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Guidance for Industry & FDA 복합제품 CGMP (Current Good Manufacturing Practice for Combination Products) DRAFT GUIDANCE This guidance document is being distributed for comment purposes only. Comments and suggestions regarding this draft document should be submitted within 60 days of publication in the Federal Register of the notice announcing the availability of the draft guidance. Submit comments to Division of Dockets Management (HFA-305), Food and Drug Administration, 5630 Fishers Lane, rm. 1061, Rockville, MD 20852. All comments should be identified with the docket number listed in the notice of availability that publishes in the Federal Register. For questions regarding this draft document, contact Patricia Y. Love at 301-427- 1934. U.S. Department of Health and Human Services Food and Drug Administration Office of the Commissioner Office of Combination Products (OCP) September 2004 1

Guidance for Industry & FDA 복합제품 CGMP (Current Good Manufacturing Practice for Combination Products) Additional copies are available from: Office of Combination Products, HFG-3 Office of the Commissioner Food and Drug Administration 15800 Crabbs Branch Way, Suite 200 Rockville, MD 20855 (Tel) 301-427-1934 (Fax) 301-427-1935 http://www.fda.gov/oc/combination U.S. Department of Health and Human Services Food and Drug Administration Office of the Commissioner Office of Combination Products (OCP) September 2004 2

[ 목차 ] I. 서론 (INTRODUCTION) II. 배경정보 (BACKGROUND INFORMATION) A. 복합제품이란무엇인가?(What is a combination product?) B. 복합제품의구성부분은?(What is a constituent part of a combination product?) C. 복합제품의규제방법은?(How are combination products regulated?) III. CGMP(CURRENT GOOD MANUFACTURING PRACTICE) A. 배경 (Background) B. 복합제품의 CGMP(Current Good Manufacturing Practice for Combination Products) C. 복합 제품 유형별 고려 사항 (Considerations for different types of IV. combination products) 복합제품개발단계에서 FDA 와의커뮤니케이션 (COMMUNICATION WITH FDA DURING DEVELOPMENT OF A COMBINATION PRODUCT) A. FDA와의 CGMP 이슈협의를 FDA는언제권고하는가?(When does FDA recommend discussing CGMP issues with the Agency?) B. 추가정보입수처 (Where can I get more information?) 3

Guidance for Industry 1 Current Good Manufacturing Practice for Combination Products This draft guidance, when finalized, will represent the Food and Drug Administration's (FDA's) current thinking on this topic. It does not create or confer any rights for or on any person and does not operate to bind FDA or the public. You can use an alternative approach if the approach satisfies the requirements of the applicable statutes and regulations. If you want to discuss an alternative approach, contact the FDA staff responsible for implementing this guidance. If you cannot identify the appropriate FDA staff, call the appropriate number listed on the title page of this guidance. 이가이드문서초안이마무리되면, 이주제에대한 FDA의방침을제시한다. 이문서는어느누구에게일체의권리를부여하거나인정하지않으며 FDA 또는일반대중을구속하지도않는다. 관련법규에제시된기준을만족시킬수있는다른방법이있다면, 그방법을활용할수도있다. 다른방법을협의하고자한다면, 해당 FDA 담당자에게연락한다. 관련 FDA 담당자가누구인지알수없다면, 이문서의표지에제시된번호로전화를한다. I. 서론 (INTRODUCTION) This document provides guidance to industry and FDA staff on the applicability of current good manufacturing practice 2 provisions to combination products as defined 1 This guidance has been prepared by the Office of Combination Products in the Office of the Commissioner in cooperation with the Center for Biologics Evaluation and Research (CBER), the Center for Drug Evaluation and Research (CDER), and the Center for Devices and Radiological Health (CDRH) at the Food and Drug Administration. 이가이드문서는 CBER, CDER, CDRH와협조하여 OC(Office of the Commissioner) 의 OCP 가작성했다. 2 For purposes of this guidance document, the term current good manufacturing practice refers to the current good manufacturing practice regulations for drugs and most biological products under 21 CFR Parts 210 and 211, for 4

under 21 CFR 3.2(e). Such provisions apply to the manufacture 3 of combination products to ensure that (1) the product is not adulterated; (2) the product possesses adequate strength, quality, identity, and purity; and (3) the product complies with performance standards as appropriate for the marketed combination product. 이문서는 21 CFR 3.2(e) 에정의된복합제품 (combination products) 에대한 CGMP 규정의적용에관하여업계와 FDA 담당자에게가이드라인을제공하기위한것이다. 상기규정은 (1) 불량제품을방지하고 (2) 제품이적절한함량, 품질, 확인, 순도를보유하도록하며 (3) 제품이시판복합제품에적적한성능표준에부합하도록하기위해복합제품제조에적용된다. This guidance does not address technical manufacturing methods or make recommendations for manufacturers' 4 selection of facilities to manufacture products. certain biological products under 21 CFR Parts 600-680, and the quality system regulations for devices under 21 CFR Part 820. 이가이드문서에서 CGMP(current good manufacturing practice) 라함은, 21 CFR 파트 210 및 211에의거한의약품과대다수생물학적제품, 21 CFR 파트 600-680 에의거한특정생물학적제품에적용되는 CGMP 규정과 21 CFR 파트 820에의거한의료용구 QSR을의미한다. 3 For purposes of this document, the term manufacture refers to the methods to be used in, and the facilities and controls to be used for, the manufacture, processing, packing, or holding of a drug (21 CFR 210.01(a)), and those used for the design, manufacture, packaging, labeling, storage, installation, and servicing of all finished devices intended for human use (21 CFR 820.1(a)). In addition, the term manufacture refers to the methods and facilities for certain biological products that are considered to supplement, not supercede, the drug provisions, unless the regulations explicitly provide otherwise (21 CFR 210.2(a)). 이문서에서제조라함은의약품의제조, 가공, 포장, 또는보관에사용되는방법과 이를위한시설및관리 (21 CFR 210.01(a)) 와사람용모든최종의료용구의디자인, 제조, 포장, 라벨작업, 보관, 설치, 서비스를위한것 (21 CFR 820.1(a)) 을의미한다. 또한규정에서별도로명확히제시하고있지않는한, 의약품규정을대체하는것이아니라보완하는것으로간주되는특정생물학적제품을위한방법과시설을의미한다. 4 For purposes of this guidance document, the term manufacturer refers to 5

이가이드문서는제품제조를위해제조업체가시설을선정하는부분에대한권고사항을 제시하거나기술적인제조방법을다루지않는다. FDA's guidance documents, including this guidance, do not establish legally enforceable responsibilities. Instead, guidances describe the Agency's current thinking on a topic and should be viewed only as recommendations, unless specific regulatory or statutory requirements are cited. The use of the word should in Agency guidances means that something is suggested or recommended, but not required. 이가이드문서를포함한 FDA 가이드문서들은법적강제성을지니지않는다. 다만가이드문서는특정주제에대한 FDA의방침을기술하고있으며, 구체적인법적기준이제시되어있지않으면일종의권고사항으로간주한다. FDA 가이드문서에서 "should" 라는표현은어떤것을제안또는권고한다는의미이지반드시그래야한다는의미는아니다. II. 배경정보 (BACKGROUND INFORMATION) A. 복합제품이란무엇인가?(What is a combination product?) A combination product is a product composed of any combination of a drug and a device; a biological product and a device; a drug and a biological product; or a drug, device, and a biological product. Under 21 CFR 3.2 (e), a combination product is defined to include: 복합제품은의약품과의료용구, 생물학적제품과의료용구, 의약품과생물학적제품, 의약품과의료용구와생물학적제품의조합으로구성된제품을의미한다. 21 CFR 3.2(e) 에따르면, 복합제품은다음을포함하는것으로정의된다. 1. A product comprising two or more regulated components (i.e., drug/device, biologic/device, drug/biologic, or drug/device/biologic) that are physically, chemically, or otherwise combined or mixed and any person who would be required to comply with current good manufacturing practice regulatory requirements for drugs, biological products, devices, or combination products. 이문서에서 " 제조업체 " 라함은, 의약품, 생물학적제품, 의료용구, 또는복합제품에대한 CGMP 규제기준을준수해야하는자를의미한다. 6

produced as a single entity; 2개이상의규제대상컴포넌트 ( 즉, 의약품 / 의료용구, 생물학적제품 / 의료용구, 의약품 / 생물학적제품, 또는의약품 / 의료용구 / 생물학적제품 ) 를포괄하며, 이들이물리적, 화학적, 또는기타의방법으로결합또는혼합되어있고하나의물품으로생산되는제품. 2. Two or more separate products packaged together in a single package or as a unit comprising drug and device products, device and biological products, or biological and drug products; 의약품과의료용구, 의료용구와생물학적제품, 또는생물학적제품과의약품을포괄하는단위로또는하나의포장물로함께포장된 2개이상의별개제품. 3. A drug, device, or biological product packaged separately that according to its investigational plan or proposed labeling is intended for use only with an approved individually specified drug, device, or biological product where both are required to achieve the intended use, indication, or effect and where, upon approval of the proposed product, the labeling of the approved product would need to be changed (e.g., to reflect a change in intended use, dosage form, strength, route of administration, or significant change in dose); or 연구계획또는예정표시사항에따라승인된지정의약품, 의료용구, 또는생물학적제품과만사용하며, 이때의두제품은의도한바의용도, 적응증, 또는효과를달성해야하며, 예정제품의승인시에승인된제품의표시자재를변경할필요가있는 ( 예, 목적용도, 제형, 함량, 투여경로, 또는용량의중대한변경을반영하여 ), 별개로포장된의약품, 의료용구, 또는생물학적제품. 4. Any investigational drug, device, or biological product packaged separately that according to its proposed labeling is for use only with another individually specified investigational drug, device, or biological product where both are required to achieve the intended use, indication, or effect. 예정표시사항에따라다른지정연구용의약품, 의료용구, 또는 7

생물학적제품과만사용하며, 이때의두제품은의도한바의용도, 적응증, 또는효과를달성해야하는, 별개로포장된연구용의약품, 의료용구, 또는 생물학적제품. B. 복합제품의구성부분은?(What is a constituent part of a combination product?) For the purposes of this guidance document, a constituent part of a combination product is an article in a combination product that can be distinguished by its regulatory identity as a drug, device, or biological product, as defined in section 201 of the Federal Food, Drug, and Cosmetic Act (the Act) or 351(i) of the Public Health Service Act. For example, a device coated or impregnated with a drug has two constituent parts, the device and the drug. For simplicity, the concepts in this guidance are described in the context of a combination product composed of two constituent parts. These concepts are also relevant for combination products with more than two constituent parts. 이가이드문서에서복합제품의구성부분은 PSH법 351(i) 또는연방식품의약품화장품법 (FD&C법) 섹션 201에규정된바에따라, 의약품, 의료용구, 또는생물학적제품으로규제대상을구분할수있는복합제품중의물품을의미한다. 예를들어의약품으로코팅또는주입한의료용구는 2개구성부분 ( 의료용구와의약품 ) 을갖는다. 이해를돕기위하여, 이가이드문서의개념을 2개구성부분으로이루어진복합제품을기반으로설명한다. 구성부분이 2개이상인복합제품에도이개념이적용된다. C. 복합제품의규제방법은?(How are combination products regulated?) A combination product is assigned to an Agency center or alternative organizational component that will have primary jurisdiction for its premarket review and regulation. Under section 503(g)(1) of the Act, assignment to a center with primary jurisdiction, or a lead center, is based on a determination of the primary mode of action (PMOA) of the combination product. 5 For example, if the PMOA of a device- 5 A proposed rule defining the primary mode of action of a combination product was published in the May 7, 2004, Federal Register, http://www.fda.gov/oc/combination/default.htm. 복합제품의주된작용방식을정의한규칙안이 2004년 5월 7일자연방관보로발표 8

biological combination product is attributable to the biological product, the Agency component responsible for premarket review of that biological product would have primary jurisdiction for the combination product. The lead center generally has responsibility for oversight of the regulation of the combination product, including the evaluation of current good manufacturing practice. 복합제품은그의시판전심사및규제에대하여일차적인관할권을갖는 FDA 센터또는다른조직부문이담당한다. FD&C법섹션 503(g)(1) 에의거하여, 일차적인관할권을갖는센터또는리드센터지정은, 해당복합제품의주된작용방식 (PMOA) 의검토결과에근거하여정한다. 예를들어의료용구-생물학적제품복합제품의 PMOA가생물학적제품에있다면, 해당생물학적제품의시판전심사를책임지는 FDA 부서가해당복합제품에대하여일차적인관할권을갖는다. 리드센터는일반적으로 CGMP 평가를포함해, 해당복합제품의규제감독을책임진다. Section 503(g)(4)(D) of the Act requires FDA to "ensure the consistency and appropriateness of postmarket regulation of like [combination] products." To achieve consistency, FDA will treat like combination products similarly. To ensure appropriateness, FDA plans to require that manufacturers use the applicable current good manufacturing practice regulations for their combination products. In the regulation of a combination product, the application of consistent and appropriate current good manufacturing practice should help to ensure that the combination product is not adulterated under section 501 of the Act and is manufactured in accordance with appropriate regulatory provisions for the combination product and its constituent parts. FD&C법섹션 503(g)(4)(D) 에의하면, FDA는 "[ 복합 ] 성제품시판후규제의일관성과적정성을확보 " 해야한다. 일관성확보를위하여 FDA는복합성제품을유사하게취급한다. 적정성보장을위해 FDA는제조업체가그의복합제품에대하여해당 CGMP 규정을준수하도록요구할계획이다. 복합제품의규제에있어서일관되고적절한 CGMP의적용은 FD&C법섹션 501에의거하여불량복합제품을방지하고복합제품이해당복합제품과그의구성부분에적절한규정에따라제조되도록하는데도움이된다. III. CGMP(CURRENT GOOD MANUFACTURING PRACTICE) A. 배경 (Background) 되었다. 9

Section 501 of the Act states the circumstances under which a drug or device is deemed adulterated and authorizes FDA to establish current good manufacturing practice to avoid adulteration. 6 Adulteration includes a failure of the drug, biological product, or device to be manufactured in accordance with current good manufacturing practice, regardless of whether the product is actually deficient in some respect. 7 Current good manufacturing practice regulatory provisions are intended to ensure that the drug, biological product, or device is not adulterated; to ensure the product possesses adequate strength, quality, identity, and purity of a drug or biological product; and to ensure compliance with performance standards for a device. The following current good manufacturing practice regulations and other applicable standards are codified for products that may be constituent parts of a combination product: 8 FD&C법섹션 501에는불량의약품또는의료용구로간주하는상황이제시되어있으며, 그런사태를방지하기위한 CGMP의설정권한을 FDA에부여하고있다. 불량의의미에는제품의특정부분이실제로결함을갖고있는지여부와상관없이, 의약품, 생물학적제품, 또는의료용구가 CGMP에따라제조되지못한경우도포함된다. CGMP 규정은불량의약품, 생물학적제품, 또는의료용구를방지하고, 의약품또는생물학적제품이적절한함량, 품질, 확인, 순도를보유하게하며, 의료용구의경우에성능기준에부합하도록하기위한것이다. 다음의 CGMP 규정과기타해당표준은복합제품의구성부분이될수있는제품에대한것이다. Current good manufacturing practice (CGMP) regulations for finished pharmaceuticals, or drug products (21 CFR Parts 210 and 211). 9 6 7 8 See also section 520(f)(1). See generally sections 501(a)(2)(B) and 501(h). FDA has also issued a proposed rule for Good Tissue Practices, Manufacturers of Human Cellular and Tissue-Based Products; Inspection and Enforcement (Federal Register Notice, January 8, 2001, Vol 66, No. 5, p 1507-1559). 사람세포및조직기반제품제조업체의실사및집행과관련된 GTP 규정안이 발행되었다 ( 연방관보공지사항, 2001 년 1 월 8 일, Vo. 66, No. 5, p 1507-1559). 9 For the purposes of this guidance document, the abbreviation "CGMP" refers only to the drug regulations at 21 CFR Parts 210 and 211, while the phrase "current good manufacturing practice" refers to the various sets of 10

Drug products not subject to these regulations (e.g., bulk drugs or active pharmaceutical ingredients) must still meet the current good manufacturing practice general standard required by the statute. 의약품 CGMP 규정 (21 CFR 파트 210 및 211). 이규정의대상이되지않는의약품 ( 예, 벌크의약품또는 API) 도법에서요구하는 CGMP 일반기준을준수해야한다. Quality system (QS) regulation for devices (21 CFR Part 820). 의료용구 QSR(21 CFR 파트 820). The biological product regulations, 21 CFR Parts 600-680, may also apply to the manufacture of drugs that are also biological products along with the drug CGMP provisions. 10 They also may apply along with the QS regulations to the manufacture of devices that are also biological products. 11 생물학적제품규정 (21 CFR 파트 600-680) 은, 의약품 CGMP 규정과함께생물학적제품이기도한의약품제조에적용될수있다. 또한생물학적제품이기도한의료용구제조에 QSR과함께적용될수있다. There is considerable overlap in the CGMP and QS regulations, and for the most part the overlap is apparent. For example, both establish requirements for management, organization, and personnel; both require documentation and record keeping; and both allow flexibility in application to the manufacture of particular products. 12 FDA considers the CGMP 13 and the QS regulations to be similar, and manufacturing practice regulations (see footnote 2). 이문서에서약어인 "CGMP" 는 21 CFR 파트 210 및 211의의약품규정을의미하며, "current good manufacturing practice" 는각종제조관리규정을의미한다 ( 각주 2 참조 ). 10 11 12 See 21 CFR 211.1(b) and 21 CFR 210.2(b). See 21 CFR 820.1(b). Each set of regulations also allows either a device or a drug manufacturer who is engaging in only some operations that are subject to the requirements in either 21 CFR 820 or 21 CFR 210 and 211 to only comply with the regulations applicable to the operations in which it is engaged. Therefore, a device manufacturer only has to comply with the regulations in 21 CFR 820 that are 11

they are meant to achieve the same goals. CGMP와 QSR은비슷한부분이상당히많으며, 대개는비슷한부분을쉽게찾을수있다. 예를들어두규정모두관리자, 조직, 작업자기준을제시하고있으며, 문서화및기록서유지를요구한다. 또한특정제품제조에적용하는데있어서유연성을허용하고있다. FDA는 CGMP와 QSR이유사하다고생각하며, 추구하는목적도동일하다고본다. Nonetheless, FDA recognizes that each set of regulations is somewhat different because each is tailored to the characteristics of the types of products for which they were designed (i.e., CGMP for drugs or biological products, QS regulation for devices). Each set of regulations contains certain express/specific requirements that may be only more generally described in the other regulation. Typically, these express/specific requirements are related to the unique characteristics of a drug, device, or biological product. For example: 그럼에도불구하고각규정은해당제품의유형과특성에맞추어져있기때문에다른점이 applicable to the operations in which it is engaged in the manufacture of the device, and a drug manufacturer only has to comply with the regulations in 21 CFR 210 and 211 that are applicable to the operations in which it is engaged in the manufacture of the drug. For example, a drug manufacturer who is only involved in the issuance of labeling of the product, 21 CFR 211.125, may not need to comply with regulations related to receipt and storage of untested components, 21 CFR 211.82. 또한 21 CFR 820 또는 21 CFR 210 및 211의대상이되는일부작업만을수행하는의료용구또는의약품제조업체인경우, 그업체가관여하는작업에적용되는규정만을준수하도록하고있다. 그러므로의료용구제조업체는그가수행하는의료용구제조작업에적용되는 21 CFR 820의규정을준수해야하며, 의약품제조업체는그가수행하는의약품제조작업에적용되는 21 CFR 210 및 211의규정을준수해야한다. 예를들어제품표시자재발행작업 (21 CFR 211.125) 만하는의약품제조업체라면, 미시험원료의입고및보관관련규정 (21 CFR 211.82) 을준수할필요가없다. 13 See FDA Guidance, "Quality System Approach to Pharmaceutical Current Good Manufacturing Practice Regulations," available at http://www.fda.gov/cder/guidance/index.htm for an explanation of how to implement a comprehensive QS model under the CGMPs. CGMP에의거한포괄적인 QS 모델의추진방법은 FDA 가이드문서 " 품질시스템 방식의제약 CGMP 규정 " 을참조한다. 12

있다 (CGMP는의약품또는생물학적제품이대상이고 QSR은의료용구가대상 ). 다른규정에서는다소일반적인수준으로기술되어있는사항이, 각규정에는명확하고구체적인기준으로제시되어있기도하다. 일반적으로이와같은명확하고구체적인기준은의약품, 의료용구, 또는생물학적제품의고유한특성과관련이있다. Calculating the yield and stability of a drug constituent part: The CGMP regulation has specific requirements for the calculation of yield (21 CFR 211.103) and for ensuring stability of the drug product (21 CFR 211.166). Under the QS regulation, for a combination product with a drug constituent part, yield and stability requirements would be incorporated more generally as part of the design validation provisions (21 CFR 820.30(g)). 의약품구성부분의안정성과수율계산 : CGMP 규정에는수율계산 (21 CFR 211.103) 과의약품의안정성 (21 CFR 211.166) 에관한구체적인기준이제시되어있다. 의약품구성부분을구비한복합제품인경우, QSR에는수율및안정성기준이디자인밸리데이션기준의한부분으로보다일반적인수준에서제시되어있다 (21 CFR 820.30(g)). Corrective and preventive action (CAPA): The QS regulation has detailed CAPA requirements (21 CFR 820.100), while CAPA principles are more generally identified in the CGMP regulation as part of Production Record Review (21 CFR 211.192). CAPA: QSR에는 CAPA 기준이구체적으로제시되어있으나 (21 CFR 820.100), CGMP 규정에는생산기록서검토의일부로보다일반적인수준에서 CAPA 원칙이기술되어있다 (21 CFR 211.192). B. 복합제품의 CGMP(Current Good Manufacturing Practice for Combination Products) FDA has not promulgated current good manufacturing practice regulations specifically for combination products. Until it does so, each constituent part (i.e., the drug, device, or biological product) remains subject only to its governing current good manufacturing practice regulations when marketed separately, see 21 CFR 3.2(e)(3) and (4), and when manufactured separately as constituent parts of a 13

combination that will later be combined, see 21 CFR 3.2(e)(1) and (2). For example, if a drug is marketed that is intended for use only with an approved individually specified device that is also marketed separately, the drug constituent must comply only with 21 CFR Parts 210 and 211, and the device constituent must comply only with 21 CFR Part 820. Similarly, during the time of separate manufacture (i.e., before drug and device combination products are produced as a single entity or are co-packaged) 21 CFR Parts 210 and 211 apply only to the drug constituent, and 21 CFR Part 820 applies only to the device constituent. FDA는복합제품을대상으로하는 CGMP 규정을아직까지제정하지않았다. 복합제품 CGMP 규정이제정될때까지, 각구성부분 ( 즉, 의약품, 의료용구, 또는생물학적제품 ) 은별개로판매되고 (21 CFR 3.2(e)(3)/(4) 참조 ) 나중에결합하여복합제품을구성하는한부분으로써별개로제조될때 (21 CFR 3.2(e)(1)/(2)) 적용되는해당 CGMP 규정의적용을받는다. 예를들어어떤의약품이승인된지정의료용구와함께사용될목적으로판매되고그의료용구역시별도로판매된다면, 의약품구성부분은 21 CFR 파트 210 및 211에부합해야하고, 의료용구구성부분은 21 CFR 파트 820에부합해야한다. 마찬가지로별도로제조되는동안에는 ( 즉의약품과의료용구복합제품이하나의물품으로생산되거나함께포장되기전에 ), 21 CFR 파트 210 및 211은의약품구성부분에만적용되고 21 CFR 파트 820은의료용구구성부분에만적용된다. However, for combination products that are produced as a single-entity or are copackaged, see 21 CFR 3.2(e)(1) and (2), both sets of current good manufacturing practice regulations are applicable during and after joining the constituent parts together. The rest of this section refers only to situations when combination products that are produced as a single entity or are co-packaged as defined in 21 CFR 3.2(e)(1) and (2) are joined together. 하지만하나의물품으로생산되거나함께포장되는복합제품인경우 (21 CFR 3.2(e)(1)/(2) 참조 ), 구성부분의결합과정과그이후에는두종류의규정이모두적용된다. 이섹션의나머지부분에서는하나의물품으로생산되거나함께포장되는 (21 CFR 3.2(e)(1)/(2)) 복합제품이함께결합되는상황만을거론한다. FDA recognizes that many manufacturing facilities operate under one type of current good manufacturing practice system (i.e., either that described by the QS or CGMP regulation). As noted above, FDA recognizes that there is considerable overlap between the QS and CGMP regulations. It should generally not be 14

necessary for manufacturers who make combination products that are produced as a single entity or are co-packaged to maintain two separate manufacturing systems to ensure compliance with both sets of regulations during and after joining the constituents together. FDA believes that compliance with both sets of regulations during and after joining these types of combination products can generally be achieved by using either the CGMP or QS regulations, e.g., by using the current good manufacturing practice system already operating at a manufacturing facility, as described below. 많은제조시설은한종류의 CGMP 시스템 ( 즉, QSR 또는 CGMP 규정 ) 에의거하여운영되고있다. 위에서지적한바와같이, QSR과 CGMP 규정사이에는겹치는부분이많다. 하나의물품으로생산하거나동시포장하는복합제품제조업체가, 구성부분의결합도중및이후에두종류의규정모두를준수하기위하여별개의두개제조시스템을운영할필요는없다. 이런유형의복합제품결합도중및이후에두종류의규정을모두준수하는것은, 일반적으로 CGMP 규정또는 QSR의적용을통해달성될수있다고본다 ( 예, 아래에서기술하고있는바와같이제조시설에서이미채택하여운영하고있는 CGMP 시스템을활용하여 ). During and after joining these types of combination products together, FDA believes that compliance with both sets of regulations can generally be achieved by following one set because under a more general requirement in one set of regulations, it will be possible to develop and implement a practice that complies with a more specific requirement in the other set of regulations. To ensure consistent and appropriate current good manufacturing practice, FDA recommends that manufacturers of these types of combination products assess how best to comply with both sets of regulations, during and after joining the constituent parts together, by carefully considering the requirements of the CGMP and QS regulations in relation to the constituent parts, and the combination product(s) they manufacture. 이런유형의복합제품결합과정및이후에, 하나의규정을준수하면두규정의준수를달성할수있다고본다. 한종류의규정에제시된보다일반적인기준에의거해도, 다른규정에제시된보다구체적인기준을준수하는업무절차의개발및구축이가능하기때문이다. 일관되고적절한 CGMP를위해, FDA는복합제품제조업체가제조하는복합제품및그의구성부분과관련하여 CGMP 규정과 QSR의기준을세심하게검토해, 구성부분의결합도중및이후에두종류의규정을모두준수하는가장바람직한방법을평가해구축할것을권고한다. 15

Table 1 identifies key provisions of the CGMP and QS regulations that differ in their specificity. FDA recommends manufacturers of combination products that are copackaged or produced as a single entity carefully consider these provisions during and after joining the constituent parts, to ensure compliance with both the CGMP and QS regulations. 표 1은 CGMP 규정과 QSR의기준가운데특이성이차이를보이는핵심조항을정리한것이다. 단일물품으로생산하거나함께포장하는복합제품제조업체는 CGMP 규정과 QSR 모두의준수를위하여구성부분결합도중과이후에이들조항을세심하게고려할것을권고한다. Table 1: Key Current Good Manufacturing Practice Provisions to Consider During and After Joining Together Co-packaged and Single-Entity Combination Products If the Operating Manufacturing Control If the Operating Manufacturing Control System is Part 820 (QS Regulation) System is Part 210/211 (CGMP Regulation) Carefully Title Carefully Title Consider These Specific CGMP Requirements Consider These Specific QS Requirements 211.84 Testing and approval or 820.30 Design controls rejection of components, drug product containers, and closures 211.103 Calculation of yield 820.50 Purchasing controls 211.137 Expiration dating 820.100 Corrective and preventative actions 211.165 Testing and release for distribution 211.166 Stability testing 211.167 Special testing requirements 211.170 Reserve samples * Including all subsections, as appropriate. 16

In addition, depending on the particular combination product, it may be important to consider other specific requirements to ensure compliance with both the CGMP and QS regulations. Examples include aseptic control assurance for drug and biological product constituent parts unable to withstand terminal sterilization (21 CFR 211.113(b) and 211.42)); 21 CFR 606 for blood and blood component constituent parts; 21 CFR 211.132 for combination products incorporating drug constituent parts that are sold over-the-counter; and any good tissue practice regulations that may be promulgated. 또한복합제품의특성에따라서는 CGMP 규정과 QSR 모두의준수를위해다른특이적인기준을고려하는것이중요할수있다. 예를들어, 사후멸균을견디지못하는의약품및생물학적제품구성부분의무균관리보증 (21 CFR 211.113(b) 및 211.42), 혈액및혈액성분구성부분인경우에 21 CFR 606, OTC 의약품구성부분을포함하는복합제품인경우에 21 CFR 211.132, 그리고 GTP 규정등을고려할필요가있다. FDA recommends that manufacturers of these types of combination products present information to the Agency when the product is being developed (e.g., during Agency meetings or during inspections) about how they intend to achieve compliance with each set of regulations during and after joining the products together, in particular by showing how they achieve compliance with the provisions identified in Table 1 above, as well as any other provisions applicable to the combination product being manufactured. 이런복합제품제조업체가제품을개발할때는, 특히표 1의조항과제조대상복합제품에적용되는다른조항의준수방법을보여줌으로써, 제품결합도중및이후에각규정을준수하는방법에대한정보를 FDA에제시할것을권고한다. If a manufacturer of these types of combination products is concerned about whether application of one set of current good manufacturing practice regulations satisfies the requirements of the other set(s), FDA encourages the manufacturer to discuss with the appropriate Agency personnel when the product is being developed how best to achieve current good manufacturing practice compliance. Further, FDA expects that this guidance will be revised as FDA modifies the existing CGMP/QS regulations. 14 14 FDA Pharmaceutical GMPs for the 21st Century: A Risk Based Approach, 2nd 17

복합제품제조업체가한종류의 CGMP 규정적용이다른규정의기준을만족하는지확신할수없다면, 가장바람직한 CGMP 준수방법을제품개발중에해당 FDA 담당자와협의하는것이좋다. 또한기존 CGMP 규정 /QSR을개정하면, 이가이드문서도개정될것이다. C. 복합제품유형별고려사항 (Considerations for different types of combination products) As described under section I.A, there are four types of combination products. To summarize, the following are considerations by type of combination product: 섹션 I.A에기술한바와같이, 4종류의복합제품이있다. 복합제품유형별고려사항을정리하면다음과같다. Combination products with constituent parts that are physically, chemically or otherwise combined or mixed and produced as a single entity (21 CFR 3.2(e)(1)), and combination products with constituent parts that are packaged together (21 CFR 3.2(e)(2)): 구성부분이물리적, 화학적, 또는기타의방법으로조합또는혼합되고하나의물품으로생산되는복합제품 (21 CFR 3.2(e)(1)) 과구성부분이함께포장되는복합제품 (21 CFR 3.2(e)(2)). Before combination or co-packaging, the manufacture of each constituent part is subject only to the current good manufacturing practice regulations associated with each constituent part. For example, for a drug-coated device, the drug constituent part would be subject only to the CGMP regulation (or to Section 501(a)(2)(B) of the Act for a bulk drug substance or active pharmaceutical ingredient), while the device constituent part would be subject only to the QS regulation. 조합또는공동포장전단계에서, 각구성부분제조업체에는해당구성부분과관련된규정이적용된다. 예를들어의약품코팅의료용구인경우, 의약품구성부분은 CGMP 규정 ( 또는벌크약효성분이나 API인경우에는 progress report and implementation plan, (http://www.fda.gov/cder/gmp/2ndprogressrept_plan.htm). 18

FD&C 법섹션 501(a)(2)(B)) 의적용을받으며, 의료용구구성부분은 QSR 의적용을받는다. Once the product is combined into a single entity or co-packaged, both sets of regulations apply to the combination. FDA recommends manufacturers follow the guidance described in section III.B above to achieve compliance with all applicable current good manufacturing practice regulations. 제품이하나의물품으로조합되거나함께포장되면, 그복합제품에는두규정이모두적용된다. 모든해당규정의준수를위하여, 상기섹션 III.B에기술된가이드라인을따르도록한다. Combination products with constituent parts that are separately marketed but intended to be used together (21 CFR 3.2(e)(3) and (e)(4)): 구성부분이별개로판매되지만함께사용되는복합제품 (21 CFR 3.2(e)(3) 및 (e)(4)). The manufacture of each constituent part is subject to the current good manufacturing practice regulations associated with each constituent part, and is not subject to both sets of regulations. For example, for a photodynamic therapy system consisting of a laser and a photosensitizing drug that are marketed separately, the laser would be subject to the QS regulation while the photosensitizing drug would be subject to the CGMP regulation. 각구성부분제조에는그와관련된규정이적용되며, 두규정모두가적용되지는않는다. 예를들어별도로판매되는레이저와광민감성의약품으로구성되는광역동치료시스템인경우, 레이저는 QSR의적용을받고, 광민감성의약품은 CGMP 규정의적용을받는다. IV. 복합제품개발단계에서 FDA 와의커뮤니케이션 (COMMUNICATION WITH FDA DURING DEVELOPMENT OF A COMBINATION PRODUCT) A. FDA 와의 CGMP 이슈협의를 FDA 는언제권고하는가?(When does FDA 19

recommend discussing CGMP issues with the Agency?) FDA recommends that manufacturers of combination products discuss with the Agency how current good manufacturing practice regulations apply to their products. Manufacturers are encouraged to seek FDA comment on their implementation of current good manufacturing practice during pre-investigational (pre-ind/ide) meetings and throughout combination product development. 15 FDA recommends that these discussions include consideration of the risks of the combination product, its technology, and any anticipated postmarket development and post approval changes. FDA recommends that the applicant(s) include all critical manufacturers in these discussions and include information on critical steps that may be conducted at source/contract firms and any special testing. 복합제품제조업체는그의제품에적용되는 CGMP 규정과관련하여 FDA와협의하는것이좋다. 임상연구대비회의 (pre-ind/ide) 를통해, 그리고복합제품개발과정중에 CGMP 이행에관한 FDA의의견을구하도록한다. 이때복합제품의리스크, 관련기술, 그리고예상가능한시판후개발및승인이후변경사항을협의할수있다. 신청업체는모든관련제조업체가이협의에참여하도록하고, 특별시험사항과위수탁업체에서수행되는핵심단계에대한정보를협의하는것이좋다. FDA staff involved in the discussions about the application of current good manufacturing practice regulations to a combination product may include, but are not limited to, reviewers in the lead and consulting product review divisions (CBER, CDER, and CDRH); the current good manufacturing practice experts in the Offices of Compliance in the lead and consulting centers and the district office; Office of Regulatory Affairs national expert advisors, as appropriate; and the Office of Combination Products. 16 FDA will document its recommendations concerning the 15 FDA recommends that manufacturers follow the lead Center s existing guidances or practices for requesting formal meetings with the lead center. 리드센터와의공식회의요청시에리드센터의기존가이드문서나업무절차를따 르도록한다. 16 FDA staff should follow the procedures outlined for the intercenter consultative/collaborative review process, http://www.fda.gov/oc/combination/consultative.html. FDA 관련자는인터센터협의 / 공조심사프로세스에제시된절차를따른다. 20

manufacturer s proposal in FDA meeting minutes, letters, or other permanent communication records, as appropriate. Also, FDA staff should communicate this information to the appropriate District Office. 복합제품에적용되는 CGMP 규정에대한협의시에, 리드센터의심사자와컨설팅제품심사부서심사자 (CBER, CDER, CDRH), 리드및컨설팅센터와지역사무소 OC의 CGMP 전문가, ORA 전문자문가, 그리고 OCP가참여할수있다. 제조업체의제안에대한 FDA의권고사항을 FDA 회의록, 서신, 또는기타영구적인커뮤니케이션기록서형식으로문서화한다. 또한 FDA 관련자는이정보를해당지역사무소에전달해야한다. B. 추가정보입수처 (Where can I get more information?) The Office of Combination Products is available as a resource to sponsors and review staff throughout the lifecycle (development, premarket review and postmarket regulation) of a combination product. The Office can be reached at (301) 427-1934 or by email at combination@fda.gov. In addition, the Office maintains an updated list of FDA guidance documents that sponsors may find helpful in determining the regulatory provisions for their products. The guidance is available at the Office s Internet Website at http://www.fda.gov/oc/combination (for FDA staff, http://intranet.fda.gov/oc/ocp/index.html). 복합제품라이프사이클 ( 개발, 시판전심사, 시판후규제 ) 전체에걸쳐스폰서와심사자는필요한정보를 OCP에서확보한다. OCP 연락처 : 전화 - (301) 427-1934, 전자우편 - combination@fda.gov. 또한 OCP는스폰서가자신의제품에적용되는규제기준을파악하는데도움이되는 FDA 가이드문서최신리스트를관리한다. 이가이드문서는 OCP 인터넷웹사이트에서구할수있다. The Office of Regulatory Affairs Website provides detailed information on inspection policies. The Office can be reached at http://www.fda.gov/ora. ORA inspectional guidances are located at http://www.fda.gov/ora/inspect_ref/igs/iglist.html. ORA 웹사이트에서는실사방침에관한정보를제공한다. ORA 웹사이트 : http://www.fda.gov/ora. ORA 실사가이드문서 : http://www.fda.gov/ora/inspect_ref/igs/iglist.html. 21