Documente Academic
Documente Profesional
Documente Cultură
Kenneth G. Chapman
Drumbeat Dimensions, Inc.
Dennis Christensen
Consultant
Robert C. Coleman
US Food & Drug Administration
Shahid Dara
Independent Consultant
JAY H. KING
LifeScan, a Johnson & Johnson Company
JOHN G. LANESE, Ph.D.
The Lanese Group, Inc.
Barbara Mullendore
AstraZeneca
ROBERT A. NASH, Ph.D.
St. Johns University
Charlie Neal, Jr.
BE&K
David R. Dills
Medtronic Xomed
TOD E. RANSDELL
Bio-Rad Laboratories
Michael Ferrante
Catalytica Pharmaceuticals
Patricia Stewart
Flaherty
Bayer Corporation
Roberta D. Goode
Consultant
CYNTHIA GREEN
Northwest Regulatory Support
Daniel Harpaz, Ph.D.
MELVIN R. SMITH
Independent Consultant
David W. Vincent
Validation Technologies, Inc.
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JOURNAL MISSION
The Journal of Validation Technology is a peer-reviewed
publication that provides an objective forum for the dissemination of information to professionals in FDA-regulated
industries. The Journals Editorial Advisory Board reviews
all submissions to ensure that they have been researched
thoroughly, reflect current industry standards, and are not
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ISSN 1079-6630
CONTENTS
TABLE
OF
by
by
Development of Total Organic Carbon (TOC) Analysis
for Detergent Residue Verification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 15
by
by
by
Mark Altier
by
LeeAnne Macaulay, Jeff Morier, Patti Hosler and Danuta Kierek-Jaszczuk, Ph.D.
BONUS
Measurement Techniques
Conventional tools used for microbial enumeration
from surfaces can be used. These include rinse water
sampling (usually with membrane filtration), swab
bing (with desorption of the swab into a sterile solu
tion and then a pour plate count), and use of a contact
plate. The choice of recovery medium and incubation
conditions is usually dictated by the expected organ
isms. As a general rule, the initial focus is on aerobic
bacteria. However, if anaerobic bacteria or molds/
yeasts are suspected problems, these should be also
evaluated.
One issue that does not translate directly from
chemical residue measurements is the idea of deter
mining percent recovery using the sampling method.
In the measurement of chemical residues, the target
residue is spiked onto a model surface and the quan
titative percent recovery is determined. The amount
recovered as a percent of the amount spiked is consid
ered the sampling method percent recovery. Percent
recoveries in chemical sampling measurement are
generally above 50 percent. This percent recovery is
then used to convert an analyzed sample value; for
example, if a chemical residue measured by a swab
bing technique gives 0.6 g of residue, then with a 50
percent recovery, this actually represents the possibil
ity of 1.2 g being on that surface. This concept can
not be applied directly to microbiological sampling.
The reason for this is partly the inherent variability in
microbiological testing. If one measured 10 CFU in
one test and 5 CFU in a duplicate test (a 50 percent
difference), one would be hard pressed to say that
11
References
12
CFU:
FDA:
PQ:
QC:
USP:
WFI:
Cleaning Validation:
Maximum Allowable Residue
Question and Answer
A:
13
15
James G. Jin
Figure 1
Oxidation
Combustion
Combustion
UV/Persulfate
Heated Persulfate
Combustion
UV/Persulfate
UV
S O -2 SO -1 + R H O + CO
2
Detergent Evaluation
Three detergents (CIP-100, CIP-200, and Sparquat
256) were tested both in-house using the Tekmar
Dohrmann Phoenix 8000 TOC Analyzer and at a
contract lab, Quantitative Technologies Inc. (QTI),
to verify the total amount of organic carbon in each
detergent at its original concentration. The method
and instrument used at QTI was a Perkin-Elmer CHN
Analyzer 2400. This experiment was performed to
make a comparison between our instrument and the
instrument in a qualified contract laboratory for infor
mation purposes only. One detergent (Chlor-Mate)
was tested in-house and compared with the available
James G. Jin
Swab Selection
It has been known for years that polyester is a
suitable material for TOC swabbing analysis. Over
20 different kinds of polyester swab samples were
received from The Texwipe Company LLC. Five
of them were chosen for TOC evaluation based on
sample design and the convenience for use. The
purpose of this experiment was to select a type of
swab that has little TOC background interference and
with consistent TOC results over time. Ultra purified
water with 0.05 to 0.08 ppm carbon was used for
swab analysis. The TOC results obtained from our
TOC analyzer are shown in Figure 3.
Swabs TX761 and TX741A showed increasing
TOC results from 0.0813 to 0.9692 ppm carbon and
from 0.1724 to 1.1246 ppm carbon over five days,
respectively. Swab TX700 showed an unacceptably
high TOC result of 46.1991 ppm carbon at the begin
ning of the experiment, and was therefore not tested
further. None of these swabs are suitable for our
TOC analysis.
Both polyester wipers AlphaSorb HC TX2412
Figure 2
17
James G. Jin
Figure 3
Swab TOC/Two Hours TOC/Four Hours TOC/One Day TOC/Two Days TOC/Five Days
Description
in H O
in H O
in H O
in H O
in H O
Polyester Alpha
0.0813
0.3221
0.3926
0.9410
0.9692
swab TX761
0.0041
0.0853
0.0166
0.0288
0.0299
Polyester Alpha
0.1724
0.2509
0.5330
0.8091
1.1246
swab TX741 A
0.0144
0.0068
0.0250
0.0200
0.0394
Polyester wipers
1.1665
0.6091
0.8602
0.7535
0.9723
AlphaSorb
0.0406
0.0490
0.0264
0.0328
0.0668
HC TX2412
Polyester wipers
0.7406
0.7269
N/A(1)
N/A(1)
N/A(1)
AlphaSorb
0.0056
0.0297
HC TX2418
Polyester Alpha
46.1991
N/A
N/A
N/A
N/A
swab TX700
8.0761
2
1. Polyester wipers AlphaSorb HC TX2412 and polyester wipers AlphaSorb HC. TX2418 is same material cut to different sizes.
Figure 4
Detergent
Percent Number
Percent
Recovery of Relative
Samples Standard
Deviation
CIP-100
CIP-200
Sparquat 256
Chlor-Mate
111.7
92.4
61.0
99.1
30
10
20
10
5.92
4.10
8.47
2.76
Note: R
esults were automatically corrected for the
instrument blank effect.
Figure 5
Detergent Lexan
Delrin
Glass Nylon
Surface Percent Percent Percent Percent
Recovery Recovery Recovery Recovery
CIP-100 106.9
CIP-200 90.3
Sparquat 83.3
256
113.8
92.3
74.0
107.6
97.4
75.1
127.0
93.2
42.5
James G. Jin
Figure 6
256
256
256
256
256
256
256
256
Chlor-Mate
Chlor-Mate
Notes:
0.5 oz/gal
0.5 oz/gal
Concentrated
0.5 oz/gal
0.5 oz/gal
0.5 oz/gal
0.5 oz/gal
0.5 oz/gal
SS a
SS a
SS a
Delrin
Delrin
Nylon
Glass
Lexan
No rinse
30/30 b
30/30 b
30/30 b
60/60 b
30/30 b
30/30 b
30/30 b
100
100
100
100
100
100
100
100
cm2
cm2
cm2
cm2
cm2
cm2
cm2
cm2
2.0928
Less than
Less than
Less than
Less than
0.7720
0.0133
Less than
0.5 oz/gal
0.5 oz/gal
Concentrated
0.5 oz/gal
0.5 oz/gal
0.5 oz/gal
0.5 oz/gal
0.5 oz/gal
SS a
SS a
SS a
Delrin
Delrin
Nylon
Glass
Lexan
No rinse
30/30 b
30/30 b
30/30 b
60/60 b
30/30 b
30/30 b
30/30 b
100
100
100
100
100
100
100
100
cm2
cm2
cm2
cm2
cm2
cm2
cm2
cm2
10.0868 c
0.2693 c
Less than
Less than
Less than
0.3866 c
Less than
Less than
0.5 oz/gal
Concentrated
SS a
SS a
30/30 b
30/30 b
100 cm2
100 cm2
blank
blank
blank
blank
blank
blank
blank
blank
blank
blank
a. Stainless steel.
b. 30/30 or 60/60 rinse time in seconds, tap water/purified water United States Pharmacopoeia (USP).
c. Result without correction factor.
19
James G. Jin
Summary
The detergent residue verification program has
been successfully established using the Tekmar
Dohrmann Phoenix 8000 TOC analyzer. This paper
has shown the program development, and presents
critical data to support the detergent verification
reports for each detergent used.
The instrument Installation Qualification (IQ),
Operational Qualification (OQ), system calibration,
and the TOC analysis method development were
performed but not discussed in this paper. The poly
ester wipers AlphaSorb HC TX2412 and TX2418
cut to 5x5 cm2 have been selected as the swabs for
sampling detergent residue from equipment surface
for TOC analysis. The AC for the detergents CIP100, CIP-200, Sparquat 256, and Chlor-Mate with
respect to TOC has been established as AC 10 ppb
carbon/cm2. Two different rinse times, 30 seconds
and 60 seconds, were evaluated. The results show
Figure 7
James G. Jin
References
21
Karen A. Clark
Figure 1
Figure 2
Linearity
CIP-100 (alkaline)
CIP-200 (acidic)
Alconox (emulsifier)
Triton-X 100 (wetting agent)
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
Figure 3
9000
8000
7000
6000
5000
4000
3000
2000
1000
0
45
40
35
30
25
20
15
10
5
0
Linearity of CIP-100
y=39.254x + 1.462
R2=0.9997
50
100
150
200
250
CIP 100 Concentration (ppm)
100
200
300
400
500
CIP 200 Concentration (ppm)
Linearity of Alconox
y=0.0355x + 1.1983
R2=0.9787
200
400
600
800 1000
Alconox Concentration (ppm)
23
Karen A. Clark
12500
y=415.76x + 16.997
R2=0.9982
10000
7500
5000
2500
Figure 5
Linearity of Sucrose
12000
Measured TOC (ppb)
5
10
15
20
25
Triton-X 100 Concentration (ppm)
y=1.003x + 45.185
R2=0.9996
10000
8000
4000
2000
0
Figure 6
Linearity of Vancomycin
8000
y=0.8758x + 62.133
R2=0.9998
6000
4000
2000
24
Linearity of Endotoxin
8000
y=0.9287x + 30.8
R2=0.9998
7000
6000
5000
4000
3000
2000
1000
2000
4000
6000
8000
Endotoxin Concentration (ppb)
6000
Figure 7
Figure 4
2000
4000
6000
8000
Vancomycin Concentration (ppb)
Karen A. Clark
Figure 8
Figure 9
Swab Recovery
Figure 10
Conclusion
This study demonstrates that TOC analysis is
suitable for measuring organic residues on stain
less steel surfaces, and that it is a reliable method
for cleaning validation as demonstrated by surface
residue recoveries of 79%-96%. This methodology
Substance
ppm C of Spike
Standard Solution
CIP-100
1810
Sucrose
2663
Vancomycin
661
Endotoxin
902
ppm C of Spiked
Plate
1710
2112
634
736
% Recovery
% RSD
94.5
79.3
95.9
80.0
1.8
4.9
3.0
2.8
25
Karen A. Clark
References
26
Advertisement
PO Box 6004
Duluth, MN 55806
Phone: 218-740-7028
U.S. Only: 888-524-9922
Fax: 218-740-6308
E-Mail:info@ivthome.com
Web Site: www.ivthome.com
Name: ____________________________________________________________________
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Topic:
Special Edition: Cleaning Validation III
27
Mark Altier
Titanium Dioxide
Acetaminophen
Zinc Oxide
Carbopols
Iron Oxide
Albuterol Sulfate
Calcium Carbonate
Neomycin Sulfate
Inorganic Salts
Water/Oil Oil/Water
Emulsions
Silicon Dioxide
Glyburide
29
Mark Altier
Figure 2
1631.22
1545.75
1454.66
1396.07
1311.04
1251.26
1077.51
1044.64
980.456
870.204
694.924
.35
.30
.15
.10
.05
2287.55
2257.66
2211.86
2165.99
2155.88
2033.97
2013.07
2958.86
2926.38
2854.86
.20
3933.71
Absorbance
.25
3500
Figure 3
3000
2500
2000
Wave Number (cm-1)
1500
1000
Counts
0.000
30
Fe
Si
Al
O
Fe
1.000
Mg
Fe
2.000
3.000
4.000
Key
5.000
6.000
7.000
8.000
Mark Altier
Figure 4
31
Mark Altier
Mark Altier
Figure 5
Scale
Corrosion
Scale and
Corrosion
Scale and
Corrosion
Scale
Scale
Scale
Scale and
Corrosion
Scale and
Corrosion
Corrosion
Corrosion
Scale
Deposit and
Corrosion
Laboratory Testing
Cleaning studies conducted in the laboratory can
be designed to closely mimic the actual applica
tion method, such as a CIP system, or they can be
Figure 6
Water Hardness
(Reported as CaCO ) Rating
3
Hardness
Soft
Moderately Hard
Hard
Very Hard
Grains
Parts Per
Per Gallon Million (PPM)
0 3.5
3.5 7.0
7.0 10.5
>10.5
0 60
60 120
120 180
>180
33
Mark Altier
Plant Optimization
34
Conclusion
Process cleaning is an integral component of any
pharmaceutical process. The five key factors that
must be addressed to help identify a detergent when
developing a cleaning program have been defined
and discussed. The interaction of these factors with
each other and with the development of a cleaning
program must be understood. Laboratory testing
is critical for documenting the appropriateness of
the detergent selection for the cleaning applica
tion. Plant optimization is a final critical step prior
to starting the validation process at the production
facility. When these steps are taken, a complete,
scientifically sound approach to the development of
a cleaning program can be documented. o
Analyzing Cleaning
Validation Samples:
What Method?
By Herbert J. Kaiser, Ph.D.
and
Maria Minowitz, M.L.S.
Steris Corporation
35
needs to be chosen.
Sampling Technique
37
Suggested Reading
Authors Lin, et. al., compared
the analysis of anionic, cationic,
and amphoteric surfactants con
taining n-dodecyl groups using
HPLC and capillary electrophore
sis.17 They found that HPLC was
best for all classes of surfactants, especially for for
mulated surfactants. Authors Carrer, et. al., utilized
ELSD for amphoteric type surfactants.18 Amphoteric
surfactants are a class of surfactants that display
cationic behavior in an acidic solution and anionic
behavior in an alkaline solution. The lowest cali
bration standard that they utilized was 50 ppm, but
they probably could have gone much lower. Authors
Guerro, et. al., obtained a limit of quantitation of
0.49 ppm for alkyl polyethylene glycol ethers using
ELSD.19
n Capillary Electrophoresis
An interesting method of analysis is Capillary
Electrophoresis (CE). There are many different types
of CE. Capillary Zone Electrophoresis (CZE) is by
far the most common. CE instrumentation is fairly
simple, consisting of a high voltage source, a capil
lary, and a detector. The high voltage source is used
to apply a potential across two solutions. One of
the solutions contains the analyte, and the potential
applied to the solutions causes the analyte to migrate
through the capillary, through the detector, and
into the other solution. The column or capillary is
typically composed of fused silica with a polyimide
coating. The diameter of the capillary is typically
25-75m in diameter. The capillary has a polyimide
38
39
41
Conclusion
There are many different analytical techniques
available that can be used to detect residues. These
range from simple titrations to more complex LCMS. The choice of technique should be based on
what equipment is available, the type of residue,
and the scientifically established residue limit. It is
important for an analytical chemist to keep abreast
of the literature and what techniques are available.
There are techniques available that will analyze any
residue at any level. At the end of the day, however,
it is always wise to choose the simplest technique
that can be used to reach the desired goal. o
43
References
45
EEF Technology
Jaisinghani7 has played a significant role in the
development and commercialization of EEF tech
nology. The most recent version (see Figure 1) of
this technology7 maintains the filter under an ion
izing (as opposed to a simple electrostatic field)
Figure 1
Technovations Ionizing
EEF Technology
Ionizing
Wires
Filter
Flow
Downstream
Ground
Electrode
Control
Electrode
Ionizer
Electrode
H.V.
Supply
47
Figure 2
24.00
(v/d1) kv/cm
0.00
0.00
#/Sq. inch
1.00E+06
No additional growth
00.0E+00
100% Killed
Control
24.00
0.00
0.00
1.02E+05
24.00
4.00
3.99
3.44E+02
99.93% Killed
0.00E+00
Some growth
EEF
EEF
EEF
EEF
EEF
EEF
EEF
EEF
EEF
24.00
24.00
24.00
24.00
24.00
48.00
48.00
48.00
4.00
4.00
4.00
4.00
4.00
7.00
4.00
4.00
4.64
4.24
0.00E+00
4.50
4.20
4.20
4.80
After 48 Hours
5.44E+02
99.9% Killed
2.16E+02
4.20
3.51E+03
Figure 3
100% Killed
0.00E+00
6.26E+03
4.20
After 24 Hours
98.75% Killed
99.95% Killed
99.3% Killed
49
Figure 4
Class
Parameter
10K
10K
1K
1K
100
100
50
209E EU USP
<10K
<2.83
<1K
NA
<100
<0.028 at rest; <0.283 Process
<2.5
NA
<0.1 Process
Class 100
Requirements
Air
Surface
Gowns
0.1 cfu/ft3
3 cfu/plate*
5 cfu/plate
Class 10,000
Requirements
Air
Surface
Gowns
0.5 cfu/ft3
5 cfu/plate (10 from floor)
10 cfu/plate
Class 100,000
Requirements
Air
Surface
Gowns
* 2 in2 surface
2.5 cfu/ft3
20/plate
30/plate
51
Figure 6
235
1959
506
786
602
1163
903
801
899
852
512
Side Corridor
555
2240
642
4559
1035
3598
762
4058
687
7989 1422
171
3649
2598
4657
Labware Processing
212
343
102
981
719
1233
1798
243
326
618
530
Gowning Room
139
236
87
853
1063
1506
913
2874 2808
957
235
40
257
88
450
539
2461
2463
595
482
671
683
1065
1187
1859
765
152
158
66
223
145
350
337
313
379
754
237
142
208
24
84
52
415
228
322
307
360
126
132
28
43
49
19
74
19
76
127
264
26
129
49
474
139
400
179
472
184
145
293
83
250
87
534
180
639
698
829
731
Refrigerator/Freezer Storage
212
262
55
233
157
832
692
427
335
659
381
910
67
43
52
83
147
271
118
329
172
289
Figure 7
Coating
0.028
0.028
0.028
Formulations
Device Manufacturing
0.085
0.085
0.085
0.057
0.057
0.057
Refrigeration
Isolation
0.085
0.085
0.085
15
0.425
0.425
0.425
0.028
0.028
0.028
0.085
0.085
0.085
Design Class 1,000
12/13/99
1/28/00
Average cfu Av. cfu/ft3 cfu/ft3/24hr* cfu/ft3/72hr* Average cfu Av. cfu/ft3 cfu/ft3/24hr* cfu/ft3/72hr*
Device Testing
0.000
0.000
Coating
0.000
0.000
Formulations
0.000
0.000
Device Manufacturing
0.000
0.000
Refrigeration
0.000
0.000
Isolation
0.000
0.000
0.000
0.000
hypochlorite solution.
Sampling Methods
Air sampling was done using Tryptic Soy Agar
(TSA) and Sabouraud Dextrose Agar (SDA). The
TSA values reflect total bacterial counts while the
SDA reflects molds and yeast, although it contains
no bacterial inhibitors. In some cases Rose Bengal
Agar (RBA) was used. This reflects a better value for
molds/yeast since the RBA contains bacterial growth
inhibitors. Surface monitoring was done using 24-30
cm2 RODAC plates with TSA and SDA. The TSA
plates were incubated for a minimum of 48 hours at
32.5 +/- 2.5C while the SDA plates were incubated
for a minimum of 72 hours at 22.5 +/- 2.5C.
Results Airborne Microorganisms
The gowning room was sampled in two zones
Special Edition: Cleaning Validation III
53
Figure 8
11/30/99 Average
cfu/ft3/24hr* cfu/ft3/72hr*
30
0.850
0.850
0.850
0.057
0.057
0.057
Side Corridor
0.085
0.085
0.850
0.058
0.085
0.085
Manufacturing Corridor
19
0.538
0.538
0.538
11
0.312
0.312
0.312
Labware Processing
0.142
0.142
0.142
0.113
0.113
0.113
Gowning Room
0.085
0.085
0.085
0.085
0.085
0.085
11
0.312
0.312
0.312
10
0.283
0.283
0.283
5.67
0.160
0.160
0.172
12/13/99
1/28/00
Design Class 10,000 Average cfu Av. cfu/ft3 cfu/ft3/24hr* cfu/ft3/72hr* Average cfu Av. cfu/ft3 cfu/ft3/24hr* cfu/ft3/72hr*
Water Filtration Area
0.057
0.057
0.057
0.057
0.057
0.057
Side Corridor
0.057
0.057
0.057
Manufacturing Corridor
0.028
0.028
0.028
Labware Processing
Gowning Room
0.057
0.057
0.057
1.17
0.033
0.033
0.033
0.333
0.009
0.009
0.009
Figure 9
Design Classification
10,000
Average number of cfu/plate grown in 72 hours
Date > 11/14/99 11/30/99 12/13/99 01/28/00
Water
Filtration Area
0
0
2
0
1
0
0
0
Side Corridor
Manufacturing Corridor 0
0
0
0
Labware Processing
1
0
0
0
Gowning Room
0
0
0
0
Materials Pass
Through
0
0
0
0
Design Classification
1,000
Average number of cfu/plate grown in 72 hours
Date > 11/14/99 11/30/99 12/13/99 01/28/00
Device Testing
0
0
0
0
0
0
0
0
Coating
Formulations
0
0
0
0
Device Manufacturing
0
0
0
0
0
0
0
0
Refrigeration
Isolation
0
0
0
0
Control
255
210
134
104
Figure 10
Area
Before Cleaning After Cleaning
TSA SDA TSA SDA
Counts Counts Counts Counts
Gowning
Table-gowning 22
5
0
0
Wall-gowning
3
0
0
0
Class 10
Tank
0
1
0
0
Fill
21
12
0
0
Filter table
9
4
0
0
Wall
1
0
0
0
the University of Wisconsin. Jaisinghani has extensive research experience in air and liquid filtration,
colloid and aerosol science, fluid mechanics, heat
transfer, and physical surface chemistry. He holds
10 patents and has many publications in technical
journals and handbooks. He can be reached by
phone at 804-744-0604, by fax at 804-744-0677, or
by e-mail at technova@sprynet.com.
Greg Smith is facilities manager at Encelle, Inc.
He holds a B.A. in Psychology from West Virginia
University and a B.S. in Chemistry from East Carolina
University. Smith has assisted in the development of
medical devices and has five years experience as
a hospital pharmacy aseptic compounding technician. He can be reached by phone at 252-355-4405
or by e-mail at gsmith@Encelle.com.
Gerald Macedo has a B.S. degree in Pharmacy and
an M.S. in Pharmaceutical Sciences. He has over
30 years experience in pharmaceutical manufacturing, with extensive experience in the manufacture
of sterile injectables. He has served as head of
manufacturing, quality control, quality assurance,
research and development, and regulatory affairs.
Macedo currently heads Med-Pharmex, Inc., a
pharmaceutical manufacturing company. He can
be reached by phone at 909-593-7875 or by fax at
909-593-7862.
References
55
he Enzyme-Linked Immuno
filtration Assay (ELIFA)
provides high sensitivity of
detection with rapid results. For this
reason we developed a very sensitive,
semi-quantitative ELIFA to determine
IgA in therapeutic WinRho SDF
immunoglobulin. In the course of the
development we noticed that non-uni
form and unusually high background
(blank) responses, that occurred infre
quently, greatly interfered with the
test results obtained. We hypothe
sized that such background responses
resulted from inadequate cleaning of
the ELIFA apparatus. Accordingly,
a cleaning program for the apparatus
has been devised and validated. In this
paper the results supporting the hypo
thesis will be presented, and the ratio
nale and core aspects of the developed
program delineated.
LeeAnne Macaulay, Jeff Morier, Patti Hosler, & Danuta Kierek-Jaszczuk, Ph.D.
Figure 1
Sample
Application
Plate
Nitrocellulose
Clamp
Microtiter
Plate
Vacuum
Relief Valve
Pump
Tubing
Port
Gaskets
Tubing
Position Stops
(Acrylic Balls)
Transfer
Cannula
Collection
Chamber
Membrane
Support
Plate
Guide Pins
57
LeeAnne Macaulay, Jeff Morier, Patti Hosler, & Danuta Kierek-Jaszczuk, Ph.D.
nC
leaning operations
n Cleaning procedures including cleaning ves
sels, agents and utensils
n Compatibility of cleaning agents with equip
ment and assay
n Decontaminating abilities of cleaning agents
n Sampling on cleaned equipment
n Analytical methods for monitoring of cleaning
processes
n Storage of cleaned parts
n Inspection of apparatus for cleanliness before use
n Recording and documenting the cleaning pro
cedures
n Establishing acceptance criteria, and
n Maintaining cleaning records
LeeAnne Macaulay, Jeff Morier, Patti Hosler, & Danuta Kierek-Jaszczuk, Ph.D.
Figure 4
Figure 5
Figure 6
Figure 7
1
2
3
4
Well B11
Well D8
Well G2
Water
277.8
235.4
228.4
185.2
271.7
234.3
219.1
165.4
268.9
225.9
255.3
167.4
272.8
231.8
234.3
172.7
4.55
5.20
4.73
10.9
1.67
2.24
8.03
6.29
59
LeeAnne Macaulay, Jeff Morier, Patti Hosler, & Danuta Kierek-Jaszczuk, Ph.D.
Conclusions
nA
comprehensive, credible CVP designed and
developed at Cangene for the Easy-Titer
ELIFA system has been shown to effectively
remove contaminants and residues entrapped
in the apparatus after the conclusion of the
experiment(s) and/or subsequent cleaning.
n The CVP has been demonstrated to vastly
reduce the analytical background of the IgA
ELIFA, improve its signal to background ratio,
increase the quality of the test results and may,
therefore, be expected to notably support the
upcoming assay validation.
n The CVP, by virtue of anti-viral and anti-bacte
rial properties of the RBS10, allows for simulta
neous decontamination and sanitization of the
ELIFA unit, thus facilitating its safe use with
infectious samples.
n The CVPs generated for R&D equipment
that fulfill the standards of industrial cleaning
validation not only improve the quality of the
assays utilizing this equipment but may become
vital components of assay validation. o
References
61
Julie A. Thomas
Introduction
Responsibilities
There are many departments and disciplines
involved in planning for and executing a cleaning
validation. It is necessary to list each contributing
area and the associated tasks for which it is respon
sible. This serves to clarify roles and to ensure that
tasks are not overlooked. Typically, representatives
from Validation, Manufacturing, Quality Control,
Engineering, and Research and Development (R&D)
will be needed. The following are some examples of
departmental responsibilities:
Validation Specialist
Review cleaning procedures
Assist the cleaning validation team in iden
tifying equipment test sites for swab or
rinse samples
Write cleaning validation protocols
Coordinate execution of the cleaning pro
cess with the appropriate departments and
laboratories
Prepare the sampling schedule
Assemble the test data into final report
form for approval
Manufacturing
Provide technical information for the devel
opment of protocols and reports
Review and approve protocols and reports
62
Julie A. Thomas
Development Phase
The initial phase of the cleaning validation plan is
63
Julie A. Thomas
Figure 1
Development Phase
Analytical Method
Validation
Analytical Method
Development
D
egradant
identification
Transfer
Recovery
Surface types
Planning Phase
Equipment
S
ample site
selection
Surface area
calculation
Schematic
Analyte Selection
and Acceptance
Criteria
Protocol
Development
rite
W
Approve
Train
ctive ingredient
A
Cleaning agent
Cleaning
SOP
rite
W
Approve
Train
Execution Phase
Protocol Execution
C
lean
Sample
Test
Pass?
No
Incident
Investigation
Yes
Validation Report
W
rite
Approve
Maintenance Phase
Monitoring
Change Control
Revalidation
64
Julie A. Thomas
Figure 2
Planning Phase
The next phase of preparation is the planning phase.
This is a broad category that focuses on equipment
information, analyte selection, acceptance criteria,
cleaning procedures, and protocol development. At this
point, you are starting to think about what equipment
will be included in the validation, which analytes will
be chosen, and how you will determine acceptance cri
teria. This leads to an in-depth review of the procedures
and, finally, to protocol development.
Figure 3
Recovery Surface:
1. Equipment Information
This section should detail the methodology for
providing specific equipment information. One
option is to prepare a binder containing detailed
surface area calculations, swab sampling sites (with
justification), photos, and schematic diagrams for
each piece of equipment. This binder can be main
tained separately and used as an attachment to the
cleaning validation protocol as needed.
a) Sample Site Selection
Explain how you will select sampling sites to rep
resent the product contact surface area of the equip
ment. One of the best sources of information is the
operator who routinely cleans the equipment. He or
she can certainly point out the areas they find most
difficult to clean. Make the operator part of a larger
team of experts to include representatives from
Validation, QA, and Operations, and let the team
determine the product contact surface areas that are
most difficult to clean and those that are most repre
sentative of the equipment. Sampling these sites will
represent the entire equipment surface area using
the assumption that residue will be evenly distrib
uted over the equipment and that the most difficult
to clean locations will represent the worst case for
residue removal. Include the basis for selecting each
Polyethylene Silicone
Material Used:
316L Coupon
Hose
To Represent:
304 Stainless
Aluminum
Brass
Teflon
Lexan
HDPE
Rubber
EPDM
Neoprene
65
Julie A. Thomas
Kason Separator
Swab Site
Surface Area
Screen/ring interface
gasket
3,171.2
15.6
Figure 6
Julie A. Thomas
Execution Phase
67
Julie A. Thomas
Maintenance Phase
The final phase of the Plan should specify how
you will maintain the conditions you have just
validated. This includes periodic monitoring, using
a control of change process, and potentially, revali
dating.
1. Monitoring
This section details how you will ensure that the
conditions used during validation remain in con
trol during routine production. This is especially
important for manual cleaning procedures, where
68
Julie A. Thomas
Summary
There are many aspects of cleaning validation
that must be carefully planned to guarantee a suc
cessful validation program. If you begin with a phi
losophy, this will set the stage for you to develop a
structured approach. By dividing the approach into
sections, such as development, planning, execu
tion, and maintenance, it breaks down the project
into manageable segments. To complete the Plan,
generate a tactical schedule and begin monitoring
progress towards your new and improved cleaning
validation status. o
References
69
VALIDATION TECHNOLOGY
Introduction
his document is the third in a series of new proposed validation standards issued by the Institute of
Validation Technology Standards Committee (IVT/SC). The initial proposed standard (Process
Validation Standard VS-l: Nonaseptic Pharmaceutical Processes) was issued in February 2000, and
is intended to help practitioners worldwide who develop, implement, control, and validate processes that produce Active Pharmaceutical Ingredients (APIs) and drug products. Our second proposed validation standard
VS-2: Computer-Related System Validation was issued in May 2001. The current document (Cleaning
Proposed Validation Standard VS-3) is intended to offer more specific proposed standards for the cleaning
processes for equipment used to manufacture APIs and drug products. These proposed standards, will be used
by reviewers of manuscripts intended for publication in the lournal of Validation Technology (1VI).
Just as with the previous proposed standards, readers are encouraged to offer comments, questions, and recommendations. Such feedback will be useful to the IVT/SC and JVT editors in updating this document and in
developing future proposed standards. Technologies are continually changing, sometimes in ways that can influence the way validation is best conducted. Therefore, the IVT/SC plans to periodically update each proposed validation standard, including its corresponding Preamble and reference list. In order to be dynamically responsive
to changing industrial practices and regulatory requirements, and make it easier for readers to cut and paste the
contents for their own use, all three proposed standards are available on the IVT web site at www.ivthome.com.
A fundamental need the IVT/SC intends to meet with its new proposed standards stems from the fact that most
Good Manufacturing Practice (GMP) regulations today call for numerous written procedures; for example, more
than 100 different kinds of written procedures are required to comply with current GMP regulations in the United
States. Many firms find it helpful to issue written policies in order to coordinate and reduce the number and length
of required Standard Operating Procedures (SOPs). Thus, the IVT proposed validation standards format includes
statements and definitions that can be excised and used directly or with minor editing in a firm's policies and SOPs.
Contents of the Proposed Cleaning Validation Standard
In order to be consistent with the prototype standard (Validation Standard VS-l) the Proposed Cleaning
Validation Standard VS-3 will be divided into the following five sections:
I.
II.
III.
IV.
V. Regulatory Excerpts - Regulatory language (United States, Australia, Canada, World Health Organization [WHO], Japan, and European Union) related to each Standard
he following proposed standard is intended to reflect desirable contemporary practices, is not binding in
any way, and can be modified to suit a firm's specific needs. This proposed standard incorporates imperative verbs (e.g., shall, will, must) to provide users with unambiguous quality assurance auditing tools,
and is prefaced by a Preamble that provides rationale for several of the more complex concepts. This document
is also directed toward users located at a given plant site that mayor may not be a part of a larger corporation.
Terms that are bold and asterisked (*) the first time they are used are defined in Section IV - Glossary.
I. POLICY STATEMENTS
POL 1.1
The critical cleaning processes associated with the manufacture of Active Pharmaceutical Ingredients
(API)*, critical Intermediates*, Drug Products*, or In-Process Materials* shall be validated or verified.
POL 1.2
The critical cleaning processes associated with products in the development stage of the product lifecycle
shall be verified. The administrative responsibility for such products will reside in either the appropriate
development group or in the Site Validation Steering Committee (SVSC)*. If the company decides that
responsibility for cleaning verification shall reside in the appropriate development group, then the documentation describing the verification procedure and the Cleaning Verification Protocols* must also be approved by the site Quality Authority*.
POL 1.3
During development of the new product, the manufacturing equipment, batch size, and formulation is constantly changing and the cleaning procedure must be appropriate and customized for each manufacturing event.
The lifecycle for the development and validation of a new cleaning procedure consists of the following steps:
l.3.1
1.3.2
1.3.3
1.3.4
l.3.5
1.3.6
1.3.7
1.3.8
l.3.9
1.3.10
1.3.11
1.3.12
1.3.13
1.3.14
1.3.15
1.3.16
1.3.17
1.3.18
1.3.19
1.3.20
POL 1.4
The cleaning processes associated with products in the marketed stage of the product lifecycle shall be validated for all products manufactured with a normal frequency of production. For rare instances where products are infrequently manufactured (e.g., one batch per year or less frequently), it may be difficult to achieve
fully validated cleaning processes and the principle of cleaning verification should be utilized. The administrative responsibility for cleaning validation and cleaning verification of products will reside in the Site
Validation Steering Committee (SVSC). The SVSC shall adjudicate cleaning validation issues and appoint
project-specific validation teams as needed that include principal(s) having experience in the cleaning
processes involved. Such SVSC responsibilities extend to cleaning processes used by contract vendors and
suppliers of the firm's drug products and/or APIs, as well as to those cleaning processes employed on-site.
POL 1.5
A written Cleaning Verification Policy (CVP) shall be used to define and describe the strategies and
approaches used to verify cleaning procedures associated with drug products, biotechnology products,
medical devices, and APIs during the development stage of the lifecycle.
POL 1.6
A written Cleaning Validation Master Plan (CVMP)* shall be used to define and coordinate validation
activities related to any cleaning process associated with the manufacture of a commercially marketed
drug product, biotechnology product, medical device, and API.
POL 1.7
Cleaning Verification Protocols shall be used to define individual cleaning verification runs.
POL 1.8
Cleaning Validation Protocols shall be used to define individual cleaning validation runs.
POL 1.9
Cleaning Verification Reports* shall be used for documenting and summarizing results of cleaning verification studies. Definite statements must be used, especially in describing the scientific rationale for the
limits chosen and whether the cleaning process was effective in meeting the limits.
POL 2.0
Cleaning Validation Reports* shall be used for documenting and summarizing results of cleaning validation studies. Definitive statements must be used, especially in describing the scientific rationale for the
limits chosen and whether the cleaning process was effective in ensuring that these limits were met.
Institute of Validation Technology
POL 2.1
All Cleaning Verification Policies, Cleaning Validation Master Plans, Cleaning Verification Protocols,
Cleaning Validation Protocols, Cleaning Verification Reports and Cleaning Validation Reports must
be approved and available to the SVSc. All such cleaning documents created on-site must be approved by
the site Quality Authority and, when production is involved, also by the site Production Authority*.
POL 2.2
Relevant cleaning process verification and validation information from other divisions, departments
(including Research and Development), production sites, and outside contract services is to be gathered,
evaluated, utilized, and maintained by the SVSC.
POL 2.3
Certain cleaning processes are considered critical manufacturing steps and thus require validation (it
should be noted that not all cleaning procedures are considered critical and thus require validation). Once
the cleaning procedures are validated, they must not be altered without prior review, and any changes
should be subjected to a formal Change Control* review process prior to making the change. The site
Quality Authority must approve all changes to validated cleaning procedures.
II. PROCEDURAL STATEMENTS
PROC - 2.a [ref. POL 1.3.2]
Critical product cleaning specifications are known factors that can influence the development of the
cleaning process. These can be physical in nature such as solubility in a variety of solvents, polymorphic
crystal form, and stability. These factors could also be chemical in nature such as reactivity with water
or other solvents. They could also include medical information such as potency, toxicity, and allergenicity. They could also be safety factors such as toxicity when inhaled and could require personal protection attire to protect the operator. These factors, which are normally determined during pre-formulation,
are vital information that must be known before meaningful cleaning procedures and limits can be developed.
PROC - 2.b [ref. POL 1.3.3]
During development, various types of equipment may be used in an effort to develop an optimum process
or effective product. This means that normally the specific equipment or the scale of the equipment may
vary from batch-to-batch. Because of this variability in the equipment used, the cleaning procedures may
also vary from batch-to-batch even for the same product. Therefore, the cleaning verification results apply
only to the specific cleaning event (i.e., the specific combination of equipment, processes, and materials)
used for the individual study. The cleaning verification report should contain the details of the specific
equipment (size, model number), formulation, and processes used.
PROC - 2.c [ref. POL 1.3.4]
During development, the formulation may vary from batch-to-batch in order to identify the combination
of ingredients that presents the best product performance 'in vitro' and 'in vivo'. Excipients may be varied as well as the concentration of active ingredient. These combinations will present different degrees
of cleaning challenges. A given cleaning procedure may be adequate for one formulation but inadequate
for another formulation of the same active ingredient. This data will be useful for the selection of the
ultimate cleaning procedure that will be used for commercial product. It will be necessary to include the
formulation in the cleaning verification study, either by reproducing in total, or by reference to a formula number.
Journal of Validation Technology
Flow rates
Concentration of cleaning agent
Time of washing
Time of rinsing
Length of time and environmental conditions (temperature, humidity) between manufacturing and
cleaning
Nature and amounts of excipients
Concentration or amount of residue left on equipment
Physical properties of residues
Chemical properties of residues
Cleaning solvent chosen
Soak times
Contact time with cleaning agent
Rinse volumes
Order of application of cleaning solvents (acid, alkaline, and organic solvents)
o Accuracy
Precision
~ Linearity
o Robustness
o Sensitivity-Limit of Detection (LOD)*, Limit of Quantitation (LOQ)*
<D Specificity
@
The specificity of the analytical method may not be as critical for cleaning validation as for process validation due to the fact that the levels of residue detected is very low, and often non-specific analytical methods are available that may be at least or more sensitive than specific methods. The assumption is often
made that all of the residue detected is composed of the most potent ingredient (usually the active) present and, if this amount is still below the established limits, then the exact nature of the residue is irrelevant, i.e., the 'worst case' assumption was made and limits were met.
Journal of Validation Technology
@)
o List of all equipment, the operation of which has potential bearing on the quality of the cleaning process
As-built drawings of all specialized cleaning equipment such as pumps, high pressure delivery devices,
and hose cleaners
@) Verification that all such equipment and the installation thereof meets original intent, including applicable building, electrical, plumbing, and other such codes
o Preventative maintenance plans and schedules for all such equipment
@
o A list identifying each step of the cleaning process that relates to the specific equipment
Process operating parameters for each piece of equipment that is critical to the cleaning process
An OQ protocol that is designed to demonstrate via appropriate tests that the equipment operates as intended throughout the cleaning process
o Report that describes the successful execution of each OQ protocol for each piece of equipment critical to the cleaning process
@
@)
product, it is not possible to validate the cleaning process during the development phase. Still it is possible
to prepare a policy describing the testing of development equipment and what criteria will be used to determine if the equipment has been suitably cleaned. The strategy and approach to cleaning in the development
areas must be in writing and clearly explain how equipment will be sampled and tested, and how limits will
be determined, recognizing that only a single set of data will be available. Since only a single set of data is
available, it would be erroneous to refer to this situation as "validation". Thus the term "cleaning verification" is a more appropriate description of this scenario.
PROC - 2.r [ref. POL 1.6]
The Cleaning Validation Master Plan (CVMP) may take different forms in companies around the world.
Some may have a separate independent document. Others may have a Standard Operating Procedure*
that describes in general terms how the cleaning program will operate. Still others will devote a section of
the Validation Master Plan* to cleaning. Regardless of the exact form taken, it is essential to have a written plan describing how the cleaning program will be organized and controlled. The essential elements of
the CVMP are:
A description of the approach and strategy to be used for controlling, verifying, and/or validating in the
various departments such as Basic Research *, Research and Development *, Scale-Up! Pilot Plant*,
Production*, Packaging*, Contract Manufacturing Facilities *, and Contract Packaging Facilities *.
A mechanism for defining what is adequate cleaning, based on the potency, toxicity, potential allergenicity, potential teratogenicity, and potential carcinogenicity of the material, as well as other factors
such as route of administration and properties of the other products made in the same equipment.
Sampling methods to be used to evaluate cleaned equipment. Examples are Swab Sampling* and Rinse
Sampling*, or a combination of these two methods depending on the nature of the equipment or product.
Selection of sampling locations to include 'worst case' and/or most difficult-to-clean locations.
For equipment used for manufacturing multiple products, how the Worst Case Product* for cleaning purposes might be selected from a group of very similar products. Typically, a Product Matrix Approach*
is used to compare the critical cleaning properties of the products in the group. Critical cleaning properties are potency/toxicity, solubility, and the inherent difficulty of cleaning.
Provision for how documentation will be developed, reviewed, and approved. This would include a list of
those responsible for preparing, reviewing, and approving Cleaning Verification Protocols, Cleaning
Verification Reports, Cleaning Validation Protocols, Cleaning Validation Reports, Cleaning Procedures,
Change Control Procedures, and Cleaning Monitoring Programs *.
Criteria for Revalidation* of cleaning procedures.
Provision for creation of a Site Validation Steering Committee (SVSC), that would serve as the group
immediately responsible for all cleaning issues. This group would normally select project teams related to cleaning activities, e.g., for a new product.
Training of development, pilot plant, sampling, and analytical testing personnel.
Definition of resources required and allocated.
Schedule of cleaning activities including cleaning validation and assignment of responsibilities.
III. ACRONYMS
API
BPC
CGMPs
CIP
CPQ
CVMP
CVP
IPEC
IQ
OQ
PIC
SOP
SVSC
IV. GLOSSARY
Reference Standard
Number
POL 1.1
PROC2.h
Analytical Method Validation - documented evidence that an analytical procedure will consistently detect and/or quantitate materials.
PROC-2.r
Basic Research - the segment of the pharmaceutical industry that evaluates new chemical
entities for potential application to treatment of disease. This includes, but is not limited to,
basic disciplines such as biochemistry, molecular biology, toxicology, pharmacology, and
pharmacokinetics.
POL 2.3
POL 1.3.9
Cleaning Agents - any chemical or solvent that facilitates the cleaning of equipment by dissolution, hydrolysis, or other chemical or physical action.
PROC-2.r
Cleaning Monitoring Program - a formal, written program describing how cleaning procedures can be monitored on a regular schedule to evaluate the effectiveness and consistency of
the cleaning process.
Journal of Validation Technology
POL 1.3.18
Cleaning Performance Qualification (CPQ) - documented evidence that a cleaning procedure is consistent in removing product residue and cleaning agent from equipment.
POL 1.3.9
Cleaning Procedure - a detailed written procedure (SOP) that describes how equipment will
be disassembled, cleaned, examined, and reassembled.
POL 1.3.12
Cleaning Validation - documented evidence that a cleaning procedure is consistent in removing product residue and cleaning agents from equipment (sometimes also referred to as
Cleaning Performance Qualification [CPQ]).
POL 1.6
Cleaning Validation Master Plan (CVMP) - a comprehensive, written plan that describes the
company's strategy in ensuring that all cleaning procedures are effective and in a state of control to ensure that all products are free of contamination and of high qUality. The plan includes
or references all appropriate cleaning procedures, and SOPs describes how protocols, cleaning
validation reports, and other documentation will be assembled, provides for the testing and
analysis of data, identifies resources to be allocated, provides for training of personnel, describes
qualification of equipment, indicates the process for assigning responsibility for the various
activities, provides a criteria for revalidation of cleaning procedures, and describes a mechanism
for controlling changes to validated procedures and equipment.
PROC-2.o
Cleaning Validation Limits - The maximum allowable amounts of material that can remain
on equipment after cleaning without compromising the safety of the consumer or the quality
of the product. These limits are applied during the cleaning validation study and depending on
the manufacturing circumstances, limits may be for:
POL 1.3.15
Cleaning Validation Protocol - a product specific plan of sampling and testing of equipment
after at least three consecutive cleanings to establish that equipment is appropriately cleaned
after a specific product is manufactured in a development area by a specific, detailed written
cleaning procedure.
POL 2.0
Cleaning Validation Reports - a written report that summarizes results and conclusions of
the cleaning validation study and includes:
Protocol
Test results
Analyses
Conclusions
Discussions of any deviations from procedures specified in the original protocol
Discussion of any failures
Indication as to whether the testing met the acceptance criteria specified in the protocol
POL 1.3.8
Cleaning Verification Limits - Maximum amount of residue that may remain on equipment
during a cleaning verification study. These limits are derived in a similar fashion to those for a
cleaning validation study, but are applied to a single cleaning event, as versus multiple cleaning runs (at least three) for cleaning validation studies. Just as for cleaning validation, the limits may be for any of the following:
POL 1.5
Cleaning Verification Policy (CVP) - a written document describing how equipment will be
verified as clean after a single manufacturing event in a development area. This is a general
document that will pertain to all cleaning in development areas.
POL 1.2
Cleaning Verification Protocol- a product specific plan of experimental sampling and testing to verify that equipment is appropriately cleaned after a specific product is manufactured
in a development area.
POL 1.9
Cleaning Verification Reports - a written report that summarizes results and conclusions of
the cleaning verification study and includes:
Protocol
Test results
Analyses
Conclusions
Discussions of any deviations in procedures from those specified in the original protocol
Discussion of any failures
Indication as to whether the testing met the acceptance criteria specified in the protocol
PROC-2.1
PROC-2.r
PROC-2.r
Contract Packaging Facilities - facilities or companies that package products for customers
on a contractual basis.
POL 1.3.9
POL 1.3.3
POL 1.1
Drug Products - a finished dosage form (e.g., tablet, capsule) that contains an API, generally in association with excipients. Synonymous with finished drug product.
POL 1.1
In-Process Materials - (as applied to drug product manufacture) - any material manufactured, blended, compacted, coated, granulated, encapsulated, tableted, or otherwise processed
that is produced for and used in the preparation of a drug product. (Corresponding materials
used in the preparation of APIs are referred to as intermediates.)
PROC-2.1
Installation Qualification (IQ) - documented verification that equipment, system, or a subsystem has been properly installed, adheres to applicable codes and approved design intentions, and supplier recommendations have been suitably addressed.
POL 1.1
Intermediate - a material produced during steps in the synthesis of an API that must undergo further molecular change or processing before it becomes an API. The degree to which a
given intermediate should be rated "critical" with respect to cleaning must be determined by
a firm's experts based on such criteria as:
Potential toxicity or other physiological activity
Degree to which equipment used is dedicated to the process, as opposed to having multiple uses
Ease or difficulty of removing process residuals when cleaning equipment
PROC-2.h
Limit of Detection (LOD) - the lowest amount or concentration of a material that can be
detected by an analytical instrument or chemical test. Although detectable, the amount of
material in the sample cannot be determined at this level.
PROC-2.h
Limit of Quantitation (LOQ) - the lowest amount or concentration of a material that can be
quantitatively determined by an analytical instrument or chemical test.
PROC-2.1
PROC-2.r
Packaging - The area or department that receives bulk product and incorporates the product
in packaging that will either be sent to the customer or sent to another area for additional packaging and/or labeling.
PROC-2.r
Production - The unit of the company responsible for the manufacture of bulk product. This
mayor may not include the packaging function depending on the size and organization.
POL-2.1
PROC-2.r
Product Matrix Approach - a chart that presents medical, toxicity, solubility, and other pertinent data so that a comparison can be made between products in the group in order that the
most risky product can be selected for cleaning validation. This 'worst case' approach obviates the need to perform cleaning validation studies on every combination of product and
equipment.
POL 1.2
Quality Authority - one or more persons who, collectively, have formal responsibilities for
specified quality-related operations, such as approval of manufacturing materials, release of
finished products, review and approval of documents, and adjudication of quality assurance
investigations. Titles of quality authority principals vary throughout the world; for example, in
the U.S., one term "the Quality Control (QC) unit," is all embracing; in the E.U. and Canada,
the head of quality control has some of the responsibilities, while a qualified person has others; terms as responsible head (or person) and quality assurance (and/or control) department are
also used in other areas.
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Research and Development - The division of a company that is responsible for developing
the optimal manufacturing techniques and dosage form for a pharmaceutical product. It is also
responsible for the development of preliminary cleaning procedures for new products.
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Revalidation - repeating the original validation or selected portions for the purpose of
demonstrating that the process is still in a state of control and delivers acceptable product and
processes. As applied to cleaning procedures, the purpose would be to demonstrate that the
cleaning procedures are still effective in removing residues. Revalidation is a natural consequence of making significant changes to equipment, manufacturing procedures, components,
cleaning procedures, and cleaning agents.
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Rinse Sampling - a type of sampling of cleaned equipment used in cleaning validation and
cleaning verification studies to determine if product-contact manufacturing surfaces are clean.
Controlled amounts of solvent are subjected to the equipment either under pressure or allowed
to stand in the equipment to allow dissolution of the residues. Mixing, spraying, and recirculation may also be used to facilitate the detection of residues. Rinse solvents are usually
selected on the basis of residue solubility in that solvent. The rinses may be either heated or
at ambient temperature.
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POL 1.2
Site Validation Steering Committee (SVSC) - a standing committee with authority and
responsibilities for validation policies, practices, and adjudication of issues. Must include
quality authority and Production Authority representation, and often includes representatives
of other involved disciplines. The name of the SVSC may vary from firm-to-firm.
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Spray Devices (Sprayballs) - a device that may be either permanently installed or inserted
into closed systems such as tanks specifically to provide a thorough, even coverage of the
equipment surfaces by the cleaning solutions. If fixed and spherical in shape, the device is
usually referred to as a "sprayball." Sprayballs may have fixed heads or they may rotate in
complex patterns.
PROC-2.1
Sprayball Pattern Analysis - a study that establishes that cleaning solution delivered by
sprayballs will reach all equipment surfaces, especially difficult to access or shadowed areas.
The study usually consists of coating equipment with easily detectable residue (dyes or fluorescent material), activating the sprayball mechanism for a normal cycle cleaning time, and
then examining the equipment to see if any material remains on the equipment surfaces.
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Standard Operating Procedure (SOP) - A written document describing, in detail, a specific process or procedure. These written procedures are required by the current Good Manufacturing Practice regulations for all critical processes. These procedures must be current,
detailed, controlled, and revised when necessary. All personnel must be trained in a new or
revised SOP prior to its implementation. Some companies have function specific procedures,
e.g., cleaning procedures, that take the place of SOPs.
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Swab Sampling - a type of sampling of cleaned equipment used in cleaning validation and
cleaning verification studies to determine if product-contact manufacturing surfaces are clean.
This type of sampling makes use of small pieces of fabric (usually polyester or other synthetic material) fused to the end of a plastic strip. The swab is typically wetted with solvent
(although they can be used dry). Defined surface areas of equipment, including the most difficult-to-clean locations, are swabbed. The swab is then immersed in a vial of solvent. The
residue on the swab is dissolved in the solvent, which is subsequently analyzed for product
residues. Limits are calculated on the basis of the area swabbed.
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Validation Master Plan (VMP) - a comprehensive, project-oriented action plan that includes
or references all protocols, key SOPs and policies, existing Validation Task Reports *, and
other relevant materials on which the specific system or process validation effort will be
based. The plan also identifies resources to be allocated, specific personnel training, and qualification requirements of relevant, organizational structure, and responsibilities of the validation team, and planned schedules. The VMP is subject to periodic revisions as defined in
change control procedures.
Validation Task Report - a written report that summarizes results and conclusions following
execution of all or any portion of a Validation Master Plan (VMP) (often referred to as a final
report if summarizing all activities of the VMP).
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Worst Case Product - the product selected from a group of similar products that presents the
greatest risk of carryover contamination to other products made in the same equipment by
virtue of its poor solubility, unstable chemical properties, potency, toxicity, or a combination
of these factors.
v.
Regulatory Reference
FDA Proposed Amendments to current Good Manufacturing
Practice Regulations Section Ill. C (May 3, 1996)
Under CGMP, a manufacturer will set contamination limits on a substance-by-substance basis, according to both
the potency of the substance and the overall level of sensitivity to that substance.
Because other substances, such as cytotoxic agents, or other antibiotics, pose at least as great a risk of toxicity
due to cross-contamination, FDA is proposing to expand the contamination control requirements to encompass
other sources of contamination.
The Agency has refrained from establishing a list of drugs or drug products that present such an unacceptable
risk, because such a list would quickly become obsolete.
The cleaning program should take into consideration the need for different procedures depending on what product or intermediate was produced.
Where mUltipurpose equipment is in use, it is important to be able to determine previous usage as an aid in investigating cross-contamination or the possibility thereof.
Cleaning of multiple use equipment is an area where validation must be carried out.
Validation data should verify that the cleaning process will remove residues to an acceptable level.
There should be a written equipment cleaning procedure that provides details of what should be done and materials to be utilized.
We expect the manufacturer to establish an appropriate impurity profile for each BPC based on adequate consideration of the process and test results.
Analytical methods including the limit of detection and the limit of quantitation of those methods
The acceptance criteria, including the rationale for setting specific limits
When revalidation will be required