Establishing
Scientifically
Justified
Acceptance Criteriafor Cleaning
Validationof FinishedDrug Products
. '"
~- .~~~L
This article presentsan approach to calculating
limits for cleaningvalidation based on calculating
limits first in the subsequentlymanufactured
product, then on the cleaned equipmentsurfaces,
and finally in the sample actually analyzedby the
appropriateanalyticaltechnique.The article dis-
cusses issues in detennining each of these limits
and covers related issues including recovery
factors, visual cleanness,nonunifonn contamin-
ation, and microbiologicalcontamination.
,.". A.L..,.., is vice-pnsidentof scientifictechnicalsup-
port at STERISCorporation,PO Box 147.St. Louis. MO
63166. tel. (314) 535-3392.fax (314) 535-2998,e-mail
(destin_leblanc@steris.com).
ne key to effective cleaning validation is determin-
ing: How clean is clean enough?This is usually de-
tennined by establishing specific analytical limits
for target residues.The limits chosenwhen setting
acceptancecriteria must be scientifically justified. Arbitrary
setting of limits is just that, arbitrary, and may raise concern
during an FDA audit. This situation is somewhatcomplicated
by the fact that the term limit sometimesis usedloosely to re-
fer either to the acceptancelimit in the next product, to the
acceptancelimit of surfacecontamination,or to the acceptance
limit of the analyzedsample.Although all of theselimits are
interrelated, they are not necessarily measuredin the same
units nor are they of the samemagnitude.For example, con-
tamination of the next product (the product subsequently
manufacturedin the cleanedequipment) typically is given in
partsper million or microgramsper gram. surfacecontamina-
tion usually is measuredin micrograms per squarecentime-
ter, and the analyzedsampletypically is given in micrograms
or microgramsper gram.
II>
It should be clear that limits per surface area are different
m units and cannotbe compareddirectly without other piecesof
information such as batch size and equipmentsurf~ area.In
addition, limits in the subsequentproduct may be given in the
sameunits as limits in the analyzedsample,but they also are
not comparable without other information such as area
swabbedand swabrecoveryfactor. This meansthat an accep-
tancelimit of 3.2 ppm in the subsequentproduct is not neces-
sarily the sameas 3.2 ppm in the analyzed sample prepared
by a swabbing procedure. One must make these proper dis-
tinctions when discussingresiduelimits so that, for example,
analytical methodsare properly validatednear the appropriate
limits for the residuein the analyzedsample.This article dis-
cussesthe calculationof residuelimits for the different partsof
a validatedsystemand exploresthe limitations and applicabil-
ity of suchcalculationsas applied to finished drug products.
One of the main objectivesof the cleaning processin drug
manufacture is to remove residue of the just-manufactured
product so that those residuesare not transferredto the sub-
sequently manufacturedproduct. A key complicating feature of
cleaning is that it involves not only the product being cleaned
but also the product subsequentlymanufactured in the cleaned
equipment. The starting point for any determination of accep-
tance residue limits is the amount of residue from the cleaning
processthat could be presentin the subsequentlymanufactured
product without posing an unreasonablerisk. Clearly, one would
prefer that no residue be present; however, it is impossible to
measure"no" residue.Even the criterion of being below the lim-
its of detection of the analytical procedureis not by itself a very
good method for selecting residue limits. As methods are im-
proved and have even lower limits of detection, a cleaning
process that was previously viewed as acceptablecan become
unacceptable.Therefore, it is preferable to expressthat limit as,
for example, ~8 ppm, rather than specifying "undetected:'
FDA?s guidancefor detenniningresiduelimits dictatesthat lim-
its be logical (i.e., based on an understanding of the process),
practical, achievable,and verifiable (1). Fortunately for thosein-
volved in cleaning validation, the sameFDA documentmentions
limits proposedby industry representatives"such as 10ppm, bio-
logical activity levels such as 1/1000 of the normal therapeutic
dose,and organolepticlevels such as no visible residue:' This is
clearly a referenceto work:.done by Fourman and Mullen at Eli
Lilly (2), whosepaperis listed in thereferencesectionof the FDA
guidance document. Although it is not officially endorsed by
FDA, the Lilly method of establishing residue limits (or some
variation of it basedon the sameprinciples) is widely usedwithin
the pbannaceuticalindustry for detennining acceptablelevels of
chemical residues(3-5).
The published Lilly criteria are that
. the equipment be visually clean
. any active agentbe presentin a subsequentlyproduced prod-
uct at maximum levels of 10 ppm
. any activeagentbe presentin a subsequentlyproducedproduct
at maximum levelsof 1/1(XX)of d1eminimum daily doseof the
activeagentin a maximumdaily <k>se of d1esubsequentproduct
Although Fourman and Mullen directly calculate the surface
areacontamination basedon theselatter two criteria, the analy-
sis in this article usesthe sameassumptionsto arrive separately
at subsequentproduct residue limits, surfacearearesiduelimits,
and analytical sample residue limits. Such a discrete analysis
may be more conducive to understandingcontributions to resi-
due limits from various factors.
UMIT .1 SUBSEQUENT PRODUCT
To calculate the limit of the active agent in any subsequently
manufactured product (LSP), the only infonnation needed is the
minimum daily dose of the active being cleaned and the maxi-
mum daily dose of the subsequently manufactured drug product.
For purposes of illustration, product A will refer to the product
being cleaned, and product B will refer to the subsequently pro-
duced product. The LSP (L]) can be expressed as
L _ (0001 min dailydoseofactiveioproductA
1 -. )X max.dailydoseofproductB [ 1.1
For an example using orally dosedliquids, assumethat prod-
oct A has an activeat a level of 2000 ~g/mL and is dosedat 5 mL
from dtreeto five times daily. The minimum daily dosewould be
(2<XX>~g/mL) X (5 mUdose) X (3 doses/day)=
30,000 ~g/day
If one also assumesthat product B is dosedat 5 mL from two
to four times a day, then the maximum daily dose of product B
would be
5 mUdose X 4 doses/day= 20 mUday
Note that this calculation for the subsequentproduct is inde-
pendent of what the active is or at what level that active is pre-
sent. The residue limit in the subsequentproduct can be calcu-
lated by substituting thesevalues into Equation I:
x 30,000 JA.g/day= 1.5
LI = 0.001 20 mL/day ~g/mL
This value of 1.5 jJ.g/mL (or -1.5 ppm, assuming a specific
gravity of 1.0) is independentof both batch size and equipment
surface area. Therefore this calculation can be done as soon as
information is availableabout the composition and relevantdos-
ing of the two products.The calculated value of 1.5 ppm should
be comparedto the 10 ppm default value from Lilly's criterion,
and the lower of the two values should be used in subsequent
calculations. For this example, 1.5 ppm would be chosen for
subsequentcalculations.
One could selectsafety factors other than 0.001. For example,
safety factors of 0.001 for orally dosedproducts and 0.0001 for
parenterals have been suggested(6). Although more stringent
safety factors may easily be justified, use of a safety factor less
stringentthan 0.001 would probably require significantjustifica-
tion. However,different safetyfactors may be appropriateif they
are applied to dosing factors other than the minimum daily
pharmacological dose. In addition to different safety factors,
companiesmay also baselimits on parametersother than thera-
peutic doses.For example,rather than using the minimum daily
dose of the active, firms may select other measures,such as the
no observableeffect level (NOEL) or the minimum pharmaco-
logical effect level. Becausethe use of these factors will result
in residue limits more stringent than limits basedon the mini-
mum daily dose, there is no scientific reasonnot to select these
criteria. It should be noted, however, that arbitrarily selecting
more stringent criteria may result in unreasonable cleaning
overkill and may also stretch the detection limits of available
analytical methods.
UMIT PERSURFACEAREA
Once the residue limit in the subsequentproduct is determined
(using the lower values in Lilly's secondand third criteria), the
next step is to determine the residue limit in terms of active in-
gredient contaminationlevel per surfaceareaof equipment.This
limit (L2, in ~g/cm2) dependson LSP (determined as the lower
of L) and 10 ppm), the batch size of the subsequentproduct B
(BSSP,in kg), and the sharedequipment surface area(SESA.in
cm2). This can be expressedmathematically as
L = LSP X BSSP X 1<XX>
2 SESA [2]
where 1(0) is a conversionfactor to account for ppm (the limit
of the subsequentbatch) and to convert kg to ILg(for BSSp).For
this example, if LSP is 1.5 ppm and assuming BSSPis 200 kg
and SESA is 60,000 cm2, then the ~ limit is
L2 = 1.5 ppmx200q X 1(XM)=S.O
~g/cm2
(i).(XX) cm2
Whendeterminingthe surface area,oneshouldconsiderall
sharedproduct contact surfaces,including piping, baffles, etc.
Estimates of surface area should be on the high side because
larger surfaceareasresult in lower ~ residue limits.
Note that this calculation for L2 assumesthat the residue will
be evenly distributed over all surfaces.This is generally not the
case. However, this assumption still representsthe worst case
in the sensethat if one is doing swab sampling on the most dif-
ficult to clean locations, then the assumptionof an even distrib-
ution will make it more difficult to meet the residue limits for
those most difficult to clean locations. In addition, it would be
difficult to scientifically justify one area of the equipment hav-
ing a residuelimit of lO l1.g/cm2and other areashaving limits of
2.5 l1.g/cm2.If a true sampling rinse is used, then issuesof dis-
tribution do not arise becauseone is sampling the entire equip-
ment surface(7).
If more than one product (e.g., products B, C, D, and E) could
possibly be manufactured following product A, then surface-
area limits (Lv for cleaning following product A should be cal-
culated for each subsequentproduct. For purposesof cleaning
validation, the residue limit should be set at the lowest of these
L2 surface-area limits. This gives the manufacturing depart-
ment greater flexibility to make products in any order. It should
be recognized, however, that there may be circumstances in
which residue limits result in restrictions on which products
can follow product A on the manufacturing schedule.
UMIT II THEANALYZED SAMPLE
Although one establishesresiduelimits for the active in the sub-
sequentproduct (LJ) and for the active per surfaceareafollowing
cleaning (L2), theselimits typically are not measureddirectly by
the analyticalprocedure.The analytical proceduretypically mea-
suresthe active agent in solution as a result of either swabbing
and desorbingthat swab into a suitable solvent or by doing rinse
sampling and measuring the active in the rinse solvent (8). For
purposesof expediency,this article focuses on swab sampling.
The reader is referred to other sourcesfor examples related to
rinse sampling (7).
For swab sampling, one assumesthat a fixed surface area of
the equipment is sampled and the swab is then desorbedinto a
fixed amount of solvent. To determine the residue limit (Lj. in
micrograms per gram or parts per million) for the analytical
sample (the solvent the swab is desorbedinto), one must know
the surface-arearesidue limit (L2)' the surface areaswabbed(in
squarecentimeters),and the amount of solvent the swab is des-
orbed into (in grams). The limit in the analyzed sample is
L = L2 x swabbedsurfacearea
j amountof desorption
solvent
Continuing with the exampleusedso far. if ~ is 5.0 JA.g/cm2.
surfaceareaswabbedis 25 cm2, and the amount of solvent used
for desorptionis 20 g, thenthe limit LJ is
LJ -- 5.0~p22Og x 25cm2= 6.3 'tJ.g/gor6.3 ppm
RECOVERYFACTORS
The limit LJ is the acceptancelimit in the analyzed sample. It
should be adjustedby a swabrecoveryfactor, which can be done
in two ways. One method is to include the swab recovery fac-
tor in the actual analytical calculation by dividing the analyti-
cal result by the recovery factor. For example, if the swab re-
covery factor is 0.80 (80%) and the analytical procedure gives
a value of 1.3 ppm, then the limit should be adjustedby dividing
the analytical result by the recovery factor to arrive at a deter-
mination of 1.3 ppm -':-0.80 = 1.6 ppm. The alternative is to
include the recovery factor in Equation 3. In this case the re-
covery factor of 0.80 should be included in the numerator. Al-
though the numbersusedwill be different, the net effect of com-
paring the analytical result to the calculated limit will be
logically the same.One should standardizehow this will be per-
formed in order to avoid situations in which the recovery factor
is usedin the calculations of both the LJ limit and the determi-
nation of the analytical result on the desorbedsolvent sample.
EFFECTS 01 AlALYTICALMETIIODVALIDAnOI
It should be noted that, at least in this example, LSP (L), 1.5
ppm) was significantly different from the limit in the analyzed
sample (y, 6.3 ppm). This is becauseL) reflects the residue of
the active being evenly distributed in a batch of the subsequent
product, whereas L 3 reflects the residue of the active concen-
trated, in most cases,in a smaller volume of matrix material (the
desorbingsolvent). One can seethat this effect can be leveraged
by either samplinga larger surfaceareaor by desorbingthe swab
into a smaller amount of solvent. When sampling a larger area,
one must consider whether sampling this larger areamight also
lower the swab recovery factor, thus adding more uncertainty to
the determination.This is significant for analytical method pur-
posesbecausethe analytical method chosenfor determining the
residue of the active agent should be validated (at least in the
example used) not basedon the LJ limit of 1.5 ppm but rather
on the L3limit of 6.3 ppm adjustedappropriatelyby the recovery
factor. In this case,one might validate dte analytical method not
in the range of 0.5 to 1.5 ppm but rather in the range of 2.1 to
6.3 ppm. This fourfold factor in limit of quantitation may be
significant for analytical method selection and validation.
VISUAL CLEAMESS
The issue of visual cleannessis also significant If a surface is
visually dirty, either the cleaning procedureis not acceptableor
an acceptableprocedure is now out of control. The standardof
visually clean can be used for purposesof both validation and
monitoring. The dividing line between visually clean and visu-
ally dirty is regardedas being in the rangeof 4 ~g/cm2 (2). If the
Pl L2 surface contamination acceptancelimit is calculated and is
found to be significantly higher than 4 ~g/cm2. and providing
the that critical surfacesare readily visible. it may be possible to de-
fault to visually clean as the only acceptancecriteria. For po-
tent drugs for which the L2 acceptancecriteria would typically
be well below I ~g/cm2, a determination of visual cleanness
would have no significance regarding the adequacy of clean-
ing. In such a case,a visually dirty surface would still be an in-
dication of cleaning failure, but a visually clean surface could
not clearly indicate whether the residue was at an acceptable
level.
For casesin which a determination of visually clean is crit-
ical, it may be appropriate to actually determine the highest
level at which the specific residue is not visible. This can be
done by spiking model surfaces (e.g., stainless steel coupons)
with different levels of the residue (e.g, 0.5. 1.0,2.0,4.0, and
8.0 ~g/cm2) and asking a trained panel to observethe coupons
in a "blinded" manner to determine whether the coupons are
visually clean. This should be done under viewing conditions
(of lighting, angle, and distance) that simulate the viewing of
actual equipment. The highest residue level at which all panel
members consider the coupons to be visually clean estab-
lishes the acceptance level for visual cleanness for that par-
ticular residue.
NONUNIFINIM COITAMllAno.
The cleaning validation acceptancecriteria usedby Lilly and re-
ferred to in the FDA guidancedocumenton cleaningvalidationdo
provide one logical construct for detennining residue limits for
chemicalresiduesof activeingredientsin finished drug manufac-
ture. One issuethat may ariseinvolves possiblenonuniform con-
tamination of the subsequentproduct (9). It should be noted that
this is different from (although it may be related to) nonunifonn
contaminationof the cleanedequipment Nonunifonn contamina-
tion of dIe subsequentproduct is more likely to ariseduring con-
tinuous processesrather than batch processes.For example,in a
batch processinvolving liquid drug blending, dIe contaminating
residue(provided dIereis adequatemixing) is likely to be evenly
distributed throughout the subsequentlymanufacturedproduct
In a continuousprocess,suchasflow througha piping systemand
through a filling nozzle during a packaging operation.it is more
likely that the contaminatingresiduewould appearin the first vials
filled. This, of course,dependson the solubility of the residuein
the subsequentlymanufactUredproduct and on product flow char-
acteristics.A specialcaseof a continuousprocessis a tablet press,
becauseany residueson dIe surfacesof dIe pressarenot likely to
be distributedevenly over all tabletsmanufactUredin a batch.
In dealing with nonuniform contamination at least two alter-
natives are possible. If it is reasonable that the contaminating
residue would appearin the first portion of a product batch (of
filled vials, for example),then calculationscan be madeto deter-
mine the maximum number of vials filled that could theoreti-
cally be at the maximum allowable contamination level. Those
vials, plus as a safety measure a reasonable number of subse-
quently produced vials, should be discarded or destroyed. For
example, supposethe acceptancelimit for the target residue is
5 ppm in the subsequentlymanufactUredproduct filled as 5-mL
vials. If the calculatedresiduelevels in the filling equipmentand
associatedpiping were 0.3 IJ.glcm2(determined from a swab-
bing procedure, for example), and if the surface area of the fill-
ing equipment and associateAipiping is 5(XX)cm2, then if all of the
contamination in the equipment were concentrated in the first vial
produced, the concentration of residue in that one vial would be
0.3 fJ.8/Cm2
X S<XX}Cm2= 300 fA.g/mLor -300ppm
SmL
This would clearly be abovethe L I acceptancelimit of 5 ppm. If
all the contaminating residue in the equipment were evenly di-
vided in the first 60 vials, then eachvial would contain 5 ppm of
residue; therefore those 60 vials and a reasonable number of
subsequentlyproduced vials should be discarded.
These determinations were based on theoretical considera-
tions of what could happen, and thus they represent a worst
case. If the number of vials to be discarded is unacceptably
large, a study could be done to deal with the nonuniform con-
tamination (of the filled vial, in this example). This study
would involve cleaning the filling equipment and then filling a
placebo product. Vials number 1, 10,20, and so forth would
then be analyzed for the target residue. If vial number 10 were
at 6 ppm and vial number 20 were at 2 ppm, then those first
20 vials and a reasonable number of subsequently produced
vials should be discarded.
MICROBIOLOOICAL CONTAMIIATiOI
A second issue in setting limits is what to do about microbio-
logical contamination, for which setting acceptable limits is
more difficult. The main issue is that merely one organism in
the equipment could possibly result in a significantly higher
contamination level in the product manufacturedin that equip-
ment. No clear guidelines exist for microbiological contami-
nation of processequipment. This may be the reason why the
FDA guidancedocumentexplicitly statesthat the document ap-
plies only to chemical residues (1). One cannot expect the
equipment to be free of all microorganisms,especially if any fi-
nal rinse involves nonsterile water, unless a final sanitizing or
sterilization step is used. As a minimum, one should employ
the criteria used for critical cleanroom surfaces(10). A second
concern is with the species of microorganism present. Obvi-
ously, the presenceof enteric organisms such as E. coli or En-
terococcusshould ordinarily be unacceptable.
Other concerns beyond the scope of this article include set-
ting limits for residuesfrom chemical sourcesother than active
ingredients (e.g., from excipients or cleaning agents), setting
limits for residuesin active phannaceuticalingredients, and ac-
counting for residues from multiple process steps. However,
considerationof residuelimits in thesecasesshould be basedon
the sameprinciples discussedhere.The first considerationis the
possible effects of any residue when it is present in any subse-
quently manufacturedfinished drug product.-It is then possible
to work backwards to determine limits for equipment surfaces
and/or bulk actives. Any residue limit determination should be
based on considerations and principles similar to those used
for finished drug products, modified as they apply to those situ-
ations. The key, as in any validation activity, should be the use
of sound scientific and logical reasoning.
fault to visually clean as the only acceptancecriteria. For p0-
tent drugs for which the L2 acceptancecriteria would typically
be well below 1 ~g/cm2, a determination of visual cleanness
would have no significance regarding the adequacy of clean-
ing. In such a case,a visually dirty surfacewould still be an in-
dication of cleaning failure, but a visually clean surface could
not clearly indicate whether the residue was at an acceptable
level.
For casesin which a determination of visually clean is crit-
ical, it may be appropriate to actually determine the highest
level at which the specific residue is not visible. This can be
done by spiking model surfaces (e.g., stainless steel coupons)
with different levels of the residue (e.g, 0.5,1.0,2.0,4.0, and
8.0 ~g/cm2) and asking a trained panel to observe the coupons
in a "blinded" manner to determine whether the coupons are
visually clean. This should be done under viewing conditions
(of lighting, angle, and distance) that simulate the viewing of
actual equipment. The highest residue level at which all panel
members consider the coupons to be visually clean estab-
lishes the acceptance level for visual cleanness for that par-
ticular residue.
NONUNIFORMCOITAMllAnO.
The cleaning validation acceptance criteria used by Lilly and re-
fen-ed to in the FDA guidance document on cleaning validation do
provide one logical construct for determining residue limits for
chemical residues of active ingredients in finished drug manufac-
ture. One issue that may arise involves possible nonuniform con-
tamination of the subsequent product (9). It should be noted that
dlis is different from (although it may be related to) nonuniform
contamination of the cleaned equipment. Nonuniform contamina-
tion of the subsequent product is more likely to arise during con-
tinuous processes rather than batch processes. For example, in a
batch process involving liquid drug blending, the contaminating
residue (provided there is adequate mixing) is likely to be evenly
distributed throughout the subsequently manufactured product.
In a continuous process, such as flow through a piping system and
through a filling nozzle during a packaging operation, it is more
likely that the contaminating residue would appear in the first vials
filled. This, of course, depends on the solubility of the residue in
the subsequently manufactmed product and on product flow char-
acteristics. A special case of a continuous process is a tablet press,
because any residues on the swfaces of the press are not likely to
be distributed evenly over all tablets manufactured in a batch.
In dealing with nonuniform contamination at least two alter-
natives are possible. If it is reasonable that the contaminating
residue would appear in the first portion of a product batch (of
filled vials, for example), then calculations can be made to deter-
mine the maximum number of vials filled that could theoreti-
cally be at the maximum allowable contamination level. Those
vials, plus as a safety measure a reasonable number of subse-
quently produced vials, should be discarded or destroyed. For
example, suppose the acceptance limit for the target residue is
5 ppm in the subsequently manufactured product filled as 5-mL
vials. H the calculated residue levels in the filling equipment and
associated piping were 0.3 ~g/cm2 (determined from a swab-
bing procedure, for example). and if the surface area of the fill-
ing equipment and associated piping is 5<XX>cm2, then if all of the
contamination in the equipment were concentrated in die first vial
produced, the concentration of residue in that one vial would be
0.3 ~g/cm2 X 5<XX>cm2
= 300 ~ g/mL or- 300 ppm
5mL
This would clearly be abovethe L 1acceptancelimit of 5 ppm. If
all the contaminating residue in the equipment were evenly di-
vided in the first 60 vials, then eachvial would contain 5 ppm of
residue; therefore those 60 vials and a reasonable number of
subsequentlyproduced vials should be discarded.
These determinations were based on theoretical considera-
tions of what could happen, and thus they represent a worst
case. If the number of vials to be discarded is unacceptably
large, a study could be done to deal with the nonuniform con-
tamination (of the filled vial, in this example). This study
would involve cleaning the filling equipment and then filling a
placebo product. Vials number 1, 10,20, and so forth would
then be analyzed for the target residue. If vial number 10 were
at 6 ppm and vial number 20 were at 2 ppm, then those first
20 vials and a reasonable number of subsequently produced
vials should be discarded.
MICROBIOLtMIICAl CONTAMIUnoN
A second issue in setting limits is what to do about microbio-
logical contamination, for which setting acceptable limits is
more difficult. The main issue is that merely one organism in
the equipment could possibly result in a significantly higher
contamination level in the product manufacturedin that equip-
ment. No clear guidelines exist for microbiological contami-
nation of processequipment. This may be the reason why the
FDA guidancedocumentexplicitly statesthat the document ap-
plies only to chemical residues (1). One cannot expect the
equipment to be free of all microorganisms,especially if any fi-
nal rinse involves nonsterile water, unless a final sanitizing or
sterilization step is used. As a minimum, one should employ
the criteria used for critical cleanroom surfaces(10). A second
concern is with the species of microorganism present. Obvi-
ously, the presenceof enteric organisms such as E. coli or En-
terococcusshould ordinarily be unacceptable.
Other concerns beyond the scope of this article include set-
ting limits for residuesfrom chemical sourcesother than active
ingredients (e.g., from excipients or cleaning agents), setting
limits for residuesin active phannaceuticalingredients, and ac-
counting for residues from multiple process steps. However,
considerationof residuelimits in thesecasesshould be basedon
the sameprinciples discussedhere.The first considerationis the
possible effects of any residue when it is present in any subse-
quently manufacturedfinished drug product. It is then possible
to work backwards to determine limits for equipment surfaces
and/or bulk actives. Any residue limit determination should be
based on considerations and principles similar to those used
for finished drug products, modified as they apply to those situ-
ations. The key, as in any validation activity, should be the use
of soundscientificandlogicalreasoning.
 6. W.A. Hall, "Cleaning for Bulk PbamlaceuticalChemicals (BPCs),"
REF£REICES in Validation of Bulk Pharmaceutical Chemicals, D. Harpaz and
1. FDA, "Guide to Inspections of Validation of Cleaning Processes,"
I.R. Barry, Eds. (Intet"pharmPress,Buffalo Grove, u.., 1997), pp.
Division of Investigations,Office of Regional operations, Office of
335-370.
Regulatory Affairs, July 1993.
7. D.A. leBlanc, "Rinse Sampling for Cleaning Validation Studies,"
2. G.L. Fourman and M. V. Mullen, "Determining Cleaning Validation
Pharm. TechnoL12 (5), 66-74 (1998).
AcceptanceUmits for PharmaceuticalManufacturing Operations,"
8. R.B. Kirsch, "Validation of Analytical Methods Used in Pharma-
Phann. Techno/.17 (4), 54-60 (1993).
ceutical Cleaning Assessmentand Validation," in 1998 Analytical
3. K.M. Vitale, "Cleaning Validation AcceptanceCriteria," presented
Validation in the Pharmaceutical Industry, supplement to Pharm.
at the 15th Annual Pharm Tech Conference '95, East Brunswick,
TechnoL40-46 (1998).
New Jersey,18-21 September 1995.
9. K.M. Jenkins and A.J. Vanderweilen, "Cleaning Validation: An
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Overall Perspective,"Pharm. TechnoL18 (4),60-73 (1994).
at lSPE seminar,Rockville. Maryland, 6-8 March 1996.
10. R. Dabbah, "Microbial Evaluation of Cleanrooms and Other Con-
5. PDA Biotechnology Cleaning Validation Subcommittee, Cleaning
trolled Environments - In-Process Revision," Pharm. Forllm 23
and Cleaning Validation: A Biotechnology Perspective (PDA,
(1),3494-3520 (Jan.-Feb. 1997).D
Bethesda, MD, 1996).

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