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1 24 October 2013 EMA/603905/2013 디자인스페이스베리피케이션에관한 Q&A(Questions and Answers on Design Space Verification) In March 2011, the EMA and FDA launched a pilot program to allow joint evaluation of QbD (Quality by Design) elements. As a result of this pilot program, the EMA and FDA reached agreements on a wide range of QbD elements. A joint question and answer (Q&A) document was published on August 20, 2013 that reflects EMA and FDA harmonization on some QbD aspects. 2011년 3월 EMA와 FDA는 QbD 요소의공동평가를위한파일럿프로그램을시작했다. 이파일럿프로그램의결과로 EMA와 FDA는다양한 QbD 요소에대하여합의를이루었다. 일부 QbD 부분에대한 EMA와 FDA의조화결과를반영해공동 Q&A 문서를 2013년 8월 20일에발행했다. The Q&A below is a reflection of EMA s and FDA s position on the topic of design space verification. 아래의 Q&A는디자인스페이스베리피케이션주제에대한 EMA와 FDA의입장을반영해정리한것이다. Design space verification is a demonstration that the proposed combination of input process parameters and material attributes are capable of manufacturing quality product at commercial scale. 디자인스페이스베리피케이션은공정파라미터와물품특성요소의예정조합이상업적스케일에서고품질의제품을제조할수있음을증명하는것이다. This document is conceptually divided into three sections. The first section includes general question and answers that are harmonized between EMA and FDA. Appendix 1 includes EMA specific expectations and Appendix 2 includes FDA specific 1

2 expectations. 이문서는세부분으로구성된다. 첫번째섹션에서는 EMA와 FDA 사이에조화된공통 Q&A를정리한다. 그리고 EMA의기대사항과 FDA의기대사항을각기부록 1과 2에서설명한다. 1. 제품라이프사이클동안디자인스페이스를베리피케이션해야하는이유가 무엇인가 (Why would a design space be verified during the product lifecycle?). In both Agencies experience, the design space verification at commercial scale is not necessarily complete at the time of submission of the application but should occur over the lifecycle of the product and process. Initial design space verification often occurs solely at or near the target operating ranges. EMA와 FDA의경험에의하면, 상업적스케일의디자인스페이스베리피케이션이신청문서제출시점에완료되지않으며, 제품과공정의라이프사이클전체에걸쳐디자인스페이스베리피케이션을실시해야한다. 초기디자인스페이스베리피케이션은목표공정범위또는그근처에서실시된다. However, movements from one area to another area within the design space (e.g., re-establishing the Normal Operating Ranges (NOR)) within the approved design space in an unverified area) may pose higher or unknown risks due to potential scale up effects and/or model assumptions. It is important that these risks are understood and evaluated utilizing an appropriate control strategy, including but not restricted to the controls submitted in the dossier. It is understood that when an applicant demonstrates that a design space is scale independent, then additional risk mitigation steps are not necessary for design space verification. 디자인스페이스이내의한영역에서다른영역으로이동하는경우에는 ( 예, 승인받은디자인스페이스의베리피케이션되지않은영역에서 NOR을다시설정하는경우 ), 스케일업영향이나모델가정때문에더크거나알려지지않은리스크가발생할수있다. 허가문서에포함시켜제출한관리전략을포함하되이에국한하지않고, 적절한관리전략으로이와같은리스크를이해하고평가하는것이중요하다. 디자인스페이스가스케일독립적임을신청업체가증명한다면, 디자인스페이스베리피케이션을위하여추가적인리스크완화조치가필요하지않을것이다. 2. 상업적스케일의디자인스페이스베리피케이션은목적이무엇인가 (What is the purpose of design space verification at commercial scale?). 2

3 Design space verification demonstrates that within design space boundaries scaleup effects are under control and do not adversely affect the expected product quality at commercial scale. 디자인스페이스경계범위안에서스케일업영향이관리아래있으며상업적스케일에서예상제품품질에부정적인영향을미치지않음을증명하는것이디자인스페이스베리피케이션의목적이다. 3. 디자인스페이스를처음에어떻게개발하고, 상업적스케일에서베리피케이션을어떻게 하는가 (How is a design space initially developed and verified at commercial scale?). Both Agencies acknowledge that when a design space is established at early stages of product development, it is typically developed based on experiments conducted at laboratory or pilot scale. The confidence in the design space at commercial scale can vary depending on the amount and type of development data generated and the knowledge of the scalability (i.e., the degree of scale dependency of the design space). Design space limits at commercial scale can be based on scale-up correlations demonstrated during development studies and/or experimentation. In addition, design space limits can be challenged with computational simulations. 제품개발단계초기에디자인스페이스를확립할때, 일반적으로실험실스케일이나파일럿스케일의실험결과를토대로디자인스페이스가정해진다. 이때생산된개발데이터의양과종류, 그리고스케일확장성 ( 즉, 디자인스페이스의스케일의존성정도 ) 에관한지식에따라, 상업적스케일의디자인스페이스에대한신뢰도가다를수있다. 개발실험이나연구단계에서증명된스케일업상관관계를토대로상업적스케일의디자인스페이스한도를정할수있다. 또한컴퓨터시뮬레이션방법으로디자인스페이스한도를평가하기도한다. The Agencies further acknowledged that the commercial process is generally operated in a specific area of the design space, sometimes called the NOR (Normal Operating Range). The NOR describes a region around the target operating conditions that contains typical operational variability. Initial process verification often occurs solely within the NOR at commercial scale. 또한 EMA와 FDA는디자인스페이스가운데 NOR(Normal Operating Range) 이라고부르기도하는특정영역에서상업적공정이진행됨을알고있다. NOR은일반적인공정변동을포괄하는목표공정조건지역에해당된다. 상업적스케일의초기공정 3

4 베리피케이션을 NOR 에서만실시하기도한다. 4. 상업적스케일에서디자인스페이스를어떻게베리피케이션할수있는가 (How can a design space be verified at commercial scale?). It is not necessary to repeat at commercial scale the experiments initially conducted to define a design space at lab or pilot scale. Furthermore, it is neither necessary to verify entire areas of design space nor to identify the edge of failure. In principle, more than one area of a design space may be verified at the time of submission but the design space can, as appropriate, also be further verified over the product lifecycle. 실험실스케일이나파일럿스케일에서디자인스페이스를규정하기위하여처음에실시했던실험을상업적스케일에서다시반복할필요는없다. 또한디자인스페이스의전영역을베리피케이션하거나 EOF(edge of failure) 를확인할필요도없다. 원칙적으로허가신청시점에는디자인스페이스가운데하나이상의영역을베리피케이션할수있고, 제품라이프사이클동안적절한경우에디자인스페이스를추가적으로베리피케이션할수있다. The approach to design space verification over the product lifecycle can be guided by the results of risk assessment on the potential effect of changes to scale dependent parameters on product quality. Depending on the specific change, the potential impact to the product quality, and the ability of the control strategy to detect product failures, the management of the risk can include additional monitoring of quality attributes and/or process parameters not included in the routine control system. 스케일의존적파라미터의변경이제품품질에미칠영향에대한리스크평가결과를토대로, 제품라이프사이클동안실시하는디자인스페이스베리피케이션의방향을정한다. 변경의종류, 제품품질에미칠파급영향, 제품이상을관리전략이찾아낼수있는능력등을고려하여, 일상관리시스템에포함시키지않았던품질특성요소나공정파라미터의추가적인모니터를리스크관리전략에포함시킬수있다. 5. 신청문서에포함시킬디자인스페이스베리피케이션프로토콜을어떻게 작성하는가 (How should design space verification protocol be addressed in the submission?). In principle, a design space verification protocol could include the following: list of scale dependent parameters whose impact on the CQAs has not been verified at 4

5 commercial scale, definition of the potential scale-up risks to the CQAs, discussion of whether the control strategy can address these risks, and description of any additional controls, as needed. 원칙적으로디자인스페이스베리피케이션프로토콜에다음과같은항목을포함시킬수있다. CQA에미칠영향을상업적스케일에서베리피케이션하지않은스케일의존성파라미터리스트, 스케일업이 CQA에미칠리스크, 관리전략으로이와같은리스크에대처할수있을지여부에대한설명, 필요에따라추가적인관리대책. EU authorities expectation is that a protocol for design space verification be submitted in section 3.2.R of the application. At the time of submission, a proposed design space not verified at commercial scale should be accompanied by an appropriate verification protocol. The protocol would be assessed at the time of review. Verification data are managed and documented in the site change management system. EU 규제기관의기대사항은디자인스페이스베리피케이션프로토콜을신청문서의섹션 3.2.R에포함시켜제출하는것이다. 허가신청문서의제출시점에상업적스케일에서베리피케이션하지않은디자인스페이스에대하여, 적절한베리피케이션프로토콜을작성해제출한다. 이프로토콜을허가신청문서의심사시에평가한다. 제조소변경관리시스템에의거하여베리피케이션데이터를관리하고문서화한다. FDA s expectation is that any plans for design space verification be available at the manufacturing site as an element of the change control, validation, and/or knowledge management strategy. Providing data for initial design space verification and a high-level overview of the plan for design space verification over the product lifecycle can be beneficial to the review of the application. FDA의기대사항은변경관리, 밸리데이션, 지식관리전략의한요소로제조소가디자인스페이스베리피케이션계획을구비하고있어야한다는것이다. 초기디자인스페이스베리피케이션데이터를제공하고제품라이프사이클동안디자인스페이스베리피케이션을위한계획에대하여전반적인정보를제출한다면, 허가신청문서의심사에도움이될수있다. 6. 디자인스페이스베리피케이션시에예상하지못한결과나이벤트가발생하면어떻게 하는가 (What if unexpected results/events are obtained during the design space verification studies?). If the verification studies prove the process does not meet the predefined product 5

6 quality attributes in a new region of the approved design space, this may indicate an underlying issue with the design space or a flaw in the assessment or verification plan. Changes to the boundaries or description of the design space and any required changes to design space verification protocol should be reported to the Agencies, using appropriate notification categories, in accordance with regional requirements. 승인받은디자인스페이스의새로운영역에서제품품질기준에부합하지않는결과가베리피케이션실험시에나오면, 이는디자인스페이스에내재적인문제가있거나평가또는베리피케이션계획에결함이있다는의미일수있다. 디자인스페이스에관한정보나경계를변경하거나디자인스페이스베리피케이션프로토콜을변경하는경우에는, 지역별기준에따라적절한보고절차에의거해규제기관에보고해야한다. Appendix 1 and 2 address regional expectations and regulations 부록 1과 2는지역별규정과기대사항을정리한것이다. Appendix 1: EU s expectations 부록 1: EU의기대사항 7. 생물학적제품의디자인스페이스를상업적스케일에서어떻게베리피케이션할수 있는가 (How can a design space be verified at commercial scale for biological products?). Principles laid down for chemical products are applicable to biological products. In addition, verification studies should provide evidence that the quality attributes of the product are comparable prior to and after the change. This could include a proposal for modular sets of tests and acceptance criteria to be deployed, taking into account the nature of the change and its associated risk. 화학제품의원칙을생물학적제품에도적용할수있다. 또한변경전과후의제품품질특성이동등하다는증거가베리피케이션실험을통해확보되어야한다. 이때변경의특성과관련리스크를고려하여, 앞으로적용할시험항목과허용기준을정할수있다. 8. 공정밸리데이션과디자인스페이스베리피케이션의차이점은무엇인가 (What is the difference between process validation and design space verification?) Design space verification should not be confused with process validation. Both take into consideration prior knowledge and development conclusions and are conducted 6

7 at commercial scale, however the scope of the studies are not the same. Whereas process validation demonstrates consistency of the process at normal operating ranges, design space verification demonstrates that scale effect and or model assumptions are under control in the new area of design space and do not affect product quality. Unlike validation which covers all the steps of the manufacturing process, verification studies refer only to those operations where a design space has been proposed. 디자인스페이스베리피케이션과공정밸리데이션을혼동해서는안된다. 모두선행지식과개발결과를바탕으로상업적스케일로실시하지만, 적용범위가다르다. 공정밸리데이션은 NOR(normal operating range) 에서공정일관성을증명하는활동이고, 디자인스페이스베리피케이션은디자인스페이스의새로운영역에서스케일영향이나모델가정이관리상태에있고제품품질에부정적인영향을주지않음을증명하는것이다. 밸리데이션은모든제조공정단계를대상으로하지만, 베리피케이션실험은디자인스페이스가제시된공정만을대상으로한다. In order to address the risks identified during the risk assessment of operating in the unverified area of the design space the verification studies may also include testing / monitoring of additional parameters or at an increased frequency as compared to the routine control strategy. 디자인스페이스가운데베리피케이션되지않은영역에서공정을실시하는것에대한리스크평가시에파악된리스크에대처하기위해, 일상관리전략과비교하여주기를강화하거나추가파라미터의시험 / 모니터를포함하여베리피케이션실험을실시할수있다. When verification data proves that the extent of movement within the design space is of high risk (e.g. critical quality attributes are met but close to edge of failure identified at laboratory/pilot scale), process validation (consistency of the process) in the new area of design space (new NOR) should also be considered. 디자인스페이스안에서이동하는것이리스크가크다는베리피케이션데이터가확보되면 ( 예, CQA를충족하지만실험실스케일이나파일럿스케일에서파악한 EOF에가까운경우 ), 디자인스페이스가운데새로운영역 ( 새로운 NOR) 에서공정밸리데이션 ( 공정일관성증명 ) 을실시할필요가있다. A protocol for design space verification should be submitted in section 3.2.R. irrespective of the validation approach. When a strategy for continuous verification is envisaged, where relevant, the elements of design space verification should be included as part of the continuous verification protocol. 7

8 밸리데이션방법과상관없이, 디자인스페이스베리피케이션프로토콜을섹션 3.2.R 에 포함시켜제출한다. 계속적베리피케이션전략을적용하고자한다면, 계속적베리피케이션 프로토콜의한부분으로디자인스페이스베리피케이션요소를포함시킨다. It is understood that when an applicant can demonstrate that the design space is scale independent then a verification protocol is not requested in the dossier. 디자인스페이스가스케일독립적임을신청업체가증명할수있다면, 베리피케이션프로토콜을허가문서에포함시킬필요는없을것이다. NB: Continuous Process Verification is an alternative approach to traditional process validation in which manufacturing process performance is continuously monitored and evaluated (ICH Q8). 주 : 계속적공정베리피케이션은전통적공정밸리데이션의대체방법으로제조공정성능을계속적으로모니터하고평가하는것이다 (ICH Q8). Appendix 2: FDA expectations 부록 2: FDA 기대사항 9. 디자인스페이스베리피케이션방법을제약품질시스템에서어떻게관리해야 하는가 (How should design space verification approach be addressed in the pharmaceutical quality system?). FDA recommends that firms have a written plan for when and how to evaluate the need for design space verification under their pharmaceutical quality system. FDA s expectation is that such plans for design space verification be available at the manufacturing site. Additionally, it can be beneficial to the review of the application for the applicant to include in the initial submission a high-level overview of the plan for design space verification over the product lifecycle. 제약품질시스템에의거하여디자인스페이스베리피케이션의필요성을평가하는시점과방법에대한계획서를구비할것을 FDA는권고한다. 이와같은디자인스페이스베리피케이션계획문서를제조소가구비해야한다는것이 FDA의기대사항이다. 또한제품라이프사이클동안디자인스페이스베리피케이션을위한계획을신청문서에기술한다면, 허가신청문서의심사에도움이될수있다. 8

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