INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE 생명공학제품의품질 : 생명공학 / 생물학적제품의안정성시험 (Quality of Biotechnological Products: Stability Testing of Biotechnological/Biological Products) Q5C Current Step 4 version dated 30 November 1995 This Guideline has been developed by the appropriate ICH Expert Working Group and has been subject to consultation by the regulatory parties, in accordance with the ICH Process. At Step 4 of the Process the final draft is recommended for adoption to the regulatory bodies of the European Union, Japan and USA. www..co.kr 1
Q5C Document History First Codification Q5C History Date New Codification November 2005 Approval by the Steering Committee under 29 March Q5C Step 2 and release for public consultation 1995 Current Step 4 version Q5C Approval by the Steering Committee under 30 Q5C Step 4 and recommendation for adoption November to the three ICH regulatory bodies. 1995 www..co.kr 2
QUALITY OF BIOTECHNOLOGICAL PRODUCTS: STABILITY TESTING OF BIOTECHNOLOGICAL/BIOLOGICAL PRODUCTS Annex to the Tripartite ICH Guideline for the Stability Testing of New Drug Substances and Products ICH Harmonised Tripartite Guideline Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 30 November 1995, this guideline is recommended for adoption to the three regulatory parties to ICH. 1. 서론 (PREAMBLE) The guidance stated in the ICH harmonised tripartite guideline Stability Testing of New Drug Substances and Products (27 October 1993) applies in general to biotechnological/biological products. However, biotechnological/biological products do have distinguishing characteristics to which consideration should be given in any well-defined testing program designed to confirm their stability during the intended storage period. For such products, in which the active components are typically proteins and/or polypeptides, maintenance of molecular conformation and, hence of biological activity, is dependent on noncovalent as well as covalent forces. The products are particularly sensitive to environmental factors such as temperature changes, oxidation, light, ionic content, and shear. In order to ensure maintenance of biological activity and to avoid degradation, stringent conditions for their storage are usually necessary. ICH 가이드라인 " 새로운원료의약품과완제의약품의안정성시험 "(1993년 10월 27일 ) 의내용을전반적으로생명공학 / 생물학적제품에적용한다. 하지만생명공학 / 생물학적제품은뚜렷한특성을갖고있으며, 예정보관기간동안안정성을확인하기위한시험프로그램을설계할때는이와같은특성을고려해야한다. 활성성분이일반적으로단백질및 / 또는폴리펩타이드인이런제품의분자형태유지와생물학적활성유지는공유결합과비공유결합의강도에따른다. 제품은특히온도변화, 산화, 빛, 이온함량, 전단력등환경요소에민감하다. 생물학적활성을유지하고분해를피하기위하여, 엄격한보관조건이필수적이다. The evaluation of stability may necessitate complex analytical methodologies. www..co.kr 3
Assays for biological activity, where applicable, should be part of the pivotal stability studies. Appropriate physicochemical, biochemical and immunochemical methods for the analysis of the molecular entity and the quantitative detection of degradation products should also be part of the stability program whenever purity and molecular characteristics of the product permit use of these methodologies. 안정성평가를위해서는복잡한분석방법이필요할수있다. 해당되는경우에는생물학적활성분석을중추안정성시험의한부분으로실시한다. 제품의분자특성과순도를감안하여적용가능하다고판단되면, 분자구조물의분석과분해산물의정량적검출에적절한이화학적, 생화학적, 면역화학적방법또한안정성프로그램의한부분으로실시한다. With the above concerns in mind, the applicant should develop the proper supporting stability data for a biotechnological/biological product and consider many external conditions which can affect the product s potency, purity and quality. Primary data to support a requested storage period for either drug substance or drug product should be based on long-term, real-time, real-condition stability studies. Thus, the development of a proper long-term stability program becomes critical to the successful development of a commercial product. The purpose of this document is to give guidance to applicants regarding the type of stability studies that should be provided in support of marketing applications. It is understood that during the review and evaluation process, continuing updates of initial stability data may occur. 신청업체는상기사항을고려하여생명공학 / 생물학적제품의근거안정성데이터를적절하게확보하고, 제품의역가, 순도, 품질에영향을줄수있는많은외적조건을고려해야한다. 원료의약품이나완제의약품의요청보관기간을뒷받침하는주요데이터를, 장기실시간, 실제조건안정성시험을통해확보한다. 그러므로적절한장기안정성프로그램의개발은성공적인제품개발에매우중요한것이다. 이문서의목적은판매허가신청문서를뒷받침하기위해제공해야할안정성시험의유형에관한가이드라인을제공하는데있다. 심사와평가과정에서초기안정성데이터를지속적으로업데이트할수도있다. 2. 적용범위 (SCOPE OF THE ANNEX) The guidance stated in this annex applies to well-characterised proteins and polypeptides, their derivatives and products of which they are components, and www..co.kr 4
which are isolated from tissues, body fluids, cell cultures, or produced using rdna technology. Thus, the document covers the generation and submission of stability data for products such as cytokines (interferons, interleukins, colony-stimulating factors, tumour necrosis factors), erythropoietins, plasminogen activators, blood plasma factors, growth hormones and growth factors, insulins, monoclonal antibodies, and vaccines consisting of well-characterised proteins or polypeptides. In addition, the guidance outlined in the following sections may apply to other types of products, such as conventional vaccines, after consultation with the appropriate regulatory authorities. The document does not cover antibiotics, allergenic extracts, heparins, vitamins, whole blood, or cellular blood components. 이부록의가이드라인은특성분석이잘이루어진단백질과폴리펩타이드, 그의유도체, 그리고이들을성분으로함유하는제품과 rdna 기술로생산되거나조직, 체액, 세포배양에서분리한것에적용한다. 그러므로이문서는사이토카인 ( 인터페론, 인터루킨, CSF(colony-stimulating factors), TNF(tumour necrosis factors)), EPO(erythropoietins), PA(plasminogen activator), 혈장인자, 성장호르몬및성장인자, 인슐린, 단클론항체, 특성분석이잘이루어진단백질또는폴리펩타이드로구성된백신등의제품에대한안정성데이터생산과제출을대상으로한다. 이외에도아래에기술된사항을, 해당규제기관과협의한다음에전통적인백신같은다른유형의제품에도적용할수있다. 항생제, 알레르기유발성추출물, 헤파린, 비타민, 전혈, 혈구성분은이문서의대상이아니다. 3. 용어정의 (TERMINOLOGY) For the basic terms used in this annex the reader is referred to the "Glossary" in the ICH harmonised tripartite guideline "Stability Testing of New Drug Substances and Products" (27 October 1993). However, since manufacturers of biotechnological/biological products sometimes use traditional terminology, traditional terms are specified in parentheses to assist the reader. A supplemental glossary is also included that explains certain terms used in the production of biotechnological/biological products. 이부록에사용된기본용어의의미는 ICH 가이드라인 " 새로운원료의약품과완제의약품의안정성시험 "(1993년 10월 27일 ) 의 " 용어정의 " 를참조한다. 하지만생명공학 / 생물학적제품제조업체가전통적인용어를사용하기도하므로, 편의를위하여전통적인용어를괄호로표기했다. 또한생명공학 / 생물학적제품생산과관련된특정용어에대한설명도보충적으로포함했다. www..co.kr 5
4. 배치의선정 (SELECTION OF BATCHES) 4.1. 원료의약품 ( 벌크물품 )(Drug Substance (Bulk Material)) Where bulk material is to be stored after manufacture but prior to formulation and final manufacturing, stability data should be provided on at least 3 batches for which manufacture and storage are representative of the manufacturing scale of production. A minimum of 6 months stability data at the time of submission should be submitted in cases where storage periods greater than 6 months are requested. For drug substances with storage periods of less than 6 months, the minimum amount of stability data in the initial submission should be determined on a caseby-case basis. Data from pilot-plant scale batches of drug substance produced at a reduced scale of fermentation and purification may be provided at the time the dossier is submitted to the regulatory agencies with a commitment to place the first 3 manufacturing scale batches into the long-term stability program after approval. 벌크물품을제조하고나서조제및최종제조에사용할때까지보관한다면, 제조및보관조건이실제제조규모를대표하는최소 3개배치에대한안정성데이터를제공해야한다. 6개월이상의보관기간을신청하는경우에는, 신청시점에최소 6개월의안정성데이터를제출해야한다. 보관기간이 6개월이하인원료의약품인경우, 각각의경우별로최초제출문서에포함시킬안정성데이터의최소량을결정한다. 최초 3개제조규모배치를승인이후에장기안정성프로그램에따라시험하겠다는이행약속과함께허가문서를규제기관에제출하는경우, 축소규모의발효및정제조건으로생산한파일럿플랜트규모의원료의약품배치에대한데이터를제공할수있다. The quality of the batches of drug substance placed into the stability program should be representative of the quality of the material used in preclinical and clinical studies and of the quality of the material to be made at manufacturing scale. In addition, the drug substance (bulk material) made at pilot-plant scale should be produced by a process and stored under conditions representative of that used for the manufacturing scale. The drug substance entered into the stability program should be stored in containers which properly represent the actual holding containers used during manufacture. Containers of reduced size may be acceptable for drug substance stability testing provided that they are constructed of the same material and use the same type of container/closure system that is intended to be www..co.kr 6
used during manufacture. 안정성프로그램에포함시킬원료의약품배치의품질은, 전임상및임상시험에사용된제품의품질과, 제조규모에서만든제품의품질을대표할수있어야한다. 이외에도파일럿플랜트규모로만든원료의약품 ( 벌크물품 ) 은, 제조규모의공정을대표하는공정에서생산하고, 실제제조상황을대표하는조건에서보관해야한다. 안정성프로그램에투입하는원료의약품은, 제조에사용하는실제보관용기를적절하게대표하는용기에담아보관한다. 제조에사용할용기 / 마개시스템과동일한유형과동일한재질로만든축소규모의용기를원료의약품안정성시험에사용할수있다. 4.2. 중간제품 (Intermediates) During manufacture of biotechnological/biological products, the quality and control of certain intermediates may be critical to the production of the final product. In general, the manufacturer should identify intermediates and generate in-house data and process limits that assure their stability within the bounds of the developed process. While the use of pilot-plant scale data is permissible, the manufacturer should establish the suitability of such data using the manufacturing scale process. 생명공학 / 생물학적제품제조과정에서특정중간제품의품질및관리가최종제품의생산에매우중요할수있다. 일반적으로중간제품을파악하고, 개발된공정범위안에서중간제품의안정성을보증하는자체데이터를확보하고공정한계를설정해야한다. 파일럿플랜트규모데이터의활용도가능하지만, 제조규모공정에서이와같은데이터의적합성을확립한다. 4.3. 완제의약품 ( 최종용기제품 )(Drug Product (Final Container Product)) Stability information should be provided on at least 3 batches of final container product representative of that which will be used at manufacturing scale. Where possible, batches of final container product included in stability testing should be derived from different batches of bulk material. A minimum of 6 months data at the time of submission should be submitted in cases where storage periods greater than 6 months are requested. For drug products with storage periods of less than 6 months, the minimum amount of stability data in the initial submission should be determined on a case-by-case basis. Product expiration dating will be based upon the actual data submitted in support of the application. Since dating is based upon the real-time/real-temperature data submitted for review, continuing updates of www..co.kr 7
initial stability data should occur during the review and evaluation process. The quality of the final container product placed on stability studies should be representative of the quality of the material used in the preclinical and clinical studies. Data from pilot-plant scale batches of drug product may be provided at the time the dossier is submitted to the regulatory agencies with a commitment to place the first 3 manufacturing scale batches into the long term stability program after approval. Where pilot-plant scale batches were submitted to establish the dating for a product and, in the event that product produced at manufacturing scale does not meet those long-term stability specifications throughout the dating period or is not representative of the material used in preclinical and clinical studies, the applicant should notify the appropriate regulatory authorities to determine a suitable course of action. 제조규모에서사용되는것을대표하는, 최소 3개배치의최종용기제품에대한안정성정보를제공해야한다. 안정성시험에포함되는최종용기제품배치는, 가능하면서로다른배치의벌크물품으로만든것이어야한다. 6개월이상의보관기간을신청하는경우에는, 신청시점에최소 6개월치의데이터를제출해야한다. 보관기간이 6개월이하인완제의약품인경우, 최초제출시에포함시킬안정성데이터의최소량은각각의경우별로결정한다. 제품유효기간은신청문서를뒷받침하기위해제출하는실제데이터에근거해야한다. 유효기간은심사를위해제출된실시간 / 실제온도데이터를근거로하므로, 심사와평가과정에서최초안정성데이터를지속적으로업데이트해야한다. 안정성시험에투입하는최종용기제품의품질은전임상및임상시험에사용된제품의품질을대표해야한다. 최초 3개제조규모배치를승인이후에장기안정성프로그램에따라시험하겠다는이행약속과함께허가문서를규제기관에제출하는경우, 파일럿플랜트규모의의약품배치데이터를제출할수있다. 파일럿플랜트규모배치를제품유효기간확립을위해제출하고, 제조규모에서생산된제품이유효기간동안장기안정성규격에부합하지못하거나전임상및임상시험에사용된제품을대표하지못하는경우에는, 해당규제기관에보고하여적합한조치방향을결정해야한다. 4.4. 검체선정 (Sample Selection) Where one product is distributed in batches differing in fill volume (e.g., 1 millilitre (ml), 2 ml, or 10 ml), unitage (e.g., 10 units, 20 units, or 50 units), or mass (e.g., 1 milligram (mg), 2 mg, or 5 mg) samples to be entered into the stability program may be selected on the basis of a matrix system and/or by bracketing. 한제품을다양한충전량 ( 예, 1 ml, 2 ml, 10 ml), 단위량 ( 예, 10단위, 20단위, 50단위 ), www..co.kr 8
또는질량 ( 예, 1 mg, 2 mg, 5 mg) 의배치로유통하는경우, 매트릭스시스템및 / 또는 브라켓방법으로안정성프로그램에포함시킬검체를선정할수있다. Matrixing, i.e., the statistical design of a stability study in which different fractions of samples are tested at different sampling points, should only be applied when appropriate documentation is provided that confirms that the stability of the samples tested represents the stability of all samples. The differences in the samples for the same drug product should be identified as, for example, covering different batches, different strengths, different sizes of the same closure and possibly, in some cases, different container/closure systems. Matrixing should not be applied to samples with differences that may affect stability, such as different strengths and different containers/closures, where it cannot be confirmed that the products respond similarly under storage conditions. 매트릭스방법은서로다른검체부분을서로다른시점에시험하는통계적인안정성시험디자인으로, 시험대상검체의안정성이모든검체의안정성을대표함을보여주는적절한문서가제공될때만적용한다. 예를들어서로다른배치, 다른함량, 동일마개의다른크기, 그리고때로는다른용기 / 마개시스템등동일한의약품의검체차이를파악한다. 제품이보관조건에서유사하게반응함을확인할수없는경우 ( 예를들어서로다른함량과서로다른용기 / 마개 ), 안정성에영향을줄수있는차이를지닌검체에매트릭스방법을적용해서는안된다. Where the same strength and exact container/closure system is used for 3 or more fill contents, the manufacturer may elect to place only the smallest and largest container size into the stability program, i.e., bracketing. The design of a protocol that incorporates bracketing assumes that the stability of the intermediate condition samples are represented by those at the extremes. In certain cases, data may be needed to demonstrate that all samples are properly represented by data collected for the extremes. 동일함량및정확한용기 / 마개시스템을 3개이상의충전함량에적용한다면, 가장작은용기크기와가장큰용기크기를안정성프로그램에투입하는방법을선택할수있다 ( 브라켓 ). 브라켓방식의프로토콜디자인은, 극단조건의검체안정성이중간조건검체의안정성을대표한다는가정을바탕으로한다. 극단조건의데이터가모든검체를적절하게대표함을증명하는데이터가필요할수있다. 5. 안정성지시성프로파일 (STABILITY-INDICATING PROFILE) www..co.kr 9
On the whole, there is no single stability-indicating assay or parameter that profiles the stability characteristics of a biotechnological/biological product. Consequently, the manufacturer should propose a stability-indicating profile that provides assurance that changes in the identity, purity and potency of the product will be detected. 생명공학 / 생물학적제품의안정성특성을보여주는하나의안정성지시성분석항목이나파라미터는없다. 그러므로제품확인, 순도, 역가의변화를감지할수있음을보증하는안정성지시성프로파일을제조업체가제시해야한다. At the time of submission, applicants should have validated the methods that comprise the stability-indicating profile and the data should be available for review. The determination of which tests should be included will be product-specific. The items emphasised in the following subsections are not intended to be all-inclusive, but represent product characteristics that should typically be documented to adequately demonstrate product stability. 문서제출당시에신청업체는안정성지시성프로파일을포함하는방법들을밸리데이션했어야하며, 관련데이터의검토가가능해야한다. 포함시켜야할시험항목을제품별로결정한다. 아래에서강조하여설명하는항목이전부는아니며, 이들항목은일반적으로제품안정성을적절하게증명하기위하여문서화를해야하는제품특성을대표하는것이다. 5.1. 프로토콜 (Protocol) The dossier accompanying the application for marketing authorisation should include a detailed protocol for the assessment of the stability of both drug substance and drug product in support of the proposed storage conditions and expiration dating periods. The protocol should include all necessary information which demonstrates the stability of the biotechnological/biological product throughout the proposed expiration dating period including, for example, welldefined specifications and test intervals. The statistical methods that should be used are described in the tripartite guideline on stability. 판매허가신청문서와함께제출하는문서에는, 예정보관조건과유효기간의근거가되는원료의약품및완제의약품의안정성평가를위한상세한프로토콜을포함시켜야한다. 예정유효기간전체에걸쳐생명공학 / 생물학적제품의안정성을증명하는모든필수정보 ( 예, www..co.kr 10
확립된규격및시험주기 ) 가프로토콜에포함되어야한다. 이때적용할통계적인방법이 안정성가이드라인에기술되어있다. 5.2. 역가 (Potency) When the intended use of a product is linked to a definable and measurable biological activity, testing for potency should be part of the stability studies. For the purpose of stability testing of the products described in this guideline, potency is the specific ability or capacity of a product to achieve its intended effect. It is based on the measurement of some attribute of the product and is determined by a suitable quantitative method. In general, potencies of biotechnological/biological products tested by different laboratories can be compared in a meaningful way only if expressed in relation to that of an appropriate reference material. For that purpose, a reference material calibrated directly or indirectly against the corresponding national or international reference material should be included in the assay. 제품의목적용도가정의가능하고측정가능한생물학적활성과연계되어있다면, 안정성시험의일부로역가시험을실시해야한다. 이가이드라인에기술된제품의안정성시험에서, 역가는목적효과를달성할수있는제품의특이적능력또는성능을의미한다. 제품의특정특성항목을측정하고적합한계량적방법으로결정한다. 일반적으로적절한참조물품의역가에대비하여표현하는경우에만, 서로다른시험실에서시험한생명공학 / 생물학적제품의역가를유의미하게비교할수있다. 이를위하여해당국가또는국제표준물품에대비하여직접적으로또는간접적으로교정한참조물품을역가시험에사용해야한다. Potency studies should be performed at appropriate intervals as defined in the stability protocol and the results should be reported in units of biological activity calibrated, whenever possible, against nationally or internationally recognised standard. Where no national or international reference standards exist, the assay results may be reported in in-house derived units using a characterised reference material. 안정성프로토콜에규정되어있는바에따라적절한주기로역가시험을실시하고, 그결과를가능하면국가또는국제적으로인정되는표준품에대비하여교정한생물학적활성단위로보고한다. 국가또는국제참조표준품이없다면, 특성분석이완료된참조물품을활용하여자체적으로정한단위로분석결과를보고할수있다. www..co.kr 11
In some biotechnological/biological products, potency is dependent upon the conjugation of the active ingredient(s) to a second moiety or binding to an adjuvant. Dissociation of the active ingredient(s) from the carrier used in conjugates or adjuvants should be examined in real-time/real-temperature studies (including conditions encountered during shipment). The assessment of the stability of such products may be difficult since, in some cases, in vitro tests for biological activity and physicochemical characterisation are impractical or provide inaccurate results. Appropriate strategies (e.g., testing the product prior to conjugation/binding, assessing the release of the active compound from the second moiety, in vivo assays) or the use of an appropriate surrogate test should be considered to overcome the inadequacies of in vitro testing. 일부생명공학 / 생물학적제품의역가는활성성분과이차부분의접합이나면역보조제의결합에의존한다. 접합또는보조성분으로사용되는캐리어와활성성분의분리여부도실시간 / 실제온도시험 ( 운송시의조건포함 ) 시에조사한다. 생물학적활성의체외시험과이화학적특성분석이실제로가능하지않거나결과가부정확한경우도있으므로, 그런제품의안정성평가가어려울수있다. 체외시험의부적절성을극복하기위하여, 적절한전략 ( 예, 접합 / 결합이전에제품시험, 이차부분에서활성화합물의방출평가, 체내분석 ) 또는적절한대체시험방법의활용을검토한다. 5.3. 순도및분자적특성분석 (Purity and Molecular Characterisation) For the purpose of stability testing of the products described in this guideline, purity is a relative term. Due to the effect of glycosylation, deamidation, or other heterogeneities, the absolute purity of a biotechnological/biological product is extremely difficult to determine. Thus, the purity of a biotechnological/biological product should be typically assessed by more than one method and the purity value derived is method-dependent. For the purpose of stability testing, tests for purity should focus on methods for determination of degradation products. 이가이드라인에기술된제품의안정성시험에서순도는상대적인개념이다. 당화, 탈아미드화, 또는기타이종성의영향때문에, 생명공학 / 생물학적제품의절대순도는결정하기가매우어렵다. 그러므로생명공학 / 생물학적제품의순도를하나이상의방법으로평가해야하며, 이에따른순도값은평가방법에따라다르다. 안정성시험에서순도시험은분해산물분석방법에중점을두어야한다. www..co.kr 12
The degree of purity, as well as individual and total amounts of degradation products of the biotechnological/biological product entered into the stability studies, should be reported and documented whenever possible. Limits of acceptable degradation should be derived from the analytical profiles of batches of the drug substance and drug product used in the preclinical and clinical studies. 가능하면안정성시험에투입된생명공학 / 생물학적제품의분해산물총량과개별분해산물의양, 그리고순도를보고하고문서화한다. 전임상및임상시험에사용된원료의약품과완제의약품배치의분석프로파일을바탕으로허용분해한도기준을도출한다. The use of relevant physicochemical, biochemical and immunochemical analytical methodologies should permit a comprehensive characterisation of the drug substance and/or drug product (e.g., molecular size, charge, hydrophobicity) and the accurate detection of degradation changes that may result from deamidation, oxidation, sulfoxidation, aggregation or fragmentation during storage. As examples, methods that may contribute to this include electrophoresis (SDS-PAGE, immunoelectrophoresis, Western blot, isoelectrofocusing), high-resolution chromatography (e.g., reversed-phase chromatography, gel filtration, ion exchange, affinity chromatography), and peptide mapping. 관련이화학적, 생화학적, 면역화학적분석방법으로, 원료의약품및 / 또는완제의약품의포괄적인특성분석 ( 예, 분자량, 전하, 소수성 ) 과보관중의탈아미드화, 산화, 설폭시화, 응집또는분전화로인해발생할수있는분해산물변화의정확한검출이가능해야한다. 예를들면전기영동 (SDS-PAGE, 면역전기영동, 웨스턴블롯, IEF(isoelectrofocusing)), 고분해능크로마토그래피 ( 예, 역상크로마토그래피, 겔여과, 이온교환, 친화성크로마토그래피 ), 펩타이드매핑등이이러한방법으로활용될수있다. Wherever significant qualitative or quantitative changes indicative of degradation product formation are detected during long-term, accelerated and/or stress stability studies, consideration should be given to potential hazards and to the need for characterisation and quantification of degradation products within the long-term stability program. Acceptable limits should be proposed and justified, taking into account the levels observed in material used in preclinical and clinical studies. 장기, 가속, 및 / 또는가혹안정성시험중에분해산물의형성을의미하는중요한정량적또는정성적변화가감지되면, 장기안정성프로그램범위안에서분해산물의특성분석및정량적평가필요성과위해요소가능성을검토해야한다. 전임상및임상시험에 www..co.kr 13
사용된제품에서관찰된수준을고려하여, 허용한도기준을제시하고그타당성을 증명한다. For substances that cannot be properly characterised or products for which an exact analysis of the purity cannot be determined through routine analytical methods, the applicant should propose and justify alternative testing procedures. 일반적인분석방법으로순도를정확히분석할수없는제품이나특성분석을적절하게할수없는성분인경우, 신청업체는대체시험방법을제시하고그타당성을증명해야한다. 5.4. 기타제품특성 (Other Product Characteristics) The following product characteristics, though not specifically relating to biotechnological/biological products, should be monitored and reported for the drug product in its final container: 다음의제품특성은생명공학 / 생물학적제품에특이적인것은아니지만, 최종용기상태의의약품에대하여모니터를실시하고그결과를보고해야한다. Visual appearance of the product (colour and opacity for solutions/suspensions; colour, texture and dissolution time for powders), visible particulates in solutions or after the reconstitution of powders or lyophilised cakes, ph, and moisture level of powders and lyophilised products. 제품성상 ( 용액 / 현탁액의색상및혼탁도, 분말의색상, 질감, 용해시간 ), 용액중의가시성미립자또는분말이나동결건조케이크의용해이후가시성미립자, ph, 분말및동결건조제품의함습도. Sterility testing or alternatives (e.g., container/closure integrity testing) should be performed at a minimum initially and at the end of the proposed shelf-life. 무균시험또는대체시험 ( 예, 용기 / 마개완전성시험 ) 을최소한초기와예정유효기간말기에실시한다. Additives (e.g., stabilisers, preservatives) or excipients may degrade during the dating period of the drug product. If there is any indication during preliminary stability studies that reaction or degradation of such materials adversely affect the quality of the drug product, these items may need to be monitored during the www..co.kr 14
stability program. 의약품유효기간동안에첨가제 ( 예, 안정제, 보존제 ) 또는부원료가분해될수있다. 예비안정성시험시에상기물품의반응또는분해가의약품품질에부정적인영향을주는것으로나타나면, 이항목도안정성시험시에모니터할필요가있다. The container/closure has the potential to adversely affect the product and should be carefully evaluated (see below). 용기 / 마개는제품에부정적인영향을줄가능성이있으며, 신중하게평가해야한다 ( 아래참조 ). 6. 보관조건 (STORAGE CONDITIONS) 6.1. 온도 (Temperature) Since most finished biotechnological/biological products need precisely defined storage temperatures, the storage conditions for the real-time/real-temperature stability studies may be confined to the proposed storage temperature. 대부분의최종생명공학 / 생물학적제품은보관온도를정밀하게규정할필요가있으므로, 실시간 / 실제온도안정성시험을위한보관조건을예정보관온도에국한시킬수있다. 6.2. 습도 (Humidity) Biotechnological/biological products are generally distributed in containers protecting them against humidity. Therefore, where it can be demonstrated that the proposed containers (and conditions of storage) afford sufficient protection against high and low humidity, stability tests at different relative humidities can usually be omitted. Where humidity-protecting containers are not used, appropriate stability data should be provided. 생명공학 / 생물학적제품은일반적으로습기로부터제품을보호하는용기에충전하여유통된다. 그러므로예정용기 ( 및보관조건 ) 가고습도및저습도로부터제품을충분히보호한다는점이증명된다면, 서로다른상대습도에서실시하는안정성시험을일반적으로생략할수있다. 습기보호용기를사용하지않으면, 적절한안정성데이터를제공해야한다. 6.3. 가속및가혹조건 (Accelerated and Stress Conditions) www..co.kr 15
As previously noted, the expiration dating should be based on real-time/realtemperature data. However, it is strongly suggested that studies be conducted on the drug substance and drug product under accelerated and stress conditions. Studies under accelerated conditions may provide useful support data for establishing the expiration date, provide product stability information for future product development (e.g., preliminary assessment of proposed manufacturing changes such as change in formulation, scale-up), assist in validation of analytical methods for the stability program, or generate information which may help elucidate the degradation profile of the drug substance or drug product. Studies under stress conditions may be useful in determining whether accidental exposures to conditions other than those proposed (e.g., during transportation) are deleterious to the product and also for evaluating which specific test parameters may be the best indicators of product stability. Studies of the exposure of the drug substance or drug product to extreme conditions may help to reveal patterns of degradation; if so, such changes should be monitored under proposed storage conditions. While the tripartite guideline on stability describes the conditions of the accelerated and stress study, the applicant should note that those conditions may not be appropriate for biotechnological/biological products. Conditions should be carefully selected on a case-by-case basis. 앞서설명한바와같이, 유효기간은실시간 / 실제온도데이터에근거하여정해야한다. 하지만가속및가혹조건에서도원료의약품과완제의약품의안정성시험을실시할필요가있다. 가속조건시험은유효기간설정에도움이되는유용한근거데이터를제공하고, 미래의제품개발에필요한제품안정성정보를제공하며 ( 예, 조제방법변경, 스케일업등예정제조변경의예비평가 ), 안정성프로그램을위한분석방법밸리데이션에도움이되고, 또는원료의약품이나완제의약품의분해산물프로파일을파악하는데도움이되는정보의확보에유용할수있다. 가혹안정성시험은예정조건이외의조건에우발적으로노출 ( 예, 운송중에 ) 되면제품이어떤부정적인영향을받는지파악하고, 제품안정성의지표로가장좋은시험파라미터가어떤것인지평가하는데유용할수있다. 원료의약품또는완제의약품을극단조건에노출시키는시험은, 분해패턴을밝히는데도도움이될수있다. 실제로분해가발생한다면, 예정보관조건에서그와같은변화를모니터해야한다. 안정성가이드라인에가속및가혹시험조건이기술되어있지만, 이들조건이생명공학 / 생물학적제품에적절하지않을수있다. 경우별로조건을신중하게선정한다. 6.4. 빛 (Light) www..co.kr 16
Applicants should consult the appropriate regulatory authorities on a case-by-case basis to determine guidance for testing. 신청업체는경우별로해당규제기관과협의하여시험에관한가이드라인을정해야한다. 6.5. 용기 / 마개 (Container/Closure) Changes in the quality of the product may occur due to the interactions between the formulated biotechnological/biological product and container/closure. Where the lack of interactions cannot be excluded in liquid products (other than sealed ampoules), stability studies should include samples maintained in the inverted or horizontal position (i.e., in contact with the closure), as well as in the upright position, to determine the effects of the closure on product quality. Data should be supplied for all different container/closure combinations that will be marketed. 생명공학 / 생물학적제품과용기 / 마개사이의상호작용에의하여제품품질변화가발생할수있다. 액상제품 ( 밀봉앰플이외의 ) 에서상호작용의부재를배제할수없다면, 뒤집거나수평상태 ( 즉, 마개와접촉한상태 ), 그리고똑바로세운상태로검체를유지하며안정성시험을실시하여마개가제품품질에미치는영향을파악한다. 판매예정인모든용기 / 마개조합에대한데이터를제공해야한다. In addition to the standard data necessary for a conventional single-use vial, the applicant should demonstrate that the closure used with a multiple-dose vial is capable of withstanding the conditions of repeated insertions and withdrawals so that the product retains its full potency, purity, and quality for the maximum period specified in the instructions-for-use on containers, packages, and/or package inserts. Such labelling should be in accordance with relevant national/regional requirements. 전통적인일회용바이알에대한표준데이터이외에도, 신청업체는다회투여용량바이알에사용되는마개가반복적인삽입 / 인출을견딜수있으며, 그에따라제품이용기, 포장, 및 / 또는포장인서트의사용설명에지정된최대기간동안완전한역가, 순도, 품질이유지됨을증명해야한다. 그와같은표시사항은관련국가 / 지역기준에부합해야한다. 6.6. 동결건조제품용해이후안정성 (Stability after Reconstitution of Freeze- Dried Product) www..co.kr 17
The stability of freeze-dried products after their reconstitution should be demonstrated for the conditions and the maximum storage period specified on containers, packages, and/or package inserts. Such labelling should be in accordance with relevant national/regional requirements. 동결건조제품용해이후안정성을용기, 포장, 및 / 또는포장인서트에지정된최대보관기간및조건에서증명해야한다. 그와같은표시사항은관련국가 / 지역기준에부합해야한다. 7. 시험주기 (TESTING FREQUENCY) The shelf-lives of biotechnological/biological products may vary from days to several years. Thus, it is difficult to draft uniform guidelines regarding the stability study duration and testing frequency that would be applicable to all types of biotechnological/biological products. With only a few exceptions, however, the shelflives for existing products and potential future products will be within the range of 0.5 to 5 years. Therefore, the guidance is based upon expected shelf-lives in that range. This takes into account the fact that degradation of biotechnological/biological products may not be governed by the same factors during different intervals of a long storage period. 생명공학 / 생물학적제품의유효기간은며칠에서몇년에이르기까지다양하다. 그러므로모든종류의생명공학 / 생물학적제품에적용할수있는통일된안정성시험기간및시험주기관련가이드라인을제시하기란어렵다. 하지만일부예외가있으나, 기존제품과미래제품의유효기간은대부분 0.5년에서 5년이다. 그러므로이범위의예상유효기간에근거하여가이드라인을제시한다. 이때생명공학 / 생물학적제품의분해는서로다른장기보관기간동안에동일요소의영향을받지않는다고생각한다. When shelf-lives of 1 year or less are proposed, the real-time stability studies should be conducted monthly for the first 3 months and at 3 month intervals thereafter. 1년이하의유효기간을제시할때는, 첫 3개월동안은매월, 그리고그이후부터는 3개월주기로실시간안정성시험을실시한다. For products with proposed shelf-lives of greater than 1 year, the studies should be conducted every 3 months during the first year of storage, every 6 months during www..co.kr 18
the second year, and annually thereafter. 1년이상의유효기간을제시할때는, 첫 1년동안은 3개월마다, 두번째연도에는 6개월 마다, 그리고그이후부터는연 1 회주기로시험을실시한다. While the testing intervals listed above may be appropriate in the pre-approval or pre-licence stage, reduced testing may be appropriate after approval or licensure where data are available that demonstrate adequate stability. Where data exist that indicate the stability of a product is not compromised, the applicant is encouraged to submit a protocol which supports elimination of specific test intervals (e.g., 9 month testing) for post-approval/post-licensure, long-term studies. 상기의시험주기는승인이전또는라이선스이전단계에적절할수있지만, 적절한안정성을증명하는데이터가있는, 승인또는라이선스이후에는단축시험도가능하다. 제품안정성이훼손되지않는다는데이터가존재하면, 신청업체는승인 / 라이선스이후장기시험시에특정시험주기 ( 예, 9개월시험 ) 를생략한프로토콜을제출할수있다. 8. 규격 (SPECIFICATIONS) Although biotechnological/biological products may be subject to significant losses of activity, physicochemical changes, or degradation during storage, international and national regulations have provided little guidance with respect to distinct release and end of shelf-life specifications. Recommendations for maximum acceptable losses of activity, limits for physicochemical changes, or degradation during the proposed shelf-life have not been developed for individual types or groups of biotechnological/biological products but are considered on a case-by-case basis. Each product should retain its specifications within established limits for safety, purity, and potency throughout its proposed shelf-life. These specifications and limits should be derived from all available information using the appropriate statistical methods. The use of different specifications for release and expiration should be supported by sufficient data to demonstrate that clinical performance is not affected as discussed in the tripartite guideline on stability. 생명공학 / 생물학적제품이보관도중에중대한활성상실, 이화학적변화, 또는분해를보일수있지만, 출하승인규격과유효기간종료시점의규격과관련하여가이드라인을제시한국가및국제규정이거의없다. 생명공학 / 생물학적제품유형또는그룹별로예정유효기간동안의최대허용활성상실, 이화학적변화의한계, 또는분해에대한권고사항이개발되어있지않은상태이므로, 이러한부분을경우별로검토한다. 각각의제품은 www..co.kr 19
예정유효기간동안확립된안전성, 순도, 역가기준범위이내에서규격을유지해야한다. 이규격과기준은적절한통계방법을이용하여모든가용정보를바탕으로도출해야한다. 안정성가이드라인에서설명하고있는바와같이, 임상성능이영향을받지않음을증명하는충분한데이터를구비하여, 출하승인규격과유효기간규격을다르게설정하여운영하는방식의타당성을뒷받침한다. 9. 표시사항 (LABELLING) For most biotechnological/biological drug substances and drug products, precisely defined storage temperatures are recommended. Specific recommendations should be stated, particularly for drug substances and drug products that cannot tolerate freezing. These conditions, and where appropriate, recommendations for protection against light and/or humidity, should appear on containers, packages, and/or package inserts. Such labelling should be in accordance with relevant national/regional requirements. 대다수생명공학 / 생물학적원료의약품과완제의약품에대하여, 보관온도를정밀하게규정하고적용해야한다. 특히동결해서는안되는원료의약품과완제의약품인경우에, 구체적인권고사항을명시해야한다. 이러한조건과적절한경우에는차광및 / 또는습도조건을용기, 포장, 및 / 또는포장인서트에표기한다. 상기표시사항은관련국가 / 지역기준에부합해야한다. 10. 용어정의 (GLOSSARY) 접합제품 (Conjugated Product) A conjugated product is made up of an active ingredient (for example, peptide, carbohydrate) bound covalently or noncovalently to a carrier (for example, protein, peptide, inorganic mineral) with the objective of improving the efficacy or stability of the product. 접합제품은제품안정성또는유효성증진을목적으로, 활성성분 ( 예, 펩타이드, 탄수화물 ) 을공유결합또는비공유결합으로캐리어 ( 예, 단백질, 펩타이드, 무기물 ) 에결합시켜만든다. 분해산물 (Degradation Product) A molecule resulting from a change in the drug substance (bulk material) brought about over time. For the purpose of stability testing of the products described in www..co.kr 20
this guideline, such changes could occur as a result of processing or storage (e.g., by deamidation, oxidation, aggregation, proteolysis). For biotechnological/biological products some degradation products may be active. 시간경과에따른원료의약품 ( 벌크물품 ) 의변화로발생되는분자. 이가이드라인에기술된제품의안정성시험과관련하여, 상기의변화는가공또는보관의결과로발생할수있다 ( 예, 탈아미드화, 산화, 응집, 단백질분해 ). 생명공학 / 생물학적제품인경우에일부분해산물은활성을띠기도한다. 불순물 (Impurity) Any component of the drug substance (bulk material) or drug product (final container product) which is not the chemical entity defined as the drug substance, an excipient, or other additives to the drug product. 원료의약품, 첨가제, 또는의약품제조시에투입되는화학물질이아닌, 원료의약품 ( 벌크물품 ) 또는완제의약품 ( 최종용기제품 ) 의성분. 중간제품 (Intermediate) For biotechnological/biological products, a material produced during a manufacturing process which is not the drug substance or the drug product but whose manufacture is critical to the successful production of the drug substance or the drug product. Generally, an intermediate will be quantifiable and specifications will be established to determine the successful completion of the manufacturing step prior to continuation of the manufacturing process. This includes material which may undergo further molecular modification or be held for an extended period of time prior to further processing. 생명공학 / 생물학적제품인경우에, 원료의약품또는완제의약품은아니지만이의제조가원료의약품또는완제의약품의성공적인생산에핵심적인, 제조과정에서생산되는물품. 일반적으로중간제품은정량평가가가능하며, 제조공정의계속에앞서제조단계의성공적인완료여부를결정하기위한규격을확립한다. 여기에는추가적인분자적변형을거치거나추가가공에앞서장기간보관되는물품이포함된다. 제조규모생산 (Manufacturing Scale Production) Manufacture at the scale typically encountered in a facility intended for product production for marketing. 판매를목적으로한제품생산용시설에서흔히채택되는규모의제조. www..co.kr 21
파일럿플랜트규모 (Pilot-Plant Scale) The production of the drug substance or drug product by a procedure fully representative of and simulating that to be applied at manufacturing scale. The methods of cell expansion, harvest, and product purification should be identical except for the scale of production. 제조규모에서적용되는것을충분히대표하고이의시뮬레이션절차에의한원료의약품또는완제의약품생산. 생산규모만을예외로하고, 세포증식, 수득, 제품정제방법은동일해야한다. www..co.kr 22