1

Table of Contents

INTRODUCTION .......................................................................................................................... 2

GENERAL CONSIDERATIONS .................................................................................................. 2

Biofilms....................................................................................................................................... 3

HACCP ....................................................................................................................................... 5

TRAINING ..................................................................................................................................... 5

VALIDATION................................................................................................................................ 6

RECORD KEEPING ...................................................................................................................... 6

Equipment Records ..................................................................................................................... 6

10

Equipment Status ........................................................................................................................ 7

11

MANUFACTURING FACILITY .................................................................................................. 7

12

Manufacturing / Production Areas .............................................................................................. 7

13

MANUFACTURING AND FILLING EQUIPMENT ................................................................... 8

14

Equipment Design....................................................................................................................... 9

15

Cleaning and Sanitization Schedule.......................................................................................... 13

16

General Procedures ................................................................................................................... 13

17

Equipment Cleaning and Sanitization................................................................................... 14

18

Special Equipment and Procedures....................................................................................... 15

19

Acceptance Criteria............................................................................................................... 18

20

CLEANERS .................................................................................................................................. 18

21

Characteristics of an Efficient Cleaner ..................................................................................... 19

22

Selection of a Cleaner or Cleaners for a Specific Process ........................................................ 19

23

SANITIZERS................................................................................................................................ 22

24

Definition .................................................................................................................................. 22

25

Physical Sanitizers .................................................................................................................... 24

26

Factors Affecting Efficacy ........................................................................................................ 24

27

Rotation of Sanitizers................................................................................................................ 25

28

SUMMARY .................................................................................................................................. 25

29

Table 3-1. Commonly Used Cleaners for Processing and Filling Equipment ............................. 26

30

Table 3-2. Commonly Used Chemical Sanitizers for Processing and Filling Equipment ........... 27

31
32

Table 3-3. Commonly Used Physical Sanitization Methods for Processing and Filling
Equipment ..................................................................................................................................... 28

33

REFERENCES ............................................................................................................................. 29

34
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CLEANING AND SANITIZATION

36
37

INTRODUCTION

38

Effective cleaning and sanitization programs are essential to ensure microbial quality in the

39

manufacture of cosmetics and personal care products. Cleaning procedures and

40

sanitization procedures should be validated in order to consistently meet hygienic

41

manufacturing requirements. The design of cleaning and sanitization procedures should

42

take into account the product formulation, engineering design of equipment, and all aspects

43

of manufacturing.

44
45

GENERAL CONSIDERATIONS

46

Specific internal programs for cleaning and sanitization should be established. These

47

programs are essential to:

48

Prevent ingredient cross-contamination

49

Assure the microbiological quality of the product;

50

Meet legal regulations where required;

51

Minimize the microbial load contributed by processing, filling, and storage

equipment;

52
53

Avoid the time and resources associated with microbial failure

54
55

If cosmetics and drug products are manufactured with the same equipment, refer to FDA

56

guidelines for the manufacture of OTC drugs.1-3 Factors such as active ingredient and cleaner

57

residues are important areas of C&S but are beyond the intended scope of this document.

58

the purpose of this document, the following definitions apply:

For

59
60

Cleaning - the process of removing product residue and contaminants such as

61

dirt, dust, and grease from surfaces. Cleaning is an essential step that needs

62

to be performed before the performance of a sanitization procedure. It is

63

important that personnel involved in cleaning have a working understanding of

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the nature of different types of soils and the chemicals required for their

65

removal.

66

Sanitization - the process utilized to reduce viable microbial contaminants to

67

an acceptable level such as the microbial count specification of the finished

68

product. All surfaces must be clean for the sanitization procedure to be

69

effective.

70

Validation - the process of substantiating that the process does what it

purports to do.

71

72

Documentation - the process of organizing all relevant information in an

73

orderly and easily understood format. This documentation is required to

74

validate a process and to maintain a historical record of the process and

75

equipment usage.

76
77

Guidance for the development of operating procedures is addressed in each section below,

78

as appropriate. Written protocols are required prior to attempting to validate any process.

79

For more information, see the "Microbial Validation and Documentation (Section 9) and

80

Microbiological Evaluation of the Plant Environment(Section 2). Additional information on

81

cosmetics Good Manufacturing Practices can be found in the CTFA Quality Assurance

82

Guidelines4. In addition, an understanding of the importance of biofilms5,6 and application

83

of hazard analysis of critical control points (HACCP)7-9 should also be considered.

84
85
86

Biofilms

87

A biofilm5,6,7 is a community of mixed microorganisms encased in an extracellular polymer

88

matrix, which they produce and secrete. Bacteria living in a biofilm may behave as a unit

89

or multicellular organism. Biofilms have the potential to develop in most aqueous systems

90

including process water systems and on those areas of manufacturing equipment that is

91

difficult to clean and sanitize. Biofilms can be also be present on equipment surfaces that

92

appear to be visually clean.

93
94

Biofilm Characteristics
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Once formed, biofilms become continuous sources of microbial contamination

96

as microorganism clumps or aggregates will break from the biofilm and

97

surfaces are colonized downstream and potentially contaminate finished

98

product.

99

Although thermal methods (e.g. 65 to 85C hot water or steam) kill

100

microorganisms within a biofilm, they are not effective in removing an

101

established biofilm. Killed but intact biofilm can become a nutrient source for

102

rapid biofilm regrowth.

103

Routine microbial sampling of water systems or equipment surfaces may not

104

be able to detect the presence of biofilms because they are not dispersed

105

homogeneously.

106
107

Microorganisms living in a biofilm on equipment are more difficult to kill and subsequently

108

remove than free floating organisms because they are protected by the polysaccharide

109

matrix structure of the biofilm. For chemical sanitization to be effective against biofilms, it

110

must be performed frequently in order to minimize the amount of biofilm development,

111

action.

112
113

The less developed and thinner the biofilm, the more effective the biocidal

Compounds such as hydrogen peroxide, peracetic acid or peroxyacetic acid,

114

and ozone oxidize microorganisms and kill biofilm organisms by the

115

formation of reactive peroxides and hydroxyl free radicals.

116

antimicrobial agents including disinfectants and sanitizers.

117
118

Microorganisms growing in a biofilm can exhibit reduced susceptibility to

Microorganisms in a well-developed biofilm can be extremely difficult to kill,

119

even by aggressive oxidizing biocides due to protection by the

120

polysaccharide layer of the biofilm.

121
122

Prevention of biofilm formation

123

Because of the difficulty in treating and removing mature biofilm, the emphasis must be

124

placed on prevention of biofilm formation. Appropriate equipment design, including

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adequate drainage and drying (See sanitary equipment design), validated cleaning and

126

sanitization procedures, and adequate frequency will help to minimize biofilm development.

127
128

HACCP

129

Hazard analysis critical control point (HACCP8-10 ) is a systematic preventive approach that

130

addresses physical, chemical and biological hazards. HACCP is a risk assessment

131

process that may be used to identify the critical control points (CCP) of the system. CCP

132

may include areas that are most difficult to reach for cleaning and sanitization and that are

133

keys to monitoring contamination in order to maintain microbial control.

134
135

HACCP typically consists of 7 steps:

136

Identify hazards and control measures

137

Determine critical control points

138

Define critical limits

139

Establish a monitoring system

140

Establish corrective actions

141

Verify that the control measures operate as defined

142

Document procedures, monitoring and events

143
144
145

TRAINING

146

Personnel should be properly trained in the cleaning and sanitization of the facility and

147

equipment.

148
149

A training program should be appropriate to the roles and responsibilities of the employee

150

and impart an understanding of the elements of cleaning and sanitization and their effect

151

on product quality. Training should include:

152

Basic equipment operation and design

153

Concepts of microbial contamination including common sources of

154

contamination
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156

Proper and safe use and appropriate disposal of cleaning and sanitization
agents

157

For further information on training, see Microbiology Staff Training (Section 4) and

158

Microbial Validation and Documentation (Section 9).

159
160

VALIDATION

161

All procedures used for cleaning and sanitization should be validated. For protocol and

162

additional information, see Microbial Validation and Documentation (Section 9).

163
164

RECORD KEEPING

165

Ongoing documentation includes routine logs that are necessary to maintain a history of

166

the equipment usage and cleaning and sanitization practices. This information can also

167

serve as part of a validation information package. It can be used for trend analysis and

168

evaluating cycle reduction. A cleaning and sanitizing record should be prepared,

169

maintained, and made readily available for each piece of equipment.

170
171

Equipment Records

172

Equipment records should include the following information:

173

Identification of the equipment

174

The product and batch to be made

175

Date, start and end times of the cleaning.

176

Date, start and end times of the sanitization, including expiration time.

177

Operating procedure, SOP, or procedure number for the cleaning and

sanitization being carried out

178
179

Any variation from the established operating procedure

180

Sign off by operator

181

Review, approval and sign off by verifier/reviewer

182

Time, date and identity of next batch start up

183

Date and description of any maintenance, repairs or equipment down

184

time
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186

Equipment Status

187

The current status of the equipment should be clearly displayed. Examples of status

188

designation labels may include:

189

In use: Contents and Batch or Lot Number

190

Needs Cleaning

191

Clean Needs Sanitizing

192

Sanitized*

193

Out of Service

194
195

Sanitization date and expiration time should be included on the label. If expiration time is

exceeded, the equipment should be re-sanitized before being put back into service.

196
197

MANUFACTURING FACILITY

198

The environment of the manufacturing facility strongly influences the microbial quality of the

199

finished product. Appropriate building design and maintenance are critical. Standard

200

procedures for facility cleaning should be written and a record of their implementation

201

should be maintained11,12. For additional information, see Microbiological Evaluation of the

202

Plant Environment. (Section 2)

203
204
205

Manufacturing / Production Areas

206

The frequency of cleaning is determined by the types of activities conducted in any given

207

area of the facility. Cleaning schedules can be adjusted, and remedial action can be

208

taken as required. Precautions should be taken to minimize airborne dust from

209

manufacturing equipment and areas during all cleaning and sanitization. Any spills of raw

210

materials, product, or packaging components should be cleaned up promptly. Based on

211

product risk, some areas may need to be under greater microbial control and therefore,

212

may require a higher degree of plant hygiene.

213
214

Walls, ceilings, pipes, fixtures, and HVAC systems

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Clean on a scheduled basis.

216
217

Floors

218

Clean floors on a scheduled basis and include the following:

219

Vacuum and/or sweep frequently

220

Wet-mop or machine scrub on a predetermined schedule

221

Sanitize as appropriate

222

Keep floors dry as much as possible

223
224

Cleaning equipment and supply storage

225

Store cleaning equipment and supplies properly in a clean area. Supplies and equipment

226

used for lavatory cleaning should be stored separately from cleaning supplies and

227

equipment used in manufacturing areas.

228
229

Warehouse Areas

230

General guidance for the warehouse area includes the following:

231

scrubbing. An appropriate, freshly prepared cleaner should be used.

232
233

236

An established, monitored, and documented insect and rodent control program

should be in place. For additional information, see Quality Assurance Guidelines6.

234
235

Aisles should be kept neat and clean by sweeping, damp mopping or machine

Stored materials and containers should be kept clean, orderly, protected and
correctly identified.

237
238

MANUFACTURING AND FILLING EQUIPMENT

239

Manufacturing and filling equipment13,14 has direct contact with product. For cleaning and

240

sanitization procedures to be effective, appropriate consideration to equipment design

241

should be made.

242

It is essential that manufacturing and filling equipment have good drainage and be

243

designed for ease of conducting proper cleaning and sanitization. In addition, the

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equipment should be durable enough to withstand sanitizing chemicals and/or physical

245

agents that are used for cleaning and sanitization.

246
247

Equipment design

248

The following guidance on overall equipment design is intended to minimize conditions that

249

may lead to microbial growth in the equipment. It also offers suggestions to reduce the

250

potential degradation of the equipment by the effects of the cleaners and sanitizers used.

251

It is essential to work with your engineering department in choosing the appropriate

252

equipment design and specifications for your facility.

253

Design manufacturing and filling equipment to minimize retention of

254

residual product and/or wash water. Where equipment is not self-

255

draining, the installation of sanitary drain valves or valves that can be

256

completely disassembled may be of value. Residual water in equipment

257

will dilute product and/or sanitizer which can lead to microbial growth

258

and the development of adaptable microorganisms.

259

and create an environment for microbial growth.

260
261

Minimize condensation in equipment. Condensation can dilute product

Design equipment so that during cleaning, all internal surfaces are in

262

contact with the cleaning solution. All internal surfaces should be as free

263

as possible of crevices that can harbor product or microorganisms.

264

External surfaces should be easily cleanable.

265

Choose materials of construction that are not easily degraded, etched, or

266

reacted when in contact with the product, cleaners or sanitizers such as

267

316L stainless steel.

268

Choose equipment with a surface finish that is easily cleanable, durable,

269

capable of being derouged and passivated; e.g., 316L stainless steel with

270

a surface finish of 25 Roughness Average (RA) or a minimum of 140

271

grit or better finish.

272
273

Threaded fittings are difficult to clean and can hold finished bulk product
residue that can lead to contamination. Choose equipment without
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threaded fittings that have a gasket and clamp connection or use bevel

275

seat connections (outside threads) which are acceptable if installed and

276

maintained properly to avoid leakage into the outside threads.

277

interface is readily contaminated when gasket integrity is not maintained.

278
279

Routinely inspect and replace gaskets when necessary, as the gasket

Use sanitary welding techniques such as orbital welding or gas tungsten

280

orbital arc welding is recommended to avoid creating crevices or rough

281

surfaces that are difficult to clean. Chemically welded joints of plastic

282

piping should be checked and be smooth to facilitate cleaning.

283
284

Common sanitary design practices for specific types of equipment are listed in the

285

following sections.

286
287

Tanks/Vessels

288

Minimize sharp corners because they are difficult to clean.

289

Avoid narrow recesses that could trap product and water.

290

Design tanks with a domed head to minimize condensation.

291

Choose tanks and vessels with conical or dish shaped bases, with a
center drain, as they allow for complete draining.

292
293

Design vessel openings and surfaces to be easily cleaned.

294

Design and maintain covers to fit well and close easily.

295

Design vents to minimize debris.

296

Eliminate pipes with dead legs.

297

Design tanks with spray ball devices that cover the entire surface area
and all shadows created by internal components.

298
299
300

Tanks with mixing capability should be equipped with welded or singe

piece mixer blades and shaft.

301
302
303
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Transfer Pipes

305

Minimize the length of pipe runs to make cleaning easier and slope the

306

pipe runs to be self-draining (>1%) to reduce the risk of biofilm

307

formation.

308

Choose a pipe diameter that is appropriate to maintain the required flow

rate for the cleaning solution.

309

310

In-line filters should be designed for easy cleaning, sanitization and

inspection.

311
312

Design piping systems to have a minimal number of T's.

313

Use sanitary welding techniques to avoid the creation of difficult-to-clean

crevices and rough surfaces.

314
315

Use sanitary fittings for all connections.

316

Avoid flange and screw-threaded piping that comes in contact with the
product.

317
318
319

Valves

320

Valves should be easily cleanable with no dead spaces to collect product residue or water.

321

Examples of sanitary valves are diaphragm valves and butterfly valves. The use of valves

322

that can collect product residue or water, such as ball valves, is not recommended due to

323

dead spaces resulting from their design.

324
325

Pumps

326

Sanitary pumps are recommended. Sanitary pumps are oriented with a vertical inlet and

327

outlet and passes and pressure relief valves are designed to prevent water and/or product

328

retention. Examples of sanitary pumps are diaphragm pumps and peristaltic or lobe

329

pumps. Examples of non-sanitary pumps for moving finished product are centrifugal

330

pumps, gear pumps, or mono pumps. It should be noted that centrifugal pumps are

331

commonly used in process water systems without having microbial contamination issues.

332

Pumps should be easily accessible for inspection, cleaning, and sanitization.

333
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Filling Equipment

335

Fillers should be designed to be easily cleaned and sanitized. Avoid drip pans and water-

336

lubricated belts. If compressed air is used in filling equipment, the lines should be

337

equipped with microbial retentive filters and air-line dryers which should be monitored to

338

prevent air-line condensate from contaminating finished product.

339
340

Gaskets

341

Gasket interfaces are potential sites for contamination. Gasket materials should be

342

compatible with the product as well as the cleaning and sanitizing solutions. Non-porous,

343

chemically inert materials such as ethylene propylene diene monomer (EPDM), silicone,

344

and TEFLON (need to use trade name properly md to look up) are recommended.

345

Care should be taken to assure that gaskets are properly installed, inspected, and

346

replaced at a preventative maintenance frequency that is performed prior to wear and

347

damage causing loss of integrity.

348
349

Hoses

350

Transfer hoses should be of a material that is compatible with product, cleaners and

351

sanitizers to be used. Common hose materials are:

352

reinforced food grade rubber or neoprene

353

TYGON tubing

354

Polyethylene

355

Polypropylene

356

nylon

357
358

They should have flush mounted sanitary fittings composed of 316L stainless steel with

359

rounded edges and a minimum grit of 180 to prevent migration of product between the

360

fitting and the hose material. Cleaned and sanitized hoses should be hung in such a

361

manner that they completely drain to dry and visually inspected. Hoses should be capped

362

after drying or stored in a protected area. If hoses are capped, a non-woven microbial

363

barrier is preferred.
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Cleaning and Sanitization Schedule

366

Frequency

367

The frequency of equipment cleaning and sanitization should be determined during

368

validation and is typically based on several factors including:

369

Vulnerability of product to contamination

370

Type of equipment used

371

Whether continuous process batching is being performed

372
373

Expiration limit

374

An expiration limit for cleaning procedures and sanitization procedures should be set for

375

each piece of manufacturing equipment. This expiration limit reflects the allowable time a

376

piece of equipment can stand before requiring recleaning and/or resanitization. This will

377

depend on the equipment, the environment in which the equipment is stored, and methods

378

used for cleaning and sanitization.

379
380

Once the cleaning and sanitization procedures have been validated, periodic monitoring of

381

equipment is essential. For additional information, see Microbiological Evaluation of the

382

Plant Environment (Section 2).

383
384

General Procedures

385

General Housekeeping Practices

386

Clean spills immediately and remove debris from the manufacturing areas.

387

Use disposable towels and discard immediately after single use. Nondisposable cleaning cloths should not be used.

388

389

manufacturing areas.

390
391
392

Container exteriors should be cleaned before transferring material into

Water

The water used to make up cleaners and sanitizers should have a low microbial

393

bioburden to avoid contaminating the cleaner and to avoid consuming the

394

sanitizer.
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Water used to rinse cleansers from cleaned equipment should be fresh, potable

396

water that has a microbiological quality that meets EPA or equivalent potable

397

water quality standards.15

398

Water used to rinse chemical sanitizers from sanitized equipment must have no

399

higher microbial bioburden then the microbial specifications of the product to be

400

made in that equipment.16

401

Water hardness should be considered when diluting sanitizers and cleaners

402

because hardness may affect the efficacy of the chemicals used. If an alkaline

403

cleaning agent is used, hardness ions in the water may precipitate out as

404

calcium carbonate and may cause a white residue on the surface. For sanitizer

405

preparation, utilize the water hardness and instructions provided on the EPA

406

approved sanitizer label.

407
408

The pH of the water may affect the cleaning ability of some cleaners and the
antimicrobial activity of sanitizers/disinfectants.

409
410

Equipment cleaning and sanitization

411

Outer surfaces of equipment should be maintained in a clean state. Clean and sanitize all

412

lines; processing, storage and filling equipment; pumps; pipe connections; flexible hoses

413

and utensils in the immediate processing and filling areas as follows:

414

Remove product residue from all contact surfaces by thoroughly rinsing

415

with water or a water/detergent solution. Rinse water for sanitized

416

equipment should not contain higher microbial content than the limits that

417

have been established for the finished product. Temperature of the rinse

418

solution is dependent on product type, equipment compatibility, and

419

detergent. NOTE: Non-aqueous-type product residues should be removed

420

by appropriate predetermined methods.

421

Pipeline pigs are devices made of non-porous materials used for recovery

422

of product, product separation, and cleaning of manufacturing pipelines. If

423

pigs are used, assure thorough cleaning and sanitization of pigging

424

equipment and of the pig itself. When not in use, pigs must be handled
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and stored under sanitary, dry conditions. The pig launcher and receiving

426

station must be sanitary in design as this equipment can easily harbor

427

microbial contaminants.

428

Circulate a cleaning solution at an appropriate flow rate for a period of

429

time and at a temperature capable of effectively removing soil residue in

430

the circuit and/or equipment. All surfaces not accessible by this cleaning

431

procedure should be cleaned manually and/or by using special equipment

432

or methods.

433

Rinse the cleaning solution thoroughly from the system with

434

microbiologically acceptable water, as determined by in-house standards.

435

When water is used to rinse equipment, the equipment should be drained

436

and used within a validated expiration time.

437

All equipment should be sanitized following cleaning or before use

438

according to the written procedure for the piece of equipment involved and

439

used within the validated expiration time. See "Special Equipment and

440

Procedures" below.

441

If chemical sanitizers are used, rinse water for sanitized equipment should

442

not contain higher microbial content than the limits established for the

443

formulated products.

444
445

Equipment should be cleaned as soon after use as possible in order to facilitate product

446

removal. Product that has dried and hardened onto equipment surfaces can be difficult to

447

remove thoroughly. Ideally, clean equipment should be sanitized as close to the next use

448

as possible. Cleaned/sanitized equipment should be properly stored before use to prevent

449

recontamination. In general, equipment should be drained dry with open ends covered to

450

prevent recontamination. Validated clean hold times and sanitized hold times should be

451

established for all equipment to be stored prior to re-use.

452
453
454

Special Equipment and Procedures

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Special cleaning and sanitizing equipment and methods may be employed for processing

456

and filling apparatus. The equipment and methods are generally designed to fit the

457

individual needs of each manufacturing facility. There are several methods for cleaning

458

and/or sanitizing.

459
460

Manual

461

Manual methods involve the preparation of cleaning solution and the scrubbing

462

of equipment or parts using a brush, single-use cloth or pad. Proper training

463

and appropriate procedures are critical to obtaining reproducible results.

464
465

Soak

466

This method involves the immersing of utensils or equipment parts in containers

467

of detergent or sanitizing solution for extended periods of time. Parts should be

468

completely immersed in the solution with no air bubbles.

469
470

Spray

471

Low or high-pressure sprays are used to remove soil. In most cases, the

472

cleaning action of the pressure spray is enhanced by the use of detergents.

473

High-pressure spray devices such as spray balls or injectors may be installed in

474

mixing or storage tanks. Piping that delivers solutions to the spray ball should

475

be sloped to allow adequate drainage. Spray balls or injectors may become

476

clogged with product residue or debris and should be removed, if possible, and

477

cleaned periodically. If spray balls or injectors are removed after cleaning and

478

sanitization, they should be stored in a clean area in a self-draining position.

479
480

High-pressure spray wand equipment is also widely used. This type of

481

equipment may be movable. It is used for general surface cleaning. Spray

482

pressures developed should range from 200 to 1000 p.s.i.. These devices

483

should not be used in an area or in a manner that creates an overspray

484

contaminating nearby clean equipment.

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486

Fog

487

Fogging is a method of generating a mist for the application of sanitizers. Large areas of

488

equipment surfaces can be treated by fogging in a very short time using small amounts of

489

sanitizers. This method of application should only be used when the EPA product label

490

clearly provides instructions for fogging of hard surfaces. The labeling may only allow

491

fogging as an adjunct to traditional surface sanitization. Fogging should only be used in

492

closed systems by properly trained personnel using the appropriate personal protective

493

equipment.

494
495
496

Clean In Place (CIP)

497

CIP is a semi- or fully automated, self-contained system for the cleaning and

498

sanitizing of equipment. Cleaning and sanitizing solutions are circulated for a

499

specific time at specified temperatures. Little or no disassembly of equipment is

500

necessary. Unless properly designed, installed and maintained, CIP systems

501

can become contaminated. Each system is unique and to work well it should

502

be properly designed, evaluated and controlled. Factors to consider when using

503

CIP are: detergent/sanitizer type; detergent/sanitizer concentration;

504

temperature; and design of equipment. Some equipment design factors include

505

type, number, positioning of spray devices, pressure to spray device, velocity

506

rates in flow paths, type of pump, and shadows in tanks created by internal

507

components such as baffles, etc. Portable and fixed CIP skids should be of

508

sanitary design and have the same validation requirements as the equipment

509

being cleaned.

510
511

Steam in Place (SIP)

512

Steam in place is a semi or fully automated system for the disinfection of

513

equipment. Steam is flushed into the equipment for a specified time at a

514

specified temperature. It is a suitable system for large volume equipment such

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as storage tanks, manufacturing vessels, transfer pipes, etc. because the

516

elevated temperature can treat complex internal geometries which may not be

517

reached by sanitizer solutions. Disinfection cycles should be determined for

518

each piece of equipment in order to take into account their complexity and

519
520
521

drainability.

Acceptance Criteria

522

Prior to validation of the cleaning and sanitization processes for equipment, the acceptance

523

criteria for each process should be determined. Criteria should take into account the types

524

of finished products that are being processed by the equipment. Criteria for cleaning

525

include no product residue and no standing water. Criteria for sanitization typically include

526

no standing water and microbial bioburden that meet specific requirements or microbial

527

release limits of the finished product. If chemical sanitizers are being used, analytical

528

specification for detecting the presence of an allowable limit of sanitizer residue may also

529

be included as part of the acceptance criteria. In general, these are the minimal criteria

530

that should be considered.

531
532

Alert and action levels for microorganisms should be established by quality assurance

533

based on finished product microbial content specifications.

534
535

CLEANERS

536

A cleaner can be defined as a chemical or blend of chemicals formulated to remove soils

537

from a contact surface. These chemicals may be solvents, acids, bases, oxidizers,

538

detergents, and/or water-based chemical blends.

539
540

Aqueous cleaners are defined as blends of water-soluble chemicals designed to remove

541

soils into a water-based solution with a water continuous phase during cleaning. These

542

consist of surface active ingredients and other cleaning chemicals that use detergency to

543

lift soils from surfaces8.

544
Page 18

545

Characteristics of an Efficient Cleaner

546

Aqueous cleaners are typically formulated to contain several ingredients to allow for

547

maximum cleaning effectiveness. The ingredient requirements depend on the intended use

548

of the cleaner. Efficient aqueous cleaners utilize surfactants (anionic, nonionic, cationic

549

and/or amphoteric), dispersants, emulsifiers, wetting agents, builders, chelating agents,

550

sequestering agents, corrosion-inhibiting agents and stabilizers. The surfactants are used

551

for emulsification, wetting and penetration; builders are used for neutralizing hard water

552

interferences, chelating inorganic soils, and saponification of natural oils; and additives for

553

corrosion inhibition, anti-redisposition and good rinseability.

554
555

General characteristics to consider in choosing a cleaner:

556

Compatibility with equipment, i.e., non-corrosive

557

Solubility

558

Wetting action

559

Penetration properties

560

Emulsification and soil-dispersion properties

561

Rinsing properties

562

Cost and availability

563

Compliance with existing environmental and occupational safety regulations

564
565

Table 3-1 gives examples of various types of cleaners. For additional information, see

566

References 13, 14, and 17.

567
568

Selection of a Cleaner or Cleaners for a Specific Process

569

Although the characteristics of an efficient cleaner may be more general, the selection of a

570

particular cleaner for a particular cleaning task requires specific information. The most

571

important considerations include knowledge of the type of substrate to be cleaned and the

572

type of soil to be removed. The cleaner type should be matched to the surface to be

573

cleaned (metal, glass, plastic, etc.), the soil type (organic, inorganic, oils, heavy soils, light

574

soils, etc) and the desired cleaning method (manual, soaking, CIP, power spray wand,
Page 19

575

etc.). Information on the level of cleanliness required (acceptance criteria) should also be

576

known. For difficult to clean materials, use of more than one cleaner in a specific order or

577

regimen may be considered. Several questions can be asked prior to the selection of a

578

cleaning system:

579

Does the cleaner have good detergency on the type of soil to be removed?

580

Is the cleaner recommended for the cleaning process to be used?

581

Is the cleaner easily rinsed without leaving residuals?

582

Does the cleaner have to be treated before being flushed to drain?

583
584

Variables Affecting Efficiency

585

Besides the selection of an efficient cleaner, several other factors are extremely relevant to

586

the success of a cleaning process. Beyond the cleaner itself, cleaning efficiency is

587

influenced by cleaner concentration, agitation, temperature, cleaning/contact time, rinse

588

method and drying method. These process variables must be considered, specified, and

589

controlled to ensure a consistent and optimized cleaning process.

590
591

Cleaner Concentration

592

The concentration of the cleaner and process optimization should be selected through

593

consultation with the supplier of the material followed by in-house validation.

594
595

Temperature

596

Temperature should be optimized for the soil being removed and the equipment and

597

cleaner being used. The process should be validated using an appropriate method.

598

Safety considerations should be addressed if risk of personnel exposure exists. Cleaners

599

efficient at lower temperatures are now available and may be considered to reduce energy

600

consumption.

601
602

Time

603

Cleaning time is dependent on several factors of the process. These factors include

604

mechanical action, temperature, cleaner effectiveness, type of equipment being cleaned,

Page 20

605

and degree and nature of the soil to be removed. For example, the mechanical action of

606

high-pressure sprays may require from seconds to minutes while soaking may require a

607

substantially longer time. Cleaning time should be determined during the validation of the

608

entire cleaning process/system.

609

Rinsing

610

It is important that the rinse procedure removes any residue left during cleaning. The

611

specified volume of rinse water should be optimized and validated for each particular rinse

612

program. Ensure there is no cleaner residue remaining.

613
614

Drying

615

To reduce the potential for corrosion, inhibit microbial growth and biofilm formation, and

616

prevent dilution of chemical sanitizers, it is essential that the equipment be completely

617

drained and dried after rinsing. Evaporation is the simplest and least-expensive drying

618

method. It is most appropriate when used after hot water rinses on equipment that can be

619

easily drained such as tanks. Drying by evaporation is not appropriate for equipment that

620

cannot be completely drained such as filling lines. Drying by evaporation after ambient

621

water rinses can require longer dry times and may lead to higher risk of microbial

622

contamination. Other methods include circulated hot air, vacuum-drying, and forced-air

623

blow drying. For these methods, high quality air must be used for drying. The air source

624

may be filtered (particulate, hydrocarbon, and microbial retentive) to provide high-quality

625

air for drying. This type of mechanical drying is especially useful for equipment that is

626

used for anhydrous products where it is essential that no moisture remain in the

627

equipment. Use of alcohol free from spore forming organisms as a finishing step can aid

628

in the evaporation of water. Alcohol can be used as a dryer/sanitizer although it is not as

629

effective as mechanical drying and is most appropriate on small pieces of equipment.

630

Caution should always be used when using alcohol on equipment as it could present a fire

631

and explosion hazard.

632
633

Validation of the Cleaning Process

Page 21

634

The development of a testing and measurement system is important for optimizing and

635

validating the effectiveness of a specific cleaning process

636

measuring the effectiveness of the cleaning process should provide information needed to

637

determine that key criteria are met. Testing of the cleaning process initially requires the

638

development of a baseline level of cleanliness and an effective method to measure

639

removal of soils and cleaner residues. In many cases, visual assessments of equipment

640

or simple gravimetric analysis will suffice. Supplemental tools for evaluation may include

641

video scopes, chemical tracer measurements (fluorescent whiteners, total organic carbon

642

(TOC) in residual water, or conductivity). The simplest method that provides appropriately

643

sensitive results should be used.

. The method selected for

17,18

644
645

After the cleaning system has been selected, it should be validated against the targeted

646

product and on the equipment where the production will occur. Either a quantitative or

647

qualitative method may be used to judge the cleaning process, and then acceptance

648

criteria should be established.

649

pilot-plant scale; however, the cleaning system should be validated on the actual

650

equipment due to concerns with scale-up. Each variable of the cleaning process (cleaner

651

concentration, time, temperature, mechanical action, etc.) should be considered to

652

determine the optimal conditions.

Experimentation may occur initially on a smaller bench or

653
654

SANITIZERS

655
656

Definition

657

A sanitizer is either a chemical or physical agent that is effective in reducing microbial

658

contamination on hard, nonporous contact surfaces. A sanitizer may be considered

659

effective if it reduces microorganisms to levels established by company standards, with no

660

detectable objectionable microorganisms, as determined by the cleaning and sanitization

661

protocol.11,17,18

662

Page 22

663

Surfaces should be cleaned and free of residue prior to sanitization since residues can

664

interfere with activity of both chemical and thermal sanitization.

665
666

Factors to consider in choosing a sanitizer:

667

Effective against a broad range of microorganisms.

668

Provides adequate microbial reduction against organisms of concern.

669

Effective in a relatively short contact time.

670

Stable and efficacious over time, both in concentrate form and at use levels.

671

Economical to use.

672

Compatible with products and equipment.

673

Meets regulatory requirements.

674

Environmental impact

675
676

Chemical Sanitizers

677

Combined cleaner/sanitizer agents are available. These one-step products are

678

registered by EPA to be effective in the presence of light to moderate soil; however, heavy

679

soil must be removed prior to use. When using a two-step process where a cleaning

680

agent is used prior to application of a sanitizer, surfaces should be free of residue prior to

681

sanitization since residues can interfere with activity of chemical sanitization.

682
683

Some useful chemical sanitizing agents are chlorine, hydrogen peroxide, peracetic acid,

684

alcohols, phenolic compounds, and quaternary ammonium compounds. See Table 3-2 for

685

information on frequently used chemical sanitizers for processing and filling equipment.

686

Chemical sanitizers should be used according to the manufacturers directions and must be

687

shown to be effective for the intended use.

688
689

For sanitization of process water and process water systems, see Microbiological Quality

690

for Process Water (Section 7) . See references #19 and 20 for additional information on

691

chemical sanitizers.

692
Page 23

693

Physical Sanitizers

694

The most common physical sanitizers are steam or hot water. A major advantage of heat

695

is its ability to penetrate into small cracks and crevices. Heat is also non-corrosive, cost-

696

effective, measurable with recording devices or thermal strips, efficient, effective against a

697

broad range of microorganisms, and leaves no residue.

698
699

Surfaces should be cleaned and free of residue prior to sanitization since residues can

700

interfere with activity of thermal sanitization.

701
702

See Table 3-3 for information on frequently used physical sanitization methods for

703

processing and filling equipment.

704
705

Factors Affecting Efficacy

706

Cleaning must always precede sanitization. In-house validation is needed to assure

707

efficacy of the sanitization process. Roughness of surface, bad welds or other defects can

708

make the equipment difficult to sanitize. Care should always be taken to follow label

709

directions and manufacturer instructions and recommendations. Water incorporated into

710

sanitizers should be of appropriate chemical and microbial quality. The presence of

711

dissolved gasses and solids within water should not be at a level that inactivates or

712

reduces the efficacy of the sanitizing agent. Operators should be properly trained.

713

Improper use may give ineffective results, release toxic fumes, or corrode equipment.

714
715

The following process variables should be considered, specified, and controlled to ensure

716

consistent sanitizer performance:

717

Condition of equipment surfaces

718

Materials of construction

719

Concentration of sanitizer

720

Contact time

721

Temperature

722

Optimal pH range
Page 24

723
724

Mechanical energy (pressure and flow rate)

725

Rotation of Sanitizers

726

While rotation of the active ingredients used in sanitizers has been suggested to reduce

727

the potential for development of bacterial resistance, the published literature has not yet

728

substantiated this recommendation21,22. It is critical to assure that the sanitizers are used at

729

the labeled strength through proper dilution and preparation. Rotation of sanitizers is not a

730

common practice in the manufacture of cosmetic products. Where rotation is desired,

731

review the active ingredients listed on the chemical sanitizer label to assure that a rotation

732

of active ingredients is achieved when changing products.

733
734

SUMMARY

735

The selection and effective use of a cleaning or sanitizing agent and/or method is

736

dependent on the manufacturing facility, the type of product processed, and the design and

737

layout of the equipment. All cleaning and sanitizing procedures should be properly

738

designed and their use documented and validated. Personnel should receive adequate

739

instruction and training in these areas. With attention to these details, a cleaning and

740

sanitizing program will ensure a sanitary manufacturing facility.

Page 25

Table 3-1. Commonly Used Cleaners for Processing and Filling Equipment
Cleaner Type
Water

pH Range

Soils Removed

Examples

0.2 - 5.5

Heavy scales to inorganic salts

Strong acids:

NA

Water soluble

Potable water

Mineral-Acid and
Mild Acid Cleaners

Soluble metal complexes e.g. metal

Hydrochloric acid

oxides

Sulfuric acid

Phosphoric acid

Weak acids (dilute solutions of organic acids):

Neutral Cleaners

5.5 - 8.5

Acetic acid

Citric acid

Light oils

Mild, surfactant solutions (may include co-solvents such as alcohols or

Small particulates

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

Ammonium hydroxide

Fats

Sodium carbonate

Grease

Sodium phosphate

Particulates

Borax solutions

Films
Corrosive Alkaline

12.5 - 14

Heavy grease and oils

Sodium hydroxide

Pseudomonad biofilm (alginic acid)

Potassium hydroxide
Sodium silicates

Page 26

Table 3-2. Commonly Used Chemical Sanitizers for Processing and Filling Equipment
General types and uses are listed below. Refer to manufacturers 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 manufacturers directions and must be shown to be effective for the intended use.
Type
Chlorine-based

Description

Comments

Sodium hypochlorite, Calcium

Better activity at slightly acidic pH (~6.5) and warmer temperatures23,24 .

hypochlorite, Chloramines

Reactive with metal surfaces -corrosive if misused; must carefully regulate exposure time
Too acidic pH will generate toxic chlorine gas

Hydrogen peroxide

Peroxy-hydrogen peroxide

Purchased as a stabilized solution

Less stable in the presence of light

(35% active)

Explosive at high levels may require monitoring

Peroxyacetic acid

Generally non-corrosive to stainless steel and aluminum. Corrosive to soft metals (iron, copper, zinc,

Peracetic acid

galvanized steel, etc.)

Breaks down to acetic acid and water
Concentrate is flammable and an explosion hazard

Alcohols

Isopropanol

No rinsing required due to evaporation

Ethanol

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 27

Table 3-3. Commonly Used Physical Sanitization Methods for Processing and Filling Equipment
Type
Steam Heat27,28

Description
Water at 100Ca,b,c

Suggested contact times / comments

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 80C

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

Heat may cause equipment damage by expansion of close-fitting and/or moving parts.

Heat must be used with thermally stable materials.

b
c

Steam and scalding water pose a potential hazard.

Page 28

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Manufacturing, Processing,

Packing, or Holding of Drugs; General, FDA 21 CFR,

Part 210.
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FDA 21 CFR, Part 211.

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pharmaceuticals.
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11. Bloomfield, S. F., and R. M. Baird (Ed) 1996, Microbial Quality Assurance in Cosmetics,
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Assurance Guidelines. Washington, DC: The Personal Care Products Council.

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Disinfection, Preservation and Sterilization, Blackwell Science, Malden, MA.

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Biotechnology; Pesticides, Volume 11.05, West Conshohocken, PA.

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sodium hypochlorite short-term stability, pulp dissolution capacity and antimicrobial
efficacy. J Endod. 31:669-71.
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Bacterial resistance to

disinfectants containing quaternary ammonium compounds. International Biodeterioration

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