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Table of Contents 1 INTRODUCTION .......................................................................................................................... 2 2 GENERAL CONSIDERATIONS .................................................................................................. 2 3
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
sequestering agents, corrosion-inhibiting agents and stabilizers. The surfactants are used 550
for emulsification, wetting and penetration; builders are used for neutralizing hard water 551
interferences, chelating inorganic soils, and saponification of natural oils; and additives for 552
corrosion inhibition, anti-redisposition and good rinseability. 553
554
General characteristics to consider in choosing a cleaner: 555
• Compatibility with equipment, i.e., non-corrosive 556
• Solubility 557
• Wetting action 558
• Penetration properties 559
• Emulsification and soil-dispersion properties 560
• Rinsing properties 561
• Cost and availability 562
• Compliance with existing environmental and occupational safety regulations 563
564
Table 3-1 gives examples of various types of cleaners. For additional information, see 565
References 13, 14, and 17. 566
567
Selection of a Cleaner or Cleaners for a Specific Process 568
Although the characteristics of an efficient cleaner may be more general, the selection of a 569
particular cleaner for a particular cleaning task requires specific information. The most 570
important considerations include knowledge of the type of substrate to be cleaned and the 571
type of soil to be removed. The cleaner type should be matched to the surface to be 572
cleaned (metal, glass, plastic, etc.), the soil type (organic, inorganic, oils, heavy soils, light 573
soils, etc) and the desired cleaning method (manual, soaking, CIP, power spray wand, 574
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etc.). Information on the level of cleanliness required (acceptance criteria) should also be 575
known. For difficult to clean materials, use of more than one cleaner in a specific order or 576
regimen may be considered. Several questions can be asked prior to the selection of a 577
cleaning system: 578
• Does the cleaner have good detergency on the type of soil to be removed? 579
• Is the cleaner recommended for the cleaning process to be used? 580
• Is the cleaner easily rinsed without leaving residuals? 581
• Does the cleaner have to be treated before being flushed to drain? 582
583
Variables Affecting Efficiency 584
Besides the selection of an efficient cleaner, several other factors are extremely relevant to 585
the success of a cleaning process. Beyond the cleaner itself, cleaning efficiency is 586
influenced by cleaner concentration, agitation, temperature, cleaning/contact time, rinse 587
method and drying method. These process variables must be considered, specified, and 588
controlled to ensure a consistent and optimized cleaning process. 589
590
Cleaner Concentration 591
The concentration of the cleaner and process optimization should be selected through 592
consultation with the supplier of the material followed by in-house validation. 593
594
Temperature 595
Temperature should be optimized for the soil being removed and the equipment and 596
cleaner being used. The process should be validated using an appropriate method. 597
Safety considerations should be addressed if risk of personnel exposure exists. Cleaners 598
efficient at lower temperatures are now available and may be considered to reduce energy 599
consumption. 600
601
Time 602
Cleaning time is dependent on several factors of the process. These factors include 603
mechanical action, temperature, cleaner effectiveness, type of equipment being cleaned, 604
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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
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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
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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
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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
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• 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
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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
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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.
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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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REFERENCES
1. U.S. Food and Drug Administration. 2010. “Current Good Manufacturing Practice in
Manufacturing, Processing, Packing, or Holding of Drugs; General”, FDA 21 CFR,
Part 210.
2. U.S. Food and Drug Administration. 2010. “Current Good Manufacturing Practice for
Finished Pharmaceuticals” FDA 21 CFR, Part 211.
3. U.S. Food and Drug Administration. 2001. Guidance for Industry – Q7A Good
Manufacturing Practice Guide for Active Pharmaceutical Ingredients.