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Table of Contents 1 INTRODUCTION .......................................................................................................................... 2 2 GENERAL CONSIDERATIONS .................................................................................................. 2 3
Biofilms....................................................................................................................................... 3 4 HACCP ....................................................................................................................................... 5 5
TRAINING ..................................................................................................................................... 5 6 VALIDATION................................................................................................................................ 6 7 RECORD KEEPING ...................................................................................................................... 6 8
Equipment Records ..................................................................................................................... 6 9 Equipment Status ........................................................................................................................ 7 10
MANUFACTURING FACILITY .................................................................................................. 7 11 Manufacturing / Production Areas .............................................................................................. 7 12
MANUFACTURING AND FILLING EQUIPMENT ................................................................... 8 13 Equipment Design....................................................................................................................... 9 14 Cleaning and Sanitization Schedule.......................................................................................... 13 15 General Procedures ................................................................................................................... 13 16
Equipment Cleaning and Sanitization................................................................................... 14 17 Special Equipment and Procedures....................................................................................... 15 18 Acceptance Criteria............................................................................................................... 18 19
CLEANERS .................................................................................................................................. 18 20 Characteristics of an Efficient Cleaner ..................................................................................... 19 21 Selection of a Cleaner or Cleaners for a Specific Process ........................................................ 19 22
SANITIZERS................................................................................................................................ 22 23 Definition .................................................................................................................................. 22 24 Physical Sanitizers .................................................................................................................... 24 25 Factors Affecting Efficacy ........................................................................................................ 24 26 Rotation of Sanitizers................................................................................................................ 25 27
SUMMARY .................................................................................................................................. 25 28 Table 3-1. Commonly Used Cleaners for Processing and Filling Equipment ............................. 26 29 Table 3-2. Commonly Used Chemical Sanitizers for Processing and Filling Equipment ........... 27 30 Table 3-3. Commonly Used Physical Sanitization Methods for Processing and Filling 31 Equipment ..................................................................................................................................... 28 32 REFERENCES ............................................................................................................................. 29 33
34
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CLEANING AND SANITIZATION 35
36
INTRODUCTION 37
Effective cleaning and sanitization programs are essential to ensure microbial quality in the 38
manufacture of cosmetics and personal care products. Cleaning procedures and 39
sanitization procedures should be validated in order to consistently meet hygienic 40
manufacturing requirements. The design of cleaning and sanitization procedures should 41
take into account the product formulation, engineering design of equipment, and all aspects 42
of manufacturing. 43
44
GENERAL CONSIDERATIONS 45
Specific internal programs for cleaning and sanitization should be established. These 46
programs are essential to: 47
• Prevent ingredient cross-contamination 48
• Assure the microbiological quality of the product; 49
• Meet legal regulations where required; 50
• Minimize the microbial load contributed by processing, filling, and storage 51
equipment; 52
• Avoid the time and resources associated with microbial failure 53
54
If cosmetics and drug products are manufactured with the same equipment, refer to FDA 55
guidelines for the manufacture of OTC drugs.1-3 Factors such as active ingredient and cleaner 56
residues are important areas of C&S but are beyond the intended scope of this document. For 57
the purpose of this document, the following definitions apply: 58
59
• Cleaning - the process of removing product residue and contaminants such as 60
dirt, dust, and grease from surfaces. Cleaning is an essential step that needs 61
to be performed before the performance of a sanitization procedure. It is 62
important that personnel involved in cleaning have a working understanding of 63
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the nature of different types of soils and the chemicals required for their 64
removal. 65
• Sanitization - the process utilized to reduce viable microbial contaminants to 66
an acceptable level such as the microbial count specification of the finished 67
product. All surfaces must be clean for the sanitization procedure to be 68
effective. 69
• Validation - the process of substantiating that the process does what it 70
purports to do. 71
• Documentation - the process of organizing all relevant information in an 72
orderly and easily understood format. This documentation is required to 73
validate a process and to maintain a historical record of the process and 74
equipment usage. 75
76
Guidance for the development of operating procedures is addressed in each section below, 77
as appropriate. Written protocols are required prior to attempting to validate any process. 78
For more information, see the "Microbial Validation and Documentation” (Section 9) and 79
“Microbiological Evaluation of the Plant Environment”(Section 2). Additional information on 80
cosmetics Good Manufacturing Practices can be found in the CTFA “Quality Assurance 81
Guidelines”4. In addition, an understanding of the importance of biofilms5,6 and application 82
of hazard analysis of critical control points (HACCP)7-9 should also be considered. 83
84
Biofilms 85 86
A biofilm5,6,7 is a community of mixed microorganisms encased in an extracellular polymer 87
matrix, which they produce and secrete. Bacteria living in a biofilm may behave as a unit 88
or multicellular organism. Biofilms have the potential to develop in most aqueous systems 89
including process water systems and on those areas of manufacturing equipment that is 90
difficult to clean and sanitize. Biofilms can be also be present on equipment surfaces that 91
appear to be visually clean. 92
93
Biofilm Characteristics 94
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• Once formed, biofilms become continuous sources of microbial contamination 95
as microorganism clumps or aggregates will break from the biofilm and 96
surfaces are colonized downstream and potentially contaminate finished 97
product. 98
• Although thermal methods (e.g. 65 to 85°C hot water or steam) kill 99
microorganisms within a biofilm, they are not effective in removing an 100
established biofilm. Killed but intact biofilm can become a nutrient source for 101
rapid biofilm regrowth. 102
• Routine microbial sampling of water systems or equipment surfaces may not 103
be able to detect the presence of biofilms because they are not dispersed 104
homogeneously. 105
106
Microorganisms living in a biofilm on equipment are more difficult to kill and subsequently 107
remove than free floating organisms because they are protected by the polysaccharide 108
matrix structure of the biofilm. For chemical sanitization to be effective against biofilms, it 109
must be performed frequently in order to minimize the amount of biofilm development, 110
• The less developed and thinner the biofilm, the more effective the biocidal 111
action. 112
• Compounds such as hydrogen peroxide, peracetic acid or peroxyacetic acid, 113
and ozone oxidize microorganisms and kill biofilm organisms by the 114
formation of reactive peroxides and hydroxyl free radicals. 115
• Microorganisms growing in a biofilm can exhibit reduced susceptibility to 116
antimicrobial agents including disinfectants and sanitizers. 117
• Microorganisms in a well-developed biofilm can be extremely difficult to kill, 118
even by aggressive oxidizing biocides due to protection by the 119
polysaccharide layer of the biofilm. 120
121
Prevention of biofilm formation 122
Because of the difficulty in treating and removing mature biofilm, the emphasis must be 123
placed on prevention of biofilm formation. Appropriate equipment design, including 124
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adequate drainage and drying (See sanitary equipment design), validated cleaning and 125
sanitization procedures, and adequate frequency will help to minimize biofilm development. 126
127
HACCP 128
Hazard analysis critical control point (HACCP8-10) is a systematic preventive approach that 129
addresses physical, chemical and biological hazards. HACCP is a risk assessment 130
process that may be used to identify the critical control points (CCP) of the system. CCP 131
may include areas that are most difficult to reach for cleaning and sanitization and that are 132
keys to monitoring contamination in order to maintain microbial control. 133
134
HACCP typically consists of 7 steps: 135
• Identify hazards and control measures 136
• Determine critical control points 137
• Define critical limits 138
• Establish a monitoring system 139
• Establish corrective actions 140
• Verify that the control measures operate as defined 141
• Document procedures, monitoring and events 142
143
144
TRAINING 145
Personnel should be properly trained in the cleaning and sanitization of the facility and 146
equipment. 147
148
A training program should be appropriate to the roles and responsibilities of the employee 149
and impart an understanding of the elements of cleaning and sanitization and their effect 150
on product quality. Training should include: 151
• Basic equipment operation and design 152
• Concepts of microbial contamination including common sources of 153
contamination 154
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• Proper and safe use and appropriate disposal of cleaning and sanitization 155
agents 156
For further information on training, see “Microbiology Staff Training” (Section 4) and 157
“Microbial Validation and Documentation” (Section 9). 158
159
VALIDATION 160
All procedures used for cleaning and sanitization should be validated. For protocol and 161
additional information, see “Microbial Validation and Documentation (Section 9). 162
163
RECORD KEEPING 164
Ongoing documentation includes routine logs that are necessary to maintain a history of 165
the equipment usage and cleaning and sanitization practices. This information can also 166
serve as part of a validation information package. It can be used for trend analysis and 167
evaluating cycle reduction. A cleaning and sanitizing record should be prepared, 168
maintained, and made readily available for each piece of equipment. 169
170
Equipment Records 171
Equipment records should include the following information: 172
• Identification of the equipment 173
• The product and batch to be made 174
• Date, start and end times of the cleaning. 175
• Date, start and end times of the sanitization, including expiration time. 176
• Operating procedure, SOP, or procedure number for the cleaning and 177
sanitization being carried out 178
• Any variation from the established operating procedure 179
• Sign off by operator 180
• Review, approval and sign off by verifier/reviewer 181
• Time, date and identity of next batch start up 182
• Date and description of any maintenance, repairs or equipment down 183
time 184
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185
Equipment Status 186
The current status of the equipment should be clearly displayed. Examples of status 187
designation labels may include: 188
• In use: Contents and Batch or Lot Number 189
• Needs Cleaning 190
• Clean Needs Sanitizing 191
• Sanitized* 192
• Out of Service 193 *Sanitization date and expiration time should be included on the label. If expiration time is 194
exceeded, the equipment should be re-sanitized before being put back into service. 195
196
MANUFACTURING FACILITY 197
The environment of the manufacturing facility strongly influences the microbial quality of the 198
finished product. Appropriate building design and maintenance are critical. Standard 199
procedures for facility cleaning should be written and a record of their implementation 200
should be maintained11,12. For additional information, see “Microbiological Evaluation of the 201
Plant Environment.” (Section 2) 202
203
204
Manufacturing / Production Areas 205
The frequency of cleaning is determined by the types of activities conducted in any given 206
area of the facility. Cleaning schedules can be adjusted, and remedial action can be 207
taken as required. Precautions should be taken to minimize airborne dust from 208
manufacturing equipment and areas during all cleaning and sanitization. Any spills of raw 209
materials, product, or packaging components should be cleaned up promptly. Based on 210
product risk, some areas may need to be under greater microbial control and therefore, 211
may require a higher degree of plant hygiene. 212
213
Walls, ceilings, pipes, fixtures, and HVAC systems 214
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Clean on a scheduled basis. 215
216
Floors 217
Clean floors on a scheduled basis and include the following: 218
• Vacuum and/or sweep frequently 219
• Wet-mop or machine scrub on a predetermined schedule 220
• Sanitize as appropriate 221
• Keep floors dry as much as possible 222
223
Cleaning equipment and supply storage 224
Store cleaning equipment and supplies properly in a clean area. Supplies and equipment 225
used for lavatory cleaning should be stored separately from cleaning supplies and 226
equipment used in manufacturing areas. 227
228
Warehouse Areas 229
General guidance for the warehouse area includes the following: 230
• Aisles should be kept neat and clean by sweeping, damp mopping or machine 231
scrubbing. An appropriate, freshly prepared cleaner should be used. 232
• An established, monitored, and documented insect and rodent control program 233
should be in place. For additional information, see “Quality Assurance Guidelines”6. 234
• Stored materials and containers should be kept clean, orderly, protected and 235
correctly identified. 236
237
MANUFACTURING AND FILLING EQUIPMENT 238
Manufacturing and filling equipment13,14 has direct contact with product. For cleaning and 239
sanitization procedures to be effective, appropriate consideration to equipment design 240
should be made. 241
It is essential that manufacturing and filling equipment have good drainage and be 242
designed for ease of conducting proper cleaning and sanitization. In addition, the 243
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equipment should be durable enough to withstand sanitizing chemicals and/or physical 244
agents that are used for cleaning and sanitization. 245
246
Equipment design 247
The following guidance on overall equipment design is intended to minimize conditions that 248
may lead to microbial growth in the equipment. It also offers suggestions to reduce the 249
potential degradation of the equipment by the effects of the cleaners and sanitizers used. 250
It is essential to work with your engineering department in choosing the appropriate 251
equipment design and specifications for your facility. 252
• Design manufacturing and filling equipment to minimize retention of 253
residual product and/or wash water. Where equipment is not self-254
draining, the installation of sanitary drain valves or valves that can be 255
completely disassembled may be of value. Residual water in equipment 256
will dilute product and/or sanitizer which can lead to microbial growth 257
and the development of adaptable microorganisms. 258
• Minimize condensation in equipment. Condensation can dilute product 259
and create an environment for microbial growth. 260
• Design equipment so that during cleaning, all internal surfaces are in 261
contact with the cleaning solution. All internal surfaces should be as free 262
as possible of crevices that can harbor product or microorganisms. 263
• External surfaces should be easily cleanable. 264
• Choose materials of construction that are not easily degraded, etched, or 265
reacted when in contact with the product, cleaners or sanitizers such as 266
316L stainless steel. 267
• Choose equipment with a surface finish that is easily cleanable, durable, 268
capable of being derouged and passivated; e.g., 316L stainless steel with 269
a surface finish of ≤25 Roughness Average (RA) or a minimum of 140 270
grit or better finish. 271
• Threaded fittings are difficult to clean and can hold finished bulk product 272
residue that can lead to contamination. Choose equipment without 273
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threaded fittings that have a gasket and clamp connection or use bevel 274
seat connections (outside threads) which are acceptable if installed and 275
maintained properly to avoid leakage into the outside threads. 276
• Routinely inspect and replace gaskets when necessary, as the gasket 277
interface is readily contaminated when gasket integrity is not maintained. 278
• Use sanitary welding techniques such as orbital welding or gas tungsten 279
orbital arc welding is recommended to avoid creating crevices or rough 280
surfaces that are difficult to clean. Chemically welded joints of plastic 281
piping should be checked and be smooth to facilitate cleaning. 282
283
Common sanitary design practices for specific types of equipment are listed in the 284
following sections. 285
286
Tanks/Vessels 287
• Minimize sharp corners because they are difficult to clean. 288
• Avoid narrow recesses that could trap product and water. 289
• Design tanks with a domed head to minimize condensation. 290
• Choose tanks and vessels with conical or dish shaped bases, with a 291
center drain, as they allow for complete draining. 292
• Design vessel openings and surfaces to be easily cleaned. 293
• Design and maintain covers to fit well and close easily. 294
• Design vents to minimize debris. 295
• Eliminate pipes with dead legs. 296
• Design tanks with spray ball devices that cover the entire surface area 297
and all shadows created by internal components. 298
• Tanks with mixing capability should be equipped with welded or singe 299
piece mixer blades and shaft. 300
301
302
303
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Transfer Pipes 304
• Minimize the length of pipe runs to make cleaning easier and slope the 305
pipe runs to be self-draining (>1%) to reduce the risk of biofilm 306
formation. 307
• Choose a pipe diameter that is appropriate to maintain the required flow 308
rate for the cleaning solution. 309
• In-line filters should be designed for easy cleaning, sanitization and 310
inspection. 311
• Design piping systems to have a minimal number of T's. 312
• Use sanitary welding techniques to avoid the creation of difficult-to-clean 313
crevices and rough surfaces. 314
• Use sanitary fittings for all connections. 315
• Avoid flange and screw-threaded piping that comes in contact with the 316
product. 317
318
Valves 319
Valves should be easily cleanable with no dead spaces to collect product residue or water. 320
Examples of sanitary valves are diaphragm valves and butterfly valves. The use of valves 321
that can collect product residue or water, such as ball valves, is not recommended due to 322
dead spaces resulting from their design. 323
324
Pumps 325
Sanitary pumps are recommended. Sanitary pumps are oriented with a vertical inlet and 326
outlet and passes and pressure relief valves are designed to prevent water and/or product 327
retention. Examples of sanitary pumps are diaphragm pumps and peristaltic or lobe 328
pumps. Examples of non-sanitary pumps for moving finished product are centrifugal 329
pumps, gear pumps, or mono pumps. It should be noted that centrifugal pumps are 330
commonly used in process water systems without having microbial contamination issues. 331
Pumps should be easily accessible for inspection, cleaning, and sanitization. 332
333
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Filling Equipment 334
Fillers should be designed to be easily cleaned and sanitized. Avoid drip pans and water-335
lubricated belts. If compressed air is used in filling equipment, the lines should be 336
equipped with microbial retentive filters and air-line dryers which should be monitored to 337
prevent air-line condensate from contaminating finished product. 338
339
Gaskets 340
Gasket interfaces are potential sites for contamination. Gasket materials should be 341
compatible with the product as well as the cleaning and sanitizing solutions. Non-porous, 342
chemically inert materials such as ethylene propylene diene monomer (EPDM), silicone, 343
and TEFLON (need to use trade name properly – md to look up) are recommended. 344
Care should be taken to assure that gaskets are properly installed, inspected, and 345
replaced at a preventative maintenance frequency that is performed prior to wear and 346
damage causing loss of integrity. 347
348
Hoses 349
Transfer hoses should be of a material that is compatible with product, cleaners and 350
sanitizers to be used. Common hose materials are: 351
• reinforced food grade rubber or neoprene 352
• TYGON tubing 353
• Polyethylene 354
• Polypropylene 355
• nylon 356
357
They should have flush mounted sanitary fittings composed of 316L stainless steel with 358
rounded edges and a minimum grit of 180 to prevent migration of product between the 359
fitting and the hose material. Cleaned and sanitized hoses should be hung in such a 360
manner that they completely drain to dry and visually inspected. Hoses should be capped 361
after drying or stored in a protected area. If hoses are capped, a non-woven microbial 362
barrier is preferred. 363
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364
Cleaning and Sanitization Schedule 365
Frequency 366
The frequency of equipment cleaning and sanitization should be determined during 367
validation and is typically based on several factors including: 368
• Vulnerability of product to contamination 369
• Type of equipment used 370
• Whether continuous process batching is being performed 371
372
Expiration limit 373
An expiration limit for cleaning procedures and sanitization procedures should be set for 374
each piece of manufacturing equipment. This expiration limit reflects the allowable time a 375
piece of equipment can stand before requiring recleaning and/or resanitization. This will 376
depend on the equipment, the environment in which the equipment is stored, and methods 377
used for cleaning and sanitization. 378
379
Once the cleaning and sanitization procedures have been validated, periodic monitoring of 380
equipment is essential. For additional information, see “Microbiological Evaluation of the 381
Plant Environment (Section 2). 382
General Procedures 383 384 General Housekeeping Practices 385
• Clean spills immediately and remove debris from the manufacturing areas. 386
• Use disposable towels and discard immediately after single use. Non-387
disposable cleaning cloths should not be used. 388
• Container exteriors should be cleaned before transferring material into 389
manufacturing areas. 390
Water 391
• The water used to make up cleaners and sanitizers should have a low microbial 392
bioburden to avoid contaminating the cleaner and to avoid consuming the 393
sanitizer. 394
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• Water used to rinse cleansers from cleaned equipment should be fresh, potable 395
water that has a microbiological quality that meets EPA or equivalent potable 396
water quality standards.15 397
• Water used to rinse chemical sanitizers from sanitized equipment must have no 398
higher microbial bioburden then the microbial specifications of the product to be 399
made in that equipment.16 400
• Water hardness should be considered when diluting sanitizers and cleaners 401
because hardness may affect the efficacy of the chemicals used. If an alkaline 402
cleaning agent is used, hardness ions in the water may precipitate out as 403
calcium carbonate and may cause a white residue on the surface. For sanitizer 404
preparation, utilize the water hardness and instructions provided on the EPA 405
approved sanitizer label. 406
• The pH of the water may affect the cleaning ability of some cleaners and the 407
antimicrobial activity of sanitizers/disinfectants. 408
409
Equipment cleaning and sanitization 410
Outer surfaces of equipment should be maintained in a clean state. Clean and sanitize all 411
lines; processing, storage and filling equipment; pumps; pipe connections; flexible hoses 412
and utensils in the immediate processing and filling areas as follows: 413
• Remove product residue from all contact surfaces by thoroughly rinsing 414
with water or a water/detergent solution. Rinse water for sanitized 415
equipment should not contain higher microbial content than the limits that 416
have been established for the finished product. Temperature of the rinse 417
solution is dependent on product type, equipment compatibility, and 418
detergent. NOTE: Non-aqueous-type product residues should be removed 419
by appropriate predetermined methods. 420
• Pipeline pigs are devices made of non-porous materials used for recovery 421
of product, product separation, and cleaning of manufacturing pipelines. If 422
pigs are used, assure thorough cleaning and sanitization of pigging 423
equipment and of the pig itself. When not in use, pigs must be handled 424
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and stored under sanitary, dry conditions. The pig launcher and receiving 425
station must be sanitary in design as this equipment can easily harbor 426
microbial contaminants. 427
• Circulate a cleaning solution at an appropriate flow rate for a period of 428
time and at a temperature capable of effectively removing soil residue in 429
the circuit and/or equipment. All surfaces not accessible by this cleaning 430
procedure should be cleaned manually and/or by using special equipment 431
or methods. 432
• Rinse the cleaning solution thoroughly from the system with 433
microbiologically acceptable water, as determined by in-house standards. 434
When water is used to rinse equipment, the equipment should be drained 435
and used within a validated expiration time. 436
• All equipment should be sanitized following cleaning or before use 437
according to the written procedure for the piece of equipment involved and 438
used within the validated expiration time. See "Special Equipment and 439
Procedures" below. 440
• If chemical sanitizers are used, rinse water for sanitized equipment should 441
not contain higher microbial content than the limits established for the 442
formulated products. 443
444
Equipment should be cleaned as soon after use as possible in order to facilitate product 445
removal. Product that has dried and hardened onto equipment surfaces can be difficult to 446
remove thoroughly. Ideally, clean equipment should be sanitized as close to the next use 447
as possible. Cleaned/sanitized equipment should be properly stored before use to prevent 448
recontamination. In general, equipment should be drained dry with open ends covered to 449
prevent recontamination. Validated clean hold times and sanitized hold times should be 450
established for all equipment to be stored prior to re-use. 451
452
453
Special Equipment and Procedures 454
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Special cleaning and sanitizing equipment and methods may be employed for processing 455
and filling apparatus. The equipment and methods are generally designed to fit the 456
individual needs of each manufacturing facility. There are several methods for cleaning 457
and/or sanitizing. 458
459
Manual 460
Manual methods involve the preparation of cleaning solution and the scrubbing 461
of equipment or parts using a brush, single-use cloth or pad. Proper training 462
and appropriate procedures are critical to obtaining reproducible results. 463
464
Soak 465
This method involves the immersing of utensils or equipment parts in containers 466
of detergent or sanitizing solution for extended periods of time. Parts should be 467
completely immersed in the solution with no air bubbles. 468
469
Spray 470
Low or high-pressure sprays are used to remove soil. In most cases, the 471
cleaning action of the pressure spray is enhanced by the use of detergents. 472
High-pressure spray devices such as spray balls or injectors may be installed in 473
mixing or storage tanks. Piping that delivers solutions to the spray ball should 474
be sloped to allow adequate drainage. Spray balls or injectors may become 475
clogged with product residue or debris and should be removed, if possible, and 476
cleaned periodically. If spray balls or injectors are removed after cleaning and 477
sanitization, they should be stored in a clean area in a self-draining position. 478
479
High-pressure spray wand equipment is also widely used. This type of 480
equipment may be movable. It is used for general surface cleaning. Spray 481
pressures developed should range from 200 to 1000 p.s.i.. These devices 482
should not be used in an area or in a manner that creates an overspray 483
contaminating nearby clean equipment. 484
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485
Fog 486
Fogging is a method of generating a mist for the application of sanitizers. Large areas of 487
equipment surfaces can be treated by fogging in a very short time using small amounts of 488
sanitizers. This method of application should only be used when the EPA product label 489
clearly provides instructions for fogging of hard surfaces. The labeling may only allow 490
fogging as an adjunct to traditional surface sanitization. Fogging should only be used in 491
closed systems by properly trained personnel using the appropriate personal protective 492
equipment. 493
494
495
Clean In Place (CIP) 496
CIP is a semi- or fully automated, self-contained system for the cleaning and 497
sanitizing of equipment. Cleaning and sanitizing solutions are circulated for a 498
specific time at specified temperatures. Little or no disassembly of equipment is 499
necessary. Unless properly designed, installed and maintained, CIP systems 500
can become contaminated. Each system is unique and to work well it should 501
be properly designed, evaluated and controlled. Factors to consider when using 502
CIP are: detergent/sanitizer type; detergent/sanitizer concentration; 503
temperature; and design of equipment. Some equipment design factors include 504
type, number, positioning of spray devices, pressure to spray device, velocity 505
rates in flow paths, type of pump, and shadows in tanks created by internal 506
components such as baffles, etc. Portable and fixed CIP skids should be of 507
sanitary design and have the same validation requirements as the equipment 508
being cleaned. 509
510
Steam in Place (SIP) 511
Steam in place is a semi or fully automated system for the disinfection of 512
equipment. Steam is flushed into the equipment for a specified time at a 513
specified temperature. It is a suitable system for large volume equipment such 514
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as storage tanks, manufacturing vessels, transfer pipes, etc. because the 515
elevated temperature can treat complex internal geometries which may not be 516
reached by sanitizer solutions. Disinfection cycles should be determined for 517
each piece of equipment in order to take into account their complexity and 518
drainability. 519 520 Acceptance Criteria 521
Prior to validation of the cleaning and sanitization processes for equipment, the acceptance 522
criteria for each process should be determined. Criteria should take into account the types 523
of finished products that are being processed by the equipment. Criteria for cleaning 524
include no product residue and no standing water. Criteria for sanitization typically include 525
no standing water and microbial bioburden that meet specific requirements or microbial 526
release limits of the finished product. If chemical sanitizers are being used, analytical 527
specification for detecting the presence of an allowable limit of sanitizer residue may also 528
be included as part of the acceptance criteria. In general, these are the minimal criteria 529
that should be considered. 530
531
Alert and action levels for microorganisms should be established by quality assurance 532
based on finished product microbial content specifications. 533
534
CLEANERS 535
A cleaner can be defined as a chemical or blend of chemicals formulated to remove soils 536
from a contact surface. These chemicals may be solvents, acids, bases, oxidizers, 537
detergents, and/or water-based chemical blends. 538
539
Aqueous cleaners are defined as blends of water-soluble chemicals designed to remove 540
soils into a water-based solution with a water continuous phase during cleaning. These 541
consist of surface active ingredients and other cleaning chemicals that use detergency to 542
lift soils from surfaces8. 543
544
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Characteristics of an Efficient Cleaner 545
Aqueous cleaners are typically formulated to contain several ingredients to allow for 546
maximum cleaning effectiveness. The ingredient requirements depend on the intended use 547
of the cleaner. Efficient aqueous cleaners utilize surfactants (anionic, nonionic, cationic 548
and/or amphoteric), dispersants, emulsifiers, wetting agents, builders, chelating agents, 549
sequestering agents, corrosion-inhibiting agents and stabilizers. The surfactants are used 550
for emulsification, wetting and penetration; builders are used for neutralizing hard water 551
interferences, chelating inorganic soils, and saponification of natural oils; and additives for 552
corrosion inhibition, anti-redisposition and good rinseability. 553
554
General characteristics to consider in choosing a cleaner: 555
• Compatibility with equipment, i.e., non-corrosive 556
• Solubility 557
• Wetting action 558
• Penetration properties 559
• Emulsification and soil-dispersion properties 560
• Rinsing properties 561
• Cost and availability 562
• Compliance with existing environmental and occupational safety regulations 563
564
Table 3-1 gives examples of various types of cleaners. For additional information, see 565
References 13, 14, and 17. 566
567
Selection of a Cleaner or Cleaners for a Specific Process 568
Although the characteristics of an efficient cleaner may be more general, the selection of a 569
particular cleaner for a particular cleaning task requires specific information. The most 570
important considerations include knowledge of the type of substrate to be cleaned and the 571
type of soil to be removed. The cleaner type should be matched to the surface to be 572
cleaned (metal, glass, plastic, etc.), the soil type (organic, inorganic, oils, heavy soils, light 573
soils, etc) and the desired cleaning method (manual, soaking, CIP, power spray wand, 574
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etc.). Information on the level of cleanliness required (acceptance criteria) should also be 575
known. For difficult to clean materials, use of more than one cleaner in a specific order or 576
regimen may be considered. Several questions can be asked prior to the selection of a 577
cleaning system: 578
• Does the cleaner have good detergency on the type of soil to be removed? 579
• Is the cleaner recommended for the cleaning process to be used? 580
• Is the cleaner easily rinsed without leaving residuals? 581
• Does the cleaner have to be treated before being flushed to drain? 582
583
Variables Affecting Efficiency 584
Besides the selection of an efficient cleaner, several other factors are extremely relevant to 585
the success of a cleaning process. Beyond the cleaner itself, cleaning efficiency is 586
influenced by cleaner concentration, agitation, temperature, cleaning/contact time, rinse 587
method and drying method. These process variables must be considered, specified, and 588
controlled to ensure a consistent and optimized cleaning process. 589
590
Cleaner Concentration 591
The concentration of the cleaner and process optimization should be selected through 592
consultation with the supplier of the material followed by in-house validation. 593
594
Temperature 595
Temperature should be optimized for the soil being removed and the equipment and 596
cleaner being used. The process should be validated using an appropriate method. 597
Safety considerations should be addressed if risk of personnel exposure exists. Cleaners 598
efficient at lower temperatures are now available and may be considered to reduce energy 599
consumption. 600
601
Time 602
Cleaning time is dependent on several factors of the process. These factors include 603
mechanical action, temperature, cleaner effectiveness, type of equipment being cleaned, 604
Page 21
and degree and nature of the soil to be removed. For example, the mechanical action of 605
high-pressure sprays may require from seconds to minutes while soaking may require a 606
substantially longer time. Cleaning time should be determined during the validation of the 607
entire cleaning process/system. 608
Rinsing 609
It is important that the rinse procedure removes any residue left during cleaning. The 610
specified volume of rinse water should be optimized and validated for each particular rinse 611
program. Ensure there is no cleaner residue remaining. 612
613
Drying 614
To reduce the potential for corrosion, inhibit microbial growth and biofilm formation, and 615
prevent dilution of chemical sanitizers, it is essential that the equipment be completely 616
drained and dried after rinsing. Evaporation is the simplest and least-expensive drying 617
method. It is most appropriate when used after hot water rinses on equipment that can be 618
easily drained such as tanks. Drying by evaporation is not appropriate for equipment that 619
cannot be completely drained such as filling lines. Drying by evaporation after ambient 620
water rinses can require longer dry times and may lead to higher risk of microbial 621
contamination. Other methods include circulated hot air, vacuum-drying, and forced-air 622
blow drying. For these methods, high quality air must be used for drying. The air source 623
may be filtered (particulate, hydrocarbon, and microbial retentive) to provide high-quality 624
air for drying. This type of mechanical drying is especially useful for equipment that is 625
used for anhydrous products where it is essential that no moisture remain in the 626
equipment. Use of alcohol free from spore forming organisms as a finishing step can aid 627
in the evaporation of water. Alcohol can be used as a dryer/sanitizer although it is not as 628
effective as mechanical drying and is most appropriate on small pieces of equipment. 629
Caution should always be used when using alcohol on equipment as it could present a fire 630
and explosion hazard. 631
632
Validation of the Cleaning Process 633
Page 22
The development of a testing and measurement system is important for optimizing and 634
validating the effectiveness of a specific cleaning process 17,18. The method selected for 635
measuring the effectiveness of the cleaning process should provide information needed to 636
determine that key criteria are met. Testing of the cleaning process initially requires the 637
development of a baseline level of cleanliness and an effective method to measure 638
removal of soils and cleaner residues. In many cases, visual assessments of equipment 639
or simple gravimetric analysis will suffice. Supplemental tools for evaluation may include 640
video scopes, chemical tracer measurements (fluorescent whiteners, total organic carbon 641
(TOC) in residual water, or conductivity). The simplest method that provides appropriately 642
sensitive results should be used. 643
644
After the cleaning system has been selected, it should be validated against the targeted 645
product and on the equipment where the production will occur. Either a quantitative or 646
qualitative method may be used to judge the cleaning process, and then acceptance 647
criteria should be established. Experimentation may occur initially on a smaller bench or 648
pilot-plant scale; however, the cleaning system should be validated on the actual 649
equipment due to concerns with scale-up. Each variable of the cleaning process (cleaner 650
concentration, time, temperature, mechanical action, etc.) should be considered to 651
determine the optimal conditions. 652
653
SANITIZERS 654
655
Definition 656
A sanitizer is either a chemical or physical agent that is effective in reducing microbial 657
contamination on hard, nonporous contact surfaces. A sanitizer may be considered 658
effective if it reduces microorganisms to levels established by company standards, with no 659
detectable objectionable microorganisms, as determined by the cleaning and sanitization 660
protocol.11,17,18 661
662
Page 23
Surfaces should be cleaned and free of residue prior to sanitization since residues can 663
interfere with activity of both chemical and thermal sanitization. 664
665
Factors to consider in choosing a sanitizer: 666
• Effective against a broad range of microorganisms. 667
• Provides adequate microbial reduction against organisms of concern. 668
• Effective in a relatively short contact time. 669
• Stable and efficacious over time, both in concentrate form and at use levels. 670
• Economical to use. 671
• Compatible with products and equipment. 672
• Meets regulatory requirements. 673
• Environmental impact 674
675
Chemical Sanitizers 676
Combined cleaner/sanitizer agents are available. These “one-step” products are 677
registered by EPA to be effective in the presence of light to moderate soil; however, heavy 678
soil must be removed prior to use. When using a “two-step” process where a cleaning 679
agent is used prior to application of a sanitizer, surfaces should be free of residue prior to 680
sanitization since residues can interfere with activity of chemical sanitization. 681
682
Some useful chemical sanitizing agents are chlorine, hydrogen peroxide, peracetic acid, 683
alcohols, phenolic compounds, and quaternary ammonium compounds. See Table 3-2 for 684
information on frequently used chemical sanitizers for processing and filling equipment. 685
Chemical sanitizers should be used according to the manufacturer’s directions and must be 686
shown to be effective for the intended use. 687
688
For sanitization of process water and process water systems, see “Microbiological Quality 689
for Process Water” (Section 7) . See references #19 and 20 for additional information on 690
chemical sanitizers. 691
692
Page 24
Physical Sanitizers 693
The most common physical sanitizers are steam or hot water. A major advantage of heat 694
is its ability to penetrate into small cracks and crevices. Heat is also non-corrosive, cost-695
effective, measurable with recording devices or thermal strips, efficient, effective against a 696
broad range of microorganisms, and leaves no residue. 697
698
Surfaces should be cleaned and free of residue prior to sanitization since residues can 699
interfere with activity of thermal sanitization. 700
701
See Table 3-3 for information on frequently used physical sanitization methods for 702
processing and filling equipment. 703
704
Factors Affecting Efficacy 705
Cleaning must always precede sanitization. In-house validation is needed to assure 706
efficacy of the sanitization process. Roughness of surface, bad welds or other defects can 707
make the equipment difficult to sanitize. Care should always be taken to follow label 708
directions and manufacturer instructions and recommendations. Water incorporated into 709
sanitizers should be of appropriate chemical and microbial quality. The presence of 710
dissolved gasses and solids within water should not be at a level that inactivates or 711
reduces the efficacy of the sanitizing agent. Operators should be properly trained. 712
Improper use may give ineffective results, release toxic fumes, or corrode equipment. 713
714
The following process variables should be considered, specified, and controlled to ensure 715
consistent sanitizer performance: 716
• Condition of equipment surfaces 717
• Materials of construction 718
• Concentration of sanitizer 719
• Contact time 720
• Temperature 721
• Optimal pH range 722
Page 25
• Mechanical energy (pressure and flow rate) 723 724 Rotation of Sanitizers 725
While rotation of the active ingredients used in sanitizers has been suggested to reduce 726
the potential for development of bacterial resistance, the published literature has not yet 727
substantiated this recommendation21,22. It is critical to assure that the sanitizers are used at 728
the labeled strength through proper dilution and preparation. Rotation of sanitizers is not a 729
common practice in the manufacture of cosmetic products. Where rotation is desired, 730
review the active ingredients listed on the chemical sanitizer label to assure that a rotation 731
of active ingredients is achieved when changing products. 732
733
SUMMARY 734
The selection and effective use of a cleaning or sanitizing agent and/or method is 735
dependent on the manufacturing facility, the type of product processed, and the design and 736
layout of the equipment. All cleaning and sanitizing procedures should be properly 737
designed and their use documented and validated. Personnel should receive adequate 738
instruction and training in these areas. With attention to these details, a cleaning and 739
sanitizing program will ensure a sanitary manufacturing facility. 740
Page 26
Table 3-1. Commonly Used Cleaners for Processing and Filling Equipment
Cleaner Type pH Range Soils Removed Examples Water NA Water soluble Potable water
Mineral-Acid and
Mild Acid Cleaners
0.2 - 5.5
Heavy scales to inorganic salts
Soluble metal complexes e.g. metal
oxides
Strong acids:
• Hydrochloric acid
• Sulfuric acid
• Phosphoric acid
Weak acids (dilute solutions of organic acids):
• Acetic acid
• Citric acid
Neutral Cleaners
5.5 - 8.5
Light oils
Small particulates
Mild, surfactant solutions (may include co-solvents such as alcohols or
glycol ethers to prevent phase separation of the surfactant solution) without
added water softening agents. Mild surfactants rely on dissolution and
emulsification.
Alkaline
8.5 - 12.5
Oils
Fats
Grease
Particulates
Films
Ammonium hydroxide
Sodium carbonate
Sodium phosphate
Borax solutions
Corrosive Alkaline 12.5 - 14 Heavy grease and oils
Pseudomonad biofilm (alginic acid)
Sodium hydroxide
Potassium hydroxide
Sodium silicates
Page 27
Table 3-2. Commonly Used Chemical Sanitizers for Processing and Filling Equipment General types and uses are listed below. Refer to manufacturer’s use directions and material safety data sheets (MSDS). Appropriate personal protective
equipment is required. Comply with existing regulations for use and disposal. Unless otherwise noted, sanitizers should be rinsed prior to use of equipment.
Chemicals should be used in accordance with the manufacturer’s directions and must be shown to be effective for the intended use.
Type Description Comments
Chlorine-based Sodium hypochlorite, Calcium
hypochlorite, Chloramines
Better activity at slightly acidic pH (~6.5) and warmer temperatures23,24.
Reactive with metal surfaces -corrosive if misused; must carefully regulate exposure time
Too acidic pH will generate toxic chlorine gas
Hydrogen peroxide Purchased as a stabilized solution
(35% active)
Less stable in the presence of light
Explosive at high levels – may require monitoring
Peroxy-hydrogen peroxide Peroxyacetic acid
Peracetic acid
Generally non-corrosive to stainless steel and aluminum. Corrosive to soft metals (iron, copper, zinc,
galvanized steel, etc.)
Breaks down to acetic acid and water
Concentrate is flammable and an explosion hazard
Alcohols Isopropanol
Ethanol
No rinsing required due to evaporation
May be used to dry small pieces of equipment or for anhydrous production
Flammability risk
Phenolic compounds Phenyl and/or chlorinated phenols Working solution may be unstable (use within 2-3 hours)
Quaternary ammonium compounds Quaternary ammonium compounds Has detergent properties
Noncorrosive
May be less effective versus pseudomonads25,26
Inactivated by anionic and non-ionic surfactants
Most effective at neutral or slightly alkaline pH
Requires analysis to confirm effective removal/rinsing.
Page 28
Table 3-3. Commonly Used Physical Sanitization Methods for Processing and Filling Equipment Type Description Suggested contact times / comments
Steam Heat27,28
Water at 100°Ca,b,c
20 minutes after temperature has been reached in furthest point of system; temperature must be validated throughout
the system
Clean steam should be used to prevent contamination from boiler treatment chemicals
Broad spectrum efficacy
Rinsing not required
Minimal risk of microbial resistance
Equipment should be dried after treatment
High energy consumption Hot Water
Water at 80°C
20 minutes after temperature has been reached in furthest point of system; temperature must be validated throughout
the system
Clean steam should be used to prevent contamination from boiler treatment chemicals
Broad spectrum efficacy
Rinsing not required
Minimal risk of microbial resistance
Equipment should be dried after treatment
High energy consumption
aHeat may cause equipment damage by expansion of close-fitting and/or moving parts. bHeat must be used with thermally stable materials. cSteam and scalding water pose a potential hazard.
Page 29
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