390

5/20

06, L

ondo

n, 2

2 Ju

ne 2

007

•C

ounc

il R

egul

atio

n N

o. (

EE

C)

1768

/92

of 1

8 Ju

ne 1

992

conc

erni

ng th

e cr

eati

on o

f a s

uppl

emen

tary

pro

tect

ion

cert

ifica

te fo

r m

edic

inal

pr

oduc

ts•

Reg

ulat

ion

(EC

) N

o. 7

26/2

004

of th

e E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 3

1 M

arch

200

4 la

ying

dow

n C

omm

unit

y pr

oced

ures

for

the

auth

oris

atio

n an

d su

perv

isio

n of

med

icin

al p

rodu

cts

for

hum

an a

nd v

eter

inar

y us

e an

d es

tabl

ishi

ng a

Eur

opea

n M

edic

ines

Age

ncy

•D

irec

tive

200

1/83

/EC

of t

he E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 6

Nov

embe

r 20

01 o

n th

e C

omm

unit

y co

de r

elat

ing

to m

edic

inal

pr

oduc

ts fo

r hu

man

use

, as

amen

ded

by D

irec

tive

200

4/27

/EC

of t

he E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 3

1 M

arch

200

4 an

d A

nnex

1

to it

(C

omm

issi

on D

irec

tive

200

3/63

/EC

of 2

5 Ju

ne 2

003)

US

•D

rug

Pric

e C

ompe

titio

n an

d Pa

tent

Ter

m R

esto

ratio

n A

ct o

f 198

4 (H

atch

-Wax

man

Act

), P

ublic

Law

98-

417,

98

Stat

ute

1585

•G

uida

nce

for

Indu

stry:

180

-Day

Gen

eric

Dru

g Ex

clus

ivity

Und

er th

e H

atch

-Wax

man

Am

endm

ent o

f the

Fed

eral

Foo

d, D

rug

and

Cos

met

ic A

ct (

July

19

98)

•G

uida

nce

for

Indu

stry:

Cou

rt D

ecisi

ons,

AN

DA

App

rova

ls, a

nd 1

80-D

ay E

xclu

sivity

Und

er th

e H

atch

-Wax

man

Am

endm

ents

to th

e Fe

dera

l Foo

d,

Dru

g, a

nd C

osm

etic

Act

(M

arch

200

0)C

anad

a •A

n A

ct r

espe

ctin

g fo

od, d

rugs

, cos

met

ics a

nd th

erap

eutic

dev

ices

(Fo

od a

nd D

rugs

Act

) (1

920)

•Fo

od a

nd D

rug

Regu

latio

ns•

Can

adia

n Re

fere

nce

Prod

uct (

5 D

ecem

ber

1995

)Sw

itze

rlan

d•

Fede

ral L

aw o

n M

edic

inal

Pro

duct

s and

Med

ical

Dev

ices

(La

w o

n T

hera

peut

ic P

rodu

cts)

dat

ed 1

5 D

ecem

ber

2000

(up

date

d on

1 M

ay 2

007)

•A

nlei

tung

zum

Ein

reic

hen

von

Zul

assu

ngsg

esuc

hen

für

Arz

neim

itte

l der

Hum

anm

ediz

in m

it b

ekan

nten

Wir

ksto

ffen

Instr

uctio

ns fo

r su

bmiss

ion

of a

pplic

atio

ns fo

r au

thor

izat

ion

for

drug

s of h

uman

med

icin

e w

ith k

now

n ac

tive

ingr

edie

nts (

Gen

eric

Instr

uctio

ns)

(31

Dec

embe

r 20

02)



Cha

pter

7

Mai

n To

pics

A g

ener

ic m

edic

ine

is a

med

icin

al p

rodu

ct th

at is

sim

ilar

to o

ne th

at h

as a

lrea

dy b

een

auth

oriz

ed (

”ref

eren

ce m

edic

inal

pro

duct

”) a

nd is

man

ufac

ture

d an

d di

stri

bute

d w

itho

ut p

aten

t pro

tect

ion

on th

e ac

tive

ingr

edie

nt. G

ener

ics

cont

ain

the

sam

e qu

anti

ty o

f act

ive

subs

tanc

e(s)

, are

use

d at

the

sam

e do

se to

trea

t the

sam

e di

seas

e, a

nd a

re e

qual

ly s

afe

and

effe

ctiv

e as

ori

gina

tor

prod

ucts

.

The

con

cept

of g

ener

ics

aris

es fr

om th

e fa

ct th

at w

hen

the

pate

nt fo

r an

ori

gina

l, br

and-

nam

e pr

oduc

t pat

ent e

xpir

es, t

he m

edic

ine

esse

ntia

lly

beco

mes

pub

lic p

rope

rty.

Com

pani

es w

ith

appr

opri

ate

expe

rtis

e an

d m

anuf

actu

ring

faci

litie

s m

ay p

rodu

ce a

nd m

arke

t the

pro

duct

, pro

vide

d th

ey

obta

in th

e ne

cess

ary

auth

oriz

atio

ns fr

om r

egul

ator

y au

thor

itie

s.

Dev

elop

ing

copi

es (

bios

imila

rs)

of w

ell-

know

n bi

opha

rmac

euti

cals

(or

igin

ator

s) is

ver

y ch

alle

ngin

g be

caus

e m

inor

mol

ecul

ar d

evia

tion

s fr

om th

e re

fere

nce

prod

uct m

ay a

ffec

t the

new

pro

duct

’s ef

ficac

y an

d/or

saf

ety.

Cha

pter

7 c

over

s re

gula

tory

fram

ewor

ks fo

r ge

neri

cs a

nd b

iosi

mila

rs, i

nclu

ding

:•

defin

itio

ns•

data

exc

lusi

vity

•Su

pple

men

tary

Pro

tect

ion

Cer

tific

ates

•B

olar

(ex

peri

men

tal a

nd te

stin

g) p

rovi

sion

s•

bioe

quiv

alen

ce•

mar

keti

ng a

utho

riza

tion

pro

cess

•re

fere

nce

med

icin

al p

rodu

cts

•va

riat

ions

•ph

arm

acov

igila

nce



Regu

latio

ns a

nd G

uide

lines

Pri

ncip

les

of O

rpha

n D

rugs

US

•O

rpha

n D

rug

Act

of 1

983,

Pub

lic L

aw 9

7-41

4, w

ith

amen

dmen

ts in

198

5 an

d 19

88E

U•

Reg

ulat

ion

(EC

) N

o. 1

41/2

000

of th

e E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 1

6 D

ecem

ber

1999

on

orph

an m

edic

inal

pro

duct

s •

Reg

ulat

ion

(EC

) N

o. 7

26/2

004

of th

e E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 3

1 M

arch

200

4 la

ying

dow

n C

omm

unit

y pr

oced

ures

for

the

auth

oris

atio

n an

d su

perv

isio

n of

med

icin

al p

rodu

cts

for

hum

an a

nd v

eter

inar

y us

e an

d es

tabl

ishi

ng a

Eur

opea

n M

edic

ines

Age

ncy

Aus

tral

ia

•A

ustr

alia

n Re

gula

tory

Gui

delin

es fo

r Pr

escr

iptio

n M

edic

ines

, Jun

e 20

04

Cha

pter

8

Mai

n To

pics

Orp

han

drug

s (o

r or

phan

med

icin

al p

rodu

cts)

are

inte

nded

for

the

tre

atm

ent

of o

rpha

n di

seas

es, w

hich

are

und

erst

ood

to b

e r

are

dise

ases

. In

mos

t le

gisl

atio

n, th

e or

phan

pri

ncip

le is

lim

ited

to d

rugs

onl

y. T

here

are

exc

epti

ons.

For

inst

ance

, in

the

US,

the

defin

itio

n of

orp

han

prod

ucts

was

ext

ende

d to

pro

duct

s ot

her

than

dru

gs s

uch

as m

edic

al d

evic

es a

nd m

edic

al fo

ods

(e.g

., pa

rent

eral

nut

riti

on).

Reg

ulat

ory

Pro

cedu

reA

ste

pwis

e ap

proa

ch is

em

ploy

ed fo

r th

e au

thor

izat

ion

of o

rpha

n dr

ugs

in m

ost j

uris

dict

ions

:•

obta

inin

g or

phan

des

igna

tion

•ap

plyi

ng fo

r m

arke

ting

aut

hori

zati

on fo

r th

e pa

rtic

ular

pro

duct

The

reg

istr

atio

n pr

oced

ure

gene

rally

fol

low

s th

e sa

me

prin

cipl

es a

s fo

r no

n-or

phan

dru

gs. I

n so

me

coun

trie

s or

reg

ions

, orp

han

drug

s au

tom

atic

ally

qu

alify

for

part

icul

ar a

utho

riza

tion

pro

cess

es, s

uch

as a

ccel

erat

ed o

r pr

iori

ty r

evie

w.

Orp

han

Dis

ease

s

O

ne g

ener

al u

nder

stan

ding

of a

n or

phan

dis

ease

is a

dis

ease

neg

lect

ed b

y do

ctor

s—or

phan

of t

he m

edic

al c

omm

unit

y. I

n a

stri

cter

sen

se, i

t des

igna

tes

dise

ases

tha

t af

fect

onl

y a

smal

l num

ber

of in

divi

dual

s. T

he la

tter

pri

ncip

le is

a c

orne

rsto

ne in

the

defi

niti

on o

f an

orp

han

dise

ase

in A

ustr

alia

, Jap

an,

the

US

and

the

EU

.

Ince

ntiv

es

E

ach

coun

try

wit

h es

tabl

ishe

d or

phan

med

icin

al p

rodu

ct le

gisl

atio

n of

fers

ince

ntiv

es to

com

pani

es th

at d

evel

op d

rugs

to tr

eat o

rpha

n di

sord

ers.

T

hese

mea

sure

s ar

e in

tend

ed to

mot

ivat

e co

mpa

nies

to in

vest

in th

ese

prod

ucts

by

nega

ting

the

impa

ct o

f exp

ecte

d lo

w s

ales

due

to th

e ra

rity

of t

he

dise

ase.

Sev

eral

mea

sure

s ex

plic

itly

add

ress

this

eco

nom

ic is

sue:

•m

arke

t exc

lusi

vity

•fe

e re

duct

ions

•ta

x in

cent

ives

•su

ppor

t of r

esea

rch

and

deve

lopm

ent a

ctiv

itie

s



Regu

latio

ns a

nd G

uide

lines

Food

Sup

plem

ents

an

d C

osm

etic

P

rodu

cts

Can

ada •

Cos

met

ic R

egul

atio

ns to

the

Food

and

Dru

gs A

ctE

U•

Cou

ncil

Dir

ecti

ve 7

6/76

8/E

EC

of 2

7 Ju

ly 1

976

on th

e ap

prox

imat

ion

of th

e la

ws

of th

e M

embe

r St

ates

rel

atin

g to

cos

met

ic p

rodu

cts,

as

amen

ded

•D

irec

tive

200

2/46

/EC

of t

he E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 1

0 Ju

ne 2

002

on th

e ap

prox

imat

ion

of th

e la

ws

of th

e M

embe

r St

ates

re

lati

ng to

food

sup

plem

ents

, as

amen

ded

US

•D

ieta

ry S

uppl

emen

t Hea

lth a

nd E

duca

tion

Act

of 1

994

•Ta

mpe

r-Re

sista

nt P

acka

ging

Act

of 1

980

•21

CFR

700

.25

Tam

per-

resi

stan

t pac

kagi

ng r

equi

rem

ents

for

cosm

etic

pro

duct

sW

HO •

Gui

delin

es fo

r V

itam

in a

nd M

iner

al F

ood

Supp

lem

ents

, CA

C/G

L 55

-200

5

Cha

pter

9

Mai

n To

pics

Food

Sup

plem

ents

Food

sup

plem

ents

—al

so k

now

n as

die

tary

sup

plem

ents

or

nutr

itio

nal s

uppl

emen

ts—

are

conc

entr

ated

sou

rces

of n

utri

ents

or

othe

r su

bsta

nces

wit

h a

nutr

itio

nal o

r ph

ysio

logi

cal e

ffec

t, al

one

or in

com

bina

tion

, usu

ally

mar

kete

d in

dos

e fo

rm, i

.e.,

pills

, tab

lets

, cap

sule

s, li

quid

s in

mea

sure

d do

ses,

et

c., a

nd u

sed

to s

uppl

emen

t the

nor

mal

die

t. T

hese

nut

rien

ts c

an b

e vi

tam

ins,

min

eral

s, h

erbs

or

othe

r bo

tani

cals

, am

ino

acid

s an

d su

bsta

nces

suc

h as

enz

ymes

, org

an ti

ssue

s, g

land

ular

s an

d m

etab

olit

es. T

he e

xact

defi

niti

on d

iffer

s by

cou

ntry

, and

pro

duct

s m

ay b

e cl

assi

fied

and

regu

late

d as

eit

her

food

s or

dru

gs.

Reco

mm

ende

d D

aily

Allo

wan

ces (

RD

As)

CA

s ha

ve e

stab

lishe

d w

hat i

s kn

own

as th

e re

com

men

ded

daily

/die

tary

allo

wan

ce, o

r R

DA

, (in

the

US

and

Can

ada

know

n as

Die

tary

Ref

eren

ce

Inta

kes

(DR

Is))

for

vari

ous

vita

min

s an

d m

iner

als.

Min

imum

and

Max

imum

Am

ount

s Bas

ed o

n Sa

fety

Apa

rt fr

om th

e R

DA

, min

imum

and

max

imum

am

ount

s of

vit

amin

s an

d m

iner

als

in fo

od s

uppl

emen

ts h

ave

been

est

ablis

hed

base

d on

upp

er s

afe

leve

ls a

nd th

e in

take

of v

itam

ins

and

min

eral

s fr

om o

ther

die

tary

sou

rces

.

Cos

met

ic P

rodu

cts

In g

ener

al, c

osm

etic

pro

duct

s ar

e su

bsta

nces

or

prep

arat

ions

inte

nded

to b

e pl

aced

in c

onta

ct w

ith

vari

ous

exte

rnal

par

ts o

f the

hum

an b

ody,

pr

imar

ily in

tend

ed to

cle

an, p

erfu

me,

pro

tect

or

mai

ntai

n th

em in

goo

d co

ndit

ion,

or

prom

ote

attr

acti

vene

ss, a

lter

appe

aran

ce o

r co

rrec

t bod

y od

ors.



Dep

endi

ng o

n lo

cal r

egul

atio

ns, t

he fo

llow

ing

prod

ucts

are

usu

ally

defi

ned

as c

osm

etic

s:•

crea

ms,

em

ulsi

ons,

loti

ons,

gel

s an

d oi

ls fo

r th

e sk

in (

hand

s, fa

ce, f

eet,

etc.

) •

face

mas

ks•

tint

ed b

ases

(liq

uids

, pas

tes,

pow

ders

) •

mak

eup

pow

ders

, aft

er-b

ath

pow

ders

, hyg

ieni

c po

wde

rs, e

tc.

•to

ilet s

oaps

, deo

dora

nt s

oaps

, etc

. •

perf

umes

, toi

lett

e w

ater

s an

d ea

u de

col

ogne

•

bath

and

sho

wer

pre

para

tion

s (s

alts

, foa

ms,

oils

, gel

s, e

tc.)

•

depi

lato

ries

•

deod

oran

ts a

nd a

ntip

ersp

iran

ts

•ha

ir c

are

prod

ucts

: o

hair

tint

s an

d bl

each

es

o

prod

ucts

for

wav

ing,

str

aigh

teni

ng a

nd fi

xing

o

sett

ing

prod

ucts

o

clea

nsin

g pr

oduc

ts (

loti

ons,

pow

ders

, sha

mpo

os)

o

cond

itio

ning

pro

duct

s (l

otio

ns, c

ream

s, o

ils)

o

hair

dre

ssin

g pr

oduc

ts (

loti

ons,

lacq

uers

, bri

llian

tine

s)

•sh

avin

g pr

oduc

ts (

crea

ms,

foam

s, lo

tion

s, e

tc.)

•

prod

ucts

for

mak

ing

up a

nd r

emov

ing

mak

eup

from

the

face

and

the

eyes

•

prod

ucts

inte

nded

for

appl

icat

ion

to th

e lip

s •

prod

ucts

for

care

of t

he te

eth

and

the

mou

th in

clud

ing

mou

thw

ashe

s•

prod

ucts

for

nail

care

and

mak

eup

•pr

oduc

ts fo

r ex

tern

al in

tim

ate

hygi

ene

•su

nbat

hing

pro

duct

s •

prod

ucts

for

tann

ing

wit

hout

the

sun

•sk

in-w

hite

ning

pro

duct

s •

anti

-wri

nkle

pro

duct

s



Regu

latio

ns a

nd g

uide

lines

Vete

rina

ry M

edic

inal

P

rodu

cts

OE

CD •

Goo

d La

bora

tory

Pra

ctic

e: O

ECD

Pri

ncip

les a

nd G

uida

nce

for

Com

plia

nce

Mon

itori

ng (

EN

V/M

C/C

HE

M(9

8)17

)

VIC

H •G

L1, V

alid

atio

n of

Ana

lytic

al P

roce

dure

s: D

efini

tion

and

Term

inol

ogy

(Ste

p 7)

•G

L2, V

alid

atio

n of

Ana

lytic

al P

roce

dure

s: M

etho

dolo

gy (

Step

7)

•G

L10,

Impu

ritie

s in

New

Vet

erin

ary

Dru

g Su

bsta

nces

(Re

visio

n) (

Step

9)

•G

L11,

Impu

ritie

s in

New

Vet

erin

ary

Med

icin

al P

rodu

cts (

Revi

sion)

(St

ep 9

)•

GL1

8, Im

puri

ties:

Resid

ual S

olve

nts i

n N

ew V

eter

inar

y M

edic

inal

Pro

duct

s, A

ctiv

e Su

bsta

nces

and

Exc

ipie

nts (

Step

7)

•G

L3, S

tabi

lity T

estin

g of

New

Vet

erin

ary

Dru

g Su

bsta

nces

and

Med

icin

al P

rodu

cts (

Revi

sion)

(St

ep 9

)•

GL4

, Sta

bilit

y Tes

ting

for

New

Vet

erin

ary

Dos

age

Form

s (St

ep 7

)•

GL5

, Sta

bilit

y Tes

ting:

Pho

tosta

bilit

y Tes

ting

of N

ew V

eter

inar

y D

rug

Subs

tanc

es a

nd M

edic

inal

Pro

duct

s (St

ep 7

)•

GL8

, Sta

bilit

y Tes

ting

for

Med

icat

ed P

rem

ixes

(St

ep 7

)•

GL1

7, S

tabi

lity T

estin

g of

New

Bio

tech

nolo

gica

l/Bio

logi

cal V

eter

inar

y M

edic

inal

Pro

duct

s (St

ep 7

)•

GL3

9, T

est P

roce

dure

s and

Acc

epta

nce

Cri

teri

a fo

r N

ew V

eter

inar

y D

rug

Subs

tanc

es a

nd N

ew M

edic

inal

Pro

duct

s: C

hem

ical

Sub

stanc

es (

Step

7)

•G

L40,

Tes

t Pro

cedu

res a

nd A

ccep

tanc

e C

rite

ria

for

New

Bio

tech

nolo

gica

l/Bio

logi

cal V

eter

inar

y M

edic

inal

Pro

duct

s (St

ep 7

)•

GL3

3, S

tudi

es to

Eva

luat

e th

e Sa

fety

of R

esid

ues o

f Vet

erin

ary

Dru

gs in

Hum

an F

ood:

Gen

eral

App

roac

h to

Tes

ting

(Ste

p 7)

•G

L36,

Stu

dies

to E

valu

ate

the

Safe

ty o

f Res

idue

s of V

eter

inar

y D

rugs

in H

uman

Foo

d: G

ener

al A

ppro

ach

to E

stabl

ish a

Mic

robi

olog

ical

AD

I (S

tep

7)•

GL2

3, S

tudi

es to

Eva

luat

e th

e Sa

fety

of R

esid

ues o

f Vet

erin

ary

Dru

gs in

Hum

an F

ood:

Gen

otox

icity

Tes

ting

(Ste

p 7)

•G

L22,

Stu

dies

to E

valu

ate

the

Safe

ty o

f Res

idue

s of V

eter

inar

y D

rugs

in H

uman

Foo

d: R

epro

duct

ion

Testi

ng (

Step

7)

•G

L32,

Stu

dies

to E

valu

ate

the

Safe

ty o

f Res

idue

s of V

eter

inar

y D

rugs

in H

uman

Foo

d: D

evel

opm

enta

l Tox

icity

Tes

ting

(Ste

p 7)

•G

L31,

Stu

dies

to E

valu

ate

the

Safe

ty o

f Res

idue

s of V

eter

inar

y D

rugs

in H

uman

Foo

d: R

epea

t-D

ose

(90

Day

s) T

oxic

ity T

estin

g (S

tep

7)•

GL3

7, S

tudi

es to

Eva

luat

e th

e Sa

fety

of R

esid

ues o

f Vet

erin

ary

Dru

gs in

Hum

an F

ood:

Rep

eat-

Dos

e C

hron

ic T

oxic

ity T

estin

g (S

tep

7)•

GL2

8, S

tudi

es to

Eva

luat

e th

e Sa

fety

of R

esid

ues o

f Vet

erin

ary

Dru

gs in

Hum

an F

ood:

Car

cino

geni

city

Tes

ting

(Ste

p 7)

•G

L46,

Stu

dies

to E

valu

ate

the

Met

abol

ism a

nd R

esid

ue K

inet

ics o

f Vet

erin

ary

Dru

gs in

Foo

d-Pr

oduc

ing

Ani

mal

s: M

etab

olism

Stu

dy to

Det

erm

ine

the

Qua

ntity

and

Ide

ntify

the

Nat

ure

of R

esid

ues (

Step

4)

•G

L47,

Stu

dies

to E

valu

ate

the

Met

abol

ism a

nd R

esid

ue K

inet

ics o

f Vet

erin

ary

Dru

gs in

Foo

d-Pr

oduc

ing

Ani

mal

s: C

ompa

rativ

e M

etab

olism

Stu

dies

in

Labo

rato

ry A

nim

als (

Step

4)

•G

L48,

Stu

dies

to E

valu

ate

the

Met

abol

ism a

nd R

esid

ue K

inet

ics o

f Vet

erin

ary

Dru

gs in

Foo

d-Pr

oduc

ing

Ani

mal

s: M

arke

r Re

sidue

Dep

letio

n St

udie

s to

Esta

blish

Pro

duct

With

draw

al P

erio

ds (

Step

4)

•G

L49,

Gui

delin

es fo

r th

e Val

idat

ion

of A

naly

tical

Met

hods

Use

d in

Res

idue

Dep

letio

n St

udie

s (St

ep 4

)•

GL9

, Goo

d C

linic

al P

ract

ice

(Ste

p 7)

•G

L24,

Pha

rmac

ovig

ilanc

e of

Vet

erin

ary

Med

icin

al P

rodu

cts:

Man

agem

ent o

f Adv

erse

Eve

nt R

epor

ts (A

ERs)

Pen

ding

ado

ptio

n of

GL3

0 an

d G

L35

(Ste

p 4)

•G

L29,

Pha

rmac

ovig

ilanc

e of

Vet

erin

ary

Med

icin

al P

rodu

cts—

Man

agem

ent o

f Per

iodi

c Su

mm

ary

Upd

ate

Repo

rts (

Step

7)

•G

L30,

Pha

rmac

ovig

ilanc

e of

Vet

erin

ary

Med

icin

al P

rodu

cts:

Con

trol

led

List

of T

erm

s (St

ep 5

)•

GL3

5, P

harm

acov

igila

nce

of V

eter

inar

y M

edic

inal

Pro

duct

s: El

ectr

onic

Sta

ndar

ds fo

r Tra

nsfe

r of

Dat

a (S

tep

3)•

GL4

2 Ph

arm

acov

igila

nce

of V

eter

inar

y M

edic

inal

Pro

duct

s: D

ata

Elem

ents

for

Subm

issio

n of

Adv

erse

Eve

nt R

epor

ts (A

ERS)

Pen

ding

ado

ptio

n of

G

L30

and

GL3

5 (S

tep

5)



EU

•D

irec

tive

200

1/82

/EC

of t

he E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 6

Nov

embe

r 20

01 o

n th

e C

omm

unit

y co

de r

elat

ing

to v

eter

inar

y m

edic

inal

pro

duct

s, a

s am

ende

d by

Dir

ecti

ve 2

004/

28/E

C

•T

he R

ules

gov

erni

ng V

eter

inar

y m

edic

inal

pro

duct

s in

the

Euro

pean

Com

mun

ity, N

otic

e to

App

lican

ts, M

edic

inal

pro

duct

s for

Vet

erin

ary

Use

, Vol

ume

6B, P

rese

ntat

ion

and

cont

ent o

f the

dos

sier—

Part

1•

Not

e fo

r gu

idan

ce o

n m

inim

ising

the

risk

of t

rans

mitt

ing

anim

al sp

ongi

form

enc

epha

lopa

thy

agen

ts vi

a hu

man

and

vet

erin

ary

med

icin

al p

rodu

cts

(EM

EA

/41

0/01

Rev

. 2)

•Po

sitio

n pa

per

on r

isk a

ssessm

ent o

f the

use

of s

tart

ing

mat

eria

ls of

rum

inan

t ori

gin

in v

eter

inar

y m

edic

inal

pro

duct

s int

ende

d fo

r us

e in

rum

inan

t sp

ecie

s (E

ME

A/C

VM

P/12

1/01

)•

Posit

ion

pape

r on

the

asse

ssmen

t of t

he r

isk o

f tra

nsm

issio

n of

ani

mal

spon

gifo

rm e

ncep

halo

path

y ag

ents

by m

aste

r se

ed m

ater

ials

used

in th

e pr

oduc

tion

of v

eter

inar

y va

ccin

es (

EM

EA

/CV

MP/

019/

01)

•R

egul

atio

n (E

C)

No.

470

/200

9 of

the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

6 M

ay 2

009

layi

ng d

own

Com

mun

ity

proc

edur

es fo

r th

e es

tabl

ishm

ent o

f res

idue

lim

its

of p

harm

acol

ogic

ally

act

ive

subs

tanc

es in

food

stuf

fs o

f ani

mal

ori

gin

•Po

licy

for

clas

sifica

tion

and

ince

ntiv

es fo

r ve

teri

nary

med

icin

al p

rodu

cts i

ndic

ated

for

min

or u

se m

inor

spec

ies (

MU

MS)

/lim

ited

mar

kets

(EM

EA

/429

080/

2009

)•

Dir

ecti

ve 2

004/

10/E

C o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

11

Febr

uary

200

4 on

the

harm

onis

atio

n of

law

s, r

egul

atio

ns a

nd

adm

inis

trat

ive

prov

isio

ns r

elat

ing

to th

e ap

plic

atio

n of

the

prin

cipl

es o

f goo

d la

bora

tory

pra

ctic

e an

d th

e ve

rific

atio

n of

thei

r ap

plic

atio

n fo

r te

sts

on c

hem

ical

sub

stan

ces

•D

irec

tive

200

4/9/

EC

of t

he E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 1

1 Fe

brua

ry 2

004

on th

e in

spec

tion

and

ver

ifica

tion

of g

ood

labo

rato

ry

prac

tice

(G

LP)

US

•21

CFR

589

Sub

stan

ces

Proh

ibit

ed F

rom

Use

in A

nim

al F

ood

or F

eed

•21

CFR

314

App

licat

ions

for

FDA

App

rova

l to

Mar

ket a

New

Dru

g•

Env

iron

men

tal A

sses

smen

t for

Am

endm

ents

to 2

1 C

FR 5

89 S

ubst

ance

s Pr

ohib

ited

from

Use

in A

nim

al F

ood

or F

eed,

Fin

al R

ule

•M

inor

Use

and

Min

or S

peci

es A

nim

al H

ealth

Act

of 2

004

(MU

MS)

•21

CFR

58

Goo

d La

bora

tory

Pra

ctic

e fo

r N

oncl

inic

al L

abor

ator

y St

udie

s



Cha

pter

10

Mai

n To

pics

Vet

erin

ary

med

ical

pro

duct

s pr

even

t, tr

eat o

r di

agno

se d

isea

ses

in a

nim

als.

The

y in

clud

e no

t onl

y dr

ugs,

vac

cine

s, d

evic

es a

nd d

iagn

osti

c te

st k

its,

bu

t als

o su

ch p

rodu

cts

as fo

od a

ddit

ives

and

feed

ingr

edie

nts

and

anim

al g

room

ing

aids

. Saf

ety

asse

ssm

ent o

f vet

erin

ary

prod

ucts

is b

ased

upo

n a

risk

/ben

efit a

naly

sis.

The

saf

ety

of v

eter

inar

y pr

oduc

ts d

epen

ds u

pon

the

targ

et a

nim

al’s

leve

l of t

oler

ance

of t

he in

gred

ient

s an

d, fo

r fo

od-p

rodu

cing

an

imal

s, th

e ac

cept

able

leve

l of r

esid

ue. T

he s

afet

y of

the

pers

on a

dmin

iste

ring

the

vete

rina

ry p

rodu

ct s

houl

d al

so b

e ta

ken

into

con

side

rati

on.

Dif

fere

nces

Bet

wee

n H

uman

and

Ani

mal

Med

icin

al P

rodu

cts

•H

uman

med

icin

es a

re d

evel

oped

for

one

spec

ies,

whe

reas

the

vete

rina

ry m

edic

ines

mar

ket i

s fr

agm

ente

d by

man

y an

imal

spe

cies

.•

Vet

erin

ary

med

icin

al p

rodu

cts

are

norm

ally

not

par

t of n

atio

nal h

ealth

pla

ns a

nd a

re n

ot r

eim

burs

ed.

•So

me

spec

ies

may

end

up

in th

e hu

man

food

cha

in; h

ence

, har

mfu

l dru

g re

sidu

es m

ust b

e st

rict

ly c

ontr

olle

d.•

Tho

se a

dmin

iste

ring

vet

erin

ary

med

icin

al p

rodu

cts

mus

t be

safe

guar

ded

from

pos

sibl

e ha

rmfu

l eff

ects

.•

Vet

erin

ary

med

icin

es m

ay h

ave

a m

ore

dire

ct e

ffec

t on

the

envi

ronm

ent t

han

hum

an m

edic

ines

.

VIC

H

T

he I

nter

nati

onal

Coo

pera

tion

on

Har

mon

isat

ion

of T

echn

ical

Req

uire

men

ts fo

r R

egis

trat

ion

of V

eter

inar

y M

edic

inal

Pro

duct

s (V

ICH

) is

a tr

ilate

ral

(EU

-Jap

an-U

S) p

rogr

am th

at a

ims

to h

arm

oniz

e te

chni

cal r

equi

rem

ents

for

vete

rina

ry p

rodu

ct r

egis

trat

ion.

Its

obj

ecti

ves

are:

•es

tabl

ish

and

impl

emen

t har

mon

ized

reg

ulat

ory

requ

irem

ents

•pr

ovid

e a

basi

s fo

r w

ider

inte

rnat

iona

l har

mon

izat

ion

of r

egis

trat

ion

requ

irem

ents

•m

onit

or a

nd m

aint

ain

exis

ting

VIC

H g

uide

lines

•en

sure

effi

cien

t pro

cess

es fo

r m

aint

aini

ng a

nd m

onit

orin

g co

nsis

tent

inte

rpre

tati

on o

f dat

a re

quir

emen

ts

Dos

sier

Req

uire

men

ts•

doss

ier

sum

mar

y: a

pplic

atio

n fo

rm, m

edic

al s

umm

ary

info

rmat

ion,

labe

ls, p

ack

leafl

et a

nd o

ther

pac

kagi

ng te

xts

and

expe

rt r

epor

ts•

qual

ity:

phy

sico

chem

ical

or

biol

ogic

al te

st r

esul

ts•

safe

ty: p

harm

acol

ogic

al, t

oxic

olog

ical

and

env

iron

men

tal s

afet

y te

st r

esul

ts•

resi

dues

: res

idue

stu

dy r

esul

ts a

nd a

naly

tica

l met

hodo

logy

(no

t for

imm

unol

ogic

al v

eter

inar

y m

edic

inal

pro

duct

s)•

effic

acy:

pre

clin

ical

and

clin

ical

tria

l res

ults

•ge

nera

l con

clus

ions

for

imm

unol

ogic

al v

eter

inar

y m

edic

inal

pro

duct

s



Regu

latio

ns a

nd G

uide

lines

Ove

r-th

e-C

ount

er

Pro

duct

s (O

TC

s)A

ustr

alia

•A

ustr

alia

n Re

gula

tory

Gui

delin

es fo

r O

ver-

the-

Cou

nter

Med

icin

es (

AR

GO

M),

200

3C

anad

a •Fo

od a

nd D

rugs

Act

and

Foo

d an

d D

rug

Regu

latio

ns, P

art C

EU

• D

irec

tive

200

4/27

/EC

of t

he E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 3

1 M

arch

200

4 am

endi

ng D

irec

tive

200

1/83

/EC

on

the

Com

mun

ity

code

rel

atin

g to

med

icin

al p

rodu

cts

for

hum

an u

se•

Eur

opea

n M

edic

ines

Age

ncy,

Gui

delin

e on

cha

ngin

g th

e cl

assifi

catio

n fo

r th

e su

pply

of a

med

icin

al p

rodu

ct fo

r hu

man

use

, The

Rul

es G

over

ning

M

edic

inal

Pro

duct

s in

the

Euro

pean

Com

mun

ity V

olum

e 2C

: Gui

delin

es (

Janu

ary

2006

)Ja

pan •

Phar

mac

eutic

al A

ffair

s Act

, Act

No.

145

of 1

960,

as

amen

ded

US

•D

urha

m-H

umph

rey

Am

endm

ent t

o th

e Fe

dera

l Foo

d, D

rug,

and

Cos

met

ic A

ct, P

ublic

Law

82-

215

(195

1)



Cha

pter

11

Mai

n To

pics

The

defi

niti

on o

f an

OT

C d

rug

and

mod

e of

dis

pens

ing

can

diff

er w

idel

y be

twee

n re

gion

s an

d co

untr

ies.

Gen

eral

ly, O

TC

pro

duct

s ca

n be

defi

ned

as m

edic

atio

ns th

at c

an b

e pu

rcha

sed

at a

pha

rmac

y, g

roce

ry o

r co

nven

ienc

e st

ore

wit

hout

a p

resc

ript

ion.

The

y ar

e us

ed to

trea

t the

sym

ptom

s of

co

mm

on a

ilmen

ts a

nd a

re s

afe

for

gene

ral c

onsu

mpt

ion

if ta

ken

exac

tly a

s pr

escr

ibed

by

the

pack

agin

g.

To a

ttai

n O

TC

sta

tus,

pro

duct

s m

ust

mee

t ce

rtai

n co

ndit

ions

:1.

Se

lf m

edic

atio

n in

the

form

of n

onpr

escr

ipti

on m

edic

ines

sho

uld

only

be

used

for

min

or a

ilmen

ts.

2.

Sinc

e th

e pa

tien

t bea

rs th

e fu

ll re

spon

sibi

lity

for

his

own

trea

tmen

t, th

e m

anuf

actu

rer

and

CA

s ar

e re

spon

sibl

e fo

r m

akin

g su

re th

at th

e te

xt u

sed

in th

e ac

com

pany

ing

Pati

ent I

nfor

mat

ion

Leafl

et (

PIL)

is c

lear

and

und

erst

anda

ble.

3.

Self

med

icat

ion

norm

ally

sho

uld

not b

e us

ed fo

r lo

ng p

erio

ds o

f tim

e to

trea

t chr

onic

con

diti

ons.

4.

If p

atie

nts

expe

rien

ce a

ny u

ndes

irab

le s

ide

effe

cts,

they

sho

uld

cons

ult t

heir

doc

tors

.5.

Se

lf m

edic

atio

n m

ust b

e us

ed v

ery

care

fully

by

preg

nant

or

lact

atin

g w

omen

, bab

ies

and

infa

nts.

Swit

chin

g P

roce

dure

sT

he s

wit

ch fr

om p

resc

ript

ion

to n

onpr

escr

ipti

on s

tatu

s (R

x-to

-OT

C)

is h

andl

ed v

ery

diff

eren

tly b

y ea

ch n

atio

n or

reg

ion.

The

dec

isio

n fo

r or

aga

inst

an

Rx-

to-O

TC

sw

itch

is m

ade

by th

e lo

cal C

A.

Lab

elin

g an

d A

dver

tisi

ngSi

nce

OT

C d

rugs

are

ava

ilabl

e w

itho

ut p

resc

ript

ion,

it is

impo

rtan

t tha

t the

y be

acc

ompa

nied

by

adeq

uate

dir

ecti

ons

for

use

and

war

ning

s to

pro

vide

a

high

deg

ree

of c

onsu

mer

pro

tect

ion.

The

info

rmat

ion

to a

ppea

r on

the

labe

l and

pac

kage

leafl

et is

cle

arly

spe

cifie

d in

nat

iona

l law

s.

Post

mar

ket

Surv

eilla

nce/

Enf

orce

men

tT

he i

ncre

asin

g nu

mbe

r of

OT

C d

rugs

has

cre

ated

a g

row

ing

need

for

sys

tem

s to

car

eful

ly m

onit

or b

oth

thei

r sa

fety

and

the

ir i

nter

acti

on w

ith

pres

crip

tion

dru

gs. T

his

is e

spec

ially

impo

rtan

t gi

ven

the

curr

ent

tren

d of

und

erre

port

ing

enge

nder

ed b

y co

mpl

icat

ed s

yste

ms,

tim

e la

gs a

nd e

xpen

ses

asso

ciat

ed w

ith

such

sys

tem

s.



Med

ical

Dev

ices

Re

gula

tions

and

Gui

delin

es

Leg

al a

nd

Reg

ulat

ory

Req

uire

men

ts

GH

TF •

SG1-

N29

R16

:200

5 In

form

atio

n D

ocum

ent C

once

rnin

g th

e D

efini

tion

of th

e Ter

m “

Med

ical

Dev

ice”

(M

ay 2

005)

•SG

1-N

41R

9:20

05 E

ssent

ial P

rinc

iple

s of S

afet

y &

Per

form

ance

of M

edic

al D

evic

es (

May

200

5)•

SG1-

N43

:200

5 La

belli

ng fo

r M

edic

al D

evic

es (

June

200

5)•

SG1-

N40

:200

6 Pr

inci

ples

of C

onfo

rmity

Asse

ssmen

t for

Med

ical

Dev

ices

(Ju

ne 2

006)

•SG

1-N

15:2

006

Prin

cipl

es o

f Med

ical

Dev

ices

Cla

ssific

atio

n (J

une

2006

)

Cha

pter

12

Mai

n To

pics

Acc

ordi

ng to

GH

TF,

a m

edic

al d

evic

e is

any

inst

rum

ent,

appa

ratu

s, im

plem

ent,

mac

hine

app

lianc

e,im

plan

t, in

vit

ro r

eage

nt o

r ca

libra

tor,

soft

war

em

ater

ial o

r ot

her

sim

ilar

or r

elat

ed a

rtic

le:

a)

inte

nded

by

the

man

ufac

ture

r to

be

used

, alo

ne o

r in

com

bina

tion

, for

hum

an b

eing

s fo

r on

e or

mor

e of

the

spec

ific

purp

ose(

s) o

f:•

diag

nosi

s, p

reve

ntio

n, m

onit

orin

g, tr

eatm

ent o

r al

levi

atio

n of

dis

ease

•di

agno

sis,

mon

itor

ing,

trea

tmen

t, al

levi

atio

n of

or

com

pens

atio

n fo

r an

inju

ry•

inve

stig

atio

n, r

epla

cem

ent,

mod

ifica

tion

, or

supp

ort o

f the

ana

tom

y or

of a

phy

siol

ogic

al p

roce

ss•

supp

orti

ng o

r su

stai

ning

life

•co

ntro

l of c

once

ptio

n•

disi

nfec

tion

of m

edic

al d

evic

es•

prov

idin

g in

form

atio

n fo

r m

edic

al o

r di

agno

stic

pur

pose

s by

mea

ns o

f in

vitr

o ex

amin

atio

n of

spe

cim

ens

deri

ved

from

the

hum

an b

ody

and

b)

whi

ch d

oes

not a

chie

ve it

s pr

imar

y in

tend

ed a

ctio

n in

or

on th

e hu

man

bod

y by

pha

rmac

olog

ical

, im

mun

olog

ical

or

met

abol

ic m

eans

, but

whi

ch

may

be

assi

sted

in it

s in

tend

ed fu

ncti

on b

y su

ch m

eans

Six

Pri

ncip

les

GH

TF

has

esta

blis

hed

six

basi

c re

quir

emen

ts th

at a

pply

to a

ll m

edic

al d

evic

es:

1.

M

edic

al d

evic

es s

houl

d be

des

igne

d an

d m

anuf

actu

red

in s

uch

a w

ay t

hat,

whe

n us

ed u

nder

the

con

diti

ons

and

for

the

purp

oses

inte

nded

,and

ta

king

into

acc

ount

the

tech

nica

l kno

wle

dge,

exp

erie

nce,

edu

cati

on o

r tr

aini

ng o

f int

ende

d us

ers,

they

will

not

com

prom

ise

the

clin

ical

con

diti

on

or th

e sa

fety

of p

atie

nts,

of u

sers

or,

whe

re a

pplic

able

, oth

er p

eopl

e. T

his

shou

ld b

e co

nsid

ered

in th

e co

ntex

t of t

he r

isk/

bene

fit r

atio

.2.

T

he s

olut

ions

ado

pted

by

the

man

ufac

ture

r fo

r th

e de

sign

and

man

ufac

ture

of t

he d

evic

es s

houl

d co

nfor

m to

the

mos

t cur

rent

saf

ety

prin

cipl

es

and

shou

ld a

ddre

ss th

e is

sue

of r

esid

ual r

isk

and

risk

red

ucti

on.

3.

Dev

ices

sho

uld

achi

eve

the

perf

orm

ance

inte

nded

by

the

man

ufac

ture

r.4.

D

evic

e ch

arac

teri

stic

s an

d pe

rfor

man

ce s

houl

d no

t be

adve

rsel

y af

fect

ed to

suc

h a

degr

ee th

at th

e he

alth

or

safe

ty o

f the

pat

ient

or

the

user

are

co

mpr

omis

ed d

urin

g th

e lif

etim

e of

the

devi

ce, u

nder

nor

mal

con

diti

ons

of u

se,.

5.

The

dev

ices

sho

uld

be d

esig

ned,

man

ufac

ture

d an

d pa

cked

in s

uch

a w

ay th

at th

eir

char

acte

rist

ics

and

perf

orm

ance

are

not

aff

ecte

d un

der

tran

spor

t and

sto

rage

con

diti

ons.

6.

The

ben

efits

mus

t be

dete

rmin

ed to

out

wei

gh a

ny u

ndes

irab

le s

ide

effe

cts

for

the

perf

orm

ance

s in

tend

ed.



Med

ical

Dev

ices

Re

gula

tions

and

Gui

delin

es

Tech

nica

l and

R

egul

ator

y R

equi

rem

ents

GH

TF •

SG1-

N11

:200

8 Su

mm

ary T

echn

ical

Doc

umen

tatio

n fo

r D

emon

strat

ing

Con

form

ity to

the

Esse

ntia

l Pri

ncip

les o

f Saf

ety

and

Perf

orm

ance

of M

edic

al

Dev

ices

(ST

ED)

(Feb

ruar

y 20

08)

•SG

1-N

44:2

008

Role

of S

tand

ards

in th

e A

ssessm

ent o

f Med

ical

Dev

ice

(Feb

ruar

y 20

08)

•SG

5 G

uida

nce

docu

men

ts•

SG1-

N40

:200

6 Pr

inci

ples

of C

onfo

rmity

Asse

ssmen

t for

Med

ical

Dev

ices

(Ju

ne 2

006)

•SG

1-N

55:2

009

Defi

nitio

n of

the T

erm

s Man

ufac

ture

r, A

utho

rise

d Re

pres

enta

tive,

Dist

ribu

tor

and

Impo

rter

(M

arch

200

9)•

SG3-

N99

-10

(Edi

tion

2)

Qua

lity

Man

agem

ent S

yste

ms—

Proc

ess V

alid

atio

n G

uida

nce

(Jan

uary

200

4)•

SG3-

N15

R8:

2005

Impl

emen

tatio

n of

Risk

Man

agem

ent P

rinc

iple

s and

Act

iviti

es W

ithin

a Q

ualit

y M

anag

emen

t Sys

tem

(M

ay 2

005)

•SG

3-N

17R

9:20

08 Q

ualit

y M

anag

emen

t Sys

tem

—M

edic

al D

evic

es—

Gui

danc

e on

the

Con

trol

of P

rodu

cts a

nd S

ervi

ces O

btai

ned

from

Sup

plie

rs

(Dec

embe

r 20

08)

ISO

•E

N I

SO 1

4971

on

Ris

k m

anag

emen

t

Cha

pter

13

Mai

n To

pics

Ess

enti

al T

echn

ical

File

Ele

men

tsT

he te

chni

cal fi

le is

a m

eans

for

man

ufac

ture

rs o

f all

devi

ce c

lass

es to

dem

onst

rate

a p

rodu

ct’s

conf

orm

ity

to th

e Es

sent

ial P

rinc

iple

s of S

afet

y an

d Pe

rfor

man

ce o

f Med

ical

Dev

ices

. The

tech

nica

l doc

umen

tati

on s

houl

d sh

ow h

ow e

ach

med

ical

dev

ice

was

dev

elop

ed, d

esig

ned

and

man

ufac

ture

d,

and

shou

ld in

clud

e de

scri

ptio

ns a

nd e

xpla

nati

ons

nece

ssar

y to

und

erst

and

the

man

ufac

ture

r’s d

eter

min

atio

n re

gard

ing

conf

orm

ity

to th

e es

sent

ial

requ

irem

ents

.

Prem

arke

t Pha

seT

he t

echn

ical

file

for

cri

tica

l dev

ices

mus

t be

sub

mit

ted

to t

he r

egul

ator

y au

thor

ity

for

eval

uati

on, w

hile

it is

suf

ficie

nt t

o ha

ve a

cop

y of

the

file

s fo

r le

ss-c

riti

cal d

evic

es r

eadi

ly a

vaila

ble

for

insp

ecti

on.

Postm

arke

t Pha

seT

he r

egul

ator

y au

thor

ity

may

, at a

ny ti

me,

req

uest

a c

opy

of th

e te

chni

cal fi

le fo

r C

lass

A a

nd B

(lo

wer

-ris

k) d

evic

es. T

he te

chni

cal fi

le m

ust f

ollo

w

the

lifec

ycle

man

agem

ent (

LCM

) pr

oces

s in

the

post

mar

ket p

hase

. Cha

nges

that

aff

ect t

he q

ualit

y sy

stem

mus

t be

repo

rted

to th

e re

gula

tory

au

thor

ity.

Con

tent

of

the

Sum

mar

y Te

chni

cal D

ocum

enta

tion

(ST

ED

)•

devi

ce d

escr

ipti

on•

prod

uct s

peci

ficat

ion

•re

fere

nce

to s

imila

r an

d pr

evio

us g

ener

atio

ns o

f the

dev

ice

•la

belin

g•

desi

gn a

nd m

anuf

actu

ring

info

rmat

ion

•Es

sent

ial P

rinc

iple

s (E

P) c

heck

list

•ri

sk a

naly

sis

and

cont

rol s

umm

ary

•pr

oduc

t ver

ifica

tion

and

val

idat

ion

•D

ecla

rati

on o

f Con

form

ity



Med

ical

Dev

ices

Re

gula

tions

and

Gui

delin

es

Post

mar

ket

Req

uire

men

tsE

C•

ME

DD

EV

2.1

2/1:

Gui

delin

es o

n a

Med

ical

Dev

ices

Vig

ilanc

e Sy

stem

(re

v 5)

(A

pril

2007

)G

HT

F •SG

2-N

8R4

Gui

danc

e on

How

to H

andl

e In

form

atio

n C

once

rnin

g V

igila

nce

Repo

rtin

g Re

late

d to

Med

ical

Dev

ices

(Ju

ne 1

999)

•SG

2-N

79R

11:2

009

Med

ical

Dev

ices

: Pos

t Mar

ket S

urve

illan

ce: N

atio

nal C

ompe

tent

Aut

hori

ty R

epor

t Exc

hang

e C

rite

ria

and

Repo

rt F

orm

(Fe

brua

ry

2009

)•

SG2-

N54

R8:

2006

Med

ical

Dev

ices

Pos

t Mar

ket S

urve

illan

ce: G

loba

l Gui

danc

e fo

r A

dver

se E

vent

Rep

ortin

g fo

r M

edic

al D

evic

es (

Nov

embe

r 20

06)

•SG

2-N

47R

4:20

05 R

evie

w o

f Cur

rent

Req

uire

men

ts on

Pos

tmar

ket S

urve

illan

ce (

May

200

5)•

SG2-

N57

R8:

2006

Med

ical

Dev

ices

Pos

t Mar

ket S

urve

illan

ce: C

onte

nt o

f Fie

ld S

afet

y N

otic

es (

June

200

6)IS

O•

ISO

134

85:2

003

Med

ical

dev

ices

—Q

ualit

y m

anag

emen

t sys

tem

s—Re

quir

emen

ts fo

r re

gula

tory

pur

pose

s•

ISO

149

71:2

007

Med

ical

dev

ices

—A

pplic

atio

n of

risk

man

agem

ent t

o m

edic

al d

evic

es

Cha

pter

14

Mai

n To

pics

Vig

ilanc

e R

epor

ting

M

anuf

actu

rers

pla

cing

med

ical

dev

ices

on

the

mar

ket m

ust h

ave

a vi

gila

nce

syst

em in

pla

ce fo

r co

llect

ing

and

eval

uati

ng r

epor

ted

inci

dent

s an

d ta

king

cor

rect

ive

acti

on, i

f nee

ded,

to p

reve

nt th

e re

curr

ence

of s

uch

inci

dent

s. T

he m

ain

purp

ose

of a

med

ical

dev

ice

vigi

lanc

e sy

stem

is to

impr

ove

the

prot

ecti

on o

f pat

ient

s’ an

d ot

her

user

s’ he

alth

and

saf

ety

by r

educ

ing

the

likel

ihoo

d th

at a

dev

ice

inci

dent

will

rec

ur.

Post

mar

ket

Surv

eilla

nce

(PM

S)A

ll re

gula

tory

sys

tem

s re

cogn

ize

that

adv

erse

eve

nt r

epor

ting

alo

ne c

anno

t cap

ture

all

risk

s re

late

d to

med

ical

dev

ices

in th

e po

stm

arke

t pha

se. F

or

cert

ain

clas

ses

of p

rodu

cts

such

as

diag

nost

ic d

evic

es, w

here

fals

e po

siti

ves

and/

or fa

lse

nega

tive

s m

ay o

ccur

, or

long

-ter

m im

plan

tabl

e de

vice

s an

d de

vice

s fo

r ho

me

use,

eva

luat

ing

the

devi

ce’s

perf

orm

ance

from

adv

erse

eve

nt r

epor

ts a

lone

wou

ld n

ot b

e su

ffici

ent.

To a

ddre

ss th

is r

equi

rem

ent,

PMS

acti

viti

es a

re m

anda

ted

in m

ost c

ount

ries

.

Fiel

d Sa

fety

Cor

rect

ive

Act

ion

(FSC

A)

Man

ufac

ture

rs p

laci

ng m

edic

al d

evic

es o

n th

e m

arke

t are

obl

iged

to p

ut in

to p

lace

cor

rect

ive

and

prev

enti

ve a

ctio

n (C

APA

) pl

ans

rela

ted

to th

eir

prod

ucts

, if t

hose

dev

ices

pos

e a

risk

to u

sers

or

othe

r in

divi

dual

s. T

hese

pla

ns in

clud

e sa

fety

-rel

ated

fiel

d co

rrec

tive

act

ions

take

n by

the

man

ufac

ture

r to

red

uce

the

risk

of h

arm

to p

atie

nts,

ope

rato

rs o

r ot

hers

and

/or

to m

inim

ize

chan

ces

the

even

t will

rec

ur.



Med

ical

Dev

ices

Re

gula

tions

and

Gui

delin

es

In V

itro

Dia

gnos

tics

GH

TF •

SG1-

N45

:200

8 Pr

inci

ples

of I

n V

itro

Dia

gnos

tic (

IVD

) M

edic

al D

evic

es C

lassi

ficat

ion

(Feb

ruar

y 20

08)

•SG

1-N

46:2

008

Prin

cipl

es o

f Con

form

ity A

ssessm

ent f

or In

Vitr

o D

iagn

ostic

(IV

D)

Med

ical

Dev

ices

(Ju

ly 2

008)

•SG

1-N

41R

9:20

05 E

ssent

ial P

rinc

iple

s of S

afet

y an

d Pe

rfor

man

ce o

f Med

ical

Dev

ices

(M

ay 2

005)

•SG

1-N

44:2

008

Role

of S

tand

ards

in th

e A

ssessm

ent o

f Med

ical

Dev

ices

(M

arch

200

8)•

SG1-

N11

:200

8 Su

mm

ary T

echn

ical

Doc

umen

tatio

n fo

r D

emon

strat

ing

Con

form

ity to

the

Esse

ntia

l Pri

ncip

les o

f Saf

ety

and

Perf

orm

ance

of M

edic

al

Dev

ices

(ST

ED)

(Feb

ruar

y 20

08)

•SG

2-N

47R

4:20

05 R

evie

w o

f Cur

rent

Req

uire

men

ts on

Pos

tmar

ket S

urve

illan

ce (

May

200

5)

Cha

pter

15

Mai

n To

pics

An

“in

vitr

o di

agno

stic

(IV

D)

med

ical

dev

ice”

is d

efine

d as

a d

evic

e th

at, w

heth

er u

sed

alon

e or

in c

ombi

nati

on, i

s in

tend

ed b

y th

e m

anuf

actu

rer

for

the

in v

itro

exam

inat

ion

of s

peci

men

s de

rive

d fr

om th

e hu

man

bod

y so

lely

or

prin

cipa

lly to

pro

vide

info

rmat

ion

for

diag

nost

ic, m

onit

orin

g or

co

mpa

tibi

lity

purp

oses

(G

HT

F: S

G1-

N45

:200

8). E

xam

ples

incl

ude:

•re

agen

ts•

calib

rato

rs•

cont

rol m

ater

ials

•sp

ecim

en r

ecep

tacl

es•

soft

war

e an

d re

late

d in

stru

men

ts•

appa

ratu

s or

oth

er a

rtic

les

IVD

med

ical

dev

ices

for

self

test

ing

are

inte

nded

by

the

man

ufac

ture

r fo

r us

e by

lay

peop

le. I

n so

me

juri

sdic

tion

s, s

ome

clas

ses

of I

VD

med

ical

de

vice

s m

ay b

e co

vere

d by

sep

arat

e na

tion

al r

egul

atio

ns.

Ele

men

ts o

f C

onfo

rmit

y A

sses

smen

t

T

he m

ain

elem

ents

of a

con

form

ity

asse

ssm

ent s

yste

m a

re:

•a

QM

S•

a PM

S sy

stem

•

sum

mar

y te

chni

cal d

ocum

enta

tion

•

a D

ecla

rati

on o

f Con

form

ity

•re

gist

rati

on o

f man

ufac

ture

rs a

nd th

eir

IVD

med

ical

dev

ices

wit

h

t

he r

egul

ator

y au

thor

ity

CL

ASS

RIS

K L

EV

EL

EX

AM

PL

ES

ALo

w I

ndiv

idua

l R

isk

and

Low

Pu

blic

Hea

lth R

isk

Clin

ical

che

mis

try

anal

yzer

, pre

pare

d se

lect

ive

cultu

re m

edia

BM

oder

ate

Indi

vidu

al R

isk

and/

or L

ow P

ublic

H

ealth

Ris

k

Preg

nanc

y se

lf te

stin

g,

anti

-nuc

lear

ant

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y,

urin

e te

st s

trip

s

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igh

Indi

vidu

al

Ris

k an

d/or

M

oder

ate

Publ

ic

Hea

lth R

isk

Blo

od g

luco

se s

elf

test

ing,

HL

A ty

ping

, PSA

sc

reen

ing,

Rub

ella

DH

igh

Indi

vidu

al

Ris

k an

d H

igh

Publ

ic H

ealth

Ris

k

HIV

blo

od d

onor

sc

reen

ing,

HIV

blo

od

diag

nost

ic

Gen

eral

Pri

ncip

les

of C

lass

ifica

tion

as

prop

osed

by

GH

TF



Med

ical

Dev

ices

Re

gula

tions

and

Gui

delin

es

In V

itro

Dia

gnos

tics

GH

TF •

SG1-

N45

:200

8 Pr

inci

ples

of I

n V

itro

Dia

gnos

tic (

IVD

) M

edic

al D

evic

es C

lassi

ficat

ion

(Feb

ruar

y 20

08)

•SG

1-N

46:2

008

Prin

cipl

es o

f Con

form

ity A

ssessm

ent f

or In

Vitr

o D

iagn

ostic

(IV

D)

Med

ical

Dev

ices

(Ju

ly 2

008)

•SG

1-N

41R

9:20

05 E

ssent

ial P

rinc

iple

s of S

afet

y an

d Pe

rfor

man

ce o

f Med

ical

Dev

ices

(M

ay 2

005)

•SG

1-N

44:2

008

Role

of S

tand

ards

in th

e A

ssessm

ent o

f Med

ical

Dev

ices

(M

arch

200

8)•

SG1-

N11

:200

8 Su

mm

ary T

echn

ical

Doc

umen

tatio

n fo

r D

emon

strat

ing

Con

form

ity to

the

Esse

ntia

l Pri

ncip

les o

f Saf

ety

and

Perf

orm

ance

of M

edic

al

Dev

ices

(ST

ED)

(Feb

ruar

y 20

08)

•SG

2-N

47R

4:20

05 R

evie

w o

f Cur

rent

Req

uire

men

ts on

Pos

tmar

ket S

urve

illan

ce (

May

200

5)

Cha

pter

15

Mai

n To

pics

An

“in

vitr

o di

agno

stic

(IV

D)

med

ical

dev

ice”

is d

efine

d as

a d

evic

e th

at, w

heth

er u

sed

alon

e or

in c

ombi

nati

on, i

s in

tend

ed b

y th

e m

anuf

actu

rer

for

the

in v

itro

exam

inat

ion

of s

peci

men

s de

rive

d fr

om th

e hu

man

bod

y so

lely

or

prin

cipa

lly to

pro

vide

info

rmat

ion

for

diag

nost

ic, m

onit

orin

g or

co

mpa

tibi

lity

purp

oses

(G

HT

F: S

G1-

N45

:200

8). E

xam

ples

incl

ude:

•re

agen

ts•

calib

rato

rs•

cont

rol m

ater

ials

•sp

ecim

en r

ecep

tacl

es•

soft

war

e an

d re

late

d in

stru

men

ts•

appa

ratu

s or

oth

er a

rtic

les

IVD

med

ical

dev

ices

for

self

test

ing

are

inte

nded

by

the

man

ufac

ture

r fo

r us

e by

lay

peop

le. I

n so

me

juri

sdic

tion

s, s

ome

clas

ses

of I

VD

med

ical

de

vice

s m

ay b

e co

vere

d by

sep

arat

e na

tion

al r

egul

atio

ns.

Ele

men

ts o

f C

onfo

rmit

y A

sses

smen

t

T

he m

ain

elem

ents

of a

con

form

ity

asse

ssm

ent s

yste

m a

re:

•a

QM

S•

a PM

S sy

stem

•

sum

mar

y te

chni

cal d

ocum

enta

tion

•

a D

ecla

rati

on o

f Con

form

ity

•re

gist

rati

on o

f man

ufac

ture

rs a

nd th

eir

IVD

med

ical

dev

ices

wit

h

t

he r

egul

ator

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thor

ity

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er T

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ns a

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ecti

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edic

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man

use

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314

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mot

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drug

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biol

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olut

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Eth

ical

Cri

teri

a fo

r M

edic

inal

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g Pr

omot

ion

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chni

cal R

epor

t Ser

ies,

No.

722

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Sel

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d U

se o

f Esse

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Eur

opea

n Fe

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harm

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tica

l Ind

ustr

ies

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Ass

ocia

tion

s, E

urop

ean

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e of

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ctic

e on

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Prom

otio

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icin

es, U

pdat

e 20

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Inte

rnat

iona

l Fed

erat

ion

of P

harm

aceu

tica

l Man

ufac

ture

rs &

Ass

ocia

tion

s, C

ode

of P

harm

aceu

tica

l Mar

keti

ng P

ract

ices

Cha

pter

16

Mai

n To

pics

Adv

erti

sing

pre

scri

ptio

n dr

ugs,

and

in m

any

case

s, m

edic

al d

evic

es, i

s a

high

ly r

egul

ated

pro

cess

in m

ost c

ount

ries

. Adv

erti

sem

ents

for

othe

r pr

oduc

t gr

oups

suc

h as

food

sup

plem

ents

and

cos

met

ics,

alth

ough

less

str

ict,

are

also

con

trol

led.

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ough

the

exac

t defi

niti

on is

diff

eren

t acr

oss

regi

ons,

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erti

sing

, as

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ted

to m

edic

inal

pro

duct

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med

ical

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eral

ly c

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e un

ders

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to

be

the

prov

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n of

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form

of i

nfor

mat

ion,

incl

udin

g do

or-t

o-do

or a

dver

tisi

ng, o

r an

y ac

tivi

ty th

at a

ims

to p

rom

ote

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pres

crip

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, sup

ply,

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e or

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sum

ptio

n of

suc

h pr

oduc

ts.

Form

s of

Adv

erti

sing

• ad

vert

isin

g of

med

icin

al p

rodu

cts,

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h as

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crip

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gs, w

hich

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ly a

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l pub

lic, w

heth

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off-

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rtis

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of p

resc

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only

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gs in

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prod

ucts

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psyc

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otic

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stan

ces

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g to

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gene

ral p

ublic

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vert

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re p

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ssio

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ical

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rese

ntat

ives

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ical

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rese

ntat

ives

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y a

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omot

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of d

rugs

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uld

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ve a

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chni

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now

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rmat

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on p

rodu

cts.

The

y sh

ould

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uate

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aine

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WH

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odes

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r 20

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isk M

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EU

•R

egul

atio

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C)

No.

726

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4 of

the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

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31

Mar

ch 2

004

layi

ng d

own

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mun

ity

proc

edur

es fo

r th

e au

thor

isat

ion

and

supe

rvis

ion

of m

edic

inal

pro

duct

s fo

r hu

man

and

vet

erin

ary

use

and

esta

blis

hing

a E

urop

ean

Med

icin

es A

genc

y•

Dir

ecti

ve 2

001/

20/E

C o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

4 A

pril

2001

on

the

appr

oxim

atio

n of

the

law

s, r

egul

atio

ns a

nd

adm

inis

trat

ive

prov

isio

ns o

f the

Mem

ber

Stat

es r

elat

ing

to th

e im

plem

enta

tion

of g

ood

clin

ical

pra

ctic

es in

the

cond

uct o

f clin

ical

tria

ls fo

r m

edic

inal

pro

duct

s fo

r hu

man

use

(C

linic

al T

rial

s Dir

ectiv

e)•

Com

mis

sion

Dir

ecti

ve 2

005/

28/E

C o

f 8 A

pril

2005

layi

ng d

own

prin

cipl

es a

nd g

uide

lines

for

good

clin

ical

pra

ctic

e as

reg

ards

inve

stig

atio

nal

med

icin

al p

rodu

cts

for

hum

an u

se, a

s w

ell a

s th

e re

quir

emen

ts fo

r au

thor

isat

ion

of th

e m

anuf

actu

ring

or

impo

rtat

ion

of s

uch

prod

ucts

(G

ood

Clin

ical

Pra

ctic

e D

irec

tive)

•C

omm

issi

on D

irec

tive

200

3/94

/EC

of 8

Oct

ober

200

3 la

ying

dow

n th

e pr

inci

ples

and

gui

delin

es o

f goo

d m

anuf

actu

ring

pra

ctic

e in

res

pect

of

med

icin

al p

rodu

cts

for

hum

an u

se a

nd in

vest

igat

iona

l med

icin

al p

rodu

cts

for

hum

an u

se (

Hum

an G

MP

Dir

ectiv

e)•

Com

mis

sion

Dir

ecti

ve 9

1/41

2/E

EC

of 2

3 Ju

ly 1

991

layi

ng d

own

the

prin

cipl

es a

nd g

uide

lines

of g

ood

man

ufac

turi

ng p

ract

ice

for

vete

rina

ry

med

icin

al p

rodu

cts

(Vet

erin

ary

GM

P D

irec

tive)

•C

ounc

il D

irec

tive

92/

25/E

EC

of 3

1 M

arch

199

2 on

the

who

lesa

le d

istr

ibut

ion

of m

edic

inal

pro

duct

s fo

r hu

man

use

•D

irec

tive

200

4/10

/EC

of t

he E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 1

1 Fe

brua

ry 2

004

on th

e ha

rmon

isat

ion

of la

ws,

reg

ulat

ions

and

ad

min

istr

ativ

e pr

ovis

ions

rel

atin

g to

the

appl

icat

ion

of th

e pr

inci

ples

of g

ood

labo

rato

ry p

ract

ice

and

the

veri

ficat

ion

of th

eir

appl

icat

ions

for

test

s on

che

mic

al s

ubst

ance

s •

Dir

ecti

ve 2

004/

9/E

C o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

11

Febr

uary

200

4 on

the

insp

ecti

on a

nd v

erifi

cati

on o

f goo

d la

bora

tory

pr

acti

ce•

Cou

ncil

Dir

ecti

ve 9

0/38

5/E

EC

of 2

0 Ju

ne 1

990

on th

e ap

prox

imat

ion

of th

e la

ws

of th

e M

embe

r St

ates

rel

atin

g to

act

ive

impl

anta

ble

med

ical

de

vice

s (A

IMD

Dir

ectiv

e)•

Cou

ncil

Dir

ecti

ve 9

3/42

/EE

C o

f 14

June

199

3 co

ncer

ning

med

ical

dev

ices

(M

edic

al D

evic

es D

irec

tive,

MD

D)

•D

irec

tive

98/

79/E

C o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

27

Oct

ober

199

8 on

in v

itro

dia

gnos

tic

med

ical

dev

ices

(IV

D D

irec

tive)

US

•Fe

dera

l Foo

d, D

rug,

and

Cos

met

ic A

ct o

f 193

8 (F

D&

C A

ct)

•Pu

blic

Hea

lth S

ervi

ce A

ct o

f 194

4 (P

HS

Act

)•

21 C

FR 8

07 E

stab

lishm

ent R

egis

trat

ion

and

Dev

ice

List

ing

for

Man

ufac

ture

rs a

nd I

niti

al I

mpo

rter

s of

Dev

ices

•21

CFR

820

Qua

lity

Syst

em R

egul

atio

n•

21 C

FR 8

03 M

edic

al D

evic

e R

epor

ting



Regu

latio

ns a

nd G

uide

lines

Enf

orce

men

t an

d C

ompl

ianc

eIC

H•

Goo

d M

anuf

actu

ring

Pra

ctic

e G

uide

for

Act

ive

Phar

mac

eutic

al In

gred

ient

s Q7

(Cur

rent

Ste

p 4

Ver

sion

, Nov

embe

r 20

00)

•Q

ualit

y R

isk M

anag

emen

t Q9

(Cur

rent

Ste

p 4

Ver

sion

, Nov

embe

r 20

05)

•Ph

arm

aceu

tical

Qua

lity

Syste

m Q

10 (

Cur

rent

Ste

p 4

Ver

sion

, Jun

e 20

08)

•Ph

arm

acov

igila

nce

Plan

ning

E2E

(C

urre

nt S

tep

4 V

ersi

on, N

ovem

ber

2004

)•

Gui

delin

e fo

r G

ood

Clin

ical

Pra

ctic

e E6

(R1)

(C

urre

nt S

tep

4 V

ersi

on, J

une

1996

)G

HT

F •SG

4-N

28R

4:20

08 G

uide

lines

for

Regu

lato

ry A

uditi

ng o

f Qua

lity

Man

agem

ent S

yste

ms o

f Med

ical

Dev

ice

Man

ufac

ture

rs—

Part

1: G

ener

al

Requ

irem

ents

(Aug

ust 2

008)

•SG

3-N

17:2

008

Qua

lity

Man

agem

ent S

yste

m—

Med

ical

Dev

ices

—G

uida

nce

on th

e C

ontr

ol o

f Pro

duct

s and

Ser

vice

s Obt

aine

d fr

om S

uppl

iers

(D

ecem

ber

2008

)•

SG3-

N15

R8:

2005

Impl

emen

tatio

n of

Risk

Man

agem

ent P

rinc

iple

s and

Act

iviti

es W

ithin

a Q

ualit

y M

anag

emen

t Sys

tem

(M

ay 2

005)

•SG

3-N

99-1

0:20

04 Q

ualit

y M

anag

emen

t Sys

tem

s—Pr

oces

s Val

idat

ion

Gui

danc

e (J

anua

ry 2

004)

EU

•R

egul

atio

n (E

C)

No.

726

/200

4 of

the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

31

Mar

ch 2

004

layi

ng d

own

Com

mun

ity

proc

edur

es fo

r th

e au

thor

isat

ion

and

supe

rvis

ion

of m

edic

inal

pro

duct

s fo

r hu

man

and

vet

erin

ary

use

and

esta

blis

hing

a E

urop

ean

Med

icin

es A

genc

y•

Dir

ecti

ve 2

001/

20/E

C o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

4 A

pril

2001

on

the

appr

oxim

atio

n of

the

law

s, r

egul

atio

ns a

nd

adm

inis

trat

ive

prov

isio

ns o

f the

Mem

ber

Stat

es r

elat

ing

to th

e im

plem

enta

tion

of g

ood

clin

ical

pra

ctic

es in

the

cond

uct o

f clin

ical

tria

ls fo

r m

edic

inal

pro

duct

s fo

r hu

man

use

(C

linic

al T

rial

s Dir

ectiv

e)•

Com

mis

sion

Dir

ecti

ve 2

005/

28/E

C o

f 8 A

pril

2005

layi

ng d

own

prin

cipl

es a

nd g

uide

lines

for

good

clin

ical

pra

ctic

e as

reg

ards

inve

stig

atio

nal

med

icin

al p

rodu

cts

for

hum

an u

se, a

s w

ell a

s th

e re

quir

emen

ts fo

r au

thor

isat

ion

of th

e m

anuf

actu

ring

or

impo

rtat

ion

of s

uch

prod

ucts

(G

ood

Clin

ical

Pra

ctic

e D

irec

tive)

•C

omm

issi

on D

irec

tive

200

3/94

/EC

of 8

Oct

ober

200

3 la

ying

dow

n th

e pr

inci

ples

and

gui

delin

es o

f goo

d m

anuf

actu

ring

pra

ctic

e in

res

pect

of

med

icin

al p

rodu

cts

for

hum

an u

se a

nd in

vest

igat

iona

l med

icin

al p

rodu

cts

for

hum

an u

se (

Hum

an G

MP

Dir

ectiv

e)•

Com

mis

sion

Dir

ecti

ve 9

1/41

2/E

EC

of 2

3 Ju

ly 1

991

layi

ng d

own

the

prin

cipl

es a

nd g

uide

lines

of g

ood

man

ufac

turi

ng p

ract

ice

for

vete

rina

ry

med

icin

al p

rodu

cts

(Vet

erin

ary

GM

P D

irec

tive)

•C

ounc

il D

irec

tive

92/

25/E

EC

of 3

1 M

arch

199

2 on

the

who

lesa

le d

istr

ibut

ion

of m

edic

inal

pro

duct

s fo

r hu

man

use

•D

irec

tive

200

4/10

/EC

of t

he E

urop

ean

Parl

iam

ent a

nd o

f the

Cou

ncil

of 1

1 Fe

brua

ry 2

004

on th

e ha

rmon

isat

ion

of la

ws,

reg

ulat

ions

and

ad

min

istr

ativ

e pr

ovis

ions

rel

atin

g to

the

appl

icat

ion

of th

e pr

inci

ples

of g

ood

labo

rato

ry p

ract

ice

and

the

veri

ficat

ion

of th

eir

appl

icat

ions

for

test

s on

che

mic

al s

ubst

ance

s •

Dir

ecti

ve 2

004/

9/E

C o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

11

Febr

uary

200

4 on

the

insp

ecti

on a

nd v

erifi

cati

on o

f goo

d la

bora

tory

pr

acti

ce•

Cou

ncil

Dir

ecti

ve 9

0/38

5/E

EC

of 2

0 Ju

ne 1

990

on th

e ap

prox

imat

ion

of th

e la

ws

of th

e M

embe

r St

ates

rel

atin

g to

act

ive

impl

anta

ble

med

ical

de

vice

s (A

IMD

Dir

ectiv

e)•

Cou

ncil

Dir

ecti

ve 9

3/42

/EE

C o

f 14

June

199

3 co

ncer

ning

med

ical

dev

ices

(M

edic

al D

evic

es D

irec

tive,

MD

D)

•D

irec

tive

98/

79/E

C o

f the

Eur

opea

n Pa

rlia

men

t and

of t

he C

ounc

il of

27

Oct

ober

199

8 on

in v

itro

dia

gnos

tic

med

ical

dev

ices

(IV

D D

irec

tive)

US

•Fe

dera

l Foo

d, D

rug,

and

Cos

met

ic A

ct o

f 193

8 (F

D&

C A

ct)

•Pu

blic

Hea

lth S

ervi

ce A

ct o

f 194

4 (P

HS

Act

)•

21 C

FR 8

07 E

stab

lishm

ent R

egis

trat

ion

and

Dev

ice

List

ing

for

Man

ufac

ture

rs a

nd I

niti

al I

mpo

rter

s of

Dev

ices

•21

CFR

820

Qua

lity

Syst

em R

egul

atio

n•

21 C

FR 8

03 M

edic

al D

evic

e R

epor

ting

Cha

pter

17

Mai

n To

pics

Enf

orce

men

t can

be

defin

ed a

s an

y ac

tion

take

n by

a r

egul

ator

y au

thor

ity

to p

rote

ct th

e pu

blic

from

pro

duct

s of

sus

pect

qua

lity,

saf

ety

or e

ffica

cy, a

nd

may

incl

ude

acti

viti

es s

uch

as:

•lic

ensi

ng•

insp

ecti

ons

•op

erat

ions

•

surv

eilla

nce

•pr

eclin

ical

and

clin

ical

test

ing

•st

orag

e an

d di

stri

buti

on•

impo

rt c

ontr

ol•

cont

rol o

f adv

erti

sing

and

pro

mot

ion

CA

s ex

erci

se a

lega

l rig

ht to

con

trol

pro

duct

use

or

sale

wit

hin

thei

r ju

risd

icti

on b

y en

suri

ng c

ompl

ianc

e w

ith

law

s, r

egul

atio

ns, s

tand

ards

and

any

po

stm

arke

t com

mit

men

ts.

Pha

rmac

euti

cals

and

Bio

logi

cal P

rodu

cts

Reg

ulat

ory

com

plia

nce

for

phar

mac

euti

cals

and

bio

logi

c pr

oduc

ts is

enf

orce

d by

insp

ecti

ons

and

mon

itor

ing.

Nat

iona

l leg

isla

tion

pro

vide

s st

atut

ory

pow

ers

to C

As

to e

nsur

e co

mpl

ianc

e vi

a su

ch s

anct

ions

as

mon

etar

y fin

es a

nd/o

r im

pris

onm

ent f

or n

onco

mpl

ianc

e.

Insp

ecti

ons

Bef

ore

med

icin

al p

rodu

cts

can

be p

lace

d on

the

mar

ket,

MA

Hs,

man

ufac

ture

rs, d

istr

ibut

ors

or w

hole

sale

rs, d

eale

rs a

nd/o

r m

arke

ters

mus

t und

ergo

se

vera

l pre

appr

oval

insp

ecti

ons

by C

As.

The

se c

over

all

area

s of

GxP

s re

late

d to

the

prod

uct’s

man

ufac

ture

and

dis

trib

utio

n:•

Goo

d La

bora

tory

Pra

ctic

e•

Goo

d C

linic

al P

ract

ice

•G

ood

Man

ufac

turi

ng P

ract

ice

•G

ood

Dis

trib

utio

n Pr

acti

ce



Pha

rmac

ovig

ilanc

e an

d C

ompl

ianc

ePh

arm

acov

igila

nce

insp

ecti

ons

shou

ld b

e co

nduc

ted

to p

rovi

de a

ssur

ance

s th

at M

AH

s ar

e co

mpl

ying

wit

h th

eir

regu

lato

ry o

blig

atio

ns a

nd to

faci

li-ta

te c

ompl

ianc

e. T

he le

gal r

equi

rem

ents

for

phar

mac

ovili

ganc

e sy

stem

s ar

e sp

ecifi

ed in

loca

l law

s an

d re

gula

tion

s.

Oth

er I

ssue

s

O

ther

pos

tmar

ket i

ssue

s in

clud

e ch

ange

con

trol

and

mon

itor

ing

adve

rtis

ing

and

prom

otio

n.

Med

ical

Dev

ices

and

In

Vit

ro D

iagn

osti

c D

evic

esLi

ke p

harm

aceu

tica

l pro

duct

s, m

edic

al d

evic

es m

ust c

ompl

y w

ith

nati

onal

and

reg

iona

l law

s an

d re

gula

tion

s en

forc

ed b

y m

onit

orin

g an

d in

spec

tion

s.

The

inno

vati

ve n

atur

e of

the

med

ical

dev

ice

indu

stry

cre

ates

uni

que

lega

l and

enf

orce

men

t ris

ks, c

ompl

ianc

e ru

les

and

indu

stry

cod

es o

f con

duct

. T

he a

reas

to b

e in

spec

ted

duri

ng th

e pr

e- a

nd p

ostm

arke

t pha

ses

for

drug

s an

d de

vice

s ar

e si

mila

r an

d co

ver

prec

linic

al a

nd c

linic

al te

stin

g, th

e m

anu-

fact

urin

g pr

oces

s an

d co

ntro

ls, v

igila

nce

repo

rtin

g, c

hang

e co

ntro

l, qu

alit

y sy

stem

s, a

nd la

belin

g an

d ad

vert

isin

g ac

tivi

ties

.

Insp

ecti

ons

Insp

ecti

ons

form

par

t of b

oth

the

pre-

and

pos

tmar

ket p

hase

s of

med

ical

dev

ice

man

ufac

ture

. In

man

y in

stan

ces,

insp

ecti

ons

are

carr

ied

out b

y th

ird

part

ies

accr

edit

ed b

y C

As,

for

exam

ple

Not

ified

Bod

ies

in th

e E

U o

r ac

cred

ited

firm

s in

the

US.

Qua

lity

Syst

ems

Mos

t jur

isdi

ctio

ns r

equi

re th

at m

edic

al d

evic

e m

anuf

actu

rers

impl

emen

t a q

ualit

y m

anag

emen

t sys

tem

. ISO

has

pub

lishe

d th

ree

stan

dard

s on

qua

lity

man

agem

ent:

•IS

O 9

000:

2005

Qua

lity

man

agem

ent s

yste

ms—

Fund

amen

tals

and

voc

abul

ary

•IS

O 1

3485

:200

3 M

edic

al d

evic

es—

Qua

lity

man

agem

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497:

2007

Med

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