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1 INTERNATIONAL CONFERENCE ON HARMONISATION OF TECHNICAL REQUIREMENTS FOR REGISTRATION OF PHARMACEUTICALS FOR HUMAN USE ICH HARMONISED TRIPARTITE GUIDELINE 원소불순물가이드라인 (Guideline for Elemental Impurities) Current Step 4 version dated 16 December 2014 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, Switzerland, Japan, USA and Canada. 1

2 Document History Code History Date Approval by the Steering Committee under Step 2a. 6 June 2013 Approval by the Steering Committee under Step 2b and release for public consultation. Post sign-off corrigendum in: Table 4.1 W and Al were removed from the list of included elemental impurities in Class 2B and 3 respectively. Table A.2.1 the Class for Ni was changed to read 3 instead of 2. Post sign-off minor editorial corrections including: removal of references to Appendix 5 (pgs i & 13); deletion of redundant text (pg 4); change of Option 2 to Option 2a (pg 10); insertion of omitted text under Safety Limiting Toxicity (pg 35); removal of duplicated redundant text (pg 41); replacing references to metals in text and metal in Table A.4.7 title with elementals and elements (pg 73); and deletion of header Table A.4.10 (pg 75). Addition of line numbers to facilitate the provision of comments by stakeholders. Approval by the Steering Committee under Step 4 and recommendation for adoption to the ICH regulatory bodies. 6 June June July September November 2014 Current Step 4 version Code History Date Corrigendum to correct: the modifying factor in the text of the safety assessment for Selenium (changed to 2 instead of 10 consistent with Section 3.1); and two references for consistency in the safety assessments for 16 December

3 Barium (deleted reference) and Vanadium (revised reference). 법적고지 (Legal notice): This document is protected by copyright and may be used, reproduced, incorporated into other works, adapted, modified, translated or distributed under a public license provided that ICH's copyright in the document is acknowledged at all times. In case of any adaption, modification or translation of the document, reasonable steps must be taken to clearly label, demarcate or otherwise identify that changes were made to or based on the original document. Any impression that the adaption, modification or translation of the original document is endorsed or sponsored by the ICH must be avoided. 이문서의저작권은 ICH에있다. 하지만공적사용허가에따라이문서의사용, 복제, 다른저작물에포함, 조정, 변형, 번역, 배포가가능하나, ICH의저작권을항상표시해야한다. 문서의조정, 변형, 또는번역시에는, 원본문서에근거했거나원본문서를변경했음을명확히표시하거나명시하거나기타방법으로알아볼수있게합리적인모든조치를취해야한다. 원본문서의조정, 변형또는번역시에 ICH가이를인정하거나지원했다는표시를피해야한다. The document is provided "as is" without warranty of any kind. In no event shall the ICH or the authors of the original document be liable for any claim, damages or other liability arising from the use of the document. 이문서는어떠한종류의보증없이 " 있는그대로 " 제공된다. ICH나원본문서의작성자는이문서의사용에따른청구, 손해배상등에대해어떠한경우에도책임을지지않는다. The above-mentioned permissions do not apply to content supplied by third parties. Therefore, for documents where the copyright vests in a third party, permission for reproduction must be obtained from this copyright holder. 상기의동의는제3자가제공하는내용에는적용되지않는다. 그러므로저작권이제3자에게있는문서인경우에는, 그저작권보유자로부터복제승인을확보해야한다. 3

4 GUIDELINE FOR ELEMENTAL IMPURITIES ICH Harmonised Guideline Having reached Step 4 of the ICH Process at the ICH Steering Committee meeting on 12 November 2014, this guideline is recommended for adoption to the regulatory parties to ICH. 목차 1. 서론 (INTRODUCTION) 2. 적용범위 (SCOPE) 3. 잠재원소불순물안전성평가 (SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES) 3.1 경구, 주사, 흡입투여경로에대한원소불순물의안전성평가 원칙 (Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and Inhalation Routes of Administration) 3.2 기타투여경로 (Other Routes of Administration) 3.3 PDE 설정값보다높은원소불순물수준의타당성증명 (Justification for Elemental Impurity Levels Higher than an Established PDE) 3.4 주사제품 (Parenteral Products) 4. 원소분류 (ELEMENT CLASSIFICATION) 5. 원소불순물의리스크평가와관리 (RISK ASSESSMENT AND CONTROL OF ELEMENTAL IMPURITIES) 5.1 일반원칙 (General Principles) 5.2 원소 불순물의 잠재적 출처 (Potential Sources of Elemental Impurities) 5.3 잠재 원소 불순물의 파악 (Identification of Potential Elemental Impurities) 5.4 리스크평가대상원소 (Recommendations for Elements to be Considered in the Risk Assessment) 5.5 평가 (Evaluation) 5.6 리스크평가요약 (Summary of Risk Assessment Process) 5.7 생명공학유래제품관련고려사항 (Special Considerations for Biotechnologically-Derived Products) 6. 원소불순물의관리 (CONTROL OF ELEMENTAL IMPURITIES) 7. PDE와 농도 한도 기준 (CONVERTING BETWEEN PDES AND CONCENTRATION LIMITS) 4

5 8. 종분포와기타고려사항 (SPECIATION AND OTHER CONSIDERATIONS) 9. 분석방법 (ANALYTICAL PROCEDURES) 10. 라이프사이클관리 (LIFECYCLE MANAGEMENT) 용어정의 (GLOSSARY) 참고문헌 (REFERENCES) Appendix 1: 노출한도기준설정방법 (Method for Establishing Exposure Limits) Appendix 2: 원소불순물의 PDE 설정값 (Established PDEs for Elemental Impurities) Appendix 3: 안전성평가 (Individual Safety Assessments) Appendix 4: 사례 (Illustrative Examples) 5

6 GUIDELINE FOR ELEMENTAL IMPURITIES 1. 서론 (INTRODUCTION) Elemental impurities in drug products may arise from several sources; they may be residual catalysts that were added intentionally in synthesis or may be present as impurities (e.g., through interactions with processing equipment or container/closure systems or by being present in components of the drug product). Because elemental impurities do not provide any therapeutic benefit to the patient, their levels in the drug product should be controlled within acceptable limits. There are three parts of this guideline: the evaluation of the toxicity data for potential elemental impurities; the establishment of a Permitted Daily Exposure (PDE) for each element of toxicological concern; and application of a risk-based approach to control elemental impurities in drug products. An applicant is not expected to tighten the limits based on process capability, provided that the elemental impurities in drug products do not exceed the PDEs. The PDEs established in this guideline are considered to be protective of public health for all patient populations. In some cases, lower levels of elemental impurities may be warranted when levels below toxicity thresholds have been shown to have an impact on other quality attributes of the drug product (e.g., element catalyzed degradation of drug substances). In addition, for elements with high PDEs, other limits may have to be considered from a pharmaceutical quality perspective and other guidelines should be consulted (e.g., ICH Q3A). 의약품에존재하는원소불순물의출처는다양하다. 합성과정에서의도적으로투입한촉매제잔류물이거나, 예를들어공정설비나용기 / 마개시스템과의상호작용에의해생성되거나의약품원료에존재하는불순물일수도있다. 원소불순물은환자에게치료효과를제공하지않으므로, 의약품중의원소불순물수준을허용한도이내로관리해야한다. 이가이드라인은잠재원소불순물의독성데이터평가, 독성학적문제를유발할가능성이있는각원소의 PDE(Permitted Daily Exposure) 설정, 그리고의약품중의원소불순물관리를위한리스크기반관리방법등세부분으로구성된다. 의약품중의원소불순물함량이 PDE를초과하지않으면, 공정능력에근거하여한도기준을엄격하게설정할필요는없다. 이가이드라인에설정된 PDE는모든환자집단의보호에적절한수준이라할수있다. 독성한계이하수준에서도의약품의품질특성에영향을미치는것으로밝혀진경우에는원소불순물수준을더낮게설정해야할필요가있을것이다 ( 예, 원소가원료의약품의분해촉매 ). 또한 PDE 값이큰원소인경우에는, 의약품품질관리 6

7 측면에서한도기준을달리설정할필요도있으며, 이런경우에는다른가이드라인 ( 예, ICH Q3A) 을참조한다. This guideline presents a process to assess and control elemental impurities in the drug product using the principles of risk management as described in ICH Q9. This process provides a platform for developing a risk-based control strategy to limit elemental impurities in the drug product. 이가이드라인은 ICH Q9의리스크관리원칙에의거하여완제의약품에존재하는원소불순물의평가및관리방법을제시한다. 이방법은의약품중의원소불순물을제한하기위한리스크기반관리전략을수립하는데토대가된다. 2. 적용범위 (SCOPE) The guideline applies to new finished drug products (as defined in ICH Q6A and Q6B) and new drug products containing existing drug substances. The drug products containing purified proteins and polypeptides (including proteins and polypeptides produced from recombinant or non-recombinant origins), their derivatives, and products of which they are components (e.g., conjugates) are within the scope of this guideline, as are drug products containing synthetically produced polypeptides, polynucleotides, and oligosaccharides. 이가이드라인은새로운최종완제의약품 (ICH Q6A와 Q6B의용어정의참조 ) 과기존원료의약품을함유하는새로운완제의약품에적용된다. 정제단백질과폴리펩타이드 ( 재조합유래와비재조합유래의단백질과폴리펩타이드포함 ), 이들의유도체, 그리고이들을구성성분으로하는제품 ( 예, 접합체 ) 을함유하는완제의약품이이가이드라인의적용대상이다. 또한합성폴리펩타이드, 폴리뉴클레오티드, 올리고사카라이드를함유하는완제의약품도적용대상에속한다. This guideline does not apply to herbal products, radiopharmaceuticals, vaccines, cell metabolites, DNA products, allergenic extracts, cells, whole blood, cellular blood components or blood derivatives including plasma and plasma derivatives, dialysate solutions not intended for systemic circulation, and elements that are intentionally included in the drug product for therapeutic benefit. This guideline does not apply to products based on genes (gene therapy), cells (cell therapy) and tissue (tissue engineering). In some regions, these products are known as advanced therapy medicinal products. 생약제품, 방사성의약품, 백신, 세포대사물질, DNA 제품, 알레르겐추출물, 세포, 전혈, 7

8 세포성혈액성분또는혈장과혈장유래물질을포함하는혈액제품, 전신순환용도가아닌투석액, 치료효과를위하여의약품에의도적으로투입한원소는적용대상이아니다. 또한유전자기반제품 ( 유전자치료제 ), 세포기반제품 ( 세포치료제 ), 조직기반제품 ( 조직공학 ) 도적용대상이아니다. 일부지역에서는이들제품을 ATMP(advanced therapy medicinal products) 라고부른다. This guideline does not apply to drug products used during clinical research stages of development. As the commercial process is developed, the principles contained in this guideline can be useful in evaluating elemental impurities that may be present in a new drug product. 임상시험단계의의약품에는이가이드라인이적용되지않는다. 상업적공정의개발시에이가이드라인에제시된원칙은새로운의약품에존재할가능성이있는원소불순물을평가하는데유용할수있다. Application of to existing products is not expected prior to 36 months after publication of the guideline by ICH. ICH가이가이드라인을발행한날로부터 36개월이내에는기존제품에 를적용하리라고기대하지않는다. 3. 잠재원소불순물안전성평가 (SAFETY ASSESSMENT OF POTENTIAL ELEMENTAL IMPURITIES) 3.1 경구, 주사, 흡입투여경로에대한원소불순물의안전성평가원칙 (Principles of the Safety Assessment of Elemental Impurities for Oral, Parenteral and Inhalation Routes of Administration) The method used for establishing the PDE for each elemental impurity is discussed in detail in Appendix 1. Elements evaluated in this guideline were assessed by reviewing the publicly available data contained in scientific journals, government research reports and studies, international regulatory standards (applicable to drug products) and guidance, and regulatory authority research and assessment reports. This process follows the principles described in ICH Q3C: Residual Solvents. The available information was reviewed to establish the oral, parenteral and inhalation PDEs. For practical purposes, the PDEs to be applied to the drug product that are presented in Appendix 2 Table A.2.1 have been rounded to 1 or 2 significant figures. 각원소불순물의 PDE 확립방법을부록 1에서자세히설명한다. 이가이드라인에서 8

9 평가하는원소는과학학술지, 정부연구보고서, 국제규제기준문서 ( 의약품에적용되는기준 ) 와가이드라인, 규제기관의연구평가보고서등을통해공개된데이터를검토하여가했다. 이때 ICH Q3C " 잔류용매 " 가이드라인에기술된원칙을적용했다. 활용가능한모든정보를평가하여경구, 주사, 흡입 PDE를확립했다. 실무적인목적에서, 부록 2의표 A.2.1에정리된의약품에적용하는 PDE 값을 1 또는 2의유효숫자로반올림했다. A summary safety assessment identifying the critical study for setting a PDE for each element is included in Appendix 3. There are insufficient data to set PDEs by any route of administration for iridium, osmium, rhodium, and ruthenium. The PDEs for these elements were established on the basis of their similarity to palladium. 원소별로 PDE 설정을위해중요연구자료를검토하고평가했으며, 원소별안전성평가요약정보를부록 3에정리했다. 이리듐, 오스뮴, 로듐, 루테늄의경우에는투여경로별 PDE를설정하는데활용할수있는데이터가충분하지않다. 이들원소는팔라듐과유사하다는점을고려하여 PDE를설정했다. The factors considered in the safety assessment for establishing the PDE are listed below in approximate order of relevance: PDE 설정을위한안전성평가시에고려했던요소를관련성순서에따라다음과같이정리할수있다. The likely oxidation state of the element in the drug product; 완제의약품에존재하는원소의산화상태 Human exposure and safety data when it provided applicable information; 타당한정보를제공하는인체노출및안전성데이터 The most relevant animal study; 가장연관성이있는동물시험자료 Route of administration; 투여경로 The relevant endpoint(s). 관련엔드포인트 Standards for daily intake for some of the elemental impurities discussed in this guideline exist for food, water, air, and occupational exposure. Where appropriate, these standards were considered in the safety assessment and establishment of the PDEs. 9

10 이가이드라인에서다루는원소불순물가운데일부는, 식품, 물, 공기, 직업적노출에대한 일일섭취량기준이설정되어있다. 적절한경우에는이기준을고려하여안전성평가를 실시하고 PDE 를설정했다. The longest duration animal study was generally used to establish the PDE. When a shorter duration animal study was considered the most relevant, the rationale was provided in the individual safety assessment. 일반적으로가장오랫동안실시한동물시험자료를바탕으로 PDE를설정했다. 더짧은기간동안실시한동물시험자료가더연관성이있다고판단되는경우에는, 그근거를각각의안전성평가시에검토하고정리했다. Inhalation studies using soluble salts (when available) were preferred over studies using particulates for inhalation safety assessment and derivation of inhalation PDEs. Depending on available data, inhalation PDEs were based on either local (respiratory system) or systemic toxicity. For PDEs established for inhalation (and oral or parenteral routes as applicable), doses were normalized to a 24-hour, 7-day exposure. 흡입안전성평가와흡입 PDE 설정시에미립자를이용한시험보다는가용성염을이용한흡입시험자료 ( 이런자료가있는경우 ) 를우선적으로평가했다. 활용가능한데이터에따라국소 ( 호흡기 ) 또는전신독성자료를활용해흡입 PDE를설정했다. 흡입경로 ( 와해당되는경우에는경구또는주사경로 ) 에대해 PDE를설정할때, 투여용량을 24시간 /7일노출상황으로정규화했다. In the absence of data and/or where data are available but not considered sufficient for a safety assessment for the parenteral and or inhalation route of administration, modifying factors based on oral bioavailability were used to derive the PDE from the oral PDE: 데이터가없거나데이터가있으나주사또는흡입투여경로의안전성평가에충분하지않다고판단되는경우에는, 경구생체이용율에근거한변형계수를활용해경구 PDE로부터 PDE를도출했다. Oral bioavailability <1%: divide by a modifying factor of 100; 경구생체이용률 < 1% 인경우 : 변형계수 100으로나눈다. Oral bioavailability 1% and <50%: divide by a modifying factor of 10; 경구생체이용율이 1% 이고 < 50% 인경우 : 변형계수 10으로나눈다. Oral bioavailability 50% and <90%: divide by a modifying factor of 2; and 10

11 경구생체이용율이 50% 이고 < 90% 인경우 : 변형계수 2 로나눈다. Oral bioavailability 90%: divide by a modifying factor of 1. 경구생체이용율이 90% 인경우 : 변형계수 1 로나눈다. Where oral bioavailability data or occupational inhalation exposure limits were not available, a calculated PDE was used based on the oral PDE divided by a modifying factor of 100 (Ref. 1). 경구생체이용율데이터나직업적흡입노출한도기준이없는경우에는, 경구 PDE를변형계수 100으로나누어구한 PDE를사용했다 ( 참고문헌 1). 총 170 페이지입니다. 파일 (Printable PDF) 으로연락주시기 바랍니다. 11

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