Pharmaceutical production an engineering guide (2003)

p r o d u c t i o n A n engineering guide Edited by Bill Bennett and Graham Cole C h e m E The information in this book is given in good faith and belief in its accuracy, but does not imply the acceptance of any legal liability or responsibility whatsoever, by the Institution, or by the editors, for the consequences of its use or misuse in any particular circumstances This disclaimer shall have effect only to the extent permitted by any applicable law All rights reserved No part of this publication may be reproduced, stored in a retrieval system, or transmitted, in any form or by any means, electronic, mechanical, photocopying, recording or otherwise, without the prior permission of the publisher Published by Institution of Chemical Engineers (IChemE) Davis Building 165-189 Railway Terrace Rugby, Warwickshire CV21 3HQ, UK IChemE is a Registered Charity Offices in Rugby (UK), London (UK) and Melbourne (Australia) © 2003 Institution of Chemical Engineers ISBN 85295 440 Typeset by Techset Composition Limited, Salisbury, UK Printed by Antony Rowe Limited, Chippenham, UK P r e f a c e The pharmaceutical industry aims to produce safe and effective medicines with efficiency and profitability In order to achieve these aims, qualified personnel from many scientific and commercial disciplines are needed The industry needs specialists with qualifications in biological, chemical, engineering and pharmaceutical sciences, but there is also a requirement for a wider knowledge of the integral parts of an innovative manufacturing company including research, development, manufacturing, distribution, marketing and sales Chapter sets the scene by introducing the essential stages, from the synthesis of a new chemical entity through to its development into a licensed medicine Further education and advanced training for staff in the industry is needed through in-house or external courses However, there is a distinct lack of detailed texts written by industrial experts This book overcomes this deficiency in the area of pharmaceutical engineering and provides detailed information in all principal areas relevant to the manufacture of medicines It will be a useful reference book for information on topics selected from the vast range of material covered in Chapters to 11 Comprehensive coverage of each major topic, written by experts, provides valuable information for both newcomers and experienced personnel working in the pharmaceutical industry Abbreviations and acronyms proliferate throughout the modern world and the pharmaceutical industry has its share Fortunately, the editors have provided a list of acronyms and a glossary of terms most commonly used in the industry The book is divided into ten main chapters, each covering specialist areas with their principal sub-sections clearly set out in the comprehensive list of contents at the beginning of the book This feature will be very useful for those who need rapid access to detailed information in a specific area Chapters to 10 cover all the important aspects of the production of licensed medicines, as indicated in the following precis Chapters and cover in detail primary and secondary production from the preparation of bulk bioactive substance by chemical synthesis, biotechnology and extraction from natural products, through to modern packaging technologies required for the finished medicine Chapter deals with the design of utilities and services, as well as the associated areas of cleaning and maintenance The design of facilities is continued in Chapter which covers the planning, furnishing and provision of services in laboratories, whereas the special requirements for process development and pilot plant are presented in Chapter 10 Having provided an outline of the chapters dealing with production, we can turn towards the beginning of the book for coverage of regulatory matters and quality assurance Chapter is an outline of the main stages in the approval process, post-marketing evaluation and the European and US perspectives The concepts and practices embodied in Good Manufacturing Practice are covered concisely in Chapter with special reference to engineering aspects of pharmaceutical production, whereas validation and safety issues are presented in great detail in Chapters and Finally, in Chapter 11, the special requirements for the development and manufacture of modern bio-pharmaceutical products are dealt with in great detail with reference to small scale and pilot facilities After six years working in research and development in the pharmaceutical industry, the rest of my career has been in academic pharmacy Close contact with the industry has been maintained through education, training, research, consultancy and involvement with the design, delivery, assessment and external examinership of postgraduate diploma and MSc courses for advanced training of personnel in the industry Such courses by universities or independent consultants provide course material of a high standard, but this should be supplemented by texts written by experts working in the industry The Engineering Guide to Pharmaceutical Production provides an authoritative and detailed treatment of all major aspects related to the manufacture of medicines Geoff Rowley Professor of Pharmaceutics, Institute of Pharmacy and Chemistry, University of Sunderland List o f a c r o n y m s The following is a list of acronyms used in this book It is followed by a glossary of the more important validation terms ADR AGMP AGV AHU ALARP ANDA ANSI API ASME BATNEEC BLl BL2 BL3 BL4 BMR BMS BOD BP BPC BPEO BS BSI cAGMP CAMMS CCTV CDER CDM Adverse Drug Reaction Automated Good Manufacturing Practice Automated Guided Vehicles Air Handling Unit As Low As Reasonably Practicable Abbreviated New Drug Application American National Standards Institute Active Pharmaceutical Ingredient American Society of Mechanical Engineers Best Available Techniques Not Entailing Excessive Costs Biosafety Level Biosafety Level Biosafety Level Biosafety Level Batch Manufacturing Record Building Management System Biological Oxygen Demand British Pharmacopeia Bulk Pharmaceutical Chemical Best Practicable Environmental Option British Standard British Standards Institution Current Automated Good Manufacturing Practice Computer Aided Maintenance Management System Closed Circuit Television Centre for Drug Evaluation and Research Construction (Design and Management) regulations CFC CFR CFU cGCP cGLP cGMP CHAZOP CHIP CIMAH CIP CMH COD COMAH COSHH CPMP CPU CSS CV DAF DIN DMF DNA DOP DQ EC EEC EMEA EPA EPDM ERP EU FAT FBD FDA FMEA FS GAMP GC GCP GLP Chlorofluorocarbons Code of Federal Regulations Colony Forming Unit Current Good Clinical Practice Current Good Laboratory Practice Current Good Manufacturing Practice Computer HAZOP Chemical Hazard Information and Packaging regulations Control of Industrial Major Accident Hazards regulations Clean In Place Continuous Motion Horizontal Chemical Oxygen Demand Control Of Major Accident Hazards regulations Control Of Substances Hazardous to Health Committee on Proprietary Medicinal Products Central Processing Unit Continuous Sterilization System Curriculum Vitae Dissolved Air Flotation Deutsches Institut fur Normung Drug Master File Deoxyribonucleic Acid Dioctyl Phthalate Design Qualification European Community European Economic Community European Agency for the Evaluation of Medical Products Environmental Protection Agency Ethyl Propylene Diene Terapolymer Enterprise Resource Planning European Union Facility Acceptance Testing Fluidized Bed Dryer Food and Drug Administration Failure Mode Effects Analysis Functional Specification Good Automated Manufacturing Practice Gas Chromatograph Good Clinical Practice Good Laboratory Practice GLSP GMP GRP GSL HAZOP HEPA HFC HIC HMAIP HMSO HPLC HS HSE HSL HVAC IBC ICH IDF IEC IEEE IMV IND I/O IPA IPC IQ ISO ISPE LAAPC LAF LIMS LTHW mAb MCA MCB MCC MEL MRA MRP MSDS Good Large Scale Practice Good Manufacturing Practice Glass Reinforced Plastic General Sales List Hazard and Operability Study High Efficiency Particulate Arrestor Hydrofluorocarbons Hydrophobic Interaction Chromatography Her Majesty's Inspectorate of Air Pollution (now defunct) Her Majesty's Stationery Office High Pressure Liquid Chromatograph Hazard Study Health and Safety Executive HAZOP Study Leader Heating Ventilation and Air Conditioning Intermediate Bulk Container International Conference on Harmonization International Diary Foundation Ion Exchange Chromatography Institute of Electrical and Electronics Engineers Intermittent Motion Vehicle Investigational New Drug Application Inputs and Outputs Iso Propyl Alcohol Integrated Pollution Control Installation Qualification International Standards Organization International Society for Pharmaceutical Engineering Local Authority Air Pollution Control Laminar Air Flow Laboratory Information Management System Low Temperature Hot Water Monoclonal Antibody Medicines Control Agency Master Cell Bank Motor Control Centre Maximum Exposure Limit Mutual Recognition Agreement Manufacturing Resource Planning Material Safety Data Sheet NCE NDA NDT NICE NMR OEL OES OQ OSHA OTC P PBTB PC PCB PDA PEG PFD PHA Ph.Eur PHS P&ID PLA PMI POM PP PPE PQ PSF PTFE PV PVC PVDF PW QA QC QRA R&D RF RH RHS New Chemical Entity New Drug Application Non-Destructive Testing National Institute for Chemical Excellence Nuclear Magnetic Resonance Occupational Exposure Limits Occupational Exposure Standards Operational Qualification Occupational Safety & Health Administration Over The Counter Pharmacy only Polybutylene Teraphthalate Programmable Controller Printed Circuit Board Personal Digital Assistants Polyethylene Glycol Process Flow Diagram Preliminary Hazard Assessment European Pharmacopeia Puck Handling Station Piping and Instrumentation Diagram Product Licence Application Positive Material Identification Prescription Only Medicines Polypropylene Personal Protective Equipment Performance Qualification Performance Shaping Factors Polytetrafluoroethylene Process Validation Polyvinyl Chloride Polyvinylidene Fluoride Purified Water Quality Assurance Quality Control Quantitative Risk Assessment Research and Development Radio Frequency Relative Humidity Rolled Hollow Section RIDDOR RP-HPLC SCADA SEC SHE SIP SOP SS THERP TOC TWA UK UPVC URS USA USP UV VDU VMP VOC WCB WFI Reporting of Injuries, Disease and Dangerous Occurrences Regulations Reverse Phase High Performance Liquid Chromatography Supervisory Control And Data Acquisition system Size Exclusion Chromatography Safety, Health and Environment Sterilize In Place/Steam In Place Standard Operating Procedure Suspended Solids Technique for Human Error Rate Prediction Total Organic Carbon Time-Weighted Average United Kingdom Unplasticized Polyvinyl Chloride User Requirement Specification United States of America United States Pharmacopeia Ultra Violet Visual Display Unit Validation Master Plan Volatile Organic Compound Working Cell Bank Water for Injection G l o s s a r y Acceptance criteria The product specifications and acceptance/rejection criteria, such as acceptable quality level and unacceptable quality level, with an associated sampling plan, that are necessary for making a decision to accept or reject a lot or batch (or any other convenient subgroups of manufactured units) Action levels Levels or ranges that may be detrimental to end product quality, signalling a drift from normal operating conditions Alert levels Levels or ranges that signify a drift from normal operating conditions These ranges are not perceived as being detrimental to end product quality, but corrective action should be taken to ensure that action levels are not obtained Audit An audit is a formal review of a product, manufacturing process, equipment, facility or system for conformance with regulations and quality standards Bulk drug substance Any substance that is represented for use in a drug and that, when used in the manufacturing, processing or packaging of a drug, becomes an active ingredient or a finished dosage form of the drug The term does not include intermediates used in the synthesis of such substances Bulk pharmaceutical Any substance that is intended for use as a component chemical in a 'Drug Product', or a substance that is repackaged or relabelled for drug use Such chemicals are usually filter cake, or if the bulk active substance is crystallized from an aqueous system, then the water should be suitably treated, such as by de-ionization, ultrafiltration, reverse osmosis or distillation, and tested to ensure routine compliance with appropriate chemical and microbiological specifications If the water is used for final rinses during equipment cleaning, then the water should be of the same quality as that used in the manufacturing process Water used in the final isolation and purification steps of non-sterile bulk actives intended for use in the preparation of parenteral products should be tested and controlled for bioburden and endotoxins The quality of water, therefore, depends on the intended use of the finished product For example, only Water for Injection (WFI) quality water should be utilized as process water; this is because, even though water may not be a component of the final sterile product, water that comes in contact with the equipment or that enters into the bioreactor can be a source of impurities such as endotoxins On the other hand, for in-vitro diagnostics purified water may suffice For heat-sensitive products where processing such as formulation is carried out cold or at room temperature, only cold WFI will suffice, and the self-sanitization of a hot WFI system at 75° to 800C is lost As with other WFI systems, if cold WFI water is needed, point-of-use heat exchangers can be used; however, these cold systems are still prone to contamination, and should be fully validated and routinely monitored both for endotoxins and microorganisms Water treatment plants and distribution systems should be designed, constructed and maintained to ensure a reliable source of water of an appropriate quality They should never be operated beyond their designed capacity For economic reasons, some biotechnology companies manufacture WFI utilizing marginal systems, such as single pass reverse osmosis, rather than by distillation Many such systems have been found to be contaminated, typically because they use plastic pipes and non-sealed storage tanks, which are difficult to sanitize Although some of the systems employ a terminal sterilizing filter to minimize microbiological contamination, the primary concern is endotoxins which the terminal filter may merely serve to mask Such systems are, therefore, totally unacceptable Moreover, the limitations of relying on a 0.1 ml sample of WFI for endotoxins from a system should also be recognized New water quality requirements were brought into effect in 1996 These updated requirements provide major cost savings to those manufacturers who needed to produce and maintain pure water systems, and allowed for the continuous monitoring of water systems with a reliance on instrumentation rather than laboratory work, thereby reducing labour and operating costs Previous standards required a battery of expensive and labour intensive chemical, physical, and microbiological testing, many of which only provided qualitative information Advances in technology and instrumentation mean that simple, cost effective replacements have become available However, before changing to the new testing standards, manufacturers should evaluate their existing water system in terms of compliance with existing operations, reliability, maintenance and improved monitoring 11.6.2 Medical air Medical air is a natural or synthetic mixture of gases consisting largely of nitrogen and oxygen, containing no less than 19.5 percent and not more than 23.5 percent by volume of oxygen Air supplied to a non-sterile preparation or formulation area, or for manufacturing solutions prior to sterilization, should be filtered at the point of use as necessary to control particulates However, air supplied to product exposure areas, where sterile bio-pharmaceuticals are processed and handled, should be filtered under positive pressure through high efficiency particulate air (HEPA) filters These HEPA filters should be certified and/or Dioctyl Phthalate tested Tests for oil (none discernible by the mirror test), odour (no appreciable odour), carbon dioxide (not more than 0.05%), carbon monoxide (not more than 0.001%), nitric oxide and nitrogen dioxide (not more than 2.5 ppm), and for sulphur dioxide (not more than ppm) should also be carried out Medical air is packaged in cylinders or in a low pressure collecting tank Containers used should not be treated with any active, sleep-inducing, or narcosis-producing compounds, and should not be treated with any compound that would be irritating to the respiratory tract Where it is piped directly from the collecting tank to the point of use, each outlet should be labelled Medical Air 11.6.3 Heating, ventilation and air conditioning (HVAC) systems A bio-pharmaceutical facility should have proper ventilation, air filtration, air heating and cooling Therefore, adequate ventilation should be provided where necessary, and equipment for the control and monitoring of air pressure, microorganisms, dust, humidity and temperature should be provided when appropriate This is especially important in areas where the product is exposed to the environment or handled in the final state Air filtration, dust collection and exhaust systems should be used when appropriate, and if the air is recirculated, appropriate measures should be taken to control contamination and cross-contamination For example, air from pre-viral inactivation areas should not be recirculated to other areas used for the manufacture of the sterile bio-pharmaceuticals Regulatory authorities require the following information to be available for pre-approval inspection: • A general description of the HVAC system(s) including the number and segregation of the air handling units, whether air is once-through or recirculated, containment features, and information on the number of air changes per hour; • Validation summary for the system with a narrative description of the validation process (or protocol), including the acceptance criteria; the certification that IQ, OQ, and certification of filters has been completed; the length of the validation period; validation data should include Performance Qualification data accumulated during actual processing; and an explanation of all excursions or failures, including deviation reports and results of investigations; • A narrative description of the routine monitoring programme including the tests performed and frequencies of testing for viable and non-viable particulate monitoring parameters; viable and non-viable particulate action and alert limits for production operations for each manufacturing area; and a summary of corrective actions taken when limits are exceeded 11.6.4 Decontamination techniques and waste recovery Air and gaseous waste streams Filtration The primary method of decontaminating exhaust gases mixed with liquid broth is through the use of filters Before filtration, the mixture may be passed through a condenser, a coalescing filter and a heat exchanger Filtration is accomplished either through pairs of high efficiency particulate air (HEPA) filters, or membrane filters used in series to decontaminate vent or exhaust gases Incineration Another method of decontaminating air and gaseous waste streams is thermal destruction or incineration Incineration may be used independently, or as a supplement to filtration, and is generally used for small volume gas streams Automatic safety devices should be used with incinerators to protect against problems resulting from power failures and overheating Irradiation Irradiation involves exposing the waste materials to x-rays, ultraviolet rays or other ionizing radiation to decontaminate them Liquid wastes Liquid wastes can be decontaminated through chemical or heat treatment When liquid wastes are of limited volume, chemical treatment is often used, whilst for large volumes of liquid wastes, heat treatment is generally preferred Also, since proteins present in liquid wastes can deactivate the sterilant used in chemical treatment, thermal sterilization may be more appropriate for wastes involving bioengineered microorganisms Solid wastes Solid wastes such as microbial cultures, cell debris, glassware, and protective clothing, are generally decontaminated by autoclaving, followed by incineration if necessary To decontaminate laboratory devices exposed to genetically engineered products, the most common practice is the use of pressurized steam that contains an appropriate chemical For heat-sensitive equipment, such as electronic instruments, decontamination is generally achieved through chemical sterilization or irradiation Gaseous sterilants are applied by a steam ejector that sprays down from overhead If decontamination by steam, liquid, or gas sterilization is not possible, ionizing or ultraviolet radiation is used However, since irradiation methods not always inactivate all types of microbes, steam or gaseous chemical sterilization should be used for devices contaminated with genetically engineered organisms Index Index terms Links A advanced packaging technologies 192 aerosols 145 ampoules 183 animal quarters 399 aseptic transfer 392 autoclaving 138 automated production systems 190 B bio-pharmaceuticals cGMP 376 change control 383 cleaning processes 434 containment 393 equipment design 424 laboratory design 421 personnel considerations 394 pilot plant design 375 417 424 primary production 388 process control 393 product recovery and purification 394 regulations 373 retesting 415 sampling 439 This page has been reformatted by Knovel to provide easier navigation 398 447 448 Index terms Links bio-pharmaceuticals (Continued) secondary production 402 sterilization 430 validation 377 biosafety cabinets 426 blister packs 179 bottle packs 178 bulk pharmaceutical chemical production 75 C capping 184 capsules production 125 cartoning 185 case packing 186 cell disruption 83 centrifuging 83 change control bio-pharmaceuticals system chromatography 91 206 383 71 84 Clean In Place (CIP) design validation 290 65 clean steam 281 cleaning 164 coating processes 123 coding 185 compressed air 274 computerized systems design criteria 32 validation 68 This page has been reformatted by Knovel to provide easier navigation 288 449 Index terms Links consumables storage 265 containment 176 contractors 300 COSHH 245 creams 133 cross-contamination 160 bio-pharmaceuticals setting limits crystallization 412 64 current Good Manufacturing Practice bio-pharmaceuticals 376 design requirements 22 Directives 13 maintenance 262 delayed release 147 direct compression 119 dispensing 149 distillation 87 drug approval process 10 drug master files 11 D dry heat sterilization drying 140 91 E effluent treatment 291 effluents gaseous 293 liquid 294 solid 297 electrodialysis 184 83 This page has been reformatted by Knovel to provide easier navigation 88 450 Index terms Links elixirs 132 emulsions 132 endotoxins 402 environmental classification 167 equipment cleaning 164 equipment design criteria 30 equipment flow criteria 29 ethylene oxide sterilization 141 extrusion 130 F fault tree analysis fermentation 227 78 media sterilization 82 pH 81 sterile design 81 temperature control 82 fermenters gas-lift 79 open tank 78 sparged-tank 79 stirred tank 79 filters 89 form-fill-seals 183 formaldehyde 140 fume cupboard design 313 G gelatin capsules hard 126 soft 129 This page has been reformatted by Knovel to provide easier navigation 144 330 451 Index terms genetically engineered organisms Links 398 Good Clinical Practice 20 Good Laboratory Practice 20 granulation 95 H handover hard gelatin capsules 58 126 hazards chemical reaction 237 dust explosion 240 environmental 246 fire and explosion 238 laboratories 251 occupational health 241 pilot plants 252 HAZOP 215 heat transfer oils 286 high-intensity pulsed light 143 human reliability estimation 227 HVAC systems design 272 hydrogen peroxide 141 I injections 136 inoculation transfer 392 intermediate bulk containers irradiation 86 143 L labeling 153 This page has been reformatted by Knovel to provide easier navigation 185 452 Index terms Links laboratory air handling 340 laboratory balance and instrument benches 328 laboratory bench design 321 laboratory extraction hoods 336 laboratory fume cupboards 329 laboratory fume extraction 337 laboratory general design 307 laboratory safety 344 laboratory service spines 326 laboratory tables 329 laboratory trolleys 329 layout and building design, principles 154 lighting selection 175 lyophilization 407 M maintenance, building design 263 maintenance, cGMP 262 material flow criteria 29 materials management systems 153 microencapsulation 148 milling 95 N New Drug Application (NDA) 11 nitrogen 283 nucleic acids 401 O occupational health exposure limits (OELs) hazards 241 241 This page has been reformatted by Knovel to provide easier navigation 288 453 Index terms Links occupational health exposure limits (OELs) (Continued) legislation 244 ointments 133 ophthalmic preparations 135 Orange Guide over-sealing 38 186 P packaging, BPC 95 packaging operations 177 palletizing 186 pellets 129 peracetic acid 140 personnel flow criteria 29 pharmacovigilance 13 pills 111 pilot plants chemical synthesis 361 dispensaries 371 final formulation and packaging 369 optimization 371 physical manipulation 368 safety 371 planned maintenance 301 plant records 298 post-marketing drug evaluation 13 postscript technology 197 powder filling systems 181 preventative maintenance 301 process development building design 356 This page has been reformatted by Knovel to provide easier navigation 184 454 Index terms Links process development (Continued) design principles 347 process optimization 58 product segregation 163 product sterilization 138 production area workshops 297 production automation systems pyrogens 96 402 Q qualification Design Qualification (DQ) 53 Installation Qualification (IQ) 55 Operational Qualification (OQ) 56 Performance Qualification (PQ) 59 protocols 51 quality control laboratories 305 R reaction, biotechnology 77 reaction, chemical synthesis 76 refrigeration regulatory environment, UK 286 12 reliability centred maintenance 301 residual contaminating proteins 400 residual host cells 400 revalidation bio-pharmaceuticals 72 383 risk assessment criteria 228 environment 250 This page has been reformatted by Knovel to provide easier navigation 455 Index terms Links risk assessment (Continued) laboratories 251 pilot plant 252 preliminary hazard analysis 212 principles 211 S sachets 180 services and utilities design criteria 26 sizing 287 specification 270 SHE inherent 209 integrated management 204 legislation 257 sieving 95 site layout brownfield sites 107 greenfield sites 101 small scale pilot facilities 352 soft gelatin capsules 129 solids drying 91 solids filtration 89 solvent recovery 95 sonocrystallization 88 specialist water supplies de-ionised water 284 purified water 284 towns water 284 WFI 284 spheronization 130 This page has been reformatted by Knovel to provide easier navigation 456 Index terms Links spray granulation 117 sprays 135 Steam in Place 290 sterile filtration 144 Sterilize in Place 290 storage, consumables 265 suppositories 134 surface finishes 173 suspensions 132 sustained release 147 syringes 183 syrups 132 T tablets 112 coating 123 compression 119 granulation 112 tubes 182 U ultrafiltration ultraviolet light 83 143 V vacuum 279 validation analytical methods 71 bio-pharmaceuticals 377 cleaning 61 computer systems 68 This page has been reformatted by Knovel to provide easier navigation 457 Index terms Links validation (Continued) directives 38 flow chart 49 policies and procedures 41 process 60 retrospective 61 of CIP systems 65 Validation Master Plan (VMP) 44 ventilation systems 171 vials 183 viruses 401 W warehousing 188 waste regulatory requirements 292 waste treatment 291 Water for Injection (WFI), system design 28 This page has been reformatted by Knovel to provide easier navigation ... product, manufacturing process, equipment, facility or system for conformance with regulations and quality standards Bulk drug substance Any substance that is represented for use in a drug and that,... animals; substances (other than food) intended to affect the structure or any function of the body of man or other animals; substances intended for use as a component of any substances specified... engineering and pharmaceutical sciences, but there is also a requirement for a wider knowledge of the integral parts of an innovative manufacturing company including research, development, manufacturing,