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International Regulations 367 “… Premises and equipment must be located, designed, constructed, adapted and maintained to suit the operations to be carried out. … 3.34 Manufacturing equipment should be designed ,located and maintained to suit its intended purpose. 3.35 Repair and maintenance operations should not present any hazard to the quality of the products. 3.36 Manufacturing equipment should be designed so that it can be easily and thoroughly cleaned. It should be cleaned according to detailed and written procedures and stored only in aclean and dry condition. 3.37 Washing and cleaning equipment should be chosen and used in order not to be asource of contamination. 3.38 Equipment should be installed in such away as to prevent any risk of error or of contamination. 3.39 Production equipment should not present any hazard to the products. The parts of the production equipment that come into contact with the product must not be reactive, additive or absorptive to such an extent that it will affect the quality of the product and thus present any hazard. …” FIGURE 7 Excerpt from chapter 3ofCommission Directive 2003/94/EC, 8October 2003, Volume 4. Source:From Ref. 6. Before reworking their rules in 2002, the Japanese differed significantly from other GMPs by containing detailed job descriptions with duties and responsibilities of the staff inapharmaceutical company. The Japanese regulations do not contain requirements, which are more specific or more detailed or more additive than the others discussed above. OTHERS In 1967, the World Health Organization (WHO) issued its own set of GMPs. Being a first attempt to provide abasic outline of the minimum steps required to establish “§ 1Business and facilities • have to be according EU GMPs • have to run aworking pharmaceutical quality management system • have to ensure that the drug has the necessary quality for the intended use … §3.1 The facility has to • ensure correct business with proper size, number, location and equipment • Facility and equipment have to be checked for suitability (Qualification) … §3.3 The facility and equipment have to be proper cleanable and have to be maintenanced” FIGURE 8 Excerpt from the Pharma-Betriebsverordnung. Source: From Ref. 8.
368 Equipment Regulation C.02.005 The equipment with which alot or batch of adrug is fabricated,… shall be designed, constructed, maintained,… in amanner that: (a) permits fective leaning of its surfaces; (b) prevents the contamination of the drug and the addition of extraneous material to the drug; and (c) permits it to function in accordance with its intended use. Rationale …toprevent the contamination of drugs by other drugs, by dust, and by foreign materials such as rust, lubricant and particles coming form the equipment. … Equipment arranged in an orderly manner permits cleaning of adjacent areas … FIGURE 9 Excerpt from Good Manufacturing Practices Guidelines, 2002 Edition, Version 2 concerning Equipment (Regulation and Rationale). Source: From Ref. 10. acceptable standards for pharmaceutical facilities throughout the world. Nevertheless there is still aglobal quality in-equilibrium as the level of quality is a function of the economic development of the country. GUIDELINES OF NON-GOVERNMENTAL ORGANIZATIONS International Society for Pharmaceutical Engineering The International Society for Pharmaceutical Engineering (ISPE) (13) is aglobal, non-governmental organization (NGO) that provides education, training, and INTERPRETATION Killinger and Höller 1. The design, construction and locaton of equipment permit cleaning, sanitizing, and inspection of the equipment. 1.1 Equipment parts that come in contact with raw materials, in-process drugs or drugs are accessible to cleaning or are removable. 1.2 Tanks used in processing liquids and ointments are equipped with fittings that con be dismantled and cleaned. Validated Clean-In-Place (CIP) equipment can be dismantled for periodic verification. … 2. Equipment does not add extraneous material to the drug. … 3. Equipment is operated in amanner that prevents contamination. … 4. Equipment is maintained in agood state of repair when in use. … 5. Production equipment is designed, located, and maintained to serve its intended purpose. … 5.3 …Equipment qualification is documented. 5.4.Automatic, mechanical, electronic, or other types of equipment including computerized systems that are used in the fabrication, packaging/labeling, and storing of adrug is routinely calibrated, inspected or checked according to awritten program designed to assure proper performance. Written records of these calibration checks and inspections are maintained. … FIGURE 10 Excerpt from Good Manufacturing Practices Guidelines, 2002 Edition, Version 2 concerning Equipment (Interpretation). Source: From Ref. 10.
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Clean-In-Place for Biopharmaceutica
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Informa Healthcare USA, Inc. 52 Van
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iv Preface period, the industry rec
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Preface iii Contents Acknowledgment
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Contributors Barry J. Andersen Seib
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2 the last step of abatch manufactu
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4 Seiberling The vessel capacity ma
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6 Seiberling any two ports. For pur
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8 AWFI (or Any Water) Supply If the
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10 Seiberling program, and through
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12 Seiberling (380 L) for the solut
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14 AWFI CIP skid Drain When steam a
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16 Seiberling products in asingle f
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18 Seiberling The literature began
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2 Project Planning for the CIPable
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Project Planning for CIPable Facili
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3 Water for the CIP System Jay C. A
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Water for the CIP System 43 FIGURE
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Water for the CIP System 45 of clea
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Water for the CIP System 51 WATER U
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54 Time Temperature FIGURE 2 The cl
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56 Classification of Cleaners by pH
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58 [mg/sec] Cleaning velocity C v ,
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60 + - Na O O C CH 2 CH 2 (CH 2 ) n
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62 CH3 -(CH2 ) n -CH2 -O -CH2 -CH2
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64 B C D E FIGURE 17 Capability of
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66 pH 13 pH 7 pH, %, Excess water h
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68 dramatically increased rinsing t
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70 desorption. If the affinity is v
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72 & Cleaning procedure inthe case
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74 effort being performed relativel
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76 Rush & A1000 Lmixing vessel, hav
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78 TABLE 2 Typical Single-Pass Chem
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80 Rush Rinse Volume (Duration) The
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82 Rush Intermediate Drain Objectiv
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84 Rush Final Drain Phase (Gravity)
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86 TABLE 4 Recirculated Chemical Wa
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88 Rush type of soil include fermen
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90 The pre-cleaning process flush w
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92 REFERENCES Rush 1. Howard T, Wie
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94 CIP return (CIPR)-piping to conv
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96 Seiberling provided, generally o
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98 Single-Tank CIP Skid Operational
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100 Single-Tank Bypass or Recycle O
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102 Seiberling Single-Tank Single P
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104 Seiberling installation of an e
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106 Chemical loop AB FE Chemical bl
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108 Chemical loop AB FCV FE Steam C
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CIP supply Transfer line (typical)
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112 Seiberling FIGURE 14 This singl
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114 Seiberling FIGURE 15 This large
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116 Seiberling FIGURE 17 This mini-
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7 CIP System Instrumentation and Co
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CIP System Instrumentation and Cont
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146 Lebowitz should be considered f
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148 Lebowitz barrels and the chemic
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150 Lebowitz Electromagnetic-Operat
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152 Lebowitz FIGURE 5 The venturi o
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154 Chemical pump enclosure Acid AL
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156 Steam Facility acid header Faci
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158 Lebowitz That is to say aweak a
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160 CIP Philosophy The production p
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162 Franks and Seiberling the numbe
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164 Franks and Seiberling Similar s
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166 Franks and Seiberling FIGURE 3
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170 (A) (B) Franks and Seiberling F
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174 The variables that impact the r
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176 There are two guiding concepts
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178 Mezz. Floor(ref.) V-5 1000L CIP
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180 return line piping, substantial
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182 Lebowitz U-bend transfer panels
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184 Lebowitz oriented vertically. T
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186 Lebowitz suction-side port on T
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CIPS loop Primary CIPS CIPSPS CIPS
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190 Lebowitz FIGURE 10 Photo of sma
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192 Drain CIP return Drain Recycle
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11 Materials of Construction and Su
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Materials of Construction and Surfa
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12 Cleanable In-Line Components INT
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Cleanable In-Line Components 213 &
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Cleanable In-Line Components 215 Al
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Cleanable In-Line Components 217 Ex
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Cleanable In-Line Components 219 FI
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Cleanable In-Line Components 221 Tr
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Cleanable In-Line Components 223 it
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Cleanable In-Line Components 229 eq
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Cleanable In-Line Components 231 Th
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Cleanable In-Line Components 233 co
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13 Cleanable Liquids Processing Equ
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Cleanable Liquids Processing Equipm
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1-9 CIPS 2 Plant steam CIPS valves
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258 8. Projectile-type thermometer
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260 Forder control of the drying pr
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262 Forder FIGURE 5 Pharmaceutical
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264 Forder FIGURE 7 Pharmaceutical
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266 FIGURE 9 Pleated filter cartrid
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268 FIGURE 12 Disassembledstainless
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270 The acid wash of 85% phosphoric
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272 FIGURE 17 Sanitary Vbenders. So
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274 one each for the upper, central
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276 CIP VS. TRADITIONAL BOIL-UP MET
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278 Cerulli were not designed to be
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280 by large flanged connections fo
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282 CIP header Once thru CIP soluti
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284 Nozzle Use A Manway B Agitator
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286 3" Stub end w/150# flange 2A 1
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288 In most cases, the pressure dro
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290 CIP fluids Process fluids 1 2 3
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292 A Vent to atm. B M Conical drye
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294 One of the designer’s first t
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16 CIP System Troubleshooting Guide
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CIP System Troubleshooting Guide 29
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17 Waste Treatment for the CIP Syst
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