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Cleaning Validationin

Active pharmaceutical Ingredient manufa

September 1999

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Guide to Cleaning Validation in API plants

Table of contents

1. Foreword..................................................................................................... ........2

2. Objective..................................................................................................... .... ... .3

3. Scope................................................................................................... .........4

4. Potential residues ........................................................ 5

5. Current regulatory guidance...........................................................6

. Cleaning validation policy......................................................................... .........7

!. "evels of cleaning....................................................................... .........8

#. $le%ents of cleaning validation................................................................ .........10

8.1 Establishment of acceptance criteria.................................................... 12

8.1.1 chemical determination ........................................................................ 12

8.1.2 physical determination ......................................................................... 13

8.1.3 microbiological determination.............................................................. 13

8.2 leaning proced!res ............................................................................... 13

8.3 "ampling ................................................................................................ 15

8.4 #nalytical methods. ............................................................................ 16

8.5 $alidation protocols ............................................................................... 17

8.6 $alidation reports................................................................................... 18

&. 'ini%u% re(uire%ents.................................................................................20

1). C*ange control................................................................................21

11. Su%%ary.................................................................................22

12. +eferences...................................................................................23

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2

1.Foreword

%his &!ideline has been prod!ced by the #cti'e (harmace!tical )ngredients ommittee

*#()+ ,or-ing gro!p.

ifferent organi/ations ill be infl!enced by their companies and the mar-ets that they

ser'e in the approaches that they ta-e and the policies that they ha'e ith respect to

the s!bect.

)t is also 'al!able to bear in mind that this is an area that is changing rapidly and hat

as considered as being acceptable 25 years ago is no not ade!ate. %herefore

companies sho!ld be aare of the need to contin!o!sly !pdate themsel'es on c!rrent

reg!latory re!irements.

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2.Objective

%he intention of this doc!ment has been to define a comprehensi'e approach to the

$alidation of leaning proced!res in #cti'e (harmace!tical )ngredient man!fact!ring

facilities.

leaning $alidation in the contet of #cti'e (harmace!tical )ngredient man!fact!re

may be defined as

The process of providing documented evidence that the cleaning methods

employed within a facility consistently controls potential carryover of product

(including intermediates and impurities), cleaning agents and extraneous

material into subsequent product to a level which is below predetermined levels.

,t is necessary to -alidate Cleaning procedures for t*e following reasons

a. )t is a c!stomer re!irement it ens!res the safety and p!rity of the prod!ct.

b. )t is a reg!latory re!irement in #cti'e (harmace!tical )ngredient prod!ct

man!fact!re.

c. )t also ass!res from an internal control and compliance point of 'ie the !ality

of the process.

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3.Scope

%his oc!ment ill ser'e to

1. efine the basic concepts and terms associated ith leaning $alidation in the

#cti'e (harmace!tical )ngredient ind!stry.

2. "er'e as a g!ide from hich asterplans (rotocols and eports may be

compiled.

Note: eneral validation principles and a glossary of terms also relevant to cleaning

validation are detailed in the !"#$! % "#&$' uide entitled ood

anufacturing &ractices for 'ctive &harmaceutical $ngredient anufacturers*.$t applies to sterile '&$*s only up to the point where the '&$ is rendered sterile.

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/. Potential residues

%he #cti'e (harmace!tical )ngredient )nd!stry in'ol'es *in general+ the man!fact!re of

#cti'e (harmace!tical )ngredients by both chemical and physical means thro!gh a

series of m!ltiple step processes. (lants or indi'id!al pieces of e!ipment incl!ding

ancillary e!ipment may be !sed in m!ltiprod!ct man!fact!re or dedicated to

indi'id!al prod!cts.

%he res!lt of inade!ate cleaning proced!res is that any of a n!mber of contaminants

may be present in the net batch man!fact!red on the e!ipment s!ch as

1. (rec!rsors to the #cti'e (harmace!tical )ngredient

2. 9yprod!cts and:or degradation prod!cts of the #cti'e (harmace!tical

)ngredient

3. %he pre'io!s prod!ct

4. "ol'ents and other materials employed d!ring the man!fact!ring process.

5. icroorganisms

%his is partic!larly the case here microbial groth may be s!stained by the

prod!ct.

6. leaning agents themsel'es and l!bricants

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5.Current regulatory guidance

efer to the reference section of this doc!ment for details of c!rrent eg!latory

&!idance.

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6.Cleaning validation policy

%he main foc!s of this doc!ment ill be to describe e!ipment and ancillary e!ipment

: process leaning $alidation in an #cti'e (harmace!tical )ngredient man!fact!ring

plant. ;oe'er it is appropriate to start by gi'ing a brief introd!ction as to ho the

concept of leaning $alidation sho!ld be approached in a facility.

)t is ad'isable for #cti'e (harmace!tical )ngredient man!fact!ring facilities to hold an

official leaning $alidation (olicy. "pecific department responsibilities sho!ld be

o!tlined in this and it sho!ld be appro'ed by senior management. %his policy sho!ld

ser'e to pro'ide a general g!ideline and direction for company personnel reg!latory

a!thorities and c!stomers as to ho the company deals ith areas associated ith

leaning $alidation.

T*e policy s*ould incorporate t*e following types of state%ents

efinition of terms employed d!ring 'alidation i.e. rinse 's. fl!sh 's. ash etc.

# statement specifying hat company policy is on 'alidation of cleaning

proced!res related to e!ipment *incl!ding ancillary+ and processes.

ompany policy re dedication of e!ipment in certain cases *if prod!cts are

deemed too dangero!s and : or highly acti'e to man!fact!re on m!ltiprod!ct

e!ipment+.

#nalytical 'alidation policy.

%he policy sho!ld also state the rational for the methods by hich acceptance

criteria is determined.

e'alidation policy.

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7."evels of cleaning

%he degree or le'el of cleaning and 'alidation re!ired for processes in #cti'e

(harmace!tical )ngredient man!fact!ring depends largely on

%he e!ipment !sage *i.e. dedicated e!ipment or not+

%he stage of man!fact!re *early intermediate or final step+

%he nat!re of the potential contaminants *toicity sol!bility etc.+

$ac* of t*e above t*ree bullets %ust be evaluated based on t*e ne0t product not

only to0icology etc. T*e rational for t*is state%ent is given below

)n general the higher the potential for finished #cti'e (harmace!tical )ngredientcontamination the greater the re!irement to 'alidate cleaning methods to ens!re

prod!ct safety.

#cti'e (harmace!tical )ngredient man!fact!rers may ha'e different le'els of cleaning

re!irements in facilities based on the stage of the process being cleaned and the

s!bse!ent prod!ct to be man!fact!red.

%able 1 on page 7 ill!strates an eample of ho a company may decide on the le'el of

cleaning beteen lots.

)t is the responsibility of the man!fact!rer to demonstrate that the le'el of cleaning and

'alidation performed is ade!ate based on each indi'id!al sit!ation and on a !stifiable

scientific rational.

leaning sho!ld be carried o!t as soon as practical after the end of processing and

sho!ld lea'e the plant in a s!itable condition for net !se.

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Table 1 levels of cleaning

$# E?@)E

"$-$" 2 i.e.

(rod!ct changeo'er of

e!ipment !sed in final

step

)ntermediates of one

batch to final step ofanother

yes A essential

"$-$" 1 i.e.

)ntermediates or final

"tep of one prod!ct to

intermediate of another

Early "tep tointermediates in a

prod!ct se!ence

progression beteen le'el

0 and 2 depending on

process and nat!re of

contaminant based on

scientific rational

"$-$" ) i.e. incampaign batch to

batch changeo'er

no 'alidation re!ired

4"" P+OC$SS$S '5ST $ $-4"54T$6 ,6,-,654""7

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10

8.$le%ents of cleaning validation

# brief o!tline of the 'ario!s elements of a basic cleaning 'alidation st!dy is gi'en

belo *see also Big!re 1 on page 11+.

%his is folloed by a more detailed 'ie of the indi'id!al elements in this section.

). Establishment of acceptance criteria

)). leaning proced!re

)dentification of the e!ipment

characteri/ation of the prod!cts *(re'io!s acti'ity:toicity

sol!bility s!bse!ent dosage lot si/e+ determination and characteri/ation of the cleaning agents

))). #nalytical method and its 'alidation

)$. "ampling (roced!re and necessary 'alidation of same

$. $alidation protocol

$). $alidation report

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DETERMINE THE MOST APPROPRIATE CLEANING PROCEDURE FOR THE EQUIPMENT -

Generate acceptance criteria data for the contaminant.he cleaning method !ill be determined b" the process# the e$uipment the cleaning agents and the cleaning techni$ues available.All aspects of the cleaning procedure should be clearl" de%ned in S&'s be the" manual ( CI' or C&'


Figure 1 Cleaning -alidation Process

ST48$ 1

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DEVELOP AND VALIDATE THE SAMPLING AND CHOSEN ANALYTICAL METHODS

FOR THE COMPOUND(S) BEING CLEANED

S!ab)inse

*determine + recover"# limit of detection# limit of $uantitation# accurac" of method# reproducibilit"# stabilit" over time ...etc.,

EVALUATE EQUIPMENT SURFACES AND DETERMINE

1. orst case locations to sample *s!ab sampling,

1. Volume and t"pe of rinse solvent to be emplo"ed *rinse sampling,

1. $uipment surface area *necessar" to calculate carr"over into subse$uent batches,

ST48$ 2 ST48$ 3 ST48$ /

8$$+4T$ 4 C"$4,8 -4",64T,O

+$PO+T 6$T4,",8 T9$ 4CC$PT4,",T7

OF T9$ C"$4,8 P+OC$65+$ FO+ T9$

$:5,P'$T 46 T9$ P+O65CT

%he report sho!ld gi'e a f!ll detailed bac-gro!nd and

introd!ction to the cleaning $alidation st!dy and

sho!ld e'al!ate all data generated ith respect to the

acceptance criteria employed for the st!dy. %he report

sho!ld also indicate the re!irement if any for

re'alidation *period of time :change control etc.+

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ERIM REPORT:)A I/)I0 CA/I/G VAIAI&/ )'&)S &/ A CA/ 34 CA/ 3ASIS AII/G 5 ACC'A3II4 &6 5 CA/I/G ')&C7) 6&) 5 87I'0/ A/ 5 ')&7C.

is onl" re$uired !here there is a long period of time bet!een manufacture of the validation runs *see stage for reporting re$uirements,. 11

6$-$"OP 4 C"$4,8 -4",64T,O P+OTOCO"

FO+ T9$ P+O65CT 46 T9$ $:5,P'$T $,8

C"$4$6

%hat sho!ld encompass for eample

1. )ntrod!ction

2. "cope

3. E!ipment

4. leaning proced!re

5. "ampling proced!res

6. #nalytical testing proced!re

7. #cceptance:leaning limits.

:. #cceptance criteria for the 'alidation.

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1

8.1 $stablis*%ent of acceptance criteria

%he leaning $alidation sho!ld demonstrate that the proced!re consistently

remo'es resid!es of the s!bstance pre'io!sly man!fact!red don to le'els that

are acceptable and that the cleaning proced!re itself does not contrib!te!nacceptable le'els of resid!al materials to the e!ipment. %he limits set

sho!ld be practical achie'able and !stifiable.

)n #cti'e (harmace!tical )ngredient man!fact!re there may be partial reactants

and !nanted byprod!cts hich may not ha'e been chemically identified.

%herefore it may be necessary to foc!s on byprod!cts as ell as the principle

reactant. ompanies sho!ld decide on hich resid!e*s+ to !antify based on

so!nd scientific rational.

8.1.1 C*e%ical deter%ination

)t is generally the resid!al #cti'e (harmace!tical )ngredient or intermediate

hich is of greatest concern rather than reaction side prod!cts or resid!al

imp!rities.

%here are a n!mber of options a'ailable hen determining acceptance criteria.

,here either toicological or therape!tic data if a'ailable then calc!lation # or

9 is preferable. )f data is not a'ailable for either of these calc!lations or if the

res!lt is more stringent calc!lation sho!ld be !sed.

#.

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B# statement (. #lcoc- in ;!man r!g c&( >otes (. otise

D!ne 8 F...e ha'e fo!nd that some firms ha'e incorrectly applied as

their acceptance limit the 0.1C imp!rity identification threshold as

disc!ssed in both the ); imp!rity g!ideline and the @.".(. &eneral

>otices. %his application of the 0.1C imp!rity threshold is

inappropriate beca!se the limit is intended for !alifying imp!rities thatare associated ith the man!fact!ring process of related compo!nd and

not etraneo!s imp!rities ca!sed by cross contamination. ...G + may be

!sed depending on the stage of the process.

)t is also necessary to e'al!ate the ability of the cleaning proced!re to

remo'e any cleaning agents introd!ced. %he acceptance criteria for the

resid!alcleaning agents sho!ld reflect the absence of these materials

ithin the range of the capabilities of the assay and sampling methods.

%he indi'id!al company m!st decide on the #cceptance riteria hich

are !stifiable for their partic!lar sit!ation.

8.1.2 P*ysical deter%ination

%here sho!ld be pro'ision d!ring ro!tine cleaning for a 'is!al eamination of

the e!ipment 'erifying that it is free of 'isible resid!es. %he 'alidation

protocol sho!ld incl!de this re!irement as an acceptance criteria. !ring

'alidation special attention sho!ld be gi'en to areas that are Hhard to cleanI

*e.g. agitator shafts thermoells discharge 'al'es etc.+ and areas that o!ld

be diffic!lt to 'erify on a ro!tine basis.

8.1.3 'icrobiological deter%ination

#ppropriate st!dies sho!ld be performed *e.g. sabs and:or rinse sampling+

here the possibility of microbial contamination of s!bse!ent prod!ct is

deemed possible and presents a prod!ct !ality ris-.

8.2 Cleaning procedures

,ritten cleaning proced!res for each piece of e!ipment and process1

m!st be

prepared. )t is 'ital that the e!ipment design is e'al!ated in detail in

con!nction ith the prod!ct resid!es to be remo'ed the a'ailable cleaning

agents and cleaning techni!es hen determining the optim!m cleaning

proced!re for the e!ipment.

1)f one cleaning proced!re has been shon to be ade!ate for a n!mber of prod!cts then it is only

necessary to ha'e one cleaning "=( for those prod!cts for each piece of e!ipment.

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leaning proced!res sho!ld be s!fficiently detailed to remo'e the possibility of

any inconsistencies d!ring the cleaning process.

#. $(uip%ent para%eters to be evaluated

)dentification of the e!ipment to be cleaned

iffic!lt to clean areas

(roperty of materials

Ease of disassembly

Bied or not

Etc.

9. +esidues to be cleaned

leaning limits

"ol!bilityJs of the resid!es

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(roced!res m!st be determined to be operator independent i.e. r!gged and

reprod!cible d!ring the 'alidation st!dies.

%he leaning doc!mentation sho!ld incl!de the folloing items in order to ens!re that

it can be folloed reprod!cibly and maintained s!bse!ent to $alidation.

etailed definition of le'els of cleaning to be performed.

etailed description of cleaning methods.

%he necessity to inspect and 'erify e!ipment cleanliness prior to man!fact!re of

net batch sho!ld be stated in the "=( and recorded on the batch record.

%he "=( sho!ld detail here 'erification of cycle parameters *if a!tomated+ and

chec-lists *for comple man!al proced!res+ is necessary.

,here microbial contamination may be an iss!e consideration sho!ld be gi'en to

the integrity of the 'essel prior to man!fact!re.

,ritten cleaning proced!res may also incl!de additional items not specified abo'e

these o!ld incl!de as an eample the steps needed to protect the e!ipment from

contamination after cleaning.

8.3 Sa%pling

)n de'eloping the sampling plan for a 'alidation st!dy it ma-es scientific sense

to

incorporate an !nderstanding of the acceptance criteria and the limitations of the

sampling method relati'e to the s!rface to be sampled.

%he to methods of sampling generally employed are sab and : or rinse

sampling. *)f neither or these methods is shon be a scientifically so!nd method

for testing in a specific instance then an alternati'e is to consider testing the net

prod!ct.+

%he selection of either of these techni!es m!st be consistent ith so!nd

scientific !dgment and m!st s!pport the obecti'e of the st!dy hich is to

demonstrate that the amo!nt of resid!al material in the e!ipment has been

red!ced to acceptable le'els.

Each method is described in brief belo.

1. ",#9

"ab sampling does not co'er the entire e!ipment s!rface area therefore

sites m!st be chosen ith care. )t is important that as a minim!m the

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sab sites represent orst case locations on the e!ipment and that the

res!lt is then etrapolated to acco!nt for the total prod!ct contact s!rface

area. %his calc!lation ma-es it possible to ma-e a orst case determination

of potential carryo'er into s!bse!ent prod!ct.

!e to the nat!re of this method hich employs physical forces as ell aschemical forces it may be necessary to perform sampling techni!e

e'al!ation.

"abbing efficiency *C reco'ery+ for the sabbing method m!st be

determined.

)t is necessary to ens!re that etractables of the sab do not interfere ith

the sampling method.

@sing this techni!e it is possible to sample insol!ble resid!es d!e to the

physical action associated it.

2. )>"E

%he sol'ent rinse occ!rs after cleaning has been completed

%his method is not as direct as sabbing b!t ill co'er the entire s!rface

area *and parts inaccessible to sabs+

)t is important to ens!re chosen sol'ent has appropriate reco'ery for

resid!es being !antified

%his method allos m!ch greater ease of sampling than sabbing

# red!ced no of samples are re!ired to generate a carryo'er fig!re.

*=ther sampling methods hich may be employed in addition to sab : rinse

sampling d!ring a 'alidation may incl!de: placebo sampling testing s!bse!ent

batches for resid!es !se of co!pons *test pieces+ etc. +

8.4 4nalytical %et*ods

)n order for the analytical testing of the cleaning 'alidation samples *sabs or

rinses+ to yield meaningf!l res!lts the analytical methods !sed sho!ld be

'alidated. %his sho!ld be doc!mented.

%he basic re!irements are

%he ability to detect the target s!bstance*s+ at le'els consistent ith the

acceptance criteria

%he ability to detect the target s!bstance*s+ in the presence of other

materials that may also be present in the sample *selecti'ity+

*ompanies might ant to consider the folloing

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,here more than one imp!rity is s!spected *hich is probably the normal

case in #() man!fact!ring+ a method co!ld be proposed that is not

necessarily specific for each of the imp!rities b!t detects them all

together. %hen additionally the ass!mption m!st be made that the orst

case *e.g. most acti'e+ imp!rity represents the hole resid!e. %his is

sec!re approach for the patients and co!ld be accepted by the a!thorities.)t is also an practicable approach for the ind!stry beca!se s!ch methods

are for eample dry resid!e determination for non 'olatile imp!rities or

%= determination for ater rinses hich are 'ery simple methods. +

%he analytical method sho!ld incl!de a calc!lation to con'ert the amo!nt

of resid!e detected in the sample to 100C if the reco'ery data generated

indicates a reco'ery o!tside of an alloed range.

"tability of samples o'er time if the time inter'al beteen remo'al and

testing of samples potentially effects sample integrity.

8.5 -alidation protocols

# $alidation (rotocol is necessary to define the specific items and acti'ities

that ill constit!te a cleaning 'alidation st!dy. )t is ad'isable for companies to

ha'e dran !p a aster $alidation plan indicating the o'erall leaning

$alidation strategy for either the prod!ct range : e!ipment type : entire site.

%he protocol m!st be prepared prior to the initiation of the st!dy and m!steither incl!de or reference the doc!mentation re!ired to pro'ide the folloing

information

T*e objective of t*e study

,hat cleaning process is to be 'alidated *indicating the prod!ct to be

remo'ed and the e!ipment from hich it is to be remo'ed+K

)f this st!dy is to be employed to demonstrate the acceptability of the

cleaning proced!re for a gro!p of prod!cts the rational for doing so

sho!ld also be detailed here.

%he cleaning proced!re*s+ to be 'alidated sho!ld be identified i.e.

cleaning agents soa-age times e!ipment parameters n!mber of

cleaning cycles etc.

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Scope of t*e study

%he company m!st e'al!ate the process and determine hich resid!es are

to be tested for and hich are not to be based on so!nd scientific

rational.

,hat resid!es *incl!ding cleaning agents+ are to be tested for hy those

resid!es *if more resid!es may be present than are being tested for all

resid!es sho!ld be !nder control see comments at 8.4+. ;o many times

sho!ld the st!dy be r!n before a report is compiled and recommendations

made.

"isting of t*e process para%eters to be verified

%his is partic!larly necessary hen a!tomated or semia!tomatedcleaning techni!es are to be employed.

Sa%pling and inspection procedure to be used.

%he types of sampling methods to be !sed here the samples are to be

remo'ed from and ho many samples are to be ta-en. #ny partic!lar

re!irements sho!ld also be stated i.e. for sterile sampling : sampling

light sensiti'e prod!cts.

#n e!ipment sampling diagram sho!ld be referenced.

Personnel responsibilities during t*e study

Test %et*ods to be used *sho!ld be referenced+ "ee "ection 8.4.

4cceptance criteria

(hysical see section 8.1.2

hemical see section 8.1.1

*%he rational for this criterion sho!ld be gi'en along ith a calc!lation

step.+

C*ange control "ee section 10.

4pproval of protocol before t*e study.

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#. -alidation reports

# 'alidation report is necessary to present the res!lts and concl!sions and

sec!re appro'al of the st!dy. %he report sho!ld incl!de the folloing

"!mmary of or reference to the proced!res !sed to clean sample and test

(hysical and analytical test res!lts or references for same as ell as any

pertinent obser'ations

oncl!sions regarding the acceptability of the res!lts and the stat!s of

the proced!re*s+ being 'alidated

#ny recommendations based on the res!lts or rele'ant information

obtained d!ring the st!dy incl!ding re'alidation practices if applicable.

#ppro'al of concl!sions

e'ie any de'iations for the protocol that occ!rred.

)n cases here it is !nli-ely that f!rther batches of the prod!ct ill be

man!fact!red for a period of time it is ad'isable to generate interim

reports on a batch by batch basis !ntil s!ch time as the cleaning 'alidation

st!dy has been completed. *%ypically in #cti'e (harmace!tical

)ngredient (harmace!tical man!fact!re 'erification is deemedappropriate d!ring de'elopment of the cleaning methods. ,here

prod!cts are man!fact!red infre!ently 'erification may be applied o'er

a period of time !ntil all meas!ring data has been collected for the

$alidation eport.+

%he report sho!ld concl!de an appropriate le'el of 'erification

s!bse!ent to 'alidation.

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20

.'ini%u% re(uire%ents

)f company policy is not to 'alidate all e!ipment cleaning proced!res for all prod!cts

then as a minim!m re!irement the 'alidation policy sho!ld encompass conditions

hich represent the most appropriate challenges *orst case+ to the proced!re.

%hese o!ld incl!de as an eample s!ch things as

emo'al of prod!cts hich contain the prod!cts ith the greatest biological

acti'ity.

emo'al of prod!cts containing the prod!cts:intermediates:byprod!cts ith the

least sol!bility.

%hese represent st!dies that are minimally re!ired as part of a 'alidation the res!lts

from hich co!ld be !sed to s!pport lesser challenges to the proced!re. )t is often

termed prod!ct gro!ping.

%he maim!m idle time before cleaning.

# 'alidation program generally encompasses three consec!ti'e s!ccessf!l replicates to

establish that the proced!re is reprod!cibly effecti'e altho!gh companies sho!ld

e'al!ate each sit!ation indi'id!ally.

,here e!ipment of similar si/e design and constr!ction is cleaned by the same

proced!re st!dies need not be cond!cted on each !nit as long as a total of three

s!ccessf!l replicates are done on similar pieces of e!ipment *e!ipment gro!ping+.

onc!rrent $alidation may be appropriate hen prod!ct is man!fact!red infre!ently.

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2

10. C*ange control

$alidated cleaning proced!res sho!ld be incl!ded in the change control program. %his

ill ens!re that any proposed changes are e'al!ated f!lly for their impact on the'alidated state of the proced!re. ,here deemed necessary the proposed re'ised

proced!re may need to be 'alidated prior to ro!tine implementation.

f. hange control chapter in the EB) : EB()# &!ide entitled H&ood

an!fact!ring (ractices for #cti'e )ngredient an!fact!rersI

)n the absence of an intentional change to a proced!re it is reasonable to ass!me that

properly trained operators or a properly !alified a!tomated system ill be able to

eec!te the proced!re reprod!cibly and obtain the desired o!tcome red!ction of

resid!e to acceptable le'els. %here may eist special circ!mstances that o!ld s!ggest

that this ass!mption be 'erified 'ia testing. %his may be addressed by periodic re'ies

or ree'al!ations.

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11. Su%%ary

# 'alidation policy sho!ld be ritten for a plant incl!ding cleaning 'alidation.

#n cleaning 'alidation program sho!ld contain the folloing elements

1. #ssess e!ipment and prod!cts *pre'io!s folloing+

2. #ssess impact of this process on ro!tine processes. )f co'ered !nder brac-eting

then no f!rther 'alidation is re!ired.

3. etermine an appropriate cleaning agent and method

4. etermine acceptance criteria for the resid!e*s+ *incl!ding cleaning agents+.

5. etermine degree of e'al!ation re!ired to 'alidate the proced!re.

6. ecide hat resid!e*s+ *incl!ding cleaning agents+ are to be tested for based on

sol!bilities toicities etc. and doc!ment rational behind decision.

7. e'elop sampling and analytical methods for reco'ery and detection of resid!es

*sab:rinse ;(

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12. +eferences

,C9

); &ood an!fact!ring (ractice &!ideline for #cti'e (harmace!tical

)ngredients. *D!ly 23 1+

P,C

(rinciples of ?!alification and $alidation in (harmace!tical an!fact!re

ecommendations on leaning $alidation. *ref. oc!ment ( 1: arch

1+

F64

&!ide to inspections of 'alidation of cleaning processes *D!ly 13+

9iotechnology inspection g!ide *11+

Boreign inspection g!ide *12+

&!ide to inspection of b!l- pharmace!tical chemicals

&!ide to inspections of topical dr!g prod!cts

an!fact!re processing or holding of acti'e pharmace!tical ingredients draft

doc!ment B# arch 18.

C$F,C ; $FP,4

&ood an!fact!ring (ractices for #cti'e )ngredient an!fact!rers #!g!st

16.

P9+'4

raft (h# 9( leaning $alidation &!ideline. *>o'ember 16 Edition+

OT9$+ P5",C4T,OS

".,. ;arder H%he 'alidation of cleaning processesI pharmace!tical technology.

*184+

Dames #galloco H(oints to consider in the 'alidation of e!ipment cleaning

proced!resI Do!rnal of parenteral science and technology. *=ctober 12+

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Copyrig*t and 6isclai%er

#ll doc!ments and information contained in this g!idance doc!ment are the property

of the #cti'e (harmace!tical )ngredients ommittee. @sers of this doc!ment may !seinformation contained therein only for personal !se. >o other !se incl!ding

reprod!ction retransmission or editing may be made itho!t the prior ritten

permission of the #cti'e (harmace!tical )ngredients ommitteeM.

4 cleaning val 99091

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