Transcript Visible-Residue Limit for Cleaning Validation and its Potential

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
Evaluations have shown that, in most cases,
visual observations are sensitive enough to
verify equipment cleanliness. An experiment
was conducted to explore the possibility of
using a visible-residue limit as an acceptable
cleaning limit in a pharmaceutical research
facility, including an evaluation of the limits
and subjectivity of “visually clean”
equipment.
Richard J. Forsyth is a senior manager in
pharmaceutical R&D, Vincent Van Nostrand
is a staff chemist in pharmaceutical R&D, and
Gregory P. Martin is a director in
pharmaceutical R&D, all at Merck & Co., Inc.,
WP78-210, West Point, PA 19486,
tel. 215.652.7462, fax 215.652.2835,
[email protected].
*To whom all correspondence should be addressed.
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OCTOBER 2004
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 lidated 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 introduced , 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 quantitative 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 performed, however, in conjunction with the analytical methods.
A visual inspection is conducted and visible cleanliness is conf i rm ed before any sample is taken for ch emical analysis (2). Visual inspecti on also is requ i red before any formu l a ti on work is
begun.
The use of on ly a visual assessment to determine equ i pm ent
cleanliness was propo s ed in 1989 by Men den h a ll (3). He found
that visible-cleanliness criteria were more rigid than quantitative calculati ons and cl e a rly adequ a te . The Food and Drug Administration, however, in its 1993 “Guide to Inspection of Validation of Cleaning Processes,” limited the po ten tial acceptabi l i ty
of a vi sually clean cri teri on to use bet ween lots of the same produ ct (4). The adequ acy of visible-re s i due limits (VRLs) has conti 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, various factors influence the determinati ons made using this
m et h od. The most obvious va ri a ble is the observer. The outcome of a visual inspecti on depends not on ly on the ob s erver ’s
visual accuracy, but also on what the observer is trained to see.
Ligh ting levels in inspecti on are a s , s h adows caused by equ i pm en t , and the ob s erver ’s viewing angle and distance from the
equipment surface also influence what is seen. In addition, the
chemical composition of the cleaning solvents can change the
appearance of the residue. Finally, the individual components
w w w. p h a rm t e ch . c o m
Table I: Light intensities in the manufacturing pilot-plant
suite.
Room
2420A
2420B
2420C
2702A
2702B
2702C
2720
2722
2723
2725
2726
2727
2729A
2729B
2730
2731
2732
2733
2734
2735
Lx
540
600
630
670
650
670
680
870
850
920
1230
640
1170
770
700
770
1190
1170
1080
1240
Room
2736
2737
2738
2740
2742
2744
2746
2747
2748
2749
2750
2751
2752
2753
2754
2755
2756
2757
2758
2759
Lx
1090
940
520
600
1050
840
1060
1120
870
1400
700
640
870
1130
1170
740
1240
1170
1240
1350
of a given formul a ti on affect the overall VRL. Fourman and
Mull en determ i n ed a visible limit of ;100 mg per 2 3 2 in. swab
a rea or approximately 4 mg/cm2 (6). Jenkins and Va n derwi el en
observed various residues as low as 1.0 mg/cm2 with the aid of
a light source (7).
The ARL for drug re s i due is of ten determ i n ed on a healthb a s ed or adu l tera ti on - b a s ed cri terion (2, 7, 8). The limit used
is the lower of the two limits. A health-based limit is gen erated
from toxicity data, wh i ch can be ex pre s s ed as allow a ble daily
intake (ADI). Based on the aut h or’s ex perien ce , if the ADI is
,0.1 mg/day, the health-based limit wi ll be the lower of the two
limits. The adu l tera ti on limit, on the other hand, will gen era lly
be lower for su b s t a n ces with ADI va lues .0.1 mg/day. The
health-based limit is calculated using the ADI and the param-
eters of the manu f acturing equ i pment (2). For the adu l terati on
limit, a constant level of 10 ppm or 100 mg/swab is often used
in the industry.
If the VRL could be quantitatively established and shown to
be lower than the A R L , then it might be reason a ble to use a
visible-residue cri teri on for cleaning validation. The ARL is logi c a lly establ i s h ed, through analytical te s ti n g, for the most potent com pon ent of a formu l a ti on, wh i ch is usu a lly the active
ph a rm aceutical ingred i ent (API ) . To con s i der a non s el ective ,
vi su a lly clean cri teri on , one would have to con s i der the indivi dual VRLs of both the exc i p i ents and APIs in the formu l a ti on.
For this stu dy, the VRLs were determ i n ed for va rious A PIs ,
com m on ly used excipients, and drug formulations. The residue
limits for the formulations were then compared with the limits for the individual formu l a ti on com pon ents. The VRLs for
the detergents used to clean the equipment also were assessed,
because the deter gents are part of the overa ll manu f actu ring
process.
Visible-residue parameters
Because determining a VRL is high ly subj ective, the va riables
associated with stu dying vi s i ble residues were def i n edand then
ex peri m ental parameters for the stu dy were established. The
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.
Stainless steel was an obvious ch oi ce for su rf ace material because more than 95% of m a nu f acturing equ i pment su rf aces are
stainless steel. For this study, representative stainless steel coupons
were used for spotting purposes in the labora tory setting. If
VRLs were used in an operating facility, ad d i ti onal materials
such as PTFE, rubber, or plastics would have to be tested.
The ligh ting conditi ons in the manu f acturing pilot plant differed from room to room. The light intensity was measured in
e ach room of the pilot plant and the wash area to determine
the range of light intensity. For consistency, the light measurem ent was taken in the center of e ach room at ;4 ft from the
f l oor. Ta ble I lists the ra n ge of light inten s i ties in the va rious
rooms in the pilot-plant suite. The light intensity ranged from
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.*
Drug/spot
mg/cm2
22.7
14.5
6.34
3.99
2.10
1.92
0.907
,0.907
0.000
A
Y
Y
Y
Y
Y
Y
Y
N
N
1400 lx
B C
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
N N
N N
N N
D
Y
Y
Y
Y
Y
Y
N
N
N
A
Y
Y
Y
Y
Y
Y
Y
Y
N
1000 lx
B C
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
Y N
N N
N N
Detection of spots by observers A–D
800 lx
D
A B C D
A
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
N
Y N N N
Y
N
Y N N N
N
N
N N N N
N
600 lx
B C
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
N N
N N
N N
D
Y
Y
Y
Y
Y
N
N
N
N
A
Y
Y
Y
Y
Y
Y
Y
Y
N
400 lx
B C
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
N N
N N
N N
D
Y
Y
Y
Y
Y
N
N
N
N
*Compound is carnauba wax in 1:1 acetonitrile:water.All spots were observed under fluorescent light.
Y indicates spot was observed. N indicates no spot was observed.
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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.*
Drug/spot
mg/cm2
74.4
40.1
14.2
12.0
7.44
5.90
2.98
1.45
0.00
A
Y
Y
Y
Y
Y
Y
Y
Y
N
1400 lx
B C
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
N N
D
Y
Y
Y
Y
Y
Y
Y
Y
N
A
Y
Y
Y
Y
Y
Y
Y
Y
N
1000 lx
B C
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
N N
Detection of spots by observers A–D
800 lx
D
A B C D
A
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
Y
Y Y Y Y
Y
N
N N N N
N
600 lx
B C
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
N N
D
Y
Y
Y
Y
Y
Y
Y
Y
N
A
Y
Y
Y
Y
Y
Y
Y
Y
N
400 lx
B C
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
Y Y
N N
D
Y
Y
Y
Y
Y
Y
Y
Y
N
*Compound is aprepitant in 1:1 acetonitrile:water.All 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
study was con du cted bet ween 400 and 1400 lx using a light
source directly above the sample. A fluorescent light provided
the same type of light that is used in the pilot plant. A plasti c
cover with va rious degrees of s h ading was placed over the bulb
and was ro t a ted to ad just and con trol light intensity. A light
meter was used to set and verify the various light intensity
levels.
To minimize ob s erver su bj ectivity, four su bj ects vi ewed all
of the samples. The angle and distance of the observer relative
to the samples were te s ted nex t . A distance of 6–18 in. f rom the
equipm ent su rf ace and a viewing angle of 0 – 9 08 were con s i dered as practical viewing parameters. The first set of spots was
prep a red and vi ewed from va rious distances and angles. The
d i s t a n ce did not have a significant ef fect, h owever, so a comfort a ble viewing distance of 12 in. was ch o s en. The viewing
angle, on the other hand, turned out to be a critical variable. A
908 angle (looking at the spots from direct ly overh e ad) was not
the optimal angle, because spots were not as easily seen. Having the observer and the light source at the same angle signific 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 addition, incre a s ed reflect a n ce interferen ce occ u rred from the
su rrounding su rf ace s . Decreasing the vi ewing angle made the
spots more visible to the observer because of the reflectance of
light off the residue. A vi ewing angle of 308 was chosen, although
s m a ll er angles occasionally provided more ref l ectance. A 308
angle provi ded the shall owest practical vi ewing angle, taking
into con s i dera tion the su rf ace locations wh ere residues are most
likely to be seen in manufactu ring equ i pm ent (i . e .,corn ers and
joints).
Finally, solubility and solvent effects were considered. A list
of solu bi l i ties for each exc i p i ent and API was compiled. Initially,
va rious solvents were used with the A PIs. That resulted in a wide
ra n ge of re s i due spot areas (3–32 cm2), however, wh i ch made
it problematic to determine a consistent amount per unit area
(mg / c m2) for each material. Al s o, several exc i p i ents were on ly
solu ble in ex trem ely harsh solvents, and bu f fers , acids, and bases
were not desira ble because they would leave their own residues
on the su rf ace . The inve s ti ga tors dec i ded to use a solvent of 1:1
aceton i tri l e : w a ter for all APIs and excipients. The solvent lef t
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OCTOBER 2004
no re s i due and provi ded adequ a te solu bi l i ty for a majority of
the substances tested, and the spot-area range (5–15 cm2) was
mu ch ti ghter. If s o lu bi l i ty was not ach i eved , the material was
su s pended and samples were spo t ted immed i a tely using the
suspension.
The solvent also had an effect on the spots them s elves. Th e
m a j ority of the re s i dues were wh i te crys t a lline spo t s . Several
m a terials left grey spots re s em bling water stains. The dissoluti on and su b s equ ent rec rystallizati on of the material most likely
gen era ted amorphous re s i dues. In all of the trials, the solven t
was spo t ted to con f i rmthat it did not leave a residue. An unspo tted stainless steel coupon was used as a control for each study.
Experiment
Samples were prep a red by dissolving or dispersing 25 mg of
material into 50 mL of solven t , re su l ting in a 0.5 mg/mL or 500
mg/mL sample. Various vo lumes of the sample were spotted
on to the stainless steel co u pons along with a com p l em en t a ry
vo lume of s o lvent so that the total vo lume spo t ted was constant. Ei ght re s i dues were spo t ted for each sample along with a
solvent blank. The resulting range of spots was between 5 and
300 mg/mL.
The spots were dried under a stream of n i trogen to aid in
drying and to prevent po tential oxidation of the materi a l , because drying spots under a stream of air can oxidize some materials that are not easily ox i d i zed. Even though the same vo lume of sample or solvent was spo t ted , d i f ferent dri ed re s i du e
areas appe a red as the liquid samples spre ad over the co u pon .
That variation in spot size resulted from differences in surface
tension of the samples and from passing nitrogen over the samples du ring dryi n g. The areas of the dri ed spots were measured
to determine the amount per unit area (mg/cm2) for each spot
of material. The ra n ge of areas for the spots ob s erved in the trials was 0.1–106 mg/cm2 (see Figure 1).
The spots were vi ewed under con tro ll ed conditions. The ligh t
s o u rce was maintained in a stati on a ry po s i ti on direct ly above
the samples. The ob s ervers were ori en ted su ch that they vi ewed
the spots from the same three-dimen s i onal loc a ti on each time.
Each ob s erver wore a wh i te lab coat to minimize vari a ti ons
c a u s ed by individual clothing co l ors. The ob s ervers vi ewed the
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.
Excipient*
Ascorbic acid
Calcium phosphate, dibasic
anhydrous
Calcium phosphate, dibasic
dihydrous
Cellulose, microcrystalline
Croscarmellose sodium
Ferric oxide, red
Ferric oxide, yellow
Hydroxypropyl cellulose
Lactose anhydrous
Lactose monohydrate
Magnesium stearate
Mannitol
Poloxamer 188
Poloxamer 407
Propyl gallate
Silicon dioxide, colloidal
Sodium lauryl sulfate
Sodium starch glycolate
Sodium stearyl fumarate
Starch, partially
pregelatinized corn
Sucrose
Titanium dioxide
Wax, carnauba
400 lx
,0.878
Visible limit (mg/cm2) at specified illuminance
600 lx
800 lx
1000 lx
,0.878
,0.878
,0.878
1400 lx
,0.878
,0.463
,0.463
,0.463
,0.463
,0.463
1.31
1.11
3.09
1.55
,0.584
,0.490
,0.684
,0.597
,0.469
,0.673
0.808
,0.366
,0.681
10.9
,0.963
,0.403
2.12
1.31
1.11
3.09
1.55
,0.584
,0.490
,0.684
,0.597
,0.469
,0.673
,0.362
,0.366
,0.681
10.9
,0.963
,0.403
1.52
3.12
2.42
3.09
1.55
,0.584
,0.490
,0.684
,0.597
,0.469
,0.673
,0.362
,0.366
,0.681
10.9
,0.963
,0.403
1.52
1.31
2.42
3.09
1.55
,0.584
,0.490
,0.684
,0.597
,0.469
,0.673
,0.362
,0.366
,0.681
10.9
,0.963
,0.403
0.511
1.31
1.11
3.09
1.55
,0.584
,0.490
,0.684
,0.597
,0.469
,0.673
,0.362
,0.366
,0.681
15.3
,0.963
,0.403
0.511
10.2
,0.61
1.92
5.15
10.2
,0.61
1.92
5.15
10.2
,0.61
1.92
5.15
10.2
,0.61
2.10
5.15
10.2
,0.61
2.10
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
the re s ponses of the other participants.
The co u pons were positi on ed for viewing and the light intensity was measured
from the same spot on the ben ch top each
time (see Figure 2).
were the first su b s t a n ces te s ted. It was
nece s s a ry to con f i rm that the deter gen t
VRLs were low enough to not interfere
with vi s i ble re s i due determinations of
formulations produ ced in the pilot plant.
A base deter gent and a neutral deter gen t
are used during different stages of the
cleaning process. The VRLs of the base
Results and discussion
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 identithe 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 reconsidered 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 socompiled 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 liqis typically the main ingredient in a foruid 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, repre 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 con64
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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 approach . 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 excipients 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 approximately 4 mg/cm2, they did not address the light intensity
and indivi dual residues (6). With light source , however, Jen kins 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 expectati 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 decreased with an increase in light intensity, and two of the limits actually increased with an increase 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 pAprepitant (Emend*)
–
1.45
1.45
1.45
1.45
itating excipient, the evaporatCyclobenzaprine 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 excipRizatriptan 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 exCompound 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 monCompound 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 limits bet ween 1 and 2 mg / c m2,
* Registered trademark of Merck & Co. in certain countries.
3 were bet ween 2 and 4 µg/cm2
** Registered trademark of E.I. du Pont de Nemours and Company (Wilmington, DE).
† The solvent used for all compounds was 1:1 acetonitrile:water, except for Simavastin and
and 5 were .4 mg / c m 2. SevenCompound 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
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OCTOBER 2004
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Table VI: Visible-residue limits (mg / c m2) of marketed formulations and formulation components.
Cozaar
Losartan potassium
Microcrystalline cellulose
Lactose hydrous
Starch, pregelatinized
Magnesium stearate
Crixivan
Indinavir sulfate
Lactose anhydrous
Magnesium stearate
Emend
Aprepitant
Microcrystalline cellulose
Sodium lauryl sulfate
Hydroxypropyl cellulose
Sucrose
Flexeril
Cyclobenzaprine HCl
Lactose hydrous
Pregelatinized starch
Starch, corn
Magnesium stearate
Ferric oxide, yellow
Fosamax
Alendronate sodium
Microcrystalline cellulose
Lactose anhydrous
Croscarmellose sodium
Magnesium stearate
Maxalt
Rizatriptan benzoate
Microcrystalline cellulose
Lactose hydrous
Starch, pregelatinized
Ferric oxide, red
Pepcid
Famotidine
Microcrystalline cellulose
Hydroxypropyl cellulose
Magnesium stearate
Titanium dioxide
Ferric oxide, red
Ingredient
formulation
API
excipient
excipient
excipient
excipient
formulation
API
excipient
excipient
formulation
API
excipient
excipient
excipient
excipient
formulation
API
excipient
excipient
excipient
excipient
dye
formulation
API
excipient
excipient
excipient
excipient
formulation
API
excipient
excipient
excipient
dye
formulation
API
excipient
excipient
excipient
excipient
dye
VRL
,0.505
,2.68
2.42
,0.597
10.2
,0.469
,1.1
,1.38
,0.684
,0.469
,0.34
1.45
2.42
,0.963
,0.490
,0.61
,0.82
,1.89
,0.597
10.2
10.2
,0.469
,0.584
,0.46
0.495
2.42
,0.684
3.09
,0.469
,0.61
,0.873
2.42
,0.597
10.2
1.55
,0.33
,1.46
2.42
,0.490
,0.469
2.10
1.55
limit of 4 mg/cm2. However, if the two lowest light intensities
were excluded, the VRLs for 4 of the 5 A PIs with VRLs .4
mg / c m2 would fall to ,2 mg / c m2 and the VRLs for 21 of the 22
2
APIs tested would be ,4 mg/cm .
The depen den ce of the VRL on light intensity was both more
d ra m a tic and more predictable for the APIs than for the exc i pients. Of the 22 A PIs te s ted, 15 of the limits were the same rega rdless of the light inten s i ty (see Ta ble V) . O n ly one of the lim68
Pharmaceutical Technology
OCTOBER 2004
Proscar
Finasteride
Microcrystalline cellulose
Lactose hydrous
Starch, pregelatinized
Magnesium stearate
Sodium starch glycolate
Ferric oxide, yellow
Singulair
Montelukast sodium
Hydroxypropyl cellulose
Microcrystalline cellulose
Lactose hydrous
Croscarmellose sodium
Magnesium stearate
Titanium dioxide
Carnauba wax
Ferric oxide, red
Vasotec
Enalapril maleate
Lactose hydrous
Starch, pregelatinized
Magnesium stearate
Starch
Ferric oxide, red
Ferric oxide, yellow
Vioxx
Rofecoxib
Microcrystalline cellulose
Lactose monohydrate
Hydroxypropyl cellulose
Croscarmellose sodium
Magnesium stearate
Ferric oxide, yellow
Zocor
Simvastatin
Cellulose
Hydroxypropyl cellulose
Hydrous lactose
Magnesium stearate
Titanium dioxide
Ascorbic acid
Ferric oxide, red
Ferric oxide, yellow
Ingredient
formulation
API
excipient
excipient
excipient
excipient
excipient
dye
formulation
API
excipient
excipient
excipient
excipient
excipient
excipient
excipient
dye
formulation
API
excipient
excipient
excipient
excipient
dye
dye
formulation
API
excipient
excipient
excipient
excipient
excipient
dye
formulation
API
excipient
excipient
excipient
excipient
excipient
excipient
dye
dye
VRL
,0.44
,2.72
2.42
,0.597
10.2
,0.469
,0.403
,0.584
,0.4
,1.47
,0.490
2.42
,0.597
3.09
,0.469
2.10
5.15
1.55
,1.4
,0.65
,0.597
10.2
,0.469
10.2
1.55
,0.584
,0.59
5.64
2.42
,0.597
,0.490
3.09
,0.469
,0.584
,0.57
0.485
2.42
,0.490
,0.597
,0.469
2.10
,0.878
1.55
,0.584
its dec re a s ed sligh t ly as light inten s i ty incre a s ed and then su bs equen t ly increased as the light inten s i ty was incre a s ed furt h er.
Six VRLs dec re a s ed with an increase in light inten s i ty. Two of
those dec reases were small , similar to those seen with the exc i pients. However, as noted above , 4 compounds dec reased from
.5 to ,2 mg/cm2. These data indicate that formu l a ti ons containing these APIs might be candidates for a vi sual cleaning ins pecti on , but light inten s i ty would have to be con s i dered. Ei t h er
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
Table VII: Variability of the visibleto verify the light intensity would be necARLs, using VRLs as cleaning va l i d a ti on
residue limits among observers.
essary.
acceptance criteria is still limited . The priAn 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
training of the ob s erver to inspect clean
Number of
of the formulations with the VRLs of the (no. of observers)
equ i pm ent. During this stu dy, not on ly
compounds
i n d ividual formulati on com pon ents.
was there vari a bi l i tyin the VRL based on
0
10
Twelve formu l a ti ons were te s ted for thei r
the light intensity, t h ere was also va ri a bi l1
32
VRLs. The amount of API and excipients
i ty among the ob s ervers . Ta ble VII shows
2
8
in a formu l a ti on differ. The amount spo tthe range of variability of the VRLs among
3
5
4
4
ted was based on the level of the API,
the observers . Of the 59 deter gents, exc i pwhich is the most po tent com pound in
i en t s , A PIs , and formulati ons te s ted, in
5
1
the formulation, ra t h er than on the moston 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 obThe 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 regto ,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 adversely affecting production schedules.
Conclusions
Using a visible-residue limit to verify
equipm ent cleanliness is an intriguing
con cept . Determining that equ i pm ent is
“visually clean” is a procedure that seems
easy to document and that saves time and
re s o u rces, both in terms of pers on n el and
labora tory te s ting. To swab equ i pm ent,
test the samples by HPLC, and doc u m en t
the results requ i res up to two pers on-days,
occupies an HPLC overnight, and consumes several liters of s o lven t s . To be able
to look at a piece of equ i pm ent and sign
a paper stating the equ i pm ent is “visu a lly
clean” is an attractive alternative.
Al t h o u ghimplem en ting a cleaning program that relies on a visible-residue limit is
an attractive possibility, ex ten s ive background work would be necessary to justify
visible-re s i due limits, and other issues also
would need to be ad d re s s ed . Pers on n el
training would be an ongoing requirement.
The procedu re for introducing new devel opm ent compounds, excipients, or formulati ons in the manu f acturing area
would have to be addressed. The resource s
necessary to introdu ce a visible re s i due
limit program would be ex tensive , wi t hout assurance of acceptance by the regulatory agencies. However, using a visibleresidue limit might be su cce s s f u lly argued
for an app l i c a ti onwith limited scope su ch
as introducing a new devel opment compound into a pilot plant.
Acknowledgments
The authors would like to thank Michael
Mc Q u ade, Tara Lu k i evics, and Jo s eph
S ch a ri ter for their ef forts as observers du ring these studies.
References
Visit us at CHPI booth Hall V-5530
Ci rcle/eINFO 56
1. Code of Federal Regulations, Title 21, Food and
Drugs (General Services Administration,Washington , DC , 1 April 1973), Pa rt 211.67.b.6.
2. R.J. Fors yth and D. Hay n e s , “Cleaning Validati on in a Pharm aceutical Re s e a rch Fac i li ty,” Pharm. Technol. 22 (9), 104–112 (1998).
3. D.W. Men denhall, “Cleaning Validati on ,”
Drug Dev. In d . Ph a rm . 15 (13), 2105–2114
(1989).
4. Food and DrugAd m i n i s tra ti on , “Guide to
In s pecti on of Validation of Cleaning
Processes” (Division of Field Investigations,
Office of Regi onal Opera tions, O f f i ce of Regulatory Affairs, July 1993).
5. D. A. LeBlanc, “‘Vi su a lly Cl e a n’ as a Sole Acceptance Criteria for Cleaning Validation Protoco l s ,” PDA J.Pharm. Sci. Technol. 56 (1),
31–36 (2002).
6. G.L. Fo u rman and M. V. Mull en ,“ Determ i ning Cleaning Validati on Accept a n ce Limits
for Pharm aceutical Ma nu f actu ring Operati on s ,” Ph a rm . Technol. 17 (4), 54–60 (1993).
7. K.M. Jenkins and A. J. Vanderwi el en ,“Cl e a ning Validati on : An Overall Perspective,”
Pharm. Technol. 18 (4), 60–73 (1994).
8. D.A. LeBlanc, D.D. Danforth, and J.M. Smith,
“Cleaning Tech n o l ogy for Pharmaceutical
Ma nufacturing,” Pharm. Tech n ol . 17 (10),
118–124 (1993). PT
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FYI
Production and manufacturing courses
The University of Wisconsin–Madison,Department
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The “Documenting Pharmaceutical Production
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For more information on either course,contact
Michael F.Waxman, tel.608.262.2101,
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