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TitleValidated Cleaning Technologies for Pharmaceutical Manufacturing
LanguageEnglish
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Total Pages305
Table of Contents
                            Front Cover
CONTENTS
PREFACE
CHAPTER 1: CLEANING OBJECTIVES
CHAPTER 2: CLEANING AND CLEANING AGENTS
CHAPTER 3: CLEANING METHODS
CHAPTER 4: PROCESS PARAMETERS IN CLEANING—PART I
CHAPTER 5: PROCESS PARAMETERS IN CLEANING—PART II
CHAPTER 6: CLEANING CYCLE DEVELOPMENT
CHAPTER 7: GROUPING STRATEGIES
CHAPTER 8: SETTING ACCEPTANCE CRITERIA
CHAPTER 9: ANALYTICAL METHODS FOR CLEANING VALIDATION
CHAPTER 10: SAMPLING METHODS FOR CLEANING VALIDATION
CHAPTER 11: MICROBIAL ISSUES IN CLEANING VALIDATION
CHAPTER 12: CHANGE CONTROL AND REVALIDATION
CHAPTER 13: SPECIAL TOPICS IN CLEANING VALIDATION
CHAPTER 14: FDA EXPECTATIONS
APPENDICES
INDEX
                        
Document Text Contents
Page 2

Validated
Cleaning

Technologies for
Pharmaceutical
Manufacturing

Destin A. LeBlanc

Interpharrn /CRC
Boca Raton London New York Washington, D.C.

Page 152

Setting Acceptance
Criteria

A n important consideration in cleaning validation is
the determination of "how clean is clean enough?"
The Food and Drug Administration (FDA) does not es-
tablish analy-hcal acceptance criteria for manufactur-
ers [l]. Specific analytical acceptance criteria for
target residues must be established by the manufac-
turer. It is important in setting acceptance criteria
that the limits are scientifically justified. An arbitrary
setting of limits is just that-"arbitrary9'-and may
raise concerns in any regulatory investigation. This
situation is somewhat complicated by the fact that
sometimes the term Limit is used loosely, referring
to the acceptance limit in the next product, of sur-
face contamination, or of the analyzed sample. While
all these are interrelated, they are not necessarily
of the same units or magnitude. For example, in
the contamination of the next product (the product

Page 153

136 Validated Cleaning Technologies

subsequently manufactured in the cleaned equip-
ment), the units typically are ppm or pg/g; for surface
contamination, the units are usually pg/cm2; for the
analyzed sample, the units are typically pg or pg/g.
It should be clear that limits per surface area are dif-
ferent units and cannot be compared directly without
other pieces of information (such as batch size and
equipment surface area). In addition, limits in the
subsequent product may be the same units as limits
in the analyzed sample, but they also are not compa-
rable without other information such as area
swabbed and the swab recovery factor. What this
means is that an acceptance limit of 3.2 ppm in the
subsequent product is not necessarily the same as
3.2 ppm in the analyzed sampled prepared by a
swabbing procedure. It is important to make these
proper distinctions when discussing residue limits.
This will insure that analytical methods are properly
validated considering the appropriate limits for the
residue in the analyzed sample. In the subsequent
discussion, the calculation of residue limits for the
different parts of a validated system will be dis-
cussed. The limitations and applicability of such cal-
culations as applied to finished drug products will
then be explored.

One of the main objectives of the cleaning
process in drug manufacture is to remove residues of
the just-manufactured product so that those residues
are not transferred to the subsequently manufactured
product. A key complicating feature of cleaning is that
it involves not only the product being cleaned but also
the product subsequently manufactured in the
cleaned equipment. The starting point for any deter-
mination of residue acceptance limits is the amount
of residue from the cleaning process that could be
present in the subsequently manufactured product

Page 304

Index 287

wetting and desorption, 176-177
worst case for, 91, 118, 141,

1 78- 179

tap water. See potable water
target analytes, 162- 164
target residue

chemical nature of, 151-152
nonspecific analytical methods for,

155-156
in placebo sampling, 185-187
in recovery studies, 188, 189. 190
in rinse sampling, 182
specific analytical methods

for. 154
in swab sampling. 177

temperature of cleaning, 84-87
for automated parts washing, 62
change control and, 2 10-2 1 1
cleaning level and, 107. 108, 1 10
concentration of cleaning agent

VS., 81-82
control of, 86, 106, 1 16
in high-pressure spraying, 65
hydrolysis and. 27
nlicrobial reduction and. 196
optimization of, 1 17
prerinsing and, 29
for protein products, 2 18
rinsing and, 99
selecting, 1 1 1, 1 13-1 15
for sink brushing, 68
soil conditions and, 75
solubility and. 2 1
temperature change profile. 87
for ultrasonic washers, 63

templates, swab sampling using, 178
testing methods for evaluating clean-

ing, 114-1 15
test until clean, FDA expectations

for, 245. 259
thin layer chromatography, 244
time limits

between cleaning and next use, 77
GMP for, 6
between processing and cleaning,

75. 76-77, 240
time of cleaning. See cleaning times
titrations, 166

nonspecificity of, 157, 158
of target analytes, 163

TOC. 164-165
in biotechnology manufac-

turing. 2 18
defined, 273
nonspecificity of. 155- 157
organic solvents and, 176
swab sampling and. 176-1 77, 180

target analytes assayed by,
163- l64

water quality and, 100- 102
total organic carbon. See TOC
training

of operators, FDA expectations
for, 240

of workers, 68, 69, 84
tunnel washers. 59
turbulence. See agitation
ultrasonic washers, 63-64
ultraviolet spectroscopy. See W

spectroscopy
underdeposit corrosion, equipment

life and, 12
uniformity in cleaning

impingement and, 80
maintaining, with mixing, 95

United States Pharmacopeia Purified
Water. See USP Purified Water

U.S. v. Barr Laboratories, 7
use-dilution, cleaning agent concen-

trate. 273
USP Purified Water

change control and, 208
rinsing with, 182, 197, 243

UV spectroscopy, 165
for HPLC analysis, 164
monitoring organic solvents

with, 102

validation, cleaning. See cleaning
validation

validation collfirmation. See
revalidation

validation for analytical methods, 157
accuracy of, 160
keys to, 161-162
linearity of, 160
LOD/LOQ of, 159-160
precision of, 160- 16 1
range of, 158- 159
specificity of, 157- l58

verification, cleaning. See cleaning
verification

viruses. 202, 203
visual cleanness test

acceptance criteria and, 144- 145.
223, 238-239

criteria for, 1 14-1 15, 170-1 72
Eli Lilly standard for, 137
numerical value for, 17 1
recontamination and, 78

waste stream, cleaning solution in, 84
water

in aqueous cleaning, 33
deionized. 97

Page 305

288 Validated Cleaning Technologies

for desorption, 176
potable, 97
PW, 96
softened, 97
wetting by, 25-26
W F I , 96

water break test. 1 14-1 15
water for injection. See WFI
water quality, 96-98

change control of, 208-209
for rinsing, 98-99. 100
in washing step, 97-98

waxy soils, 75, 85
weight loss test, 1 15
wetting, 25-26

cleaning temperature and. 86
dispersants and. 35
dissolution rates and, 80
in high-pressure spraying. 65
microbial reduction by, 196
surfactants and, 29, 33
in ultrasonic washers, 63
in wiping. 67

WFI
change control and, 208, 209
defined, 273
rinsing with, 197
standards for, 96
washing with, 97

wiping, 66-68
visual cleanness and. 173

worker safety, 13
with aqueous cleaners, 37
automated parts washing and, 62

CIP systems and, 52, 53
cleaning agent concentration

and, 84
equipment brushing and, 70
high-pressure spraying and. 65
with organic solvent cleaners. 32
wiping and, 67

worker training
for cleaning agent concentra-

tion, 84
for sink brushing. 69
for wiping. 68

worst case
for analyhcal method, 1 58
for cleaning, 76, 90. 92, 95, l 10.

112-113, 198
defined, 273-274
for grouping. 13. 123-126.

131, 132
for locations, 16, 91, 92-93, 112.

118-119, 210-211. 242
for sampling. 93, 141. 169,

178-179. 190
for water quality. 98

written procedures. See also docu-
mentation

GMPs for, 5, 6

yeasts, 202

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