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Establishing

Scientifically
Justified
Acceptance Criteriafor Cleaning
Validationof FinishedDrug Products

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
~- .~~~L m units and cannotbe compareddirectly without other piecesof
This article presentsan approach to calculating information such as batch size and equipmentsurf~ area.In
limits for cleaningvalidation based on calculating addition, limits in the subsequentproduct may be given in the
limits first in the subsequentlymanufactured sameunits as limits in the analyzedsample,but they also are
not comparable without other information such as area
product, then on the cleaned equipmentsurfaces,
swabbedand swabrecoveryfactor. This meansthat an accep-
and finally in the sample actually analyzedby the
tancelimit of 3.2 ppm in the subsequentproduct is not neces-
appropriateanalyticaltechnique.The article dis-
sarily the sameas 3.2 ppm in the analyzed sample prepared
cusses issues in detennining each of these limits by a swabbing procedure. One must make these proper dis-
and covers related issues including recovery tinctions when discussingresiduelimits so that, for example,
factors, visual cleanness,nonunifonn contamin- analytical methodsare properly validatednear the appropriate
ation, and microbiologicalcontamination. limits for the residuein the analyzedsample.This article dis-
cussesthe calculationof residuelimits for the different partsof
a validatedsystemand exploresthe limitations and applicabil-
,.". A.L..,.., is vice-pnsidentof scientifictechnicalsup- ity of suchcalculationsas applied to finished drug products.
port at STERISCorporation,PO Box 147.St. Louis. MO One of the main objectivesof the cleaning processin drug
63166. tel. (314) 535-3392.fax (314) 535-2998,e-mail manufacture is to remove residue of the just-manufactured
(destin_leblanc@steris.com). product so that those residuesare not transferredto the sub-
sequently manufacturedproduct. A key complicating feature of oct A has an activeat a level of 2000 ~g/mL and is dosedat 5 mL
cleaning is that it involves not only the product being cleaned from dtreeto five times daily. The minimum daily dosewould be
but also the product subsequentlymanufactured in the cleaned (2<XX>~g/mL) X (5 mUdose) X (3 doses/day)=
equipment. The starting point for any determination of accep- 30,000 ~g/day
tance residue limits is the amount of residue from the cleaning If one also assumesthat product B is dosedat 5 mL from two
processthat could be presentin the subsequentlymanufactured to four times a day, then the maximum daily dose of product B
product without posing an unreasonablerisk. Clearly, one would would be
prefer that no residue be present; however, it is impossible to 5 mUdose X 4 doses/day= 20 mUday
measure"no" residue.Even the criterion of being below the lim- Note that this calculation for the subsequentproduct is inde-
its of detection of the analytical procedureis not by itself a very pendent of what the active is or at what level that active is pre-
good method for selecting residue limits. As methods are im- sent. The residue limit in the subsequentproduct can be calcu-
proved and have even lower limits of detection, a cleaning lated by substituting thesevalues into Equation I:
process that was previously viewed as acceptablecan become x 30,000 JA.g/day= 1.5
unacceptable.Therefore, it is preferable to expressthat limit as,
LI = 0.001 20 mL/day ~g/mL
for example, ~8 ppm, rather than specifying "undetected:'
FDA?s guidancefor detenniningresiduelimits dictatesthat lim- This value of 1.5 jJ.g/mL (or -1.5 ppm, assuming a specific
its be logical (i.e., based on an understanding of the process), gravity of 1.0) is independentof both batch size and equipment
practical, achievable,and verifiable (1). Fortunately for thosein- surface area. Therefore this calculation can be done as soon as
volved in cleaning validation, the sameFDA documentmentions information is availableabout the composition and relevantdos-
limits proposedby industry representatives"such as 10ppm, bio- ing of the two products.The calculated value of 1.5 ppm should
logical activity levels such as 1/1000 of the normal therapeutic be comparedto the 10 ppm default value from Lilly's criterion,
dose,and organolepticlevels such as no visible residue:' This is and the lower of the two values should be used in subsequent
clearly a referenceto work:.done by Fourman and Mullen at Eli calculations. For this example, 1.5 ppm would be chosen for
Lilly (2), whosepaperis listed in thereferencesectionof the FDA subsequentcalculations.
guidance document. Although it is not officially endorsed by One could selectsafety factors other than 0.001. For example,
FDA, the Lilly method of establishing residue limits (or some safety factors of 0.001 for orally dosedproducts and 0.0001 for
variation of it basedon the sameprinciples) is widely usedwithin parenterals have been suggested(6). Although more stringent
the pbannaceuticalindustry for detennining acceptablelevels of safety factors may easily be justified, use of a safety factor less
chemical residues(3-5). stringentthan 0.001 would probably require significantjustifica-
The published Lilly criteria are that tion. However,different safetyfactors may be appropriateif they
. the equipment be visually clean are applied to dosing factors other than the minimum daily
. any active agentbe presentin a subsequentlyproduced prod- pharmacological dose. In addition to different safety factors,
uct at maximum levels of 10 ppm companiesmay also baselimits on parametersother than thera-
. any activeagentbe presentin a subsequentlyproducedproduct peutic doses.For example,rather than using the minimum daily
at maximum levelsof 1/1(XX)of d1eminimum daily doseof the dose of the active, firms may select other measures,such as the
activeagentin a maximumdaily <k>se of d1esubsequentproduct no observableeffect level (NOEL) or the minimum pharmaco-
Although Fourman and Mullen directly calculate the surface logical effect level. Becausethe use of these factors will result
areacontamination basedon theselatter two criteria, the analy- in residue limits more stringent than limits basedon the mini-
sis in this article usesthe sameassumptionsto arrive separately mum daily dose, there is no scientific reasonnot to select these
at subsequentproduct residue limits, surfacearearesiduelimits, criteria. It should be noted, however, that arbitrarily selecting
and analytical sample residue limits. Such a discrete analysis more stringent criteria may result in unreasonable cleaning
may be more conducive to understandingcontributions to resi- overkill and may also stretch the detection limits of available
due limits from various factors. analytical methods.

UMIT .1 SUBSEQUENT PRODUCT UMIT PERSURFACEAREA


To calculate the limit of the active agent in any subsequently Once the residue limit in the subsequentproduct is determined
manufactured product (LSP), the only infonnation needed is the (using the lower values in Lilly's secondand third criteria), the
minimum daily dose of the active being cleaned and the maxi- next step is to determine the residue limit in terms of active in-
mum daily dose of the subsequently manufactured drug product. gredient contaminationlevel per surfaceareaof equipment.This
For purposes of illustration, product A will refer to the product limit (L2, in ~g/cm2) dependson LSP (determined as the lower
being cleaned, and product B will refer to the subsequently pro- of L) and 10 ppm), the batch size of the subsequentproduct B
duced product. The LSP (L]) can be expressed as (BSSP,in kg), and the sharedequipment surface area(SESA.in
L _ (0001 min dailydoseofactiveioproductA cm2). This can be expressedmathematically as
1 -. )X max.dailydoseofproductB [ 1.1 L = LSP X BSSP X 1<XX>
2 SESA [2]
For an example using orally dosedliquids, assumethat prod- where 1(0) is a conversionfactor to account for ppm (the limit
of the subsequentbatch) and to convert kg to ILg(for BSSp).For surfaceareaswabbedis 25 cm2, and the amount of solvent used
this example, if LSP is 1.5 ppm and assuming BSSPis 200 kg for desorptionis 20 g, thenthe limit LJ is
and SESA is 60,000 cm2, then the ~ limit is
LJ -- 5.0~p22Og x 25cm2= 6.3 'tJ.g/gor6.3 ppm
L2 = 1.5 ppmx200q X 1(XM)=S.O
~g/cm2
(i).(XX) cm2
RECOVERYFACTORS
Whendeterminingthe surface area,oneshouldconsiderall The limit LJ is the acceptancelimit in the analyzed sample. It
sharedproduct contact surfaces,including piping, baffles, etc. should be adjustedby a swabrecoveryfactor, which can be done
Estimates of surface area should be on the high side because in two ways. One method is to include the swab recovery fac-
larger surfaceareasresult in lower ~ residue limits. tor in the actual analytical calculation by dividing the analyti-
Note that this calculation for L2 assumesthat the residue will cal result by the recovery factor. For example, if the swab re-
be evenly distributed over all surfaces.This is generally not the covery factor is 0.80 (80%) and the analytical procedure gives
case. However, this assumption still representsthe worst case a value of 1.3 ppm, then the limit should be adjustedby dividing
in the sensethat if one is doing swab sampling on the most dif- the analytical result by the recovery factor to arrive at a deter-
ficult to clean locations, then the assumptionof an even distrib- mination of 1.3 ppm -':-0.80 = 1.6 ppm. The alternative is to
ution will make it more difficult to meet the residue limits for include the recovery factor in Equation 3. In this case the re-
those most difficult to clean locations. In addition, it would be covery factor of 0.80 should be included in the numerator. Al-
difficult to scientifically justify one area of the equipment hav- though the numbersusedwill be different, the net effect of com-
ing a residuelimit of lO l1.g/cm2and other areashaving limits of paring the analytical result to the calculated limit will be
2.5 l1.g/cm2.If a true sampling rinse is used, then issuesof dis- logically the same.One should standardizehow this will be per-
tribution do not arise becauseone is sampling the entire equip- formed in order to avoid situations in which the recovery factor
ment surface(7). is usedin the calculations of both the LJ limit and the determi-
If more than one product (e.g., products B, C, D, and E) could nation of the analytical result on the desorbedsolvent sample.
possibly be manufactured following product A, then surface-
area limits (Lv for cleaning following product A should be cal- EFFECTS 01 AlALYTICALMETIIODVALIDAnOI
culated for each subsequentproduct. For purposesof cleaning It should be noted that, at least in this example, LSP (L), 1.5
validation, the residue limit should be set at the lowest of these ppm) was significantly different from the limit in the analyzed
L2 surface-area limits. This gives the manufacturing depart- sample (y, 6.3 ppm). This is becauseL) reflects the residue of
ment greater flexibility to make products in any order. It should the active being evenly distributed in a batch of the subsequent
be recognized, however, that there may be circumstances in product, whereas L 3 reflects the residue of the active concen-
which residue limits result in restrictions on which products trated, in most cases,in a smaller volume of matrix material (the
can follow product A on the manufacturing schedule. desorbingsolvent). One can seethat this effect can be leveraged
by either samplinga larger surfaceareaor by desorbingthe swab
UMIT II THEANALYZED SAMPLE into a smaller amount of solvent. When sampling a larger area,
Although one establishesresiduelimits for the active in the sub- one must consider whether sampling this larger areamight also
sequentproduct (LJ) and for the active per surfaceareafollowing lower the swab recovery factor, thus adding more uncertainty to
cleaning (L2), theselimits typically are not measureddirectly by the determination.This is significant for analytical method pur-
the analyticalprocedure.The analytical proceduretypically mea- posesbecausethe analytical method chosenfor determining the
suresthe active agent in solution as a result of either swabbing residue of the active agent should be validated (at least in the
and desorbingthat swab into a suitable solvent or by doing rinse example used) not basedon the LJ limit of 1.5 ppm but rather
sampling and measuring the active in the rinse solvent (8). For on the L3limit of 6.3 ppm adjustedappropriatelyby the recovery
purposesof expediency,this article focuses on swab sampling. factor. In this case,one might validate dte analytical method not
The reader is referred to other sourcesfor examples related to in the range of 0.5 to 1.5 ppm but rather in the range of 2.1 to
rinse sampling (7). 6.3 ppm. This fourfold factor in limit of quantitation may be
For swab sampling, one assumesthat a fixed surface area of significant for analytical method selection and validation.
the equipment is sampled and the swab is then desorbedinto a
fixed amount of solvent. To determine the residue limit (Lj. in VISUAL CLEAMESS
micrograms per gram or parts per million) for the analytical The issue of visual cleannessis also significant If a surface is
sample (the solvent the swab is desorbedinto), one must know visually dirty, either the cleaning procedureis not acceptableor
the surface-arearesidue limit (L2)' the surface areaswabbed(in an acceptableprocedure is now out of control. The standardof
squarecentimeters),and the amount of solvent the swab is des- visually clean can be used for purposesof both validation and
orbed into (in grams). The limit in the analyzed sample is monitoring. The dividing line between visually clean and visu-
L = L2 x swabbedsurfacearea ally dirty is regardedas being in the rangeof 4 ~g/cm2 (2). If the
j amountof desorption
solvent Pl L2 surface contamination acceptancelimit is calculated and is
found to be significantly higher than 4 ~g/cm2. and providing
Continuing with the exampleusedso far. if ~ is 5.0 JA.g/cm2.
the that critical surfacesare readily visible. it may be possible to de-
fault to visually clean as the only acceptancecriteria. For po- bing procedure, for example), and if the surface area of the fill-
tent drugs for which the L2 acceptancecriteria would typically ing equipment and associateAipiping is 5(XX)cm2, then if all of the
be well below I ~g/cm2, a determination of visual cleanness contamination in the equipment were concentrated in the first vial
would have no significance regarding the adequacy of clean- produced, the concentration of residue in that one vial would be
ing. In such a case,a visually dirty surface would still be an in- 0.3 fJ.8/Cm2
X S<XX}Cm2= 300 fA.g/mLor -300ppm
dication of cleaning failure, but a visually clean surface could SmL
not clearly indicate whether the residue was at an acceptable
level. This would clearly be abovethe L I acceptancelimit of 5 ppm. If
For casesin which a determination of visually clean is crit- all the contaminating residue in the equipment were evenly di-
ical, it may be appropriate to actually determine the highest vided in the first 60 vials, then eachvial would contain 5 ppm of
level at which the specific residue is not visible. This can be residue; therefore those 60 vials and a reasonable number of
done by spiking model surfaces (e.g., stainless steel coupons) subsequentlyproduced vials should be discarded.
with different levels of the residue (e.g, 0.5. 1.0,2.0,4.0, and These determinations were based on theoretical considera-
8.0 ~g/cm2) and asking a trained panel to observethe coupons tions of what could happen, and thus they represent a worst
in a "blinded" manner to determine whether the coupons are case. If the number of vials to be discarded is unacceptably
visually clean. This should be done under viewing conditions large, a study could be done to deal with the nonuniform con-
(of lighting, angle, and distance) that simulate the viewing of tamination (of the filled vial, in this example). This study
actual equipment. The highest residue level at which all panel would involve cleaning the filling equipment and then filling a
members consider the coupons to be visually clean estab- placebo product. Vials number 1, 10,20, and so forth would
lishes the acceptance level for visual cleanness for that par- then be analyzed for the target residue. If vial number 10 were
ticular residue. at 6 ppm and vial number 20 were at 2 ppm, then those first
20 vials and a reasonable number of subsequently produced
NONUNIFINIM COITAMllAno. vials should be discarded.
The cleaning validation acceptancecriteria usedby Lilly and re-
ferred to in the FDA guidancedocumenton cleaningvalidationdo MICROBIOLOOICAL CONTAMIIATiOI
provide one logical construct for detennining residue limits for A second issue in setting limits is what to do about microbio-
chemicalresiduesof activeingredientsin finished drug manufac- logical contamination, for which setting acceptable limits is
ture. One issuethat may ariseinvolves possiblenonuniform con- more difficult. The main issue is that merely one organism in
tamination of the subsequentproduct (9). It should be noted that the equipment could possibly result in a significantly higher
this is different from (although it may be related to) nonunifonn contamination level in the product manufacturedin that equip-
contaminationof the cleanedequipment Nonunifonn contamina- ment. No clear guidelines exist for microbiological contami-
tion of dIe subsequentproduct is more likely to ariseduring con- nation of processequipment. This may be the reason why the
tinuous processesrather than batch processes.For example,in a FDA guidancedocumentexplicitly statesthat the document ap-
batch processinvolving liquid drug blending, dIe contaminating plies only to chemical residues (1). One cannot expect the
residue(provided dIereis adequatemixing) is likely to be evenly equipment to be free of all microorganisms,especially if any fi-
distributed throughout the subsequentlymanufacturedproduct nal rinse involves nonsterile water, unless a final sanitizing or
In a continuousprocess,suchasflow througha piping systemand sterilization step is used. As a minimum, one should employ
through a filling nozzle during a packaging operation.it is more the criteria used for critical cleanroom surfaces(10). A second
likely that the contaminatingresiduewould appearin the first vials concern is with the species of microorganism present. Obvi-
filled. This, of course,dependson the solubility of the residuein ously, the presenceof enteric organisms such as E. coli or En-
the subsequentlymanufactUredproduct and on product flow char- terococcusshould ordinarily be unacceptable.
acteristics.A specialcaseof a continuousprocessis a tablet press, Other concerns beyond the scope of this article include set-
becauseany residueson dIe surfacesof dIe pressarenot likely to ting limits for residuesfrom chemical sourcesother than active
be distributedevenly over all tabletsmanufactUredin a batch. ingredients (e.g., from excipients or cleaning agents), setting
In dealing with nonuniform contamination at least two alter- limits for residuesin active phannaceuticalingredients, and ac-
natives are possible. If it is reasonable that the contaminating counting for residues from multiple process steps. However,
residue would appearin the first portion of a product batch (of considerationof residuelimits in thesecasesshould be basedon
filled vials, for example),then calculationscan be madeto deter- the sameprinciples discussedhere.The first considerationis the
mine the maximum number of vials filled that could theoreti- possible effects of any residue when it is present in any subse-
cally be at the maximum allowable contamination level. Those quently manufacturedfinished drug product.-It is then possible
vials, plus as a safety measure a reasonable number of subse- to work backwards to determine limits for equipment surfaces
quently produced vials, should be discarded or destroyed. For and/or bulk actives. Any residue limit determination should be
example, supposethe acceptancelimit for the target residue is based on considerations and principles similar to those used
5 ppm in the subsequentlymanufactUredproduct filled as 5-mL for finished drug products, modified as they apply to those situ-
vials. If the calculatedresiduelevels in the filling equipmentand ations. The key, as in any validation activity, should be the use
associatedpiping were 0.3 IJ.glcm2(determined from a swab- of sound scientific and logical reasoning.
fault to visually clean as the only acceptancecriteria. For p0- bing procedure, for example). and if the surface area of the fill-
tent drugs for which the L2 acceptancecriteria would typically ing equipment and associated piping is 5<XX>cm2, then if all of the
be well below 1 ~g/cm2, a determination of visual cleanness contamination in the equipment were concentrated in die first vial
would have no significance regarding the adequacy of clean- produced, the concentration of residue in that one vial would be
ing. In such a case,a visually dirty surfacewould still be an in- 0.3 ~g/cm2 X 5<XX>cm2
= 300 ~ g/mL or- 300 ppm
dication of cleaning failure, but a visually clean surface could 5mL
not clearly indicate whether the residue was at an acceptable
This would clearly be abovethe L 1acceptancelimit of 5 ppm. If
level.
For casesin which a determination of visually clean is crit- all the contaminating residue in the equipment were evenly di-
ical, it may be appropriate to actually determine the highest vided in the first 60 vials, then eachvial would contain 5 ppm of
level at which the specific residue is not visible. This can be residue; therefore those 60 vials and a reasonable number of
done by spiking model surfaces (e.g., stainless steel coupons) subsequentlyproduced vials should be discarded.
with different levels of the residue (e.g, 0.5,1.0,2.0,4.0, and These determinations were based on theoretical considera-
8.0 ~g/cm2) and asking a trained panel to observe the coupons tions of what could happen, and thus they represent a worst
in a "blinded" manner to determine whether the coupons are case. If the number of vials to be discarded is unacceptably
visually clean. This should be done under viewing conditions large, a study could be done to deal with the nonuniform con-
(of lighting, angle, and distance) that simulate the viewing of tamination (of the filled vial, in this example). This study
actual equipment. The highest residue level at which all panel would involve cleaning the filling equipment and then filling a
members consider the coupons to be visually clean estab- placebo product. Vials number 1, 10,20, and so forth would
lishes the acceptance level for visual cleanness for that par- then be analyzed for the target residue. If vial number 10 were
ticular residue. at 6 ppm and vial number 20 were at 2 ppm, then those first
20 vials and a reasonable number of subsequently produced
NONUNIFORMCOITAMllAnO. vials should be discarded.
The cleaning validation acceptance criteria used by Lilly and re-
fen-ed to in the FDA guidance document on cleaning validation do MICROBIOLtMIICAl CONTAMIUnoN
provide one logical construct for determining residue limits for A second issue in setting limits is what to do about microbio-
chemical residues of active ingredients in finished drug manufac- logical contamination, for which setting acceptable limits is
ture. One issue that may arise involves possible nonuniform con- more difficult. The main issue is that merely one organism in
tamination of the subsequent product (9). It should be noted that the equipment could possibly result in a significantly higher
dlis is different from (although it may be related to) nonuniform contamination level in the product manufacturedin that equip-
contamination of the cleaned equipment. Nonuniform contamina- ment. No clear guidelines exist for microbiological contami-
tion of the subsequent product is more likely to arise during con- nation of processequipment. This may be the reason why the
tinuous processes rather than batch processes. For example, in a FDA guidancedocumentexplicitly statesthat the document ap-
batch process involving liquid drug blending, the contaminating plies only to chemical residues (1). One cannot expect the
residue (provided there is adequate mixing) is likely to be evenly equipment to be free of all microorganisms,especially if any fi-
distributed throughout the subsequently manufactured product. nal rinse involves nonsterile water, unless a final sanitizing or
In a continuous process, such as flow through a piping system and sterilization step is used. As a minimum, one should employ
through a filling nozzle during a packaging operation, it is more the criteria used for critical cleanroom surfaces(10). A second
likely that the contaminating residue would appear in the first vials concern is with the species of microorganism present. Obvi-
filled. This, of course, depends on the solubility of the residue in ously, the presenceof enteric organisms such as E. coli or En-
the subsequently manufactmed product and on product flow char- terococcusshould ordinarily be unacceptable.
acteristics. A special case of a continuous process is a tablet press, Other concerns beyond the scope of this article include set-
because any residues on the swfaces of the press are not likely to ting limits for residuesfrom chemical sourcesother than active
be distributed evenly over all tablets manufactured in a batch. ingredients (e.g., from excipients or cleaning agents), setting
In dealing with nonuniform contamination at least two alter- limits for residuesin active phannaceuticalingredients, and ac-
natives are possible. If it is reasonable that the contaminating counting for residues from multiple process steps. However,
residue would appear in the first portion of a product batch (of considerationof residuelimits in thesecasesshould be basedon
filled vials, for example), then calculations can be made to deter- the sameprinciples discussedhere.The first considerationis the
mine the maximum number of vials filled that could theoreti- possible effects of any residue when it is present in any subse-
cally be at the maximum allowable contamination level. Those quently manufacturedfinished drug product. It is then possible
vials, plus as a safety measure a reasonable number of subse- to work backwards to determine limits for equipment surfaces
quently produced vials, should be discarded or destroyed. For and/or bulk actives. Any residue limit determination should be
example, suppose the acceptance limit for the target residue is based on considerations and principles similar to those used
5 ppm in the subsequently manufactured product filled as 5-mL for finished drug products, modified as they apply to those situ-
vials. H the calculated residue levels in the filling equipment and ations. The key, as in any validation activity, should be the use
associated piping were 0.3 ~g/cm2 (determined from a swab- 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
4. R. Brewer. "Regulatory Aspectsof Cleaning Validation," presented
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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