PDA TR34 隔离罩系统验证2001

PDA Isolation Technology Task Force Members James P. Agalloco (Co-Chairman), Agalloco & Associates James E. Akers, Ph.D. (Co-Chairman), Akers Kennedy & Associates Uwe-Peter Dammann, ASTA Medica AG Thomas G. Freund, Mallinckrodt Inc. William R. Frieben, Ph.D., Pharmacia Corporation Richard M. Johnson, Abbott Laboratories, Inc. Kunio Kawamura, Ph.D., Otsuka Pharm. Co., Ltd. Jean-Michel Khoury, Aventis Pharma Bengt C. Ljungqvist, Ph.D., Royal Institute of Technology Jack P. Lysfjord, TL Systems Corp. Russell E. Madsen, Jr., PDA Didier A. Meyer, La Calhéne George O. Phariss, Abbott Laboratories, Inc. Scott L. Pool, B. Braun Medical, Inc. Berit M. Reinmüller, Royal Institute of Technology Scott Sutton, Ph.D., Alcon Laboratories, Inc. Carmen M. Wagner, Ph.D., Merix Bioscience, Inc. License to FDALicense to FDAwww.pda.org/bookstore Design and Validation of Isolator Systems for the Manufacturing and Testing of Health Care Products Technical Report No. 34 PDA September/October 2001 Vol. 55, No. 5, September/October 2001, Supplement TR34 i PDA TECHNICAL REPORT NO. 34 DESIGN AND VALIDATION OF ISOLATOR SYSTEMS FOR THE MANUFACTURING AND TESTING OF HEALTH CARE PRODUCTS Table of Contents 1.0 INTRODUCTION 1.1 Preface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.2 Scope . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.3 Key Definitions . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 1 1.4 Purpose . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.0 TYPES OF ISOLATORS 2.1 Closed Isolators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1.1 Closed Isolators Intended for Aseptic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1.2 Closed Isolators Intended for Containment Applications. . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.1.3 Closed Isolators Intended for Asepsis and Containment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 2 2.2 Open Isolators . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.2.1 Open Isolators Intended for Aseptic Applications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 2.2.2 Open Isolators Intended for Asepsis and Containment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.0 ISOLATOR DESIGN AND GENERAL CONSTRUCTION 3.1 Materials of Construction . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.1.1 Polyvinyl Chloride (PVC) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 3 3.1.2 Stainless Steel . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.1.3 Glazing Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.1.4 Other Materials . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.2 Operator Interface . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 4 3.2.1 Gloves/Sleeves . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.2.2 Suits or Half-Suits . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 5 3.2.3 Air Handling System . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4.0 FUNCTIONAL SPECIFICATIONS FOR ISOLATORS 4.1 Air Supply Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 6 4.1.1 Air Change Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.1.2 Air Velocity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.1.3 Particulate Air Specification . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 7 4.1.4 Recirculation Rate . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4.1.5 Temperature and Humidity . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4.1.6 Aeration of the Decontaminating Agent . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4.2 Leak Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 8 4.2.1 Pressure Decay Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4.2.2 Tracer Gas Detection Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 9 4.3 Ergonomics . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 4.4 Rapid Transfer Ports (RTPs) . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 10 Vol. 55, No. 5, September/October 2001, Supplement TR34 iii 5.0 FACILITY REQUIREMENTS 5.1 Classification of the Isolator Room . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.2 Temperature and Humidity Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 5.3 Process Utilities . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 6.0 USER REQUIREMENT SPECIFICATIONS (URS) 6.1 General User Requirement Specifications . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 6.1.1 Sterility Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 11 6.1.2 Cleaning and Cleaning Validation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 6.1.3 Containment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 14 6.1.4 Environmental Control . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 16 6.1.5 Leak Testing . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 6.1.6 Monitoring Systems . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 6.1.7 Microbiological Monitoring of the Environment . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 17 6.1.8 Process Simulation . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 7.0 RE-QUALIFICATION TESTING . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 18 8.0 CONCLUSION . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 19 APPENDIX A: Glossary . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 APPENDIX B: Ljungqvist/Reinmüller (L-R) Method . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 20 APPENDIX C: Test Methods, Pressure Drop Test . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 21 APPENDIX D: Isolators and Sterility Assurance . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 22 REFERENCES AND TEXT NOTES . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . . 23 iv PDA Journal of Pharmaceutical Science and Technology 1.0 INTRODUCTION are widely used in the clinical pharmacy setting. These devices have some general features in common with 1.1 Preface isolators as defined in this document, however, they are distinctly different from the isolator systems currently In recent years, isolation technology has rapidly in use for sterile product manufacturing and testing in emerged as an alternative to human-scale classified the health care product industry. This technical report environments for the production and testing of many does not pertain to devices that do not meet the mini- different types of health care products. The operational mum performance criteria defined and explained in this characteristics of isolators make them ideally suited for document. use in the preparation of sterile materials, as well as in the containment of potent materials. Additional appli- 1.3 Key Definitions cations can be found in the preparation of clinical sup- plies, sterile bulk drugs/bio-pharmaceuticals, sterile The establishment of a clear distinction between what cytotoxic materials, and in sterility testing. is and what is not an isolator is essential to understand- ing this document. PDA suggests the following defini- The absence of authoritative implementation and vali- tion of isolator be adopted by the worldwide health care dation guidance for this technology and the consider- industry: able confusion that has emerged between “isolators” and “barriers” were prime motivators for PDA to de- An isolator is sealed or is supplied with air through a velop this document. It is the product of an interna- microbially retentive filtration system (HEPA minimum) tional committee made up of representatives of PDA and may be reproducibly decontaminated (1). When U.S., PDA’s Japan Chapter, A3P, The Parenteral Soci- 3 closed, it uses only decontaminated (where necessary)ety, and R -Nordic. interfaces or Rapid Transfer Ports (RTPs) for materi- als transfer. When open, it allows for the ingress and/ This document should be considered as guidance; it or egress of materials through defined openings that is not intended to establish any mandatory or implied have been designed and validated to preclude the trans- standard. fer of contamination. It can be used for aseptic pro- cessing activities, for containment of potent compounds, 1.2 Scope or simultaneously for both asepsis and containment. This technical report addresses essential user require- In marked contrast to the “isolator” definition above, ments for the application of isolator technology to a PDA suggests the following definition for “barrier sys-broad range of manufacturing, development, and test- tems:”ing applications in the health care product manufactur- ing industry. This technical report covers not only prod- uct sterility assurance, but also the use of isolators for A barrier system is an open system that can exchange the containment of hazardous materials. contaminants with the surrounding area, and cannot be decontaminated to the extent possible in an isolator. An important component of this technical report is the glossary (Appendix A). The health care industry has Isolators, whether operated in a closed or open man- lacked a uniform set of definitions with respect to iso- ner, offer significant advantages over barrier systems: lator technology. The committee recognizes that, in or- isolators can be decontaminated using reproducible and der to suggest truly usable technical information, we validated methods, do not allow the ingress of airborne must ensure that there can be no confusion among read- contamination from the surrounding environment, and ers as to the application of recommendations made prevent the introduction of personnel borne contami- within this technical report. nation into the isolator. In contrast, a barrier system is an open system which can exchange unfiltered air with The committee also recognizes that in some regions of the surrounding environment, can only be manually dis- the world, processing environments called “isolators” infected, and is directly accessed by gowned personnel. Vol. 55, No. 5, September/October 2001, Supplement TR34 1 1.4 Purpose processing of sterile materials adhere to the following general principles: The increased use of isolators in the health care prod- • They must not exchange air with the surrounding uct industry over the last decade and a half has been environment except when that air passes through a remarkable. In fact, isolators now clearly represent the microbially retentive filter. most rapidly growing technology for the production of • They must be decontaminated in a reproducible andhealth care products. In spite of the rapid growth this quantifiable manner.segment of the industry has enjoyed, very little techni- cal guidance exists for those who work in this field. • All work or handling of materials within the isolator enclosure must be accomplished remotely; no human It was often said at the beginning of the “isolator era” operator or part thereof can directly enter the isola- that isolators could be considered nothing more than tor during operation. small clean rooms. Experience has taught scientists and • All materials that enter the isolator must be decon- engineers that functional requirements for isolators are, taminated or sterilized and must enter either directlyin fact, distinctly different from those for human scale through a decontaminating or sterilizing system, or or “conventional” clean rooms. Although human scale via a rapid transfer port. clean rooms and isolators have much in common, they have many important differences and this technical re- 2.1.2 Closed Isolators Intended for Containmentport endeavors to focus on and discuss these differences. Applications 2.0 TYPES OF ISOLATORS These units generally operate under negative pressure and are cleared of all potentially hazardous materials2.1 Closed Isolators prior to opening. Isolators intended for containment ap- plications adhere to the following general principles:Isolators operated as closed systems do not exchange unfiltered air or contaminants with adjacent environ- • They must not exchange air with the surrounding en- ments. Their ability to operate without personnel ac- vironment except when that air passes through a fil- cess to the critical zone makes isolators capable of lev- ter capable of retaining the materials being processed. els of separation between the internal and external en- • All work or handling of materials within the isolator vironment unattainable with other technologies. Be- enclosure must be accomplished remotely. No human cause of the effectiveness of this separation, closed iso- operator or part thereof can directly enter the isola- lators are ideally suited for application in the prepara- tor during operation. tion of sterile and/or toxic material. • All materials exiting the isolator must be cleaned or contained in such a way that hazardous materials areThere are two types of closed isolators: aseptic and con- not released to the surrounding environment.tainment. Aseptic isolators are intended to exclude ex- ternal contamination from the critical zone inside the • They must be cleanable in a reproducible and quanti- isolator. Containment isolators are intended to prevent fiable manner. the release of toxic materials processed inside the iso- lator to the surrounding environment in which person- 2.1.3 Closed Isolators Intended for Asepsis and nel are located. Containment 2.1.1 Closed Isolators Intended for Aseptic These units are subject to the constraints of sections Applications 2.1.1 and 2.1.2, above. They are typically operated un- der positive pressure, with additional safety measures These units are typically operated under positive such as negative pressure airlocks. The use of supple- pressure and are subject to validatable decontamination mentary personal protective equipment by the workers procedures prior to use. Isolators intended for the may be considered. 2 PDA Journal of Pharmaceutical Science and Technology 2.2 Open Isolators Open isolators differ from closed isolators in that they are designed to allow for the continuous or semi-con- tinuous ingress and/or egress of materials during op- eration, while maintaining a level of protection over the internal environment. Open isolators do not exchange unfiltered air or contaminants with adjacent environ- ments. Open isolators are decontaminated while closed, and then opened during manufacturing. Open isolators typically are used for the aseptic filling of finished phar- maceuticals. 2.2.1 Open Isolators Intended for Aseptic Applications With the exception of the presence of openings during manufacturing, open isolators satisfy the same general principles as noted above for closed isolators. There are numerous designs that can successfully manage the ingress and egress of components of filled containers, while preventing the ingress of contamination from the surrounding environment. 2.2.2 Open Isolators Intended for Asepsis and Containment These isolators share similarities with the ordinary open isolator (see 2.2.1) and the containment isolator (see 2.1.1). For these systems, the design usually incorpo- rates a cleaning process to allow for removal of any toxic contaminant from the exterior of the sealed con- tainer prior to exit from the isolator. The design must also prevent the ingress of air in order to preserve the aseptic nature of the internal environment. The following diagram provides an overview of isola- tors, barrier systems, and clean rooms depicting some of their o