cleaning and sanitization

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

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

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

• 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

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

• 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

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

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

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

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

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

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

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

• 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

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

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

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

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

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

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

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

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

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

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

• 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

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

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.

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.

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