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| Slide 1 of 57 October 2007

Dr A J van Zyl

Technical Officer

HTP/PSM/QSM

World Health Organization (WHO!eneva" S#itzerland

vanzyla$#ho%int

Training Workshop on PharmaceuticalDevelopment with a focus on Paediatric

Formulations

15 October 2!

Tallinn" #stonia

1

!ood Man&fact&ring Practice' (!MP and n')ection'


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Outline and Ob$ectives of presentation

ntrod&ce WHO !MP te*t'

+ Main )rinci)le'

+ S&))le,ent'

+ Other'

n the conte*t of Pre-&alification

.&rrent and f&t&re a))roache'

n')ection' in )re-&alification


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WHO !MP te*t Main )rinci)le'WHO Technical 0e)ort Serie'" 1o% 234" 5336

+ Anne* 7

0eg&larly revie#ed and &)dated

Divided into 8cha)ter'8 or 8-&ality 'y'te,'8

Q&ality a''&rance"


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9% Q&ality a''&rance

5% !ood ,an&fact&ring )ractice' for )har,ace&tical )rod&ct'(!MP

6% Sanitation and hygiene

7% Q&alification and validation

:% .o,)laint'

;% Prod&ct recall'


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2% Per'onnel

93% Training

99% Per'onal hygiene

95% Pre,i'e'

96% >-&i),ent

97% Material'

9:% Doc&,entation

9;% !ood )ractice' in )rod&ction

9


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Other te*t'Sterile )rod&ct'

Her?al ,edicine'

0adio)har,ace&tical'

H@A.

Water 'y'te,'

Sa,)ling etc


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Al'o to con'ider #hen nece''ary

P./S g&ideline'

SO g&ideline'+ Sa,)ling

+ 0i' ,anage,ent+ .lean roo,'

.H g&ideline'+ .H Q2

BSA CDA

+ !&ideline' and g&idance


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.onte*t in Pre-&alificationProd&ct ')ecific (do'age for, in')ection'

SOP' follo#ed

+ Planning" )re)aration" cond&ct" re)ort+ n')ection tea,

A))ro)riate g&ideline' &'ed

0e)ort #ith reference' to te*t" and rating+ .ritical" ,aor" ,inor


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A critical deficiency#a' defined a' a deficiency #hich had)rod&ced" or led to a 'ignificant ri'of )rod&cing" either a)rod&ct #hich #a' har,f&lto the h&,an )atient or a )rod&ct#hich co&ld re'&lt in a har,f&l re'id&e in a food )rod&cingani,al%

A ,aor deficiency#a' defined a' a non=critical deficiency"#hich had )rod&ced or ,ight )rod&ce a )rod&ct #hich did notco,)ly #ith it' ,areting a&thori'ation%

A ,inor deficiency #a' defined a' a deficiency #here ano?'ervation ,ade co&ld i,)rove the -&ality 'y'te, and -&ality

a''&rance a))roach of the ,an&fact&rer" ?&t #hich did not havea ,aor i,)act on the -&ality of the )rod&ct%


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n')ection a))roach

1or,ally a 8ro&tine ty)e8 of !MP in')ection

O)ening ,eeting" follo# the flo#" clo'ing ,eeting

On 'ite in')ection ()rod&ction and -&ality control and

doc&,entation revie#

Q&ality 'y'te,' a))roach

Modern challenge' incl&ding ri' a''e'',ent


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!&iding )rinci)le'

0i' ?a'ed orientation

Science ?a'ed )olicie' and 'tandard'

ntegrated -&ality 'y'te,'

nternational 'tandard'

P&?lic intere't


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Prod&ct -&ality and )erfor,ance en'&red thro&gh+ de'ign (,an&fact&ring )roce''e'

Prod&ct and )roce'' ')ecification'

+ Bnder'tanding of affect of for,&lation and )roce'' factor'

on )rod&ct -&ality and )erfor,ance

Q&ality ?y de'ign (?&ild -&ality into the )rod&ct

nteraction ?et#een revie#" co,)liance and in')ection


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Where to 'tartE


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12%1

Premises

Principle

,)ortant a')ect' to ?e e)t in ,ind to en'&re the '&ita?ility of

the o)eration' to ?e carried o&t for different do'age for,' and

)rod&ct range

Focation

De'ign

.on'tr&ction

Ada)tation

Maintenance


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12%&

Premises

Principle

Pre,i'e' ,&'t ?elocated to ,ini,izeri'' of cro''=conta,ination" e%g%notlocated ne*t to a,alting factory #ithhigh air?orne level' ofyea't


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12%2

Premises

'eneral

The layo&t and de'ign 'ho&ld ai, to

Mini,ize ri'' of error'

Per,it effective cleaning

Per,it effective ,aintenance

Avoid cro''=conta,ination" ?&ild=&) of dirt and d&'t

Avoid any adver'e effect on the -&ality of )rod&ct'


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Premises

Design Principles

Gee) in ,ind

Material flo#

Peo)le flo#

Proce'' flo#

#nsure logical flow

12%1


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Q C Ofces

Gowning

Canteen

Incoming

goods

Corridor

CorridorShipping

Corridor

Packaging

Weighing Processing

Filling

Raw

Materials

&

Packaging

Storage

Washing MachineShop

Finished

ProdctsStorage

Corridor

!tilities and Ser"ices

Waste #reatment

Premises

#(ample of )aterials and People Flow

Arrival of good' >ntrance for vi'itor' >ntrance for Worer' Shi),ent of good'

Material Clo#

Peo)le Clo# Zone .lean

Zone Pacaging

Zone .ontrolled


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12%*" 12%+2

Premises

,onstructionS&ita?le ,aterial'

>lectrical '&))ly

S&ita?le lighting (e')ecially for vi'&al on=line chec'

Te,)erat&re and relative h&,idity control

A))ro)riate and effective ventilation

The'e ,ay affect )rod&ct' d&ring ,an&fact&re or 'torage a' #ella' f&nctioning of e-&i),ent


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Premises

The te,)erat&re and relative

h&,idity 'ho&ld ?e

controlled" ,onitored in

accordance #ith an SOP" andthe re'&lt' recorded% The

li,it' 'ho&ld ?e a))ro)riate

according to the ,aterial'

'tored and )rod&ct

)roce''ed


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Premises


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12%11 - 12%+.

Premises

/pecific areas

0evie# 'o,e reco,,endation' for ')ecific area' in the follo#ing

'lide' (Part 5

Ancillary area'

Storage area'

Weighing area'

Prod&ction area'

Q&ality control area'


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Premises

T O ( F > T S

A (0

F O . G

. A 1 T > > 1

C A . T O 0 . H A 1 ! >

0 O O M


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Premises


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Premises

Se)arate receiving and

di')atch ?ay'

Materials and

products protectedfrom weather

Area to clean inco,ing

,aterial' )rovided


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Premises


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Premises


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Premises


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12%1." 12%1!

Premises

/torage areas 0 2

A))ro)riate te,)erat&re and relative h&,idity condition' #ithin

defined li,it'

Provided, controlled, monitored and recorded

!ood 'torage condition' clean" dry and a))ro)riate light'


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12%21

Premises

/torage areas - &

Printed )acaging ,aterial'

.ritical to en'&re co,)liance #ith correct la?elling of )rod&ct'

S)ecial attention to 'a,)ling

S)ecial attention to 'afe and 'ec&re 'torage

>n'&re co,)liance #ith ')ecification'" )revent ,i*=&)'


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12%2+

Premises

Weighing areas

Weighing o)eration' + in 'e)arated area'

A))ro)riate de'ign ('ee al'o training ,aterial on H@A.

Provi'ion for d&'t control

S,ooth" i,)ervio&'" d&ra?le" ea'y=to=clean fini'he'

.leaning )roced&re' and record'

Doc&,entation" e%g% SOP'" log' and record'


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Premises

De'ign of area' for #eighing of

,aterial'

Pro)er air '&))ly

D&'t control ,ea'&re'

(incl&ding e*traction of d&'t

and air >a'ily cleana?le '&rface'

1o area' for d&'t

acc&,&lation

Protection of ,aterial"

)rod&ct and o)erator


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Premises


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12%2&

Premises

Production areas 0 1

Mini,ize ri' of cro''=conta,ination

Dedicated and 'elf=contained facilitie' for 'o,e )rod&ct' '&cha' highly 'en'itizing ,aterial' (e%g% )enicillin' or ?iological

)re)aration' (e%g% live ,icroorgani','

Se)arate facilitie' for other )rod&ct' '&ch a' 'o,e anti?iotic'"hor,one'" cytoto*ic '&?'tance'

1on=)har,ace&tical' nor,ally not in the 'a,e facility" e%g%)e'ticide'" her?icide'


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Equipment

All a')ect' incl&ding

De'ign" in'tallation"

o)eration" )erfor,ance"

')ecification'" log'",aintenance" &'e"

cleaning" -&alification"

cali?ration etcI


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Equipment

.ontent' and direction of flo#

indicated

e%g% #ater line'" e-&i),ent

co,)onent'" air=handling

'y'te,'


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1&%! - 1&%1

Materials

/tarting )aterials -

P&rcha'ing + i,)ortant o)eration

Cro, a))roved '&))lier' + if )o''i?le" direct fro, the,an&fact&rer

S)ecification' for ,aterial'

.on'ign,ent chec' Integrity of packageSeal intactCorresponds with the purchase orderDelivery noteSuppliers labels

.leaned and la?elled #ith infor,ation


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Materials


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Documentation


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alidation

/copeWHO g&ideline foc&'e' ,ainly on the overall conce)t of

validation

t 'erve' a' general g&idance only

Princi)le' ,ay ?e &'ef&l

+ in production and control of active pharmaceutical

ingredients !PIs" and finished pharmaceutical products

@alidation of ')ecific )roce''e' and )rod&ct' (e%g% 'terile

)rod&ct ,an&fact&re re-&ire' ,&ch ,ore con'ideration and a

detailed a))roach ?eyond the 'co)e of the g&ideline 2%1


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alidation

/copeMany factor' affecting the different ty)e' of validation

Man&fact&rer' 'ho&ld )lan validation to en'&re

+ regulatory compliance and

+product #uality, safety and consistency

The general te*t in the g&ideline ()art 9 of )re'entation ,ay ?ea))lied to validation and -&alification of

+premises, e#uipment, utilities and systems

+processes and procedures

More ')ecific )rinci)le' addre''ed in the a))endice' ()art' 5 to


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Qualification and Validation



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Btilitie'

H@A.

Water

.o,)re''ed air

Stea, % % %


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Prefilter3ir flow patterns

34

)ain filter

Bni=directional T&r?&lentT&r?&lent

1 2 +

43,


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+

Prod&ction 0oo,

#(haust air treatment

,entral air handling unit

Terminal air treatment

at production room level

Fresh air treatment

6make0up air7

43, )ain subs8stems


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9ualification - e(amples of aspects to consider in:ualification 6O9" P97

Test

Differential )re''&re on filter'

Turbulent ; mi(ed

airflowDescription

ni0directional

airflow ;


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raw water in

S trap to sewer

Water i' e)t

circ&lating

To #ater

'oftener K

D )lant

Pretreatment -

schematicdrawing

cartride

filter

5 !icro!eters

acti"ated

carbon

filter

spra# ball

brea$ tan$

air brea$ to drain centrif%al p%!p

air filter

float

operated

"al"esand filter

e&cess water rec#cled

fro! deioniser

Water for Pharmaceutical se


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/eparate guideline in addition to basic ')PPart 9 Manage,ent and organization

Part 5 Material'" e-&i),ent" in'tr&,ent' and device'

Part 6 Woring )roced&re' and doc&,ent'" and

'afety in the la?oratory

Part 7 n')ecting the la?oratory

9ualit8 ,ontrol



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Q&ality control (al'o ,icro" #ater" environ,entI

Sa,)ling and te'ting

0eference Standard'

S)ecification'

Sta?ility te'ting

So&rce/ra# data

Q&alification and validation



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Other a')ect' to loo at incl&de

@alidation ()roce''" cleaning etc

.APA" fail&re inve'tigation

.hange control

Deviation'

.o,)laint'

Prod&ct -&ality revie#



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Bnli,ited re'o&rce' E

n')ector' E

Day' E

!&ideline' E

Q&ality 0i' Manage,ent Proce''


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Planning and cond&ct of in')ection

Ty)e of )rod&ct('

Ty)e of ,aterial('

Pre,i'e'

.hange' (deviation'" additional )rod&ct'" cleaning

)roced&re" ca,)aign' etc

Btilitie' and a))lication'



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S&,,ary

!MP re,ain' i,)ortant co,)onent of en'&ring QA and-&ality

1e# a))roache' in -&ality (incl&ding ri' ,anage,ent"

.APA" PAT

,)act on total a))roach incl&ding+ Prod&ct de'ign" )rod&ct develo),ent" )ilot ?atche'"

)rod&ction ?atche'

Q&ality 'y'te,' and -&ality a''&rance



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Acno#ledge,ent'

WHO Training ,od&le'

+ La'ic and '&))le,entary

.H Q2

S !al'on and F &



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Than yo&

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