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1 2002 년 5 월런던 CPMP/QWP/158/01 Revision EMEA/CVMP/115/01 Revision COMMITTEE FOR PROPRIETARY MEDICINAL PRODUCTS (CPMP) COMMITTEE FOR VETERINARY MEDICINAL PRODUCTS (CVMP) 제약용수품질가이드라인 (NOTE FOR GUIDANCE ON QUALITY OF WATER FOR PHARMACEUTICAL USE) Discussion in the Quality Working Party October 2000, January 2001 Transmission to the CPMP/CVMP February 2001 Release for Consultation February 2001 Deadline for Comments August 2001 Discussion in the Quality Working Party October 2001 Transmission to CPMP/CVMP November 2001 Adoption by CPMP/CVMP November 2001 Discussion in QWP Following Industry Representation Modification to Tables 3 and 5 April 2002 Adoption by CPMP/CVMP May 2002 Date for Coming into Operation 1 June 2002 Changes are in: Table 3 (Final isolation and purification of API - not sterile but intended for use in sterile parenteral product) Table 5 - Initial rinse of containers/closures for sterile products Table 5 - Final rinse of containers closures for sterile parenteral products (addition of footnote) 1

2 NOTE FOR GUIDANCE ON QUALITY OF WATER FOR PHARMACEUTICAL USE 1. 서론 (INTRODUCTION) Water is one of the major commodities used by the pharmaceutical industry. It may be present as an excipient, or used for reconstitution of products, during synthesis, during production of the finished product or as a cleaning agent for rinsing vessels, equipment, primary packaging materials etc. 물은제약산업에서사용되는주요원료가운데하나이다. 첨가물이나제품희석용도로사용되기도하며, 합성이나최종제품생산도중에도사용되고, 각종용기나설비, 일차포장자재등을세척할때도사용된다. Different grades of water quality are required depending on the different pharmaceutical uses. Control of the quality of water, in particular, the microbiological quality, is a major concern and the pharmaceutical industry devotes considerable resource to the development and maintenance of water purification systems. 용도에따라용수품질등급이다양하다. 용수품질, 특히미생물학적품질의관리는매우중요하며, 제약업계는용수정제시스템의개발과유지관리에상당한자원을투자하고있다. 2. 배경 (BACKGROUND) The European Pharmacopoeia (Ph Eur) contains standards for grades of water for pharmaceutical use including Water for Injections (WFI) and Purified Water. The use of reverse osmosis (RO) as a means of preparing WFI has been the subject of ongoing discussion within the Ph Eur Commission for a number of years. In 1999, in response to requests from national delegations to permit the use of RO for WFI production, a major international symposium was organised to discuss the issue. The meeting concluded that there was insufficient evidence at the present time to support the use of RO to produce WFI and in view of the safety concerns, WFI should be prepared only by distillation as laid down in the Ph Eur. 유럽약전에는주사용수 (WFI) 와정제수를포함하여각종제약용수기준이포함되어있다. RO 방식의주사용수제조방법은오랫동안유럽약전위원회안에서논란의대상이되었다. 1999년에는 RO 방식의주사용수제조를허용하자는국가대표자들의요청에따라, 이 2

3 문제를논의하기위한국제심포지엄이열렸다. 그리고현재는 RO 방식의주사용수생산을 뒷받침할증거가충분하지않으며, 안전성측면에서 WFI 는유럽약전에제시된바에따라 증류방식으로만제조해야한다는결론을내렸다. The meeting agreed that further guidance on the use of the different grades of pharmaceutical water would be beneficial to the industry as the Ph Eur monographs themselves do not address some of the aspects of when particular grades should be used. Furthermore as a result of this activity a new Ph Eur monograph entitled Highly Purified Water has been adopted and will be implemented in the Ph Eur from 1st January 또한유럽약전자체는특정등급의용수를사용해야하는경우를제시하고있지않으므로, 각종제약용수의사용에관한가이드라인을만들면제약업계에도움이되리라는의견일치를보았다. 이활동의결과로 " 고도정제수 " 라는제목의새로운유럽약전모노그래프가채택되었으며, 이모노그래프는 2002년 1월 1일부터채택될예정이다. The CPMP/CVMP Quality Working Party and Inspectors Working Party have recently reconsidered the use of RO water for the preparation of WFI. They have concluded on the available evidence, that the production of water by RO and associated technologies is considered to lack the robustness of distillation and concerns remain about the potential risks associated with, for example, fouling of the membrane (chemical and biological), failure of membrane integrity and lack of effective validation. Hence the current view is that Highly Purified Water is not acceptable for WFI. CPMP/CVMP QWP와 IWP는 RO 방식의주사용수제조를다시검토했다. 그리고활용가능한증거자료에근거하여, RO 방식의용수생산은증류방식이갖고있는완건성을결여하고있으며, 예를들어멤브레인의오염 ( 화학적, 생물학적 ), 멤브레인완전성이상, 효과적인밸리데이션의결여등과관련된리스크에대한우려를배제할수없다는결론을내렸다. 그러므로현재는 " 고도정제수 " 가 WFI에적합하지않다는입장이다. 3. 적용범위 (SCOPE) This document is intended to provide guidance to the industry on the pharmaceutical use of different grades of water in the manufacture of active pharmaceutical ingredients and medicinal products for human and veterinary use. 이문서는사람의약품과동물의약품, 그리고활성제약성분제조에사용되는각종 3

4 용수에대한가이드라인을제공한다. This guidance is not intended to cover situations where, for example, medicinal products are prepared extemporaneously or where preparations are reconstituted/diluted with water prior to use by a pharmacist (eg. oral antibiotic mixtures) or in the case of veterinary products, by the user (eg. sheep dips). 예를들어의약품을즉석에서조제하거나약사가투약전에물로희석 / 용해하는경우 ( 예, 경구항생제혼합물 ) 나동물의약품인경우에는사용자가 ( 예, 세양제 ) 물로희석 / 용해하는경우는이문서의대상이아니다. 4. 유럽약전기준 (REQUIREMENTS OF THE EUROPEAN PHARMACOPOEIA) The European Pharmacopoeia provides standards for the following grades of water: 유럽약전에는다음 3 등급의용수기준이제시되어있다. Water for Injections 주사용수 Purified Water 정제수 Highly Purified Water 고도정제수 4.1 Potable Water is not covered by a pharmacopoeial monograph but must comply with the regulations on water laid down by the competent authority. Testing should be carried out at the manufacturing site to confirm the quality of the water. Potable water may be used in chemical synthesis and in the early stages of cleaning pharmaceutical manufacturing equipment unless there are specific technical or quality requirements for higher grades of water. It is the prescribed source feed water for the production of pharmacopoeial grade waters. 음용수는약전모노그래프의대상이아니지만, 관계당국이정한용수규정에부합해야한다. 제조장소에서시험을실시하여용수품질을확인한다. 더높은등급의용수사용을정한구체적인기술또는품질기준이없으면, 음용수는화학적합성과제약제조설비의초기세척단계에서사용할수있다. 약전등급용수생산을위한지정공급수에해당된다. 4

5 4.2 Water for Injections (WFI) is water for the preparation of medicines for parenteral administration when water is used as a vehicle (water for injections in bulk) and for dissolving or diluting substances or preparations for parenteral administration before use (sterilised water for injections). 주사용수는주사제의약품조제시에용매로사용하거나 (water for injections in bulk), 주사용성분이나제제를투여하기전에용해또는희석 (sterilized water for injections) 할때사용한다. 생산 (Production) Control of the chemical purity of WFI presents few major problems. The critical issue is that of ensuring consistent microbiological quality with respect to removal of bacteria and bacterial endotoxins. Distillation has a long history of reliable performance and can be validated as a unit operation, hence it currently remains the only official method for WFI. WFI의화학적순도관리는큰문제가별로없다. 하지만세균과세균성엔도톡신제거와관련하여, 일관된미생물학적품질보증은매우중요한이슈이다. 증류방식은오랜기간에걸쳐신뢰성이확보되었으며, 단위작업으로밸리데이션을할수있다. 그러므로증류방식은유일한공식 WFI 생산방법이다. WFI in bulk is obtained from water that complies with the regulation on water intended for human consumption laid down by the competent authority, or from purified water, by distillation in an apparatus of which the parts in contact with the water are of neutral glass, quartz or suitable metal and which is fitted with an effective device to prevent the entrainment of droplets. The correct maintenance of the apparatus is essential. During production and storage, appropriate measures are taken to ensure that the total viable aerobic count is adequately controlled and monitored. 벌크 WFI는관계당국이정한사람음용수규정에부합하는용수나정제수를증류하여만드는데, 이때사용하는장치의용수접촉부분은중성유리, 석영또는적합한금속으로만들며물방울의반출을방지하는효과적인장치를구비해야한다. 이장치의올바른유지관리가필수적이다. 생산및보관과정에서전체호기생균수를적절하게관리하고모니터하는대책을구비한다. WFI complies with the tests for Purified Water with additional requirements for 5

6 bacterial endotoxins (not more than (nmt) 0.25 IU of endotoxin per ml), conductivity and Total Organic Carbon. WFI는정제수기준에부합하고, 여기에추가하여세균성엔도톡신 (0.25 IU/mL 이하 ), 전도도, TOC 기준에도부합해야한다. 4.3 Purified Water is water for the preparation of medicinal products other than those that require the use of water which is sterile and/or apyrogenic. Purified Water which satisfies the test for endotoxins may be used in the manufacture of dialysis solutions. 정제수는무균및 / 또는발열성물질부재용수의사용이요구되는것이외의다른의약품조제에사용된다. 엔도톡신기준을만족시키는정제수는투석액제조에사용할수있다. 생산 (Production) Purified Water is prepared by distillation, by ion exchange or by any other suitable method, from water that complies with the regulations on water intended for human consumption laid down by the competent authority. 정제수는관계당국이정한사람음용수규정에부합하는물을증류, 이온교환, 또는기타적합한방법으로만든다. 4.4 Highly Purified Water is intended for use in the preparation of products where water of high biological quality is needed, except where Water for Injections is required. 고도정제수는 WFI가요구되는경우를제외하고, 생물학적품질이높은용수가필요한제품제조에사용된다. 생산 (Production) Highly Purified Water is obtained from water that complies with the regulations on water intended for human consumption laid down by the competent authority. Current production methods include, for example, double-pass reverse osmosis coupled with other suitable techniques such as ultrafiltration and deionisation. Highly Purified Water meets the same quality standards as WFI but the production methods are considered less reliable than distillation and thus it is considered unacceptable for use as WFI. 6

7 고도정제수는관계당국이정한음용수규정에부합하는물로만든다. 현재의생산방법으로는예를들어다른적합한기법 ( 예, 한외여과, 탈이온화 ) 과결합한 DPRO(doublepass reverse osmosis) 가있다. 고도정제수는 WFI 품질기준에부합해야하지만, 생산방법은증류보다신뢰성이덜한것으로생각되므로, WFI 용도로사용할수는없다. 5. 제약용수의품질 (QUALITY OF WATER FOR PHARMACEUTICAL USE) Validation and qualification of water purification, storage and distribution systems are a fundamental part of GMP and form an integral part of the GMP inspection. 용수정제, 보관, 분배시스템의적격성평가와밸리데이션은 GMP의기본요소이며, GMP 실사의핵심적인부분을형성한다. The grade of water used at different stages in the manufacture of the active pharmaceutical ingredients and pharmaceutical products should be discussed in the pharmaceutical dossier. The grade of water used should take account of the nature and intended uses of the finished product and the stage at which the water is used. 활성제약성분과의약품제조단계별로사용되는용수의등급을의약품허가서류에서설명해야한다. 용수가사용되는단계와최종제품의특성및목적용도를감안하여용수등급을정한다. The following tables provide some general examples for guidance: 일반적인가이드라인이다음표에정리되어있다. 5.1 최종제제에첨가물로사용되는용수 (Water present as an excipient in the final formulation) Water is the most commonly used excipient in medicinal products: the minimum quality of water selected depends on the intended use of the product. Table 1 summarises the main categories of sterile products. WFI is required for those products intended for parenteral administration and this includes solutions for haemofiltration and haemodiafiltration, and peritoneal dialysis. 용수는의약품첨가물로흔히사용된다. 제품의목적용도에따라용수의최소품질수준을결정한다. 무균제품종류별로용수의최소품질수준이표 1에정리되어있다. 주사방식으로투여할제품에는 WFI가요구되며, 혈액여과와혈액투석여과, 그리고복막투석용도용액제품도여기에포함된다. 7

8 For convenience the pharmaceutical industry often uses WFI for the preparation of ophthalmic, sterile nasal/ear and cutaneous preparations. In such situations, Highly Purified Water represents a useful alternative with the added advantage of satisfying the industry s need for large volumes. 안과제품, 무균비강 / 귀제품, 피부제품조제시에 WFI를사용하기도한다. 이런경우에는고도정제수가대안이될수있으며, 많은양을필요로하는업계의필요를충족시킨다는부가적인장점도있다. Table 1: 무균의약품 (Sterile Medicinal Products) 무균의약품 (Sterile medicinal products) 주사제 (Parenteral) 안약 (Ophthalmic) 혈액여과용액 (Haemofiltration Solutions) 혈액투석여과용액 (Haemodiafiltration Solutions) 복막투석용액 (Peritoneal Dialysis Solutions) 관류용액 (Irrigation Solutions) 비강 / 귀제제 (Nasal/Ear Preparations) 피부제제 (Cutaneous Preparations) 최소용수품질 (Minimum acceptable quality of water) WFI 정제수 (Purified) WFI WFI WFI 정제수 (Purified) 정제수 (Purified) Table 2 summarises the main categories of non-sterile dosage forms. With the exception of some nebuliser preparations, Purified Water is the acceptable grade of water for all non-sterile products. 주요비무균제제카테고리가표 2에요약되어있다. 일부분무제제를예외로하면, 정제수가모든비무균제품제조에적합하다. Table 2: 비무균의약품 (Non-sterile Medicinal Products) 비무균의약품 (Non-sterile medicinal products) 경구제제 (Oral Preparations) 분무액 (Nebuliser Solutions) 피부제제 (Cutaneous Preparations) 비강 / 귀제제 (Nasal/Ear Preparations) 직장 / 질제제 (Rectal/Vaginal Preparations) 최소용수품질 (Minimum acceptable quality of water) 정제수 (Purified) 정제수 (Purified)* 정제수 (Purified)** 정제수 (Purified) 정제수 (Purified) 8

9 * In certain disease states eg. cystic fibrosis, medicinal products administered by nebulisation are required to be sterile and non-pyrogenic. In such cases WFI or sterilised Highly Purified Water should be used. 일부질환 ( 예, 낭포성섬유증 ) 의경우에분무방식으로투여되는의약품은무균적이고발열성물질이없어야한다. 이럴때는 WFI 또는멸균고도정제수를사용한다. ** For some products such as veterinary teat dips it may be acceptable to use potable water where justified and authorised taking account of the variability in chemical composition and microbiological quality. 동물유두침지액같은일부제품은, 화학적조성과미생물학적품질의변동성을감안하여허가를받았고타당한이유가있을때는음용수사용도가능하다. 5.2 최종제제에첨가물로사용되는용수를제외하고, 활성제약성분과의약품의제조시에사용되는용수 (Water used during manufacture of active pharmaceutical ingredients and medicinal products excluding water present as an excipient in the final formulation) The acceptable grade of water will depend heavily on the stage at which it is to be used during manufacture, the subsequent processing steps and the nature of the final product. Tables 3 and 4 summarise the acceptable quality of water for the manufacture of active pharmaceutical ingredients and for sterile and non-sterile medicinal products. 제조단계, 이후의가공단계, 그리고최종제품의특성에따라용수등급을정한다. 활성제약성분과무균및비무균의약품제조에적합한용수품질등급이표 3과 4에요약되어있다. Table 3: API 제조에사용되는용수 (Water used during the manufacture of Active Pharmaceutical Ingredients) 제조종류 (Type of manufacture) 최종분리및정제단계 이전의 모든 API 중간제품합성 (Synthesis of all intermediates of APIs 제품기준 (Product requirements) API 자체나 API를투입하여만드는의약품이무균적이거나발열성물질이없어야한다는기준이없는경우 (No requirement for sterility or apyrogenicity in API or the 최소용수품질 (Minimum acceptable quality of water) 음용수 (Potable Water)* 9

10 prior to final isolation and purification steps) 발효배지 (Fermentation media) 식물추출 (Extraction of herbals) 최종분리및정제 (Final isolation and purification) 최종분리및정제 (Final isolation and purification) 최종분리및정제 (Final isolation and purification) 최종분리및 정제 (Final isolation and purification) pharmaceutical product in which it will be used.) API 자체나 API를투입하여만드는의약품이무균적이거나발열성물질이없어야한다는기준이없는경우 (No requirement for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used) API 자체나 API를투입하여만드는의약품이무균적이거나발열성물질이없어야한다는기준이없는경우 (No requirement for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used) API 자체나 API를투입하여만드는의약품이무균적이거나발열성물질이없어야한다는기준이없는경우 (No requirement for sterility or apyrogenicity in API or the pharmaceutical product in which it will be used) API가무균상태일필요는없지만, 무균비주사제제품제조에사용되는 API인경우 (API is not sterile, but is intended for use in a sterile, non-parenteral product) API가무균적이어야하지만, 주사제용도가아닌경우 (API is sterile and not intended for parenteral use) API가무균상태는아니지만무균주사제제조에사용되는경우 (API is not sterile, but is intended for 음용수 (Potable Water)* 음용수 (Potable Water)** 음용수 (Potable Water)* 주사제 (Purified Water) 정제수 (Purified Water) 정제수, 엔도톡신 (0.25 EU/mL) 과지정미생물관리 (Purified Water with 10

11 use in a sterile, parenteral an endotoxin limit of product) 0.25EU/ml and control of specified organisms.) 최종분리및 API가무균적이고발열성물질이 WFI(Water For 정제 (Final isolation 없어야하는경우 (API is sterile Injections) and Purification) and apyrogenic) * Purified Water should be used where there are technical requirements for greater chemical purity. 더좋은화학적순도가요구된다면, 정제수를사용해야한다. ** The Applicant would need to demonstrate that potential variations in the water quality, particularly with respect to mineral composition, would not influence the composition of the extract. 특히미네랄조성과관련하여용수품질의변동이추출물조성에영향을주지않는다는점을증명할필요가있다. Table 4: 최종제제중에는존재하지않고, 의약품제조도중에사용되는용수 (Water used during manufacture of medicinal products which is not present in the final formulation) 최소용수품질 (Minimum 제조 (Manufacture) acceptable quality of water) 과립화 (Granulation) 정제수 (Purified)* 정제코팅 (Tablet coating) 정제수 (Purified) 비무균동결건조이전단계의조제에사용 (Used in 정제수 (Purified) formulation prior to non-sterile lyophilisation) 무균동결건조이전단계의조제에사용 (Used in WFI formulation prior to sterile lyophilisation) * For some veterinary premix products eg. granulated concentrates it may be acceptable to use potable water where justified and authorised taking account of the variability in chemical composition and microbiological quality. 일부동물용프리믹스제품인경우 ( 예, 농축과립 ), 화학적조성과미생물학적품질의변동성을감안하여허가를받았고타당한이유가있을때는음용수사용도가능하다. 5.3 설비, 용기, 마개세척 / 린스용용수 (Water used for cleaning/rinsing of equipment, containers and closures) 11

12 In general, the final rinse used for equipment, containers/closures should use the same quality of water as used in the final stage of manufacture of the API or used as an excipient in a medicinal product. 일반적으로설비, 용기 / 마개의최종린스에는해당 API의최종제조단계에사용되거나의약품첨가물로사용되는것과동일한품질수준의용수를사용해야한다. Table 5: 세척 / 린스용수 (Water used for cleaning/rinsing) 설비, 용기, 마개세척 / 린스최소용수품질 (Cleaning/Rinsing of 제품종류 (Minimum acceptable Equipment, Containers, (Product type) quality of water) Closures) 초기린스 (Initial rinse) 중간제품과 API 음용수 (Potable Water) (Intermediates and API) 마지막린스 (Final rinse) API API 제조에사용되는것과동일수준의품질 (Use same quality of water as used in the API manufacture) 해당되는경우, 설비, 용기, 마개의 CIP를포함한초기 의약품 - 비무균 (Pharmaceutical products 음용수 (Potable Water) 린스 (Initial rinse including non sterile) CIP* of equipment, containers and closures, if applicable) 해당되는경우, 설비, 용기, 마개의 CIP를포함한마지막 의약품 - 비무균 (Pharmaceutical products 정제수또는정제수보다더높은수준의용수를의약품 린스 (Final rinse including non sterile) 제조에 사용한다면, 그와 CIP* of equipment, 동일한수준의용수 (Purified containers and closures, if Water or use same quality applicable) of water as used in manufacture of medicinal product, if higher quality than Purified Water) 해당되는경우, 설비, 용기, 무균제품 정제수 (Purified Water) 12

13 마개의 CIP를포함한초기 (Sterile products) 린스 (Initial rinse** including CIP* of equipment, containers and closures, if applicable) 해당되는경우, 설비, 용기, 무균 비주사 제품 (Sterile 정제수또는정제수보다더 마개의 CIP를포함한마지막 non-parenteral products) 높은수준의용수를의약품 린스 (Final rinse*** 제조에 사용한다면, 그와 including CIP* of 동일한수준의용수 (Purified equipment, containers Water or use same quality and closures, if of water as used in applicable) manufacture of medicinal product, if higher quality than Purified Water) 해당되는경우, 설비, 용기, 무균 주사 제품 (Sterile WFI **** 마개의 CIP를포함한마지막 parenteral products) 린스 (Final rinse*** including CIP* of equipment, containers and closures, if applicable) * CIP = Clean In Place ** Some containers, e.g. plastic containers for eyedrops may not need an initial rinse, indeed this may be counter-productive since particulates counts could be increased as a result. In some cases e.g. blow-fill-seal processes rinsing cannot be applied. 일부용기 ( 예, 안약용플라스틱용기 ) 는초기린스가필요하지않을수있으며, 실제로초기린스때문에미립자수가증가될수있으므로오히려좋지않다. 린스를적용할수없는경우도있다 ( 예, blow-fill-seal 공정 ) *** If equipment is dried after rinsing with 70% alcohol, the alcohol should be diluted in water of the same quality as the water used for the final rinse. 70% 알코올로린스하고나서설비를건조한다면, 그알코올은최종린스에 사용하는것과동일한품질의용수로희석해야한다. **** Where a subsequent depyrogenisation step is employed the use of Highly Purified Water may be acceptable subject to suitable justification and 13

14 validation data. 다음에발열성물질제거단계가있다면, 적합한타당성증명과밸리데이션데이터가 있는경우에고도정제수를사용할수도있다. 14

Validation Plan Template

Validation Plan Template 문서번호(Document No.) : 개정번호(Revision No.) : 00 시행일자(Effective Date) : 페이지번호(Page No.) : 1 of 9 작성자 (Prepared By) 부서 (Dept.) 직위 (Position) 이름 (Name) 서명 / 날짜 (Signature / Date) 검토자 (Reviewed By) 부서 (Dept.)