1、18.1CHAPTER 18CLEAN SPACESTerminology . 18.1Clean Spaces and Cleanroom Applications. 18.2Airborne Particles and Particle Control 18.3Air Pattern Control 18.4Airflow Direction Control Between Clean Spaces. 18.8Testing Clean Air and Clean Spaces 18.9Pharmaceutical and Biomanufacturing Clean Spaces 18.
2、9Start-Up and Qualification of Pharmaceutical Cleanrooms 18.14Semiconductor Cleanrooms . 18.15High-Bay Cleanrooms 18.17Environmental Systems. 18.19Sustainability and Energy Conservation 18.22Noise and Vibration Control 18.24Room Construction and Operation 18.24Cleanroom Installation and Test Procedu
3、res . 18.24Integration of Cleanroom Design and Construction 18.27Life and Property Safety. 18.27LEAN SPACES are defined as areas in which particle concen-Ctration and environmental conditions are controlled at or withinspecified limits. Design of clean spaces (or cleanrooms) covers muchmore than tra
4、ditional control of air temperature and humidity. Addi-tional factors may include control of particle, microbial, electrostaticdischarge (ESD), molecular, and gaseous contamination; airflow pat-terns; air pressurization; sound and vibration; environmental health;life safety; industrial engineering a
5、spects; and manufacturing equip-ment layouts. The objective of good cleanroom design is to maintaineffective contamination control while ensuring required levels of reli-ability, productivity, installation, and operating costs.1. TERMINOLOGYAcceptance criteria. Upper and lower limits of a pharmaceut
6、icalcritical parameter required for product or process integrity. If theselimits are exceeded, the pharmaceutical product may be consideredadulterated.ach. Air changes per hour.Air lock. A small transitional room between two adjacent roomsof different cleanliness classification and air pressure set
7、points.As-built cleanroom. A cleanroom that is completely con-structed, with all services connected and functional, but not contain-ing production equipment, materials, or personnel in the space.Aseptic space. A space controlled such that bacterial growth iscontained within acceptable limits. This i
8、s not a sterile space, inwhich absolutely no life exists.At-rest cleanroom. A cleanroom that is complete with produc-tion equipment and materials and is operating, but without personnelin the room.CFU (colony-forming unit). A measure of bacteria present in apharmaceutical processing space, measured
9、by sampling as part ofperformance qualification or routine operational testing.Challenge. An airborne dispersion of particles of known sizesand concentration used to test filter integrity and filtration efficiency.Cleanroom. A specially constructed enclosed space with environ-mental control of parti
10、culates, temperatures, humidity, air pressure,airflow patterns, air motion, vibration, noise, viable organisms, andlighting.Clean space. A defined area in which particle concentration andenvironmental conditions are controlled at or within specified limits.Contamination. Any unwanted material, subst
11、ance, or energy,including vibration, noise, lighting, radiation, etc.Commissioning. A quality-oriented process for achieving, veri-fying, and documenting that the performance of facilities, systems,and assemblies meets defined objectives and criteria, usually begin-ning at the user requirements spec
12、ification (URS) generation stage.Conventional-flow cleanroom. A cleanroom with nonunidirec-tional or mixed airflow patterns and velocities.Critical parameter. A space variable (e.g., temperature, humid-ity, air changes, room pressure, particulates, viable organisms) that,by law or per pharmaceutical
13、 product development data; affectsproduct strength, identity, safety, purity, or quality (SISPQ).Critical surface. The surface of the work part to be protectedfrom particulate contamination.Design conditions. The environmental conditions for which theclean space is designed.DOP. Dioctyl phthalate, a
14、n aerosol formerly used for testing effi-ciency and integrity of HEPA filters.ESD. Electrostatic discharge.EU GMP. European Union guidelines for GMP pharmaceuticalmanufacturing.Electrically enhanced filtration (EEF). System that reduces fanenergy requirements by using an electrical ionizing device t
15、o chargeincoming particles and a high-voltage electrical field across the airfilter to enhance filtration efficiency of the filter media.Exfiltration. Air leakage from a room through material transferopenings; gaps between personnel/pass-through access doors andtheir respective jambs, window frame/g
16、lass interfaces; wall/ceilingand wall/floor interfaces; electrical/data outlets and other roomboundary penetrations. The air leakage results from differentialpressure across gaps in walls or barriers.FDA. U.S. Food and Drug Administration.First air. Air supplied directly from the HEPA filter before
17、itpasses over any work location.GMP. Good manufacturing practice, as defined by Code ofFederal Regulations (CFR) 21CFR210, 211 (also, cGMP = currentGMP).High-efficiency particulate air (HEPA) filter. A filter with aminimum efficiency of 99.97% of 0.3 m particles.IEST. Institute of Environmental Scie
18、nces and Technology.Infiltration. Air leakage into a space from adjoining space(s) orareas, such as interstitial spaces.ISPE. International Society for Pharmaceutical Engineering.ISO. International Organization for Standardization.ISO 14644-1. Specifies airborne particulate cleanliness classesin cle
19、anrooms and clean zones. ISO (International Organizationfor Standardization) Standard 14644-1 is an international standardfor cleanrooms. Table 1 and Figure 1 summarize the ISO standardclasses.Laminar flow. Air flowing in parallel paths, without mixingbetween paths.Leakage. The movement of air into
20、or out of a space due to un-controlled enclosure leaks and its pressure relationship to surround-ing space(s).The preparation of this chapter is assigned to TC 9.11, Clean Spaces.18.2 2015 ASHRAE HandbookHVAC Applications (SI)Makeup air. Outdoor air introduced to the air system for venti-lation, pre
21、ssurization, and replacement of exhaust air.Minienvironment/Isolator. A barrier, enclosure, or glove boxthat isolates products from production personnel and other contam-ination sources to control or improve process consistency whilereducing resource consumption.Monodispersed particles. An aerosol w
22、ith a narrow band ofparticle sizes, generally used for challenging and rating HEPA andUPLA air filters.Nonunidirectional flow workstation. A workstation withoutunidirectional airflow patterns and velocities.Offset flow. The sum of all space leakage airflows; the net flowdifference between supply air
23、flow rate and exhaust and return air-flow rates.Operational cleanroom. A cleanroom in normal operationmode with all specified services, production equipment, materials,and personnel present and performing their normal work functions.Oral product. A pharmaceutical product to be taken by mouthby the p
24、atient.PAO. Polyalphaolefin, a substitute for DOP in testing HEPAfilters.Parenteral product. A pharmaceutical product to be injected intothe patient. Parenterals are manufactured under aseptic conditions orare terminally sterilized to destroy bacteria and meet aseptic require-ments.Particle concentr
25、ation. The number of individual particles perunit volume of air.Particle size. The apparent maximum linear dimension of a par-ticle in the plane of observation.Polydispersed particles. An aerosol with a broad band of particlesizes, generally used to leak-test filters and filter framing systems.Quali
26、fication. Formal, quality-driven, thoroughly documentedpharmaceutical commissioning activities undertaken to demon-strate that utilities and equipment are suitable for their intended use,and perform properly and consistently. These activities necessarilyprecede manufacturing drug products at the com
27、mercial scale, andusually consist of installation, operational, and performance testingprocedures generated by engineering and quality teams.Qualification protocol. A written description of activities nec-essary to qualify a specific cleanroom and its systems, with requiredapproval signatures.Room c
28、lassification. Room air cleanliness class (Figure 1,Table 1).SOP. Standard operating procedure.Topical product. A pharmaceutical product to be applied to theskin or soft tissue as a liquid, cream, or ointment, which thereforedoes not need to be aseptic. Sterile ophthalmic products, though, areusuall
29、y manufactured aseptically.ULPA (ultralow-penetration air) filter. A filter with a mini-mum of 99.999% efficiency at 0.12 m particle size.Unidirectional flow. Air flowing in a constant direction uni-formly over a defined space or region (different from laminar flow).Validation. A systematic, quality
30、-driven approach for verifyingand documenting that a pharmaceutical process is designed, in-stalled, functions, and is maintained properly involving sequentialexecutions of installation qualification, operational qualification,and performance qualification activities.Workstation. An open or enclosed
31、 work surface with direct airsupply.2. CLEAN SPACES AND CLEANROOM APPLICATIONSUse of clean space environments in manufacturing, packaging,and research continues to grow as technology advances and the needfor cleaner work environments increases. This chapter focuses onstate-of-the-art facility design
32、 and operations to improve quality andresource efficiency in a worldwide industry that provides great ben-efits and consumes significant energy. The following major indus-tries use clean spaces for their products:Table 1 Airborne Particle Concentration Limits by Cleanliness Class per ISO Standard 14
33、644-1ISO 14644 Class0.1 m0.2 m0.3 m0.5 m1.0 m5.0 mParticles per m3110 22 100 24 10 43 1000 237 102 35 84 10 000 2370 1020 352 835 100 000 23 700 10 200 3520 832 296 1 000 000 237 000 102 000 35 200 8320 2937 352 000 83 200 29308 3 520 000 832 000 29 3009 35 200 000 8 320 000 293 000Source: ISO Stand
34、ard 14644-1.Note: Values shown are the concentration limits for particles equal to and larger than the sizes shown.Cn= 10N(0.1/D)2.08where Cn= concentration limits in particles/m3, N = ISO class, and D = particle diameter in mFig. 1 Air Cleanliness Classifications in ISO Standard 14644-1Clean Spaces
35、 18.3 Pharmaceuticals/Biotechnology. Preparations of pharmaceuti-cal, biological, and medical products require clean spaces to con-trol viable (living) particles that could impact product sterility.Microelectronics/Semiconductors. Advances in semiconductormicroelectronics drive cleanroom design. Sem
36、iconductor facili-ties are a significant percentage of all cleanrooms in operation inthe United States, with most newer semiconductor cleanroomsbeing ISO Standard 14644-1 Class 5 or cleaner.Aerospace. Cleanrooms were first developed for aerospace appli-cations to manufacture and assemble satellites,
37、 missiles, and aero-space electronics. Most applications involve large-volume spaceswith cleanliness levels of ISO Standard 14644-1 Class 8 orcleaner.Hospitals. Operating rooms may be classified as cleanrooms, buttheir primary function is more to limit particular types of contam-ination than to cont
38、rol the quantity of particles present. Clean-rooms are used in patient isolation and surgery where risks ofinfection and cross contamination must be controlled, and in hos-pital pharmacies, where compounding sterile pharmaceuticalsrequires stringent control of the immediate and surrounding envi-ronm
39、ents. For more information, see Chapter 8.Miscellaneous Applications. Cleanrooms are also used in asep-tic food processing and packaging, microelectronic and nanotechapplications, manufacture of artificial limbs and joints, automo-tive paint booths, crystal, laser/optic industries, and advancedmater
40、ials research.3. AIRBORNE PARTICLES AND PARTICLE CONTROLAirborne particles occur in nature as pollen, bacteria, miscella-neous living and dead organisms, and windblown dust and seaspray. Industry generates particles from combustion, chemicalvapors, manipulation of material, and friction in moving eq
41、uipment.Personnel are a prime source of particle generation (e.g., skin flakes,hair, clothing lint, cosmetics, respiratory emissions, bacteria fromperspiration). These airborne particles vary from 0.001 m to sev-eral hundred micrometers. Particles larger than 5.0 m tend to settlequickly by gravity,
42、whereas those smaller than 1.0 m can take daysto settle. In many manufacturing processes, these airborne particlesare viewed as a source of contamination and can provide a pathwayfor biological contaminants. Cleanroom designs must accommo-date particulate sources and focus on particulate control to
43、maintainacceptable environmental conditions. Locations and sizes of returnand exhaust registers are important considerations, as well as lay-outs of equipment and locations and sizes of supply registers.Particle Sources in Clean SpacesIn general, the origins of cleanroom particles are described asei
44、ther external and internal.External Sources. Externally sourced particles enter the cleanspace from the outside via infiltration through doors, windows,wall penetrations, surface contamination on personnel, materialand equipment entering the space, and outdoor makeup air enter-ing through the HVAC s
45、ystem. In a typical cleanroom, externalparticle sources normally have little effect on overall cleanroomparticle concentration because HEPA filters remove particulatesfrom the supply air and the cleanroom is operated at a higher pres-sure than surrounding spaces to prevent infiltration. However, the
46、particle concentration in clean spaces at rest relates directly toambient particle concentrations. Particles from external sourcesare controlled primarily by air filtration, room pressurization, andsealing space penetrations.Internal Sources. People, cleanroom surface shedding, processequipment, and
47、 the manufacturing process itself can generateparticles in clean spaces. Cleanroom personnel, if not properlygowned, may be the largest source of internal particles, generatingseveral thousand to several million particles per minute. Personnel-generated particles are controlled with proper gowning p
48、rocedures,including new cleanroom garments, and airflow designed to con-tinually shower critical areas with clean air and direct less-cleanairstreams toward the return/exhaust registers. As personnel workin the cleanroom, their movements may reentrain airborne parti-cles from other sources by creati
49、ng turbulent air movement,eddies, and vortexes. Other activities, such as writing, printing, ormoving and bumping equipment may also cause higher particleconcentrations. Door swings or equipment challenges can producestrong additional transient differential pressure excursions, whichmay lead to particle infiltration through crack and crevices.Though particle concentrations in the cleanroom may be used todefine its cleanliness class, actual particle deposition on the productcritical surface is of greater concern. The sciences of aerosols, filtertheory, and fluid motions are
