Visible-Residue Limit for

Cleaning Validation
and its Potential Application in a Pharmaceutical
Research Facility
Richard J. Forsyth,* Vincent Van Nostrand, and Gregory P. Martin

V
isual inspecti ons for equ i pment cleanliness have alw ays
been con du cted in ph a rm aceutical fac i l i ties opera ting
according to good manu f actu ring practi ces. Before va l-
idated cleaning programs existed, formulators visually
inspected equ i pment before com m encing formulati on work
(1). Si n ce formalized cleaning va l i d a ti onprograms were intro-
duced , however, analytical testing has been the preferred met h od
for veri f ying and va l i d a ting accept a bl e - re s i due limit (ARLs) for
equipment cleanliness. Because analytical test methods are quan-
titative and validated, the results provide solid documentation
of the equipment cleaning process. Analytical testing removes
much, if not all, of the subjectivity of residue determination.
Visual inspections for cleanliness have continued to be per-
formed, however, in conjunction with the analytical methods.
Evaluations have shown that, in most cases, A visual inspection is conducted and visible cleanliness is con-
f i rm ed before any sample is taken for ch emical analysis (2). Vi-
visual observations are sensitive enough to
sual inspecti on also is requ i red before any formu l a ti on work is
verify equipment cleanliness. An experiment begun.
was conducted to explore the possibility of The use of on ly a visual assessment to determine equ i pm ent
using a visible-residue limit as an acceptable cleanliness was propo s ed in 1989 by Men den h a ll (3). He found
cleaning limit in a pharmaceutical research that visible-cleanliness criteria were more rigid than quantita-
facility, including an evaluation of the limits tive calculati ons and cl e a rly adequ a te . The Food and Drug Ad-
ministration, however, in its 1993 “Guide to Inspection of Val-
and subjectivity of “visually clean”
idation of Cleaning Processes,” limited the po ten tial acceptabi l i ty
equipment. of a vi sually clean cri teri on to use bet ween lots of the same prod-
u ct (4). The adequ acy of visible-re s i due limits (VRLs) has con-
ti nu ed to be a topic of d i s c u s s i onsince then . A recent arti cle by
Le Blanc again raised the question of whether a vi s i ble limit
could be justified as the sole accept a n ce cri teri on for equ i pm en t
cleanliness (5).
Vi s i ble cleanliness is the absen ce of a ny vi s i ble re s i due after
cleaning. Although this definition seems straightforward, var-
Richard J. Forsyth is a senior manager in ious factors influence the determinati ons made using this
pharmaceutical R&D, Vincent Van Nostrand m et h od. The most obvious va ri a ble is the observer. The out-
is a staff chemist in pharmaceutical R&D, and
come of a visual inspecti on depends not on ly on the ob s erver ’s
Gregory P. Martin is a director in
pharmaceutical R&D, all at Merck & Co., Inc., visual accuracy, but also on what the observer is trained to see.
WP78-210, West Point, PA 19486, Ligh ting levels in inspecti on are a s , s h adows caused by equ i p-
tel. 215.652.7462, fax 215.652.2835, m en t , and the ob s erver ’s viewing angle and distance from the
richard_forsyth@[Link]. equipment surface also influence what is seen. In addition, the
*To whom all correspondence should be addressed. chemical composition of the cleaning solvents can change the
appearance of the residue. Finally, the individual components
58 Pharmaceutical Technology OCTOBER 2004 w w w. p h a rm t e ch . c o m
 eters of the manu f acturing equ i pment (2). For the adu l terati on
Table I: Light intensities in the manufacturing pilot-plant limit, a constant level of 10 ppm or 100 mg/swab is often used
suite. in the industry.
Room Lx Room Lx If the VRL could be quantitatively established and shown to
2420A 540 2736 1090 be lower than the A R L , then it might be reason a ble to use a
2420B 600 2737 940 visible-residue cri teri on for cleaning validation. The ARL is log-
2420C 630 2738 520 i c a lly establ i s h ed, through analytical te s ti n g, for the most po-
2702A 670 2740 600 tent com pon ent of a formu l a ti on, wh i ch is usu a lly the active
2702B 650 2742 1050 ph a rm aceutical ingred i ent (API ) . To con s i der a non s el ective ,
2702C 670 2744 840 vi su a lly clean cri teri on , one would have to con s i der the indi-
2720 680 2746 1060 vi dual VRLs of both the exc i p i ents and APIs in the formu l a ti on.
2722 870 2747 1120 For this stu dy, the VRLs were determ i n ed for va rious A PIs ,
2723 850 2748 870 com m on ly used excipients, and drug formulations. The residue
2725 920 2749 1400 limits for the formulations were then compared with the lim-
2726 1230 2750 700 its for the individual formu l a ti on com pon ents. The VRLs for
2727 640 2751 640 the detergents used to clean the equipment also were assessed,
2729A 1170 2752 870 because the deter gents are part of the overa ll manu f actu ring
2729B 770 2753 1130 process.
2730 700 2754 1170
2731 770 2755 740 Visible-residue parameters
2732 1190 2756 1240 Because determining a VRL is high ly subj ective, the va riables
2733 1170 2757 1170 associated with stu dying vi s i ble residues were def i n edand then
2734 1080 2758 1240 ex peri m ental parameters for the stu dy were established. The
2735 1240 2759 1350 para m eters con s i dered were su rf ace material, s o lvent ef fects,
light intensity, and observer distance, angle, and subjectivity.
of a given formul a ti on affect the overall VRL. Fourman and Stainless steel was an obvious ch oi ce for su rf ace material be-
Mull en determ i n ed a visible limit of ;100 mg per 2 3 2 in. swab cause more than 95% of m a nu f acturing equ i pment su rf aces are
a rea or approximately 4 mg/cm2 (6). Jenkins and Va n derwi el en stainless steel. For this study, representative stainless steel coupons
observed various residues as low as 1.0 mg/cm2 with the aid of were used for spotting purposes in the labora tory setting. If
a light source (7). VRLs were used in an operating facility, ad d i ti onal materials
The ARL for drug re s i due is of ten determ i n ed on a health- such as PTFE, rubber, or plastics would have to be tested.
b a s ed or adu l tera ti on - b a s ed cri terion (2, 7, 8). The limit used The ligh ting conditi ons in the manu f acturing pilot plant dif-
is the lower of the two limits. A health-based limit is gen erated fered from room to room. The light intensity was measured in
from toxicity data, wh i ch can be ex pre s s ed as allow a ble daily e ach room of the pilot plant and the wash area to determine
intake (ADI). Based on the aut h or’s ex perien ce , if the ADI is the range of light intensity. For consistency, the light measure-
,0.1 mg/day, the health-based limit wi ll be the lower of the two m ent was taken in the center of e ach room at ;4 ft from the
limits. The adu l tera ti on limit, on the other hand, will gen era lly f l oor. Ta ble I lists the ra n ge of light inten s i ties in the va rious
be lower for su b s t a n ces with ADI va lues .0.1 mg/day. The rooms in the pilot-plant suite. The light intensity ranged from
health-based limit is calculated using the ADI and the param- 520 to 1400 lx. To account for this va ri a ti on as well as for shad-

Table II: Observer variability of visual cleanliness of carnauba wax versus light intensity.*
Detection of spots by observers A–D
Drug/spot 1400 lx 1000 lx 800 lx 600 lx 400 lx
mg/cm2 A B C D A B C D A B C D A B C D A B C D
22.7 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
14.5 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
6.34 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
3.99 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
2.10 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
1.92 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y N Y Y Y N
0.907 Y N N N Y Y N N Y N N N Y N N N Y N N N
,0.907 N N N N Y N N N Y N N N N N N N Y N N N
0.000 N N N N N N N N N N N N N N N N N N N N
*Compound is carnauba wax in 1:1 acetonitrile:[Link] spots were observed under fluorescent light.
Y indicates spot was observed. N indicates no spot was observed.

60 Pharmaceutical Technology OCTOBER 2004 w w w. p h a rm t e ch . c o m

 Table III: Observer variability of visual cleanliness of aprepitant versus light intensity.*
Detection of spots by observers A–D
Drug/spot 1400 lx 1000 lx 800 lx 600 lx 400 lx
mg/cm2 A B C D A B C D A B C D A B C D A B C D
74.4 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
40.1 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
14.2 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
12.0 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
7.44 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
5.90 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
2.98 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
1.45 Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y Y
0.00 N N N N N N N N N N N N N N N N N N N N
*Compound is aprepitant in 1:1 acetonitrile:[Link] spots were observed under fluorescent light.
Y indicates spot was observed. N indicates no spot was observed..

ows and different locations within a room, the visible-residue no re s i due and provi ded adequ a te solu bi l i ty for a majority of
study was con du cted bet ween 400 and 1400 lx using a light the substances tested, and the spot-area range (5–15 cm2) was
source directly above the sample. A fluorescent light provided mu ch ti ghter. If s o lu bi l i ty was not ach i eved , the material was
the same type of light that is used in the pilot plant. A plasti c su s pended and samples were spo t ted immed i a tely using the
cover with va rious degrees of s h ading was placed over the bulb suspension.
and was ro t a ted to ad just and con trol light intensity. A light The solvent also had an effect on the spots them s elves. Th e
meter was used to set and verify the various light intensity m a j ority of the re s i dues were wh i te crys t a lline spo t s . Several
levels. m a terials left grey spots re s em bling water stains. The dissolu-
To minimize ob s erver su bj ectivity, four su bj ects vi ewed all ti on and su b s equ ent rec rystallizati on of the material most likely
of the samples. The angle and distance of the observer relative gen era ted amorphous re s i dues. In all of the trials, the solven t
to the samples were te s ted nex t . A distance of 6–18 in. f rom the was spo t ted to con f i rmthat it did not leave a residue. An unspo t-
equipm ent su rf ace and a viewing angle of 0 – 9 08 were con s i d- ted stainless steel coupon was used as a control for each study.
ered as practical viewing parameters. The first set of spots was
prep a red and vi ewed from va rious distances and angles. The Experiment
d i s t a n ce did not have a significant ef fect, h owever, so a com- Samples were prep a red by dissolving or dispersing 25 mg of
fort a ble viewing distance of 12 in. was ch o s en. The viewing material into 50 mL of solven t , re su l ting in a 0.5 mg/mL or 500
angle, on the other hand, turned out to be a critical variable. A mg/mL sample. Various vo lumes of the sample were spotted
908 angle (looking at the spots from direct ly overh e ad) was not on to the stainless steel co u pons along with a com p l em en t a ry
the optimal angle, because spots were not as easily seen. Hav- vo lume of s o lvent so that the total vo lume spo t ted was con-
ing the observer and the light source at the same angle signifi- stant. Ei ght re s i dues were spo t ted for each sample along with a
c a n t ly redu ced the vi s i ble ref l ect a n ce from the re s i du e . In ad- solvent blank. The resulting range of spots was between 5 and
dition, incre a s ed reflect a n ce interferen ce occ u rred from the 300 mg/mL.
su rrounding su rf ace s . Decreasing the vi ewing angle made the The spots were dried under a stream of n i trogen to aid in
spots more visible to the observer because of the reflectance of drying and to prevent po tential oxidation of the materi a l , be-
light off the residue. A vi ewing angle of 308 was chosen, although cause drying spots under a stream of air can oxidize some ma-
s m a ll er angles occasionally provided more ref l ectance. A 308 terials that are not easily ox i d i zed. Even though the same vo l-
angle provi ded the shall owest practical vi ewing angle, taking ume of sample or solvent was spo t ted , d i f ferent dri ed re s i du e
into con s i dera tion the su rf ace locations wh ere residues are most areas appe a red as the liquid samples spre ad over the co u pon .
likely to be seen in manufactu ring equ i pm ent (i . e .,corn ers and That variation in spot size resulted from differences in surface
joints). tension of the samples and from passing nitrogen over the sam-
Finally, solubility and solvent effects were considered. A list ples du ring dryi n g. The areas of the dri ed spots were measured
of solu bi l i ties for each exc i p i ent and API was compiled. Initially, to determine the amount per unit area (mg/cm2) for each spot
va rious solvents were used with the A PIs. That resulted in a wide of material. The ra n ge of areas for the spots ob s erved in the tri-
ra n ge of re s i due spot areas (3–32 cm2), however, wh i ch made als was 0.1–106 mg/cm2 (see Figure 1).
it problematic to determine a consistent amount per unit area The spots were vi ewed under con tro ll ed conditions. The ligh t
(mg / c m2) for each material. Al s o, several exc i p i ents were on ly s o u rce was maintained in a stati on a ry po s i ti on direct ly above
solu ble in ex trem ely harsh solvents, and bu f fers , acids, and bases the samples. The ob s ervers were ori en ted su ch that they vi ewed
were not desira ble because they would leave their own residues the spots from the same three-dimen s i onal loc a ti on each time.
on the su rf ace . The inve s ti ga tors dec i ded to use a solvent of 1:1 Each ob s erver wore a wh i te lab coat to minimize vari a ti ons
aceton i tri l e : w a ter for all APIs and excipients. The solvent lef t c a u s ed by individual clothing co l ors. The ob s ervers vi ewed the
62 Pharmaceutical Technology OCTOBER 2004 w w w. p h a rm t e ch . c o m
 Table IV: Visible-residue limits of commonly used excipients versus light intensity.
Visible limit (mg/cm2) at specified illuminance
Excipient* 400 lx 600 lx 800 lx 1000 lx 1400 lx
Ascorbic acid ,0.878 ,0.878 ,0.878 ,0.878 ,0.878
Calcium phosphate, dibasic
anhydrous ,0.463 ,0.463 ,0.463 ,0.463 ,0.463
Calcium phosphate, dibasic
dihydrous 1.31 1.31 3.12 1.31 1.31
Cellulose, microcrystalline 1.11 1.11 2.42 2.42 1.11
Croscarmellose sodium 3.09 3.09 3.09 3.09 3.09
Ferric oxide, red 1.55 1.55 1.55 1.55 1.55
Ferric oxide, yellow ,0.584 ,0.584 ,0.584 ,0.584 ,0.584
Hydroxypropyl cellulose ,0.490 ,0.490 ,0.490 ,0.490 ,0.490
Lactose anhydrous ,0.684 ,0.684 ,0.684 ,0.684 ,0.684
Lactose monohydrate ,0.597 ,0.597 ,0.597 ,0.597 ,0.597
Magnesium stearate ,0.469 ,0.469 ,0.469 ,0.469 ,0.469
Mannitol ,0.673 ,0.673 ,0.673 ,0.673 ,0.673
Poloxamer 188 0.808 ,0.362 ,0.362 ,0.362 ,0.362
Poloxamer 407 ,0.366 ,0.366 ,0.366 ,0.366 ,0.366
Propyl gallate ,0.681 ,0.681 ,0.681 ,0.681 ,0.681
Silicon dioxide, colloidal 10.9 10.9 10.9 10.9 15.3
Sodium lauryl sulfate ,0.963 ,0.963 ,0.963 ,0.963 ,0.963
Sodium starch glycolate ,0.403 ,0.403 ,0.403 ,0.403 ,0.403
Sodium stearyl fumarate 2.12 1.52 1.52 0.511 0.511
Starch, partially
pregelatinized corn 10.2 10.2 10.2 10.2 10.2
Sucrose ,0.61 ,0.61 ,0.61 ,0.61 ,0.61
Titanium dioxide 1.92 1.92 1.92 2.10 2.10
Wax, carnauba 5.15 5.15 5.15 5.15 5.15
* The solvent used for all excipients was 1:1 ACN:water.

co u pons sep a ra tely so as not to influ en ce were the first su b s t a n ces te s ted. It was
the re s ponses of the other participants. nece s s a ry to con f i rm that the deter gen t
The co u pons were positi on ed for view- VRLs were low enough to not interfere
ing and the light intensity was measured with vi s i ble re s i due determinations of
from the same spot on the ben ch top each formulations produ ced in the pilot plant.
time (see Figure 2). A base deter gent and a neutral deter gen t
are used during different stages of the
Results and discussion cleaning process. The VRLs of the base
VRLs were established for 23 commonly and neutral deter gents were ,0.37 and
used excipients and 22 A PIs. E ach visible ,0.56 mg / c m 2, respectively. Because
limit was designated as the concen trati on these limits were sufficiently lower than
at which all ob s ervers po s i tively identi- the adu l tera ti on limit of 4 mg/cm2, the
fied a visible residue. The actual amount testing of lower re s i due levels was not
of m a terial spo t ted (in mg/cm2) was a re- considered necessary.
sult of the amount of exc i p i ent or A PI A list of commonly used excipients was
wei gh ed for the sample, the volume of so- compiled for evaluation. Most of the
lution or su s pension spotted on the com m on fill ers were tested because fill er
co u pon , the su b s equent area of the liq- is typically the main ingredient in a for-
uid on the coupon, and the resulting Figure 1: Representative residues on mu l a ti on after the A PI . In ad d i ti on, rep-
re s i due are a . The four ob s ervers vi ewed stainless steel. resen t a tive samples of lubricants, bi n ders ,
the spots and indicated whet h er or not disintegra n t s , antioxidants, and co l orants
t h ey saw any visible residue. Examples of were te s ted . Table IV lists the excipients
the results of one excipient and one API are shown in Tables II te s ted. The data showed that the VRL ra n ged from ,0.366 to
and III, respectively. 15.3 mg / c m2 ac ross the light inten s i ties mon i tored in the stu dy.
The deter gents used to clean the equ i pm ent at this fac i l i ty The highest VRL obtained across the light intensities was con-
64 Pharmaceutical Technology OCTOBER 2004 w w w. p h a rm t e ch . c o m
 sidered the VRL because this was the most con s ervative ap-
proach . Fo u rteen of the excipients had limits ,1.0 mg/cm2, two
had limits between 1 and 2 mg/cm2, five were between 2 and 4
mg / c m2, and three were .4 mg/cm2. Twen ty - one of the 23 ex-
cipients tested were at or below the adulterati on limit of 4
mg/cm2. This would indicate that formulations containing these
exc i p i ents might be candidates for a vi sual cleaning inspecti on .
Light inten s i ty was the on ly stu dy con d i ti on that was va ri ed .
Wh en Fo u rman and Mu ll en determ i n ed a vi s i ble limit at ap-
proximately 4 mg/cm2, they did not address the light intensity
and indivi dual residues (6). With light source , however, Jen k-
ins and Va n derwi el en ob s erved va rious re s i dues as low as 1.0
mg/cm2 (7). One could logi c a lly ex pect the VRL to dec rease with
increasing light inten s i ty. The exc i p i ent re sults obt a i n ed in this
study, however, were significantly different from that expecta-
ti on. Of the 23 exc i p i ents te s ted, 17 of the limits were the same
Figure 2: Observer examining stainless steel coupons for residues. rega rdless of the light inten s i ty (see Ta ble IV) . O n ly 2 limits de-
creased with an increase in light intensity, and two of the lim-
its actually increased with an in-
crease in light inten s i ty. Three
Table V: Visible residue limits of formulations versus light intensity. of the limits incre a s ed as light
Visible-residue limit (mg/cm2) at specified illuminance i n tensity increased and then
API† 400 lx 600 lx 800 lx 1000 lx 1400 lx su b s equ en t ly decre a s ed as the
Losartan potassium ,2.68 ,2.68 ,2.68 ,2.68 ,2.68 light intensity was incre a s edfur-
(Cozaar**) ther. It was hypo t h e s i zed that
Indinavir sulfate ,1.38 ,1.38 ,1.38 ,1.38 ,1.38 the ch a n ge in VRL was caused
(Crixivan*) by the interacti on of the prec i p-
Aprepitant (Emend*) – 1.45 1.45 1.45 1.45 itating excipient, the evaporat-
Cyclobenzaprine HCL ,1.89 ,1.89 ,1.89 ,1.89 ,1.89 ing solvent, and the stainless
(Flexeril*) steel plate. Although there were
Alendronate sodium 0.495 0.495 0.495 0.495 0.239 changes in the detected VRL, the
(Fosamax*) changes were minor. No excip-
Rizatriptan benzoate ,0.873 ,0.873 ,0.873 ,0.873 ,0.873 ient went from bel ow to above
(Maxalt*) the 4 mg / c m2 limit or vi ce vers a.
Famotidine (Pepcid*) ,1.46 ,1.46 ,1.46 ,1.46 ,1.46 Twenty - t wo APIs also were
Finasteride (Proscar*) ,2.72 ,2.72 ,2.72 ,2.72 ,2.72 evaluated for their VRLs (see
Montelukast sodium ,1.47 ,1.47 ,1.47 ,1.47 ,1.47 Table V). A com binati on of
(Singulair*) marketed and developmental
Enalapril maleate ,0.65 ,0.65 ,0.65 ,0.65 ,0.65 compounds was tested. The
(Vasotec*) marketed produ cts con t a i n ed
Rofecoxib (Vioxx*) 5.64 0.871 0.871 0.871 0.871 APIs that were te s ted sep a ra tely
Simvastatin (Zocor*) 0.485 0.485 0.400 0.485 0.485 in this stu dy. Testing marketed
Compound A 0.552 0.552 0.552 0.552 0.552 products provi ded a more ex-
Compound B ,0.591 ,0.591 ,0.591 ,0.591 ,0.591 ten s ive database for the stu dy.
Compound C 0.666 0.666 0.666 0.666 0.666 The data showed that the VRLs
Compound D 5.59 1.61 1.61 1.61 1.61 ranged from 0.40 to 6.25 mg/cm2
Compound E 5.85 1.85 1.85 1.85 1.85 across the light intensities mon-
Compound G – 6.25 6.25 6.25 6.25 itored in the stu dy. The highest
Compound H 1.75 1.75 1.75 1.75 1.10 VRL obtained ac ross the light
Compound I 3.01 3.01 3.01 3.01 3.01 inten s i ties was again con s i dered
Compound J – 5.43 0.930 0.930 0.930 the VRL. Seven of the A PIs had
Compound K 1.97 1.97 1.97 1.97 1.97 limits ,1.0 mg/cm2, 7 had lim-
* Registered trademark of Merck & Co. in certain countries. its bet ween 1 and 2 mg / c m2,
** Registered trademark of E.I. du Pont de Nemours and Company (Wilmington, DE). 3 were bet ween 2 and 4 µg/cm2
† The solvent used for all compounds was 1:1 acetonitrile:water, except for Simavastin and
and 5 were .4 mg / c m 2. Seven-
Compound K, for which 4:1 acetonitrile:water was used, and Compound D, for which 4:1 teen of the 22 A PIs te s ted were
methanol:water was used.
at or bel ow the adu l terati on
66 Pharmaceutical Technology OCTOBER 2004 w w w. p h a rm t e ch . c o m
 Table VI: Visible-residue limits (mg / c m2) of marketed formulations and formulation components.
Ingredient VRL Ingredient VRL
Cozaar formulation ,0.505 Proscar formulation ,0.44
Losartan potassium API ,2.68 Finasteride API ,2.72
Microcrystalline cellulose excipient 2.42 Microcrystalline cellulose excipient 2.42
Lactose hydrous excipient ,0.597 Lactose hydrous excipient ,0.597
Starch, pregelatinized excipient 10.2 Starch, pregelatinized excipient 10.2
Magnesium stearate excipient ,0.469 Magnesium stearate excipient ,0.469
Crixivan formulation ,1.1 Sodium starch glycolate excipient ,0.403
Indinavir sulfate API ,1.38 Ferric oxide, yellow dye ,0.584
Lactose anhydrous excipient ,0.684 Singulair formulation ,0.4
Magnesium stearate excipient ,0.469 Montelukast sodium API ,1.47
Emend formulation ,0.34 Hydroxypropyl cellulose excipient ,0.490
Aprepitant API 1.45 Microcrystalline cellulose excipient 2.42
Microcrystalline cellulose excipient 2.42 Lactose hydrous excipient ,0.597
Sodium lauryl sulfate excipient ,0.963 Croscarmellose sodium excipient 3.09
Hydroxypropyl cellulose excipient ,0.490 Magnesium stearate excipient ,0.469
Sucrose excipient ,0.61 Titanium dioxide excipient 2.10
Flexeril formulation ,0.82 Carnauba wax excipient 5.15
Cyclobenzaprine HCl API ,1.89 Ferric oxide, red dye 1.55
Lactose hydrous excipient ,0.597 Vasotec formulation ,1.4
Pregelatinized starch excipient 10.2 Enalapril maleate API ,0.65
Starch, corn excipient 10.2 Lactose hydrous excipient ,0.597
Magnesium stearate excipient ,0.469 Starch, pregelatinized excipient 10.2
Ferric oxide, yellow dye ,0.584 Magnesium stearate excipient ,0.469
Fosamax formulation ,0.46 Starch excipient 10.2
Alendronate sodium API 0.495 Ferric oxide, red dye 1.55
Microcrystalline cellulose excipient 2.42 Ferric oxide, yellow dye ,0.584
Lactose anhydrous excipient ,0.684 Vioxx formulation ,0.59
Croscarmellose sodium excipient 3.09 Rofecoxib API 5.64
Magnesium stearate excipient ,0.469 Microcrystalline cellulose excipient 2.42
Maxalt formulation ,0.61 Lactose monohydrate excipient ,0.597
Rizatriptan benzoate API ,0.873 Hydroxypropyl cellulose excipient ,0.490
Microcrystalline cellulose excipient 2.42 Croscarmellose sodium excipient 3.09
Lactose hydrous excipient ,0.597 Magnesium stearate excipient ,0.469
Starch, pregelatinized excipient 10.2 Ferric oxide, yellow dye ,0.584
Ferric oxide, red dye 1.55 Zocor formulation ,0.57
Pepcid formulation ,0.33 Simvastatin API 0.485
Famotidine API ,1.46 Cellulose excipient 2.42
Microcrystalline cellulose excipient 2.42 Hydroxypropyl cellulose excipient ,0.490
Hydroxypropyl cellulose excipient ,0.490 Hydrous lactose excipient ,0.597
Magnesium stearate excipient ,0.469 Magnesium stearate excipient ,0.469
Titanium dioxide excipient 2.10 Titanium dioxide excipient 2.10
Ferric oxide, red dye 1.55 Ascorbic acid excipient ,0.878
Ferric oxide, red dye 1.55
Ferric oxide, yellow dye ,0.584

limit of 4 mg/cm2. However, if the two lowest light intensities its dec re a s ed sligh t ly as light inten s i ty incre a s ed and then su b-
were excluded, the VRLs for 4 of the 5 A PIs with VRLs .4 s equen t ly increased as the light inten s i ty was incre a s ed furt h er.
mg / c m2 would fall to ,2 mg / c m2 and the VRLs for 21 of the 22 Six VRLs dec re a s ed with an increase in light inten s i ty. Two of
2
APIs tested would be ,4 mg/cm . those dec reases were small , similar to those seen with the exc i p-
The depen den ce of the VRL on light intensity was both more ients. However, as noted above , 4 compounds dec reased from
d ra m a tic and more predictable for the APIs than for the exc i p- .5 to ,2 mg/cm2. These data indicate that formu l a ti ons con-
ients. Of the 22 A PIs te s ted, 15 of the limits were the same re- taining these APIs might be candidates for a vi sual cleaning in-
ga rdless of the light inten s i ty (see Ta ble V) . O n ly one of the lim- s pecti on , but light inten s i ty would have to be con s i dered. Ei t h er
68 Pharmaceutical Technology OCTOBER 2004 w w w. p h a rm t e ch . c o m
a light source could be used or a light meter Al t h o u gh the VRLs were lower than the
to verify the light intensity would be nec-
Table VII: Variability of the visible- ARLs, using VRLs as cleaning va l i d a ti on
essary. residue limits among observers. acceptance criteria is still limited . The pri-
An ad d i ti onal re a s on for te s ting mar- Observer variability m a ry limitati on for the use of VRLs is the
keted products was to compare the VRLs re: light intensity Number of training of the ob s erver to inspect clean
of the formulations with the VRLs of the (no. of observers) compounds equ i pm ent. During this stu dy, not on ly
i n d ividual formulati on com pon ents. 0 10 was there vari a bi l i tyin the VRL based on
Twelve formu l a ti ons were te s ted for thei r 1 32 the light intensity, t h ere was also va ri a bi l-
VRLs. The amount of API and excipients 2 8 i ty among the ob s ervers . Ta ble VII shows
in a formu l a ti on differ. The amount spo t- 3 5 the range of variability of the VRLs among
ted was based on the level of the API, 4 4 the observers . Of the 59 deter gents, exc i p-
which is the most po tent com pound in 5 1 i en t s , A PIs , and formulati ons te s ted, in
the formulation, ra t h er than on the most- on ly 10 of the cases did all four ob s ervers
abundant excipient. Table VI shows a comparison of the VRLs a gree on the VRL. In more than 80% of the tests there was some
of various marketed formulations compared with the individ- differen ce of op i n i on as to what was vi s i bly clean. Most of these
ual com pon ents of the formulations. The VRLs for the formu- d i f ferences were minor, but there were several cases that co u l d
l a ti ons com p a red favora bly with the limits for the indivi du a l be cause for concern .
components. For several of the excipients or A PIs , a poorly tra i n ed ob-
The VRL is of most value wh en it is bel ow the ARL for the server or equ i pm ent inspector could incorrect ly determine that
corresponding swab samples for the same compounds. The a piece of equipment was clean when residue was above the
VRLs for the formu l a ti ons from Table VI ra n ged from ,0.33 ARL. This could potentially place a facility in violation of reg-
to ,1.4 mg/cm2. They are all significantly lower than the adul- ulatory requirements.
teration limit of 4 mg/cm2. Therefore, the margin of safety, i.e., It is far more likely, however, as evi den ced from this stu dy,
the difference between the VRL and the 4 mg/cm2 limit, is rea- that even a tra i n ed equ i pm ent inspector would determine that
sonably wide. This indicates that these formulations might be a piece of equ i pm ent needed furt h er cleaning wh en it was, in
candidates for visual cleaning inspection. fact , well bel ow the ARL. That could lead to needless equ i pm en t

70 Pharmaceutical Technology OCTOBER 2004

Ci rcle/eINFO 54 w w w. p h a rm t e ch . c o m
 recleaning, wasting resources, and ad- 5. D. A. LeBlanc, “‘Vi su a lly Cl e a n’ as a Sole Ac-
ceptance Criteria for Cleaning Validation Pro-
versely affecting production schedules.
toco l s ,” PDA [Link]. Sci. Technol. 56 (1),
31–36 (2002).
Conclusions 6. G.L. Fo u rman and M. V. Mull en ,“ Determ i n-
Using a visible-residue limit to verify ing Cleaning Validati on Accept a n ce Limits
equipm ent cleanliness is an intriguing for Pharm aceutical Ma nu f actu ring Opera-
ti on s ,” Ph a rm . Technol. 17 (4), 54–60 (1993).
con cept . Determining that equ i pm ent is
7. K.M. Jenkins and A. J. Vanderwi el en ,“Cl e a n-
“visually clean” is a procedure that seems ing Validati on : An Overall Perspective,”
easy to document and that saves time and Pharm. Technol. 18 (4), 60–73 (1994).
re s o u rces, both in terms of pers on n el and 8. D.A. LeBlanc, D.D. Danforth, and J.M. Smith,
labora tory te s ting. To swab equ i pm ent, “Cleaning Tech n o l ogy for Pharmaceutical
Ma nufacturing,” Pharm. Tech n ol . 17 (10),
test the samples by HPLC, and doc u m en t
118–124 (1993). PT
the results requ i res up to two pers on-days,
occupies an HPLC overnight, and con-
sumes several liters of s o lven t s . To be able Please rate this article.
On the Reader Service Card, circle a number:
to look at a piece of equ i pm ent and sign
333 Very useful and informative
a paper stating the equ i pm ent is “visu a lly 334 Somewhat useful and informative
clean” is an attractive alternative. 335 Not useful or informative
Al t h o u ghimplem en ting a cleaning pro- Your feedback is important to us.
gram that relies on a visible-residue limit is
an attractive possibility, ex ten s ive back-
ground work would be necessary to justify
visible-re s i due limits, and other issues also FYI
would need to be ad d re s s ed . Pers on n el Production and manufacturing courses
training would be an ongoing requirement. The University of Wisconsin–Madison,Department
The procedu re for introducing new de- of Engineering Professional Development has
vel opm ent compounds, excipients, or for- scheduled courses for engineers and other
mulati ons in the manu f acturing area professionals in the pharmaceutical and
would have to be addressed. The resource s biopharmaceutical production industry.
necessary to introdu ce a visible re s i due The “Documenting Pharmaceutical Production
limit program would be ex tensive , wi t h- and Laboratory Operations”course is intended for
out assurance of acceptance by the regu- those who are involved in writing, managing, and
latory agencies. However, using a visible- handling standard operating procedures (SOP)
residue limit might be su cce s s f u lly argued documents for pharmaceutical production and
for an app l i c a ti onwith limited scope su ch laboratory [Link] covered will include
as introducing a new devel opment com- SOP, master production, and control documents;
pound into a pilot plant. complying with FDA requirements; elements of
design and control;applying appropriate writing
Acknowledgments techniques; and determining the adequacy of
The authors would like to thank Michael existing [Link] course is slated to run 8–9
Mc Q u ade, Tara Lu k i evics, and Jo s eph December 2004 in Las Vegas,Nevada.
S ch a ri ter for their ef forts as observers du r- A separate course,entitled “Tablet and Capsule
ing these studies. Manufacturing:Introduction and Update for
Competitive Organizations,”will be held 19–21
References January 2005 in Las Vegas, [Link] course will
1. Code of Federal Regulations, Title 21, Food and provide a broad overview of the entire processing
Drugs (General Services Administration,Wash- sequence and will cover the fundamentals of solid
ington , DC , 1 April 1973), Pa rt 211.67.b.6. dose manufacturing; tablet and soft/hard gelatin
2. R.J. Fors yth and D. Hay n e s , “Cleaning Vali-
dati on in a Pharm aceutical Re s e a rch Fac i l-
technology; current practices and advances in
i ty,” Pharm. Technol. 22 (9), 104–112 (1998). equipment and technology;problem-solving
3. D.W. Men denhall, “Cleaning Validati on ,” approaches; and good manufacturing practices
Drug Dev. In d . Ph a rm . 15 (13), 2105–2114 standards.
(1989). For more information on either course,contact
4. Food and DrugAd m i n i s tra ti on , “Guide to
In s pecti on of Validation of Cleaning
Michael [Link], tel.608.262.2101,
Processes” (Division of Field Investigations, waxman@[Link],or visit
Visit us at CHPI booth Hall V-5530 Office of Regi onal Opera tions, O f f i ce of Reg- [Link]
ulatory Affairs, July 1993).
Ci rcle/eINFO 56
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