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EM_doc_FINAL DRAFT FOR PUBLICATION ON WEB_Rev_Nora_RolD

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EM_doc_FINAL DRAFT FOR PUBLICATION ON WEB_Rev_Nora_RolD

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    9 Environmental Monitoring of Clean Rooms in

    10 Vaccine Manufacturing Facilities 11 疫苗生产厂房洁净室环境监测

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    13 Points to consider for manufacturers of human vaccines

    14 适用于人用疫苗生产商

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    21 Eighth draft, 27 February 2011 22 8稿, 2011.02.27

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    28 Vaccine Quality and Regulations (VQR), Quality, Safety, and Standards (QSS)

    29 Immunization, Vaccines, and Biologicals (IVB) 30 World Health Organization (WHO), Geneva, Switzerland 31

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33 Table of Contents

    34 目录

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    39 1. INTRODUCTION简介 ................................................................................................................. 4

    40 2. RISK ASSESSMENT APPLIED TO CLEAN ROOM GRADE RECOMMENDATIONS FOR

    41 VACCINE PRODUCTION ACTIVITIES风险评估法用于疫苗生产活动的洁净室分级 .................... 5

    42 2.1. Recommended clean room grades for operations during the manufacture 43 of prequalified vaccines推荐的预认证疫苗生产的洁净室级别 ......................... 7 44 3. CLASSIFICATION AND ENVIRONMENTAL MONITORING (EM) OF CLEAN ROOMS

    45 AND LAMINAR FLOW WORKSTATIONS洁净室和层流罩工作台的分级和环境监测................. 17

    46 3.1. Clean room classification schemes洁净室分级方案 .............................. 17 47 3.2. Clean room classification based on airborne particulates以尘埃粒子为基

    48 础的洁净室分级 ............................................................................................... 18

    49 3.2.1. WHO requirementsWHO要求 ....................................................... 18 50 3.2.2. Use of other standards for prequalification purposes预认证的其它标

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    52 …………………………………………………………………………

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    54 3.2.3 Particulate sampling methods粒子采样法...................................... 19 55 3.2.4. Clean room classification洁净室分级 ............................................ 19 56 3.2.5. Routine monitoring for particulates粒子的日常监测 ..................... 20

    57 3.2.6. Sampling frequencies for routine monitoring of particulates日常粒

    58 子监测的采样频率 ........................................................................................ 22

    59 3.2.7. Particulate routine monitoring data analysis粒子日常监测数据分析 .. 23

    60 3.3. Environmental monitoring of microorganisms微生物环境监测 ............ 24

    61 3.3.1. WHO requirementsWHO的要求 ................................................... 24 62 3.3.2. Monitoring of microorganisms微生物监测 .................................... 24 63 3.3.4. Growth promotion testing灵敏度实验 ........................................... 25 64 3.3.5. Volumetric air sampling for microorganisms微生物空气采样....... 26

    65 3.3.6. Surface sampling for microorganisms微生物表面采样 ................. 28

    66 3.3.7. Microbiological classification of clean rooms洁净室微生物分级 .. 29

    67 3.3.8. Routine monitoring of microorganisms微生物的日常监测 ........... 29

    68 3.3.9. Laboratory testing of environmental samples环境样品实验室检定

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    70 3.3.10. Future trends未来趋势 .................................................................. 31

    71 4. INVESTIGATIONS AND CORRECTIVE AND PREVENTIVE ACTIONS (CAPA)调查和预

    72 防纠正措施............................................................................................................................................ 32

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73 4.1. Action and alert limits for environmental monitoring环境监测的行动限

    74 和警戒限 ........................................................................................................... 33 75 4.2. Investigations调查 ................................................................................. 34 76 4.3. Corrective and Preventive Actions预防和纠正措施 .............................. 36

    77 5. ACKNOWLEDGEMENTS鸣谢 ................................................................................................ 37

    78 6. REFERENCES参考.................................................................................................................... 38

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    80 On behalf of the United Nations, the World Health Organization maintains a list of

    vaccines that are prequalified for procurement by UN agencies. Prequalified vaccines 81

    82 have been assessed by WHO to verify that the product has been manufactured and tested

    in accordance with the relevant Technical Report Series (TRS) monographs and WHO 83

    84 Good Manufacturing Practices (GMP), that preclinical and clinical evidence supports 85 the quality, safety and efficacy of the vaccine, and that the product meets relevant UN

    tender specifications. WHO collaborates closely with the national regulatory authorities 86

    87 in the country of manufacture to ensure that the regulatory oversight of the product meets

    international standards. This Points to consider provides manufacturers with non-88

    89 binding information concerning the criteria currently used by WHO for the assessment of 90 prequalified human vaccines.

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    93 1. Introduction

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    95 Medicinal products must be pure, that is, free of contaminants that are not part of the 96 product's intended composition. Purity is however a relative term, with its definition 97 varying significantly by pharmaceutical class. For orally-administered chemical 98 pharmaceuticals, the limits set for bacteria or fungi are relatively high. For parenterally-99 administered vaccines, the possibility of injecting even minimum amounts of unwanted 100 virus, mycoplasma, or bacteria is considered unacceptable.

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    102 Quality is built into a product produced by aseptic manufacture when sound process, equipment, 103 and facility design is employed to minimize or eliminate potential contamination hazards. Modern 104 design approaches include systematic evaluation of potential process vulnerabilities and 105 awareness of how daily dynamic operational factors can interact.

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    107 A carefully planned and executed environmental monitoring (EM) program provides increased 108 assurance of sterility for aseptically produced products. However, environmental monitoring data 109 is only one of a number of measures used to indicate the state of control in an aseptic 110 manufacturing process. Besides, environmental monitoring is not a direct measure of product 111 batch sterility due to the inherent variability of environmental monitoring methods and more 112 importantly; the lack of a correlation between specific numerical environmental monitoring levels 113 and batch sterility.

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    115 EM represents an important means by which the effectiveness of contamination control 116 measures can be assessed and the specific threats to the purity of products being 117 manufactured can be identified. The results of environmental monitoring must be 118 considered when making the decision whether a production batch can be released. 119

    120 EM describes the microbiological testing undertaken in order to detect changing trends of 121 microbial counts and micro-flora growth within clean rooms or controlled environments. 122 The results obtained provide information about the physical construction of the room, the 123 performance of the Heating, Ventilation, and Air-Conditioning (HVAC) system, 124 personnel cleanliness, gowning practices, the equipment, and cleaning operations. 125

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    126 Over the past decade, environmental monitoring has become more sophisticated in

    moving from random sampling, using an imaginary grid over the room and testing in 127

    128 each grid, to the current focus on risk assessment and the use of risk assessment tools to

    determine the most appropriate methods for environmental monitoring. 129

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    131 Significant differences in clean room design and EM practices exist between vaccine

    manufacturers in different countries, and GMP inspectors often have very different 132

    133 interpretations of GMP requirements for clean rooms and their monitoring.

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    135 Two recent events are changing the way clean rooms are to be designed and monitored. 136 The first is the adoption of the ISO clean room definitions by the US, EU, and

    subsequently, WHO. A common standard should help reduce the number of divergent 137

    138 norms that companies serving the international market must conform to (ISO standards

    like ISO 14644 and ISO 14698 do not always fit with regulatory guidance documents 139

    140 because they apply to controlled environments across a range of industries other than 141 pharmaceuticals, where standards can be higher). The second event is the emerging 142 acceptance of a risk-based approach. In it, risks inherent to product-specific 143 manufacturing steps are analysed and specific measures needed to manage or reduce 144 those risks are determined. Using risk approaches, GMP requirements that better address 145 the specific problems inherent in the production of vaccines should be possible. 146

    147 This paper presents how a group of technical and regulatory experts active in assessing 148 prequalification applications interprets current WHO requirements for clean rooms and 149 EM as they are applied to the production of human vaccines. As such, the analysis may 150 be helpful to manufacturers and inspectors of prequalified vaccines in understanding how 151 current WHO requirements are being assessed. Readers are cautioned that views 152 provided here are non-binding and subject to change over time; the official WHO 153 requirements continue to be those approved by the WHO Expert Committee on 154 BiologicalStandardization and by the WHO Expert Committee on Specifications for 155 Pharmaceutical Products published in the respective WHO technical report series (TRS). 156

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    158 2. Risk assessment applied to clean room grade

    159 recommendations for vaccine production activities 160

    161 Regardless of how well clean rooms function, potential contaminants can be continuously 162 introduced into production facilities through entry of materials and equipment. Operators 163 are another major source of particulates and microorganisms, shedding particles and 164 microbes from skin, mucous membranes, and through respiratory secretions. 165 Manufacturing procedures such as mixing, concentration, centrifugation, or transfer may 166 also generate spills or aerosols that spread widely through production areas. Where 167 bacteria and fungi are allowed to grow in recesses or when cleaning and sanitation 168 procedures are ineffective, continuous or even resistant environmental strains can be 169 developed.

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    171 In a strict interpretation of the WHO GMP for sterile pharmaceutical products annex, for

    sterile bacterial and viral vaccines where heat sterilization or filtration are impossible due 172

    173 to the nature of the product, the entire manufacturing scheme should be conducted in full

    aseptic processing in Grade A with a Grade B background. . The selection of which 174

    175 grade or class of clean room to use at each stage of manufacture remains one of the most 176 misunderstood areas in GMP for biological medicinal products. For this reason, a risk-

    based approach in selecting the clean room grade needed for the various steps in vaccine 177

    178 production is considered an essential component in establishing environmental

    monitoring practices. 179

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    181 The use of risk assessment approaches is an important current Good Manufacturing

    Practice (cGMP) tool in microbiological environmental monitoring. However, each suite 182

    183 of clean rooms or isolator will be subtly different. Every aspect of the environment must

    be considered and what level of monitoring best suits the system decided; and the 184

    185 techniques used and the locations selected must be justified.

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    189 As biological medicinal products, vaccines present risks to the patient that must be 190 managed:

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    192 a. Some vaccines are not "pure" or well defined / characterized products, but contain 193 complex mixtures of proteins, lipids, and other inherent biological materials. As 194 such, the identification and complete removal of "impurities" can be difficult if 195 not impossible;

    196 b. Some vaccines are produced from highly pathogenic and transmissible 197 microorganisms. These microorganisms are present in high concentrations in the 198 production environment, and cross-contamination of products with viable 199 production microorganisms represent a major GMP risk and risk to the vaccinee; 200 c. The formulation of some vaccines may be optimized for the survival of 201 microorganisms, making it likely that viable contaminants derived from the 202 production environment (starting materials, operators, and those endemic to the 203 facility) will survive in product substance and be administered to vaccinees; 204 d. A number of parenterally administered live viral and live bacterial vaccines 205 cannot be sterilized by filtration. Moreover, some viruses and mycoplasma found 206 in the manufacturing environment may potentially pass through sterilizing filters, 207 making the effectiveness of filtration as a method of reducing environmentally-208 derived microorganisms not completely reliable.

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    211 1. Vaccine production methods and GMP, when properly implemented, provide 212 significant safety measures:

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    214 a. Many vaccines are produced in dedicated facilities or under campaign conditions 215 that significantly reduce the possibility of carry-over between products or batches;

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    216 b. Many vaccines are produced on highly attenuated strains that have greatly

    reduced pathogenicity, transmissibility, or survival in the environment; 217

    218 c. Many vaccine production schemes use antibiotics, antimycotics, specific media,

    or preservatives that prevent the growth and survival of unwanted microorganisms; 219

    220 final bulk and finished medicinal product may contain traces of these substances 221 (e.g.: antibiotics in viral vaccines).

    d. Many vaccines are extensively purified by precipitation, chromatography, or 222

    223 density ultracentrifugation, processes likely to remove most or all environmental

    contaminants; 224

    225 e. Many vaccines are subjected to standardized chemical inactivation (e.g., using 226 formaldehyde or β-propiolactone) that kill all bacteria, viruses, mycoplasma, and

    fungi, as well as detoxifying bacterial toxins. 227

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    229 2.1. Recommended clean room grades for operations during the 230 manufacture of prequalified vaccines

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    232 Given the risk assumptions presented above, the clean room grades presented in Table 1 233 can be viewed as acceptable in most cases for vaccines to be prequalified for procurement 234 by UN agencies. It is stressed that while the grades stated represent the 'normal' situation 235 in vaccine production for different types of products, factors that increase risk in a 236 particular facility may demand a higher clean room grade. In facilities where sterility or 237 contamination failures have occurred at such levels, higher clean room grades for any or 238 all manufacturing steps may be justified.

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    240 2. The assumptions upon which the clean room grade recommendations for each activity 241 are based include conformity with WHO GMP standards. Where these standards are 242 not met, the clean room grades provided in Table 1 are not relevant and higher grades 243 may be required.

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    245 3. Clean rooms must be designed, qualified, and operated according to international 246 standards, including their layouts, personnel and material flows, air handling systems, 247 utilities, and operator qualifications.

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    249 4. Vaccines must be produced according to WHO technical specifications, including 250 those regarding seed and cell bank qualification, adventitious agents’ safety, and

    251 transmissible spongiform encephalopathy safety.

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    253 5. Purification procedures must be effective in removing likely contaminants. Size 254 fractionation columns where the vaccine substance elutes in the void volume may be 255 effective in eliminating molecular contaminants, but inefficient in separating out 256 contaminating microorganisms or macromolecules. The use of sequential 257 chromatography steps (size exclusion, ion exchange, hydrophobic interaction, or 258 affinity columns) may result in highly purified vaccine products. Ultracentrifugation 259 in a density gradient may also yield a highly purified product provided the sample is 260 of limited size.

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    261 6. Inactivation with formalin, β-propiolactone, or other chemical inactivating agent or

    neutralization steps must be conducted by a procedure where the inactivation time, 262

    263 temperature, and concentration of the inactivating agent has been validated to be

    effective. Testing is conducted to verify that the inactivating chemical was effective 264

    265 in its purpose; and where appropriate, tests for reversion are carried out 266

    For early steps in vaccine production the common approach of manufacturers has been 267

    268 the use of unidirectional airflow (UDAF) systems in Grade C or even, in some cases,

    Grade D environments for short time aseptic operations such as aseptic quick connection 269

    270 of tubes or rapid transfers of sterile solutions from one container to another. Normally 271 unidirectional airflow systems should be located in grade B background, but other

    backgrounds may still be acceptable provided a risk assessment has been done and risks 272

    273 have been eliminated or reduced to an acceptable level. In acknowledgement of this

    wide-spread practice, definitions of unidirectional airflow systems in Grade C and Grade 274

    275 D environments are provided, and standards by which such units are to be monitored are 276 included. The table below therefore utilizes two important measures for the production 277 of vaccines, closed systems and unidirectional airflow systems in Grade C and D clean 278 rooms.

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    280 7. Closed systems are effective in protecting product materials from operator and 281 environmental contamination, and protect employees and facilities against pathogenic 282 vaccine strains. Systems are considered closed when materials are added and 283 removed so that product is not exposed to the room environment at any time. To do 284 so they must be equipped with a barrier technologies allowing the aseptic transfer of 285 solids, liquids, and gasses, such as tube welders, steam-through valves, isolator port 286 assemblies, and other validated transfer systems. Contamination can occur any time 287 materials in a system come into contact with the surrounding room (e.g., opening 288 hatches to add or remove materials, the use of unsealed hoses or stop-cocks for filling 289 sample bottles, the connection of open-ended tubes in the manufacturing 290 environment), these semi closed or intermittently closed systems for the purpose of 291 defining clean room grades are considered open systems. Containers are considered 292 closed when hermetically sealing closures are held in place by a mechanical cap or 293 ring. The closure must prevent contact of material within the container with 294 environmental microorganisms. It is acknowledged that an open activity of short 295 duration and limited exposure poses less risk of contamination than activities where 296 operators must extensively manually manipulate product materials. However, 297 because contamination can even occur instantaneously, maintaining a completely 298 closed system is currently the only situation where a reduction of clean room grade 299 can be unambiguously recommended.

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    301 8. Where the scale or nature of production operations restrict the use of aseptic 302 processing, such as in early manufacturing steps where microorganisms are being 303 replicated or manipulated, unidirectional airflow systems in a Grade C or Grade D 304 environment are widely used throughout the industry to protect critical operations. A 305 unidirectional airflow system is defined as a stand-alone work station or biosafety 306 cabinet that effectively flushes the work space with clean, HEPA-filtered air that

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    307 corresponds to Grade A regulatory limits. Where the scale or type of operations does

    not allow the use of an enclosed cabinet, ceiling- or wall-mounted filtration units or 308

    309 mobile carts can offer equivalent conditions, and for purposes of this document

    "unidirectional airflow" is taken to include any acceptable configuration that supplies 310

    311 HEPA-filtered Grade A unidirectional air to the workspace. For unidirectional 312 airflow systems in Grade B surroundings, all Grade A standards should be met. For

    unidirectional air flow systems in Grade C or Grade D surroundings, the limits for 313

    314 particulates under "at rest" conditions should be equivalent to those recommended for

    Grade A, and the limits for microorganisms detected by volumetric samples or settle 315

    316 plates should be equivalent to those recommended for Grade B.

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    319 9. When formulations are used that optimize the survival of viruses (such as solutions

    used during the preparation or storage of live vaccines), contamination of product 320

    321 materials by microorganisms derived from operators, the facility, or adventitious 322 agents may survive until the point of administration to the patient. To reduce this 323 possibility, operators working in the vicinity of open materials in Grade D and Grade 324 C operations should wear gloves and face masks in addition to the gowning 325 requirements specified for the grade by WHO GMP for sterile pharmaceutical 326 preparations.

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    328 10. Airlocks are clean room areas to be monitored. The grade of the airlock should 329 correspond to that of the adjoining area with the highest grade. For specialized 330 material airlocks (pass-through boxes), qualification results indicating the number of 331 air changes necessary to reduce particulate and microbial counts to below the 332 regulatory limit (and a strict observance of the time required for such changes during 333 operations) may substitute for routine static and dynamic monitoring. For pass-334 through boxes too small to admit sampling devices, qualification sampling should be 335 conducted through specially fitted probes. Unqualified, unmonitored material 336 airlocks without HEPA air supply or fumigation capabilities that are connected to 337 grade C or higher clean rooms should not be used.

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    339 11. Vaccines that cannot be sterilized represent a class of atypical medicinal products not 340 adequately described in pharmacopoeial or GMP texts, and there is a high degree of 341 variability concerning the clean room classes required for these products. The 342 pharmacopoeial definition of "sterility" is the lack of all viable microorganisms -6343 (technically defined as a sterility assurance level of 10 for all replicating

    344 microorganisms). In both pharmacopoeial and GMP definitions sterility cannot be 345 defined by testing, but only by a validated sterilization process (steam, dry heat, 346 ionizing radiation, or filtration through a 0.22 μm bacterial retaining filter). In

    347 contrast, a product may be labelled as "sterile" simply by passing the pharmacopoeial

    348 sterility test. This test cannot detect the viral active ingredients of live vaccines, or 349 viral, mycoplasma, or fastidious species that are common adventitious agents found in 350 tissue or cell cultures. Without GMP or pharmacopoeial recommendations for these 351 atypical products, inspectors predictably vary considerably in their interpretations and 352 approaches. While acknowledging that such products are not sterilized, an

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    353 interpretation where some but not all aspects of aseptic processing are required is

    favored by WHO. 354

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    356 Table 1. Recommended clean room grades for general activities in the manufacture 1357 of prequalified vaccines

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    General Activities

    Activity Open Systems Closed Systems Raw materials receipt and ? UNC (unclassified)? N/A (not applicable) storage

    Raw materials sampling ? Non-growth promoting ? N/A

    materials: Sampling

    hoods with dust control/ (1)fume control in UNC

    ? Growth-promoting

    materials: Sampling hood

    with HEPA air supply

    and dust control in D

    ? Sterile materials: in (2)specialized areas

    Preparation of glassware ? D ? N/A

    and accessory equipment for

    sterilization by heat

    Storage of glassware and ? D (fully enclosed ? UNC (pharma-sealed accessory equipment after wrapping, such as containers) heat sterilization autoclave bags) or C

    (with barrier protection,

    such as flask openings

    covered with aluminum

    foil)

Preparation of media to be ? Component weighing, ? N/A

    sterilized by heat mixing: D

    Preparation of media to be ? Component weighing, ? Media final filtration:

    sterilized by filtration mixing: C UDAF in D (a closed

     system is normally

    required)

    Storage of media after ? C for sealed but "open" ? D for closed sterilization containers containers Preparation of excipients to ? Component weighing, ? N/A

     1 Recommended clean room grades for general activities in the manufacture of prequalified vaccines are

    provided as guidance and do not intend to be restrictive.

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