슬라이드 1

Transcription

1 이해 정경희 오송바이오의약생산센터

2 목차 1. ICH Guideline 이해 2. QbD 적용

3 Focus on Quality 의약품품질 고품질의약품이란 다음제품을지속적으로신뢰할수있게공급 바람직한상태 임상적성능및 라벨에표기된특성 오염이없이, 항상공급가능. 고품질의약품을신뢰할수있게생산하는 최대로효율적이고, 빠르며, 유연한의약품제조 엄격한규제감시없이 (Janet Woodcock, FDA) 의약품제조의문제 고비용의 cgmp/ 규제준수 혁신 & 효율의장려부족 민첩성부족 긴회전시간 규모확대 / 신규생산지역변경에대한어려움 FDA Vision for the 21 st Century A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight 21 세기를위한 CGMP 공정분석기술 (PAT)

4 Paradigm Shift

5 Paradigm Shift 공정이제품이다 어떤변수가제품의품질에중요한가? Starting Materials Variable Processing Parameters Product Statistically designed experiment ICH Q8 Fixed Paradigm Shift Variable Process Analytical Technology 공정변수의영향 단순한시험이아닌 공정의이해 라는철학 end-product testing 보다는공정중관리 원료특성 On or at line 측정 낮은품질위험의최소화 Starting Materials Variable Processing Parameters Variable Product Fixed

6 Prospective Quality Initiatives CGMP for the 21st Century (QbD) : Focus areas for FDA regulatory : Process Analytical Technology Risk-based (ICH Q9) Material Attributes Quality systems (ICH Q10) On or at line Measurements Linking material attributes and Impact Process Parameters process parameters to DS CQAs (ICH Q11) QbD는의약품개발을위한체계적인접근방법 미리정해진목표를가지고시작하며, 제품과공정이해, 그리고공정관리를강조하고 합리적인과학과품질위험관리를기반으로함 A systematic approach to development that begins with predefined objectives and emphasizes products and process understanding and process control, based on sound science and quality risk management (ICH Q8R2) FDA 21st Century Initiative (2004) 의목적 : Patient-centric approach to the assessment of quality -신기술조기도입장려 Integrated approaches for review and inspection -현대적품질경영기술도입 Risk-based approaches to review and inspection -위험기반접근법의활용 Efficiency and risk-based work prioritization -첨단과학기술에기초한규제기관의심사, 규제준수, 실사정책확립 Modern regulatory science approaches -지속적개선을가능케하는규제유연성 (e.g., clinically relevant specifications, statistically sampling) 확보

7 의약품개발의목적

8 QbD Takes a Step Forward with PV 어떻게품질의기초로서공정의이해를보여줄것인가 Since 2004 of FDA initiatives, industry has been struggling 1.Q6-Q10 이우수한실행원칙으로해답을제공 하지만품질의기초로서공정이해로의발전은느림 2. FDA new guidance on process validation in 2011 공정의이해로발전을촉진하기위하여 기본적으로 QbD(ICH Q8~11) 의핵심요소의일부를 stages 1 and 2 에의무화. 3. EMA Guideline on Process Validation for finished product (2014) Guideline on PV for Biotechnology-derived active substance (2014)

9 QbD Takes a Step Forward with Q11 원료의약품의관리와 GMP 적용 DS 공급자와 DP 제조자가같은 ICH Q7A 를 GMP 결정의기초로사용 (final intermediate (FI) and the regulatory starting material (RSM)). DP 와 DS 에같은요구사항을적용하는것은불합리 공정이현저하게다름 ICH issued Q11: Development and manufacture of Drug Substance (Chemical & Biological Entities) FDA 는공식적으로 ICHQ11 채택 (Nov. 2012) 목적은 첫번째, CTD 2.2.S S.2.6 Module 3 작성을위한 guidance 제시 두번째이며더중요한것은원료의약품의개발과제조에관련된 ICH Q8, Q9, Q10 에정의된개념의명확화

10 Applying ICH Q8(R2), Q9, and Q10 Principles to CMC Review (FDA OPQ, MAPP , Effective Date: 05/18/2016) 목적 QbD 접근방식을적용한신청서류들이증가함에따라센터의문서심사에 ICH 가이던스를일관성있게적용할필요성을인식. 정책 OPQ 제품품질심사관은 QbD 접근방식을포함하거나또는포함하지않은신청건을심사할때에 ICH Q8, Q9, Q10 의권고를고려할것임 책임과절차 : 심사관은신청문서가 ICH Q8(R2) 에서언급한최소요구사항을반드시확인하여야한다. ICH Q8(R2) Annex 최소요구사항은 : - Quality target product profile (QTPP). - Critical quality attributes (CQAs) of the drug product. - CQAs of the drug substance and excipients. - Selection of an appropriate manufacturing process. - Control strategy. Process, Formulation Understanding is Critical 부가적으로모든신청은다음을포함해야한다 - 완제의약품과그제조공정의개발과정의이해를위해수행된정보 - 완제의약품의안전성과유효성보장을위한제품품질에중요한원료의약품, 첨가물, container closure systems, 제조공정사항확인 - 관리전략에대한정당한근거

11 Applying ICH Q8(R2), Q9, and Q10 Principles to CMC Review (FDA OPQ, MAPP , Effective Date: 05/18/2016) 신청에는좀더유연한규제적접근을위하여제품 / 공정의강화된지식에대한정보를포함시킬수있다. 심사자는제안된유연한규제적접근을보증할수있도록물질특성과공정변수, 그리고제품품질관리에대한신청자의이해를보여주는충분히강화된지식을포함하고있는지여부를확인하여야한다. 유연한규제적접근의예는다음과같다. - 규제기관에신고하지않는제조공정개선 ( 예, 설계공간내에서의변수이동 ). - Change protocols 제출을통한승인후변경신청의축소 - 최종제품시험을대신하는공정중시험 (RTRT 포함, - 전통적최종제품시험을대체하는수학적모델 ( 예, multivariate models) RTRT 가제안된경우심사자는관련된방법이간접적으로제어되는특성의규격에포함되어있음을확인해야한다 ICH Q9 은 QRM 에체계적인접근법을제공하며, 위험평가는일반적으로관리전략의기초로서신청시에제출된위험평가는제안된유연한규제적접근방법을정당화할수있다. 심사자는신청서에제시된각각의위험평가를평가하여야한다. 심사자는신청서류검토시과학적이고위험기반의접근을하여야한다. - 심사자는품질에대한위험과그위험을적절하게제어할수있는관리전략의능력을평가하여야한다. 심사자는이평가를위하여 ICH Q9 의방법을사용한공식적인위험평가를독립적으로수행을선택할수도있다. - 리뷰의정도는검토하는물질이나공정의중요도나그것의제품품질에미치는심각도에따라결정되어야한다. - IH Q10 에언급되었듯이, 제조사의품질시스템은지속적인제품품질을보장하기위하여중요한부분이다

12 ICH Mission ICH : International Council for Harmonisation of Technical Requirement for Pharmaceuticals for Human Use Mission To make recommendations towards achieving greater harmonization in the interpretation and application of technical guidelines and requirements for pharmaceutical product registration, thereby reducing or obviating duplication of testing carried out during research and development of new human medicines Harmonisation is achieved through the development of ICH Tripartite Guidelines. The Guidelines are developed through a process of scientific consensus with regulatory and industry experts working side-by-side. Key to the success of this process is the commitment of the ICH regulators to implement the final Guidelines. Regulatory Environment

13 What is ICH Qx? The ICH topics are divided into four categories and ICH topics codes are assigned according to these categories : Quality Guidelines (Q-series) Harmonisation achievements in the Quality area include pivotal milestones such as the - conduct of stability studies, - defining relevant threshold for impurities testing and a more flexible approach to pharmaceutical quality based on Good Manufacturing Practice (GMP) risk management Safety Guideline (S-series) eg Pharmacovigilance Efficacy Guidelines (E-series) eg GCP Multidisciplinary Guidelines (M-series) eg CTD

14 ICH Quality Guidelines Process - Development & Manuf. of APIs (ICH Q11) - Pharmaceutical Development (ICH Q8) - Biotechnological Products (ICH Q5A-E) Patient Systems - Pharmaceutical Quality System (ICH Q10) - GMP for APIs (ICH Q7) - Analytical Validation (ICH Q2) - Life Cycle Management (ICH Q12) Product - Specifications (ICH Q6A-B) - Pharmacopoeias (ICH Q4) - Impurities (ICH Q3A-D & ICH M7) Enabler - Stability (ICH Q1A-F) Quality Risk Management (ICH Q9) Common Technical Document (CTD) (ICH M4Q, ectd: ICH M8) Managing regulatory expectations throughout the product lifecycle : Tom Sam

15 ICH Qx support Framework of Pharmaceutical development ICH Q8(R2)-Part II: Annex Current ICH Q Activities Q3C Guideline for Residual Solvents Q3D Guideline on Elemental Impurities Development of Drug (medicinal) product (P2 part of CTD) ICH Q8(R2)-Part I Pharmaceutical Quality System (ICH Q10) Development of Analytical methods based on ICH Q6a/b Life Cycle Management ICH Q12 Development and Manufacture of Drug substances (S2 part of CTD) ICH Q11 Enabler: Knowledge Management as part of Quality Risk Management (ICH Q9) Q11 Q&As: Selection and Justification for Starting Materials for the Manufacture of Drug Substances Q12 Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management M4Q Addressing CTD-Q Related Questions/Change Requests Raised by ectd ICH-M: BCS-based Biowaivers ICH-M: Bioanalytical method validation Managing regulatory expectations throughout the product lifecycle : Tom Sam

16 What is ICH Q8, 9, 10, 11, 12? They are all about quality : Q8 ( Pharmaceutical Development ) How to design quality Q9( Quality Risk Management) How to analyse, assess and manage risk Q10( Pharmaceutical Quality System ) How to establish and maintain quality system Q11( Development and Manufacture of Drug Substance ) How to design quality from the very beginning, mainly API (DS) Q12( Technical and Regulatory Considerations for Pharmaceutical Product Lifecycle Management ) (Step 2, Nov. 2017) How to maintain quality during lifetime of product

17 ICH Q8 : Pharmaceutical Development & Life Cycle Approach First step in the product s lifecycle is pharmaceutical development This topic is dealt with in ICH Q8 : ICH Q8 describes the beginning of the life-cycle with Pharmaceutical Development The goal of pharmaceutical development is to design a product and its manufacturing process to consistently deliver the intended performance of the product. (definition similar to that of Q10) Information from PharmDev studies can be a basis for quality risk management. ( link to ICH Q9) ICH Q8 is based on the paradigm that quality cannot be tested into a product but has to be built in by design Describes science and risk-based approaches for pharmaceutical product and manufacturing process development Introduced concepts of design space and flexible regulatory approaches Introduced concepts of (QbD) and provided examples of QbD development approaches and design space

18 Challenge: How are these general QbD principles applied by ICH Q8? Q8 starts with QTPP which actually is a spec Which needs a decision making process Anybody has to say and decide what we want Once we know what we want, we can continue : QTPP is a prerequisite for setting up CQAs (Critical Quality Attributes) The CQAs again need to be specified Specification of CQAs requires to identify, assess and manage CQAs Criticality is usually managed by risk considerations A specification describes an acceptable range (CQA-AC) The limits of the spec are subject to discussion about CQAs are prerequisites to decide upon CPPs (Critical Process Parameters) Critical are quality attributes and process parameters if and when they potentially have an undesired impact on product quality and thus patient s safety Identification of critical issues requires a RISK analysis

19 QbD in ICH Q8 Product profile CQAs Optimized Formulation Target the quality product profile Determine critical quality attributes (CQAs) Select an optimal formulation Target the product profile Determine critical quality attributes (CQAs) Link material attributes and process parameters to CQAs and perform risk assessment Selected Process Control Strategy Select an appropriate process Define and implement a control strategy 의약품개발의최소구성요소 (ICH Q8): 품질, 안전성, 유효성과관련된제품품질목표선정 핵심품질특성 (CQA) 의선정및이에영향을주는성분의특성연구 제형및조성에필요한첨가물의결정 적절한제조공정선택 관리전략의정의 필수 추가 Develop a design space Design and implement a control strategy Manage product lifecycle, including continual improvement (not for submission) 강화된 QbD 방식의추가적요소 (ICH Q8): 제제와제조공정의체계적평가, 이해, 구체화를통하여 제품 CQA 에영향을줄수있는물품특성과공정변수의파악. ( 선행지식, 실험, 위험평가방법을사용 ) 물품특성과공정변수를 CQA 와연계시키는기능적 ( 함수적 ) 관계결정 제품및공정의이해이용한적절한관리전략확립 ( 설계공간, 실시간출하승인시험등포함 ) 결과적으로제품전주기에걸쳐지속적인개선과혁신을가능케함

20 ICH Q9 : Quality Risk Management Quality Risk Management is handled by ICH Q9: Having initially been adopted as EU GMP annex 20 (withdrawn) Now included in Part III of the GMP Guide Some definitions from ICH Q9 : Risk the combination of the probability of occurrence of harm and the severity of that harm (ISO/IEC Guide 51) Q9 (Annex 20) Risk identification the systematic use of information to identify potential source of harm (hazards) referring to the risk question or problem description Risk analysis the estimation of the risk associated with the identified hazards Risk Management the systematic application of quality management policies, procedures, and practices to the tasks of assessing, controlling, communicating and reviewing risk

21 Challenges : Adequate Risk Identification and Assessment First priority risk is patient risk! All other risks have to subordinate under this consideration Technically spoken : Quality risks are dependent from specs Specs must thus be meaningful and SMART Specific (for the product and its related manufacturing process) Measure ( PAT ) Achievable ( design space) Relevant (quality by design) Timely (eg in-process PAT ) Specs are taken for assessment of Product quality Process performance and robustness Validation and Qualification Risk assessment requires qualified knowledge of Patient need Product target profile Pharmaceutical interactions and product performance Critical process parameters Regulatory requirements Any risk based approach applied to QbD thus requires a multidisciplinary understanding of how to achieves this : Process understanding

22 Challenges : Adequate Risk Identification and Assessment

23 ICH Q10 : Pharmaceutical Quality System Pharmaceutical Quality System - Q10

24 ICH Q8, 9, 10, 11 working together The Utility of ICH Q8, 9, 10&11 The implementation of Q8, 9, 10 &11 is valuable for all drug products, pharmaceutical development approaches and regulatory systems - New/innovator, marketed/legacy and generics - Simple and complex dosage forms - Small molecule and biotech - Traditional development and QbD - Within and outside ICH regions Good scientific development (Q8, Q11) in combination with QRM (Q9) and PQS (Q10) will improve drug quality and efficiency of pharmaceutical manufacturing - Quality is important for all drug products throughout product lifecycle (new, legacy and generics)

25 ICH Q8, 9, 10, 11 working together Benefit from these concepts Reduce the burden of validation (Continuous Process Verification*) Reduce analytical testing at the end Speed up release decision making process Predict product s quality from the very beginning Assess changes in product quality once a change in the process has taken place All these result in Efficiency gain Cost reduction No OOS results Less batch rejected 100% quality (not based on sample only) No rework No delay in manufacture and release Improved yield Reduced cycle time Less stock required. All this means : Better quality at lower costs!

26 ICH Q8, 9, 10, 11 working together Formulation Activities: QTPP Definition Pre-Formulation Studies Formulation Screening Optimization & Selection Process Development Activities: Process Screening Lab Scale Development Scale-Up Studies Manufacturing Activities: Commercial Scale Manufacturing Batch Release Continual Verification & Improvement Q8, Q11 Pharmaceutical Development Q9 Quality Risk Management Q10 Pharmaceutical Quality Systems

27 ICH Q8, 9, 10, 11 working together Formulation Development Activities

28 ICH Q8, 9, 10, 11 working together Process Development Activities

29 ICH Q8, 9, 10, 11 working together Technology Transfer

30 ICH Q8, 9, 10, 11 working together Commercial Manufacturing Activities

31 Life Cycle Approach Monitor the product (and its quality & manufacturing process) throughout its life-cycle from cradle to grave i.e.: From early development over API development Formulation & process development Clinical manufacture Scale-up Submission SUPACs* Changes of Site Equipment Specifications Raw materials Formulation Scale Until discontinuation of production * Scale-up and post approval changes Some guidance on how to handle the lifecycle for drugs is given in ISPE s Product Quality Lifecycle Initiatives (PQLI)

32 Life Cycle Approach : Product Quality Management Regulatory quality expectations for the pharmaceutical product: Developed with the patient in mind Manufactured with appropriate apparatus and robust processes with adequate control Manufactured under GMP and distributed under GDP How can this be achieved? Quality itself is not the issue, but pharmaceutical development and manufacturing has to be improved Improve how: we need to get it right first time and then continue to improve The problem is (uncontrolled) variability Variability is reduced by obtaining increased process and product understanding leading to first time right performance Paradigm change: from regulatory compliance to enhanced product and process understanding Managing regulatory expectations throughout the product lifecycle : Tom Sam

33 Life Cycle Approach Quality By Design The Lifecycle Approach The overall goal of QbD is to maintain a state of control for pharmaceutical products and their manufacturing processes over their life cycles. (Cooney B, Jones SD, and Levine H, Quality By Design for Monoclonal Antibodies, Part 1, BioProcess International, 14(6): 28-35, 2016.) 2004, 2007, 2009 ICH Q8 Pharmaceutical Development 2005 ICH Q9 Quality Risk Management 2008 ICH Q10 Pharmaceutical Quality System 2012 ICH Q11 Development and Manufacture of Drug Substances 2017 ICH Q12 Pharmaceutical Product Lifecycle Management ICH Harmonised Tripartite Guideline Q8- Pharmaceutical Development, 2009 PAT - A Framework for Innovative Pharmaceutical Manufacturing and Quality Assurance, 2004 QbD- GMP for the 21 st century

34 Life Cycle Approach 개발과정흐름은인체임상시험을통한임상개발단계에따라반복되어진다. 임상데이터를피드백하여제품개발과궁극적으로는제품설계공간을정의 임상제조로부터얻어진지식은후속라운드의공정개발에도움을줄수있다. 품질위험은개발공정의발전에따라상업적허가및제조에적용가능할때까지감소 지속적인개발공정모니터링및검증은시간경과에따라공정개선을가능하게한다. Product Learning Process Learning Product Development Discovery and Research Preclinical Research Target Product Profile Quality Target Product Profile Critical Quality Attributes Process & Analytical Development Parameter Impact Assessments Process Development Analytical Development Process Characterization Parameter Classification Process & Analytical Control Strategy Product Specification Clinical Manufacturing Clinical Trials Process & Assay Implementation Process Transfer Assay Transfer Master Batch Records Commissioning Equipment Validation Overall Control Strategy Process Qualification Stage 1 Process Design Stage 2 Process Performance Qualification Commercial Manufacturing & Life Cycle Management Instrument Calibration and Preventative Maintenance Batch Record Maintenance Alarm System Management Deviations Management Process Monitoring Process Requalification Continuous Improvement Commercial Product Continuous Improvement Stage 3 Continued Process Verification

35 Life Cycle Approach 제품개발 : 기본적공정성능목표로서제품의중요품질특성 (CQA) 에집중 합리적개발을위한구조 / 기능의관계및예비제형연구 발전된고속대량분석방법사용 공정 & 분석법개발 : 잘기록된위험평가 (QRM!!) 사용 적격한 Small Scale 모델사용 실험설계 (DOE) 및통계적데이터분석 중요한공정변수 (CPPs) 확인 공정이해를관리전략구축에사용 공정 & 분석시험실행 : 기술이전및 PC/PV 공정특이적관리, 제조 / 품질시스템통합 >> 종합적관리전략수립 임상 / 상업제조 : 지속적감시및공정검증 성능경향및개선기회확인

36 Life Cycle Approach QbD is a process defined by documentation requirement Primary QbD Documents Risk Assessment Report(s) Performed throughout QbD Process Particularly important to process development Quality Target Product Profile (QTPP) Defines the desired product characteristics and sets development goals. Control Strategy Summary Defines the process, its inputs and outputs,and how it is controlled. PPQ Report(s) Formal verification that the process Control Strategy has been defined appropriately and repeatedly produces the desired results. Continued Process Verification (CPV) Reports Assuring that during routine commercial production, the process remains in a state of control (FDA); involvesfeedback loops into the QbD process where intentional process changes and/or observed variability is assessed for risk, characterized, re-validated, etc.

37 Change during the Product Lifecycle Investigational Product Pharmaceutical Development Change is an inherent part of the development process and its documention is good scientific practice Changes could be incorporated in and tracked through the development plan The formality of application of the change management process should be consistent with the stage of pharmaceutical development: clin phase III > clin phase II > clin phase I Investigational products are subject to formal change management - adapt EU Product Specification File and Investigational Medicinal Product Dossier (IMPD) Changes can potentially impact on INDs/CTAs notification of competent authorities (if applicable) Technology Transfer Technology Transfer may take place at different points in the lifecycle e.g. - prior to phase III clinical manufacture, - post-approval to additional or alternative manufacturing site, and - to contract manufacturingpartners. Technology Transfer forms the basis for commercial manufacturing and supply and strongly benefits from QbD practice. GMP standards for Technology Transfer when close to or equal to commercial manufacture requiers full application of the change management system Changes could be part of the Technology Transfer plan Need to consider impact on emerging or approved regulatory filings since Technology Transfer may trigger the need for many changes in the registration file. Impact on existing facilities (if not new build or dedicated) Commercial Manufacturing Full GMP standards apply as is full application of change management Extent of markets supplied and different GMP requirements need to be considered during change management to evaluate the impact on regulatory filings. Impact of change on upstream activities e.g. component and raw material supplies Impact of change on on downstream activities e.g. subsequent manufacturing packaging and distribution steps Impact on Control Strategy Managing regulatory expectations throughout the product lifecycle : Tom Sam

38 Change during the Product Lifecycle Expression System Development Clone Evaluation Media Flasks Development Process Optimization Scale Up Identify target, isolate gene, and develop expression system Screen and select the highest producing and most stable clone Develop optimal growth and production media for each cell line Optimize conditions for biomanufacturing process in a scaledown version Scale up process for use in large bioreactors for production of therapeutic Knowing gene for the protein you want is great, but what cell line to use? What clone form that cell line is best. 100s of possibilities! 60 or more nutritional components in culture media, how many combinations? When to feed them? Inducers, promoters? What temperature? What oxygen level? CO 2? ph any shifts? When to harvest? A strategy of multi-factorial design is the natural way to attack this type of problem, but is difficult to execute in cell culture because the parameters interact strongly-requiring a lot of experiments. This means models!

39 Change during the Product Lifecycle Clinical vs Commercial Manufacturing Clinical Production Typically there is the need to make only a few batches per campaign Use of most advanced and expensive chromatography resins is costly on a per batch basis Disposable manufacturing for Phases I and II can be very attractive

40 Change during the Product Lifecycle Scale-up & Down in Manufacturing Process Development Potential Changes to process during development - Modify the cell line (to improve stability of productivity) - Modify the culture medium (to improve productivity - Modify the process steps (to reduce HCP or HCD ) - Scale-up of process (to reduce unit cost) - Change of facility (for process scale-up or site change) - Change of technology (MU to SU ) Each modification must be evaluated for regulatory impact and comparability demonstrated by means of thorough analytical testing

41 Change during the Product Lifecycle Utilization of QbD ensures a robust Technology Transfer Form a diverse/skilled and collaborative development team Review the process flow diagram for key inputs/outputs that could impact quality (QRM) Uni/multi variant experiments should have been completed to study relationships and gain information on potential sources of variability. (need to know where quality could be impacted) Make sure you understand your measurement capability (i.e. repeatability, precision) Critical Process Parameters (CPPs), Critical Quality Attributes (CQAs) and other important parameters are identified Design space should be defined and understood consisting of a set of input ranges (CPPs) that provide high probability that CQAs will meet specification. A control strategy needs to be in place to assure focus on critical points Tech Transfer risk assessment Richard Dennett, Modern Technology Transfer Strategies for Biopharmaceutical Companies, BioProcess Int. 2015

42 Change during the Product Lifecycle Change management often is a major hurdle to achieve continual improvements during the latter parts of the product lifecycle: - non-harmonized between ICH-regions and beyond! - assessment of impact of change varies both in risk and in time - no agreement on use of comparability protocol - no agreement how to define regulatory change in registration file - differences in task division between assessors and inspectors Managing regulatory expectations throughout the product lifecycle : Tom Sam

43 Life Cycle Approach FDA 3 Stage Process Validation Stage Intent Typical Activities Process Design Process Qualification Continued Process Verification To define the commercial process on knowledge gained through development and scale up activities The outcome is the design of a process suitable for routine manufacture that will consistently deliver product that meets its critical quality attributes To confirm the process design as capable of reproducible commercial manufacturing To provide ongoing assurance that the process remains in a state of control during routine production through quality procedures and continuous improvement initiatives. A combination of product and process design () Product development activities Experiments to determine process parameters, variability and necessary controls Risk assessments Other activities required to define the commercial process Design of Experiment testing Facility design Equipment & utilities qualification Process Performance qualification (PPQ)* Strong emphasis on the use of statistical analysis of process data to understand process consistency and performance Product review SOP data collection from every batch Data trending and statistical analysis Equipment and facility maintenance Calibration Management review and production staff feedback Improvement initiatives through process experience

44 Life Cycle Approach Keeping a process in its validated state requires a Lifecycle Approach Regulatory agencies are emphasizing the need for a more thorough understanding of product and process prior to validation. Validation Information At-Scale Process Qualification Runs Scale-Down Process Parameter Studies Scale-Down Process Performance Studies Traditional Information 3 consecutive runs at manufacturing scale in the commercial facility KPIs and process-related impurity clearance All lots meet specifications Characterization of proven acceptable ranges for manufacturing parameters Generally univariate studies. Not all CQAs studied, but specified attributes assured Description of scale-down models Process-related impurity clearance Virus removal and refiltration Pool hold times Resin lifetime Limit of in vitro cell age Membrane carry-over Filter leachables and extractable Enhanced Approach Greater transparency of experimental design & data analysis Impact of parameter ranges on all relevant CQAs studied in multivariate studies Performance of Linkage Studies ensures product quality within the claimed ranges Statistical evaluation of scale-down models Managing regulatory expectations throughout the product lifecycle : Tom Sam

45 Life Cycle Approach The FDA/EMA QbD Pilot Program Announced on 2011 in an attempt to establish greater collaboration Goals 1. Helping to ensuring consistent implementation of ICH guidelines for manufacturing quality in the application evaluation process 2. Increasing awareness of concepts by staff that review marketing applications and inspect manufacturing facilities. 3. Defining the reviewer and inspector interaction for QbD applications 4... way for EMA and FDAassessors/ reviewers to share full knowledge. 5. Developing and harmonizing regulatory decisions.. The QbD Work Flow The Pilot focused on CMC filing content for a QbD Submission DEVELOPMENT Development QbD Control Strategy Validation CMC Filing Approved! CPV Process Changes Design of Experiment (DOE), Process Characterization Design Space definition, Scale-down Models Risk Assessment, Failure mode identification, in-process tests and controls Process Performance Qualification (PPQ), Assay Validation, Design Space definition, Scale-down Model Qualification Development History, Design Space Specification, Product Characterization and Comparability (Continued Process Verification), Process & Assay Monitoring, Trending, Variability Detection and Identification Supporting Data, Risk Assessments, Product Comparability Leveraging Process Understanding for a QbD Filing. Can a QbD Filing deliver post-launch regulatory flexibility? DEVELOPMENT IMPLEMENTATION MANUFACTURING Development QbD Control Strategy Process Validation CPV Conventional Filing CMC Filing Approved! Connecting Pharmaceutical Knowledge QbD Filing Work Flow Additional Information Process Changes Leveraging Process Understanding for a QbD Filing. Concerted collaborative effort by key industry players Development QbD Control Strategy Process Validation CPV Conventional Filing CMC Filing Approved! QbD Filing Process Changes Regulatory Flexibility ispe.org AmAb, A Case Study was published by the CMC-Biotech Working Group. The companies involved were Abbott Laboratories, Amgen, Genentech, GlaxoSmithKline, Eli Lilly and Company, MedImmune, and Pfizer Regulatory Flexibility 21

46 Life Cycle Approach Year Activity Non-Clinic Phase I Phase II Phase III BLA IND Phase I Phase II Phase III Commercial Expression System Defined Primary Definition of Process Refinement of process operational control parameters Finalization of process control parameters Validated manufacturing process Process Scalability Qualified Analytical Methods Viral safety dossiers No Process Validation Development of scale down process models Process outer limit definition Fixed and defined process and products Pivotal process validation and characterization studies Well-characterized product

47 Life Cycle Approach Process Development Analytical Methods & Specification Characterization & Comparability QbD IND Phase I Phase II Phase III BLA/Post Approval Expression System Defined Process Scalability Primary Definition of Process No Process Validation Validated Analytical Methods assays for safety specifications to be validated (Viral safety) based on prior product knowledge and limited manufacturing experience Initial Between tox material and Phase I CTM Quality attributes determined; Initial criticality assessment based on prior product knowledge and limited experience with molecule Refinement of process parameters Development of scale down process models outer limit definition Re-evaluate specifications and analytical methods; Understanding degradation Pathways As needed to support process and analytical method changes Process assessment identify parameters, which impact Critical Quality Attributes (CQAs) Finalization of process parameters Fixed and defined process and products Pivotal PC and PV Re-evaluate specifications and analytical methods Product variants, impact to safety and efficacy (potency) Strongly recommended not to change process and assay during phase III Multivariate: DOE studies; risk assessment to determine final control strategy Validated manufacturing Well-characterized product Fully validated analytical methods with justification of acceptance criteria for drug substance and drug product Complete assessment of material used in non-clinical and pivotal clinical studies to support safety and efficacy of commercial material Continuous process improvement based on extended manufacturing experience; verification of small scale models CQA Defined wide limits CQA update Final limit No change

48 Change during the Product Lifecycle Control Strategy is the quintessential element of QbD Control over the Control Strategy must be managed during the entire product lifecycle Despite ICH Q8 Q11, in daily practice QbD did not deliver regulatory flexibility and continual product and process improvement. Managing regulatory expectations throughout the product lifecycle : Tom Sam

49 Change during the Product Lifecycle Regarding the Regulatory Dossier the ICH-Q12 IWG will o Explore the development of a harmonised approach to regulatory commitments for inclusion in the guideline. Such approaches could enable post approval changes that facilitate continual improvement and encourage the adoption of innovative technologies. o Delineate the appropriate level of detail and information necessary for regulatory assessment and inspection in the dossier, in order to create a more enabling post approval change management system. Regarding Pharmaceutical Quality System aspects the ICH- Q12 IWG will o Establish criteria for a harmonised risk-based change management system based on product, process and/or clinical knowledge that effectively evaluates the impact of change on quality, and, as applicable to safety and efficacy. o Clarify expectations and reinforce the need to maintain a knowledge management system that ensures continuity of product and process information over the product lifecycle. Regarding Post-Approval Change Management Plans and Protocols the ICH-Q12 IWG will o Introduce a) the concept of a post-approval management plan that can be used to proactively identify post-approval changes and b) the mechanism to submit and assess these changes by regulatory authorities (Assessors and Inspectors) o Establish criteria for post-approval change management protocols that can be adopted by the ICH regions (enabling a harmonised proactive approach for lifecycle management) o Encourage enhanced product development and control strategy approaches ( (QbD)) providing opportunities for scientific and risk based foundations for post-approval change management plans. Managing regulatory expectations throughout the product lifecycle : Tom Sam

50 Change during the Product Lifecycle Dealing with changes according to ICH Q12 1. Established andnon-established conditions? 2. Pre-approval change management plan Product Development and Lifecycle Strategy (PDLS) - product development - control strategy - proposed established conditions - proposed regulatory regulatory filing for future changes (optional?) Managing regulatory expectations throughout the product lifecycle : Tom Sam

51 Change during the Product Lifecycle In the CMC area is the way forward, since it is based on science and risk, rather then case by case and it enables continual improvement. ICH QbD standardization process to bring even better quality medicines to patients - Q12 는유연성과승인후변경을강화하는방향을제시 지식과위험관리의기대 변경된다면보고해야할대상의정의방법 승인후관리계획또는절차 Managing regulatory expectations throughout the product lifecycle : Tom Sam

52 QbD Application in Japan (PMDA) QbD 적용이점차로증가하고있으며현재는대부분의신청이 QbD 접근방식을적용 - QbD Filing : 설계공간을정의하고이를주장하여관리전략에포함시키는것 - QbD approach : QbD 접근방식은적용하지만설계공간을주장하지는않음 변화 - ICH Q-trio 도입초기 : 공정, 규제유연성을위한설계공간을설정하기위하여노력 현재 : 신청자들이설계공간개발은하더라도설계공간을주장하지는않음이유는? 가장큰가능성으로 설계공간의입증 (verification) 설계공간의유효한설명과입증을위하여들어가는노력에비하면적은유연성밖에얻을수없음

53 FDA Perspective on PACM for PAT and RTRT (Christine MV Moore, 01/26/2016) FDA 21st Century Initiative (2004) 의목적 : 지속적개선을가능케하는규제유연성확보 QbD의현재상황 - 과학과위험기반의 QbD 접근방식은많은회사들이개발에적용하고있음. - QbD 접근은발전된제조관리보다는강화된제품과공정에대한이해에더초점을맞추고있음 - 강화된지식이 규제유연성 ( 예, design space, RTRT, protocols) 을정당화하는데자주사용되고있지는않음 실제지속적개선 에도달하지는못함 지속적개선의장애물 - 변경에대한규제사항의투명성부족 - 변경신고에대한지역적차이 - 여러규제기관의변경승인시간적차이 - 변경승인비용 PAT, RTRT 의현상황 - PAT 가제조운전에서규제적관리도구로는거의사용되고있지않음 연속식제조에관심이증가하고있음 -PAT 를공정모니터링과추세분석에자주사용 예, multivariate statistical process control 신청에포함된경우는적으며채택되기어려움 -RTRT 는매우제한적으로만사용되고있음 ICH Q12 의범위 ICH Q12: 의약품의전주기관리를위한기술및규제적고려 Step 2 (Nov. 2017) -제품군 : 신규, 기존의약품, 화학, 생물공학생물학의약품지역별로제네릭은선택가능 Q12 의주요사항 -PQS 측면위험기반의변경관리시스템전주기적지식관리기대 - 규제문서 규제준수사항 의통일된접근모색신청서류세부사항의적절한수준명시 - 승인후변경관리계획및절차개념및정의에대한절차확립및도입 QbD 를승인후변경관리의기반으로장려

54 의변화

55 의변화 Shift of focus as PAT/QbD/RTRT is getting 'older' Problems in the Past Technical Limitations and executing Feasibility Trials Validation Procedures and Acceptance Criteria How to file a QbD application (level of detail) Current Challenges Skill set and the question of ownership at the site Handling deviations and changes with new technologies Robust Automation Solution Past Support for Design Space submission Holistic QbD Control Strategy Roll out for a paradigm change Fundamental Replacement of QC end product testing Idealistic Vision (Dreams) and objectives of the Present Focus on Process Development Opportunistic approach for certain tests based on business case Process Validation and CPV Enabler for CMC innovation (continuous manufacturing) Realistic 55

56 QbD 의한계 완전한 QbD 개발방식적용의장점과한계 장점한계 제품과공정에대한보다나은이해 공정성능및견고성증대 ( 배치성공율증가 ) 제품 / 공정개발과관련된보다나은위험평가 적어지고더의미있는공정관리 ( 수 ) 빠른승인 설계공간내에서의규제유연성 개발초기단계에서추가적인비용및자원 부적절한 QbD 원칙적용으로인한서류제출 ( 승인 ) 의연기 Scale-up 효과로인한설계공간한계의유효성인정실패 ( 대부분설계공간은 small scale 에서만들어짐 ) 변화에대한저항, 불투명성및경제적이익평가에대한어려움등으로인한회사의문화 제품전주기에서전체적원가감소

57 전망 QbD 는의약품의구조와기능사이의관계에대한지식을활용하여안전성, 효능, 제품성능보장에중요한제품품질특성을정의한다. 의도한특성의제품을일관성있게생산하는상업생산공정및공정관리는과학적이며위험기반의접근을통해정의되며, 로트검사와안정성기준, 지속적인제품및공정모니터링프로그램을포함한특성시험전략을통해확인된다. 이러한요소들이모여제품에적합한종합적인관리전략을구성한다. 제품및공정에대한깊이있는이해는제품전주기에걸쳐일탈평가및변경관리를강화 QbD 신청시설계공간에중요공정변수 (CPP) 와비중요공정변수 (non-cpp) 를모두포함하여정의할필요가있다. 설계공간을승인한다는것은제약사가사전허가없이정의된변경을할수있음을규제당국이동의하는것이다. 향후중요도가떨어지는변수는설계공간에서완전히제외될수도있고, 이러한변수의범위변경은전적으로품질시스템내에서관리할수있다면좋을것이다. 이는유연성을증대시키고 QbD 접근법의핵심적인목표를보다충실하게달성하는데도움 현재 ICH Q12 실무그룹과 확립된조건 (Established Condition) 에대한 FDA 가이드라인초안상의전주기관리는규제와관련한변수 ( 및다른세부사항 ) 가무엇이며이러한관련요소내에서의변경을어떻게관리할것인지를상술하여국제적으로수용가능한위험기반접근법을통해설계공간을대체하거나강화할가능성이있다.

58 How do we do QbD? QbD Tools QbD Approach showing Overarching Principles and some Enabling Tools (ISPE PQLI Guide)

59 How do we do QbD? Success Factors : Protein Analytical Chemistry

60 How do we do QbD? Success Factors : HTS in USP and DSP Development

61 How do we do QbD? Statistical tools Product Design & Development: Initial Scoping Product Characterization Product Optimization Design of Experiments (DOE) Process Design & Development: Initial Scoping Process Characterization Process Optimization Process Robustness Model Building And Evaluation Manufacturing Development and Continuous Improvement: Develop Control Systems Scale-up Prediction Tracking and trending Statistical Process Control

62 Manufacturer s Perspective on Innovations in Biomanufacturing : Titer Improvement

63 Manufacturer s Perspective on Innovations in Biomanufacturing : Titer Improvement

64 Manufacturer s Perspective on Innovations in Biomanufacturing : Single Use Technology 64

65 Manufacturer s Perspective on Innovations in Biomanufacturing Industry Growth New Technology Smaller Markets Cost Pressures 15% annual avg. Better process yields Fewer blockbusters Health care reform >15 approved mabs Potent compounds Personalized medicine Pricing controls >150 mabs in clinic Drug delivery Genetic screening Biosimilar drugs expanding pipelines Capacity demands Smaller batch sizes Smaller R&D budgets. Need for more efficient PD & Mfg. fast, flexible and inexpensive manufacturing capacity

66 Innovation in Biomanufacturing : Capacity Needs Change Decentralized Production Personalized Medicine Market Forces Economies of Scale Increased Control / Consistency Frequency (Number of Products Produced) Future? Multi-modal? Current Capacity Distribution Limit of SUT ,000 40,000 Nominal Bioreactor Capacity Requirement for Product Manufacture Better productivity and lower cost of goods More rapid process development Greater control of process output Better control of product physical form Enable newer classes of molecules to be manufactured BioPhorum Operations Group Ltd

67 이해 : 바이오의약품적용및사례

68 바이오의약품에의적용 : 가이드라인 ICH 가이드라인의바이오의약품개발및제조에적용

69 바이오의약품에의적용 : mab Platform Process Cell Banks Upstream Process Downstream Process Drug Substance Drug Product Thaw Working cell bank Seed Culture Expansion Production Bioreactor Harvest And Clarify Protein A Affinity chromatography Low ph incubation Cation Exchange chromatography Anion Exchange chromatography Virus Retentive Filtration Formulation and UF/DF Monoclonal Antibody (API) Fill & Finish What are unique issues to CMC perspectives 1 Cell Bank 2 Bioburden 3 Process Control 4 Resin Reuse 5 Viral Clearance 6 Cell Removal 7 Host Cell DNA and Protein

70 Biomanufacturing process : Regulatory Concerns Living Production System Rather than Synthetic Importance of Cell Bank Variability of Living Organisms Complex Physiology Balancing Growth vs Production Spent Culture Medium is Full of Enzymatic Activity Impurity Profile Adventitious Agents, a Host for Propagation Endogenous Adventitious Both Theoretical and Demonstrated Concerns Often Complex Molecules Post-translational modification may / may not be important to: Biological activity --- increase or decrease Purity Profile Serum Half Life Immunogenic Nature of the Molecule(s) Stability Subsequent Chemical Modification Family of molecules rather than single entity Differential Toxicity or Clinically Relevant Activity Differences

71 Overall CMC Development Program The overall goal of CMC development program is to develop a reliable, robust, and reproducible process to manufacture a product that is safe to administer to humans. 1. Analytical Method Development 2. Upstream Process Development 1 Expression Vectors and Cell Line 2 Cell Banks 3 Cell Culture Process 3. Downstream Process Development 4. Formulation Development 5. Scale-up and Bulk Drug Substance Manufacturing 1 Manufacture of Clinical Trial Material 2 Commercial Manufacturing 6. Drug Product Manufacturing (Fill/Finish)

72 Biomanufacturing GMP (H/W & S/W) Platform Illustrative guide to manufacturing activities within the scope of Annex 2. Type and source of material 2. Virus or bacteria /fermentation / cell culture 3. Biotechnology - fermentation/ cell culture 6. Human sources 7. Human and / or animal sources Example prod.uct Viral or bacterial vaccines; enzym es, proteins Recombinant. products, MAb, allergens, vac cines Gene Therapy viral and non-viral v ectors, plasmids) Urine derived enzymes, hormones Gene therapy: genetically modifi ed cells Somatic cell therapy Tissue engineered products Increasing GMP requirements Application of this guide to manufacturing steps shown in grey Establishment & maintenance of MCB, WCB, MVS, WVS Establishment & maintenance of MCB 2 and WCB, MSL, WSL Collection offluid Donation, procurement and testing of starting tissue / cells 7 Donation, procurement and testing of starting tissue / cells Donation, procurement and testing of starting tissue / cells 7 Cell culture and/or fermentation Cell culture and / or fermentation Mixing, and/or initial processing Manufacture vector and cell purification and processing, Establish MCB, WCB or cell stock Inactivation when applicable, isolation and purification Isolation, purification, modification Isolation and purification Ex-vivo genetic modification of cells, Establish MCB, WCBor cell stock Cell isolation, culture purification, combination with non-cellular components Initial processing, Cell isolation, culture, isolation purification, and purification, combination with establish MCB, non-cellular WCB, primary cell components stock Formulation, filling Formulation, filling Formulation, filling Formulation, filling Formulation, combination, fill formulation, combination, fill

73 바이오의약품에의적용 바이오의약품의 QbD 접근과제 많은유전자재조합제품들은유기합성에의한 API 와같은단일성분보다는 heterogeneous하여 product variation이존재 제품의특성분석은의미있게발전했지만최신의바이오제품의분석과학은합성 API 특성분석처럼완전하거나유용하지못하다. 미생물과바이러스제어 ( 예, HCP나마이코플라즈마, 외래성바이러스같은것들 ) 은바이오의약품의생산측면에있어서중요한요소이다. 필수적으로모든재조합제품들은주사제품이어서 1) 제품생산동안무균공정을요구하고 2) 용기밀폐시스템을강조한다. 또한냉장관리는유통상에서제품의품질을유지하는데있어서매우중요상온에서의재조합제품의불안정성이야기될수있기때문 단백질의고차구조가공정과보관기간중에유지되어야하고복잡한 bioassay를통해평가되어야한다

74 바이오의약품에의적용 생명공학제품에 QbD 적용은사소한것이아니며제시되는어려움중일부로는다음이포함된다 : (i) 생명공학원료의약품의구조적복잡성 (ii) 원료의약품과제조부형제및전달시스템간의상호작용이해부족 (iii) 생명공학제품에대한임상적으로타당한규격지정 (iv) 다양한규모에서생명공학제품에대한다차원적설계공간구축 생명공학제품의분자복잡성및이질성은 효능과안전성에영향을미치는제품특성및제품품질에영향을미치는공정변수의확인에 어려움을준다.. (i) 교반탱크생물반응기에서물질세포배양은특별한관심분야임 생물학적물질생성을위한살아있는시스템활용의높은비용과복잡성때문에 - 최종의약품을향해아래로이동할수있는회복불가능한손상가능성 - QbD 접근을확립할수있는공정이해강화에대한막대한수요가있다. (ii) 액체제형 - 하위정제공정말단에서액체제형으로조제되는생물제제 - 다양한완충액시스템, ph, 이온강도, 안정제및보존제에서의반감기중안정성이해는중요한품질특성이다. - there is a growing trend towards more complex delivery systems - 더욱복잡한전달시스템에대한경향성이증가하고있음 바이알 > 사전충전주사기 > 자동주입기 (iii) 규격의정당성입증은성능, 안정성, 안전성, 효능등과의연결을포함해야한다. 그러므로 QbD 는임상적으로타당하거나의미있는규격을설정하는데도움이될수있다. (iv) 규모확대연관성은실험실규모에서실험을실시할때도중요하다. 큰규모에서의검증실험은다양한규모에서의설계공간과의연관성에이입증되어야한다.

75 바이오의약품의적용현황 생명공학제품에내포된비균질성과고도의물리화학적복잡성때문에대부분의저분자의약품에비해생명공학제품에 QbD 를도입하는것이더어렵다. 단일클론항체 (mab) 는공통구조를가지고있어견고한제조공정 (Platform) 개발이가능케됨. 최초의 mab 제품이 FDA 의상업승인을받은지 25 년이지났으며, 지금까지 mab 의특성적구조 / 기능관계를이해하기위해상당한투자가이루어져왔다. 이러한지식기반과한 mab 제품에서다른제품으로적용시킬수있는플랫폼제조지식이 mab 제품에서 QbD 접근법을선도하고있다. 플랫폼제조란 (ICH Q11) " 동일신청인이기타같은종류의의약품제조에사용하는것과유사한제조공정에서새로운의약품을위한생산전략을개발하는접근법이다. ( 예 : 이미상당수준의선행경험이축적되어있는사전정의된숙주세포, 세포배양, 정제공정을사용한단일클론항체생산 ) Advancements in knowledge and understanding Product Structure & Modification Structure/Function Stability/Formulation Process Scale-up Platform/Platform-like Technology Manufacturing Analytical

76 Progress of QbD Program QbD Pilot Program (OBP, FDA) 목적 임상관련특성을정의하고이를제조공정과연결 단위공정에 QbD 접근방식을고려하고자 in supplements and original application QbD 가포함된제출서류의검토 진행 6 BLAs accepted (5MAbs, 1 fusion protein) 4 Supplements (2 MAbs, 1 therapheutic protein, 1 multi product) QbD Approvals One manufacturing supplement with an expanded change protocol covering multiple product One pilot BLA approved, but DS not accepted - Issues with CQAs, scale down models and other problems One BLA approved with a design space - Not in pilot A-Mab (2009) First Full QbD Submission Perjeta (2012) A-VAX (2012) First Full QbD Approval Gazyva (2013) Tecentriq (2015)

77 Progress of QbD Program Gazyva Idelvion Tecentriq

78 New Biological vs Biosimilar Product Development Development Decision IND BLA Biologic Research Early purification studies Immuno-assay based lot release Developmental Research Protein selection Bioassay Development IND Enabling Limited structure characterization Preliminary biological characterization Limited viral clearance Limited stability Phase I, (II),II In depth characterization Assay development Validated lot release assay development Specification setting Manufacturing scale up Stability Viral clearance IV Post Marketing Lot release Stability Postmarketing surveillance Biosimilar Purchase reference product lots Analyze reference product lots Develop biosimilar construct and cell line Manufacturing process development In depth characterization assay development Preliminary analytical/ functional similarity studies Formulation studies Analytical and functional similarity studies Qualified/ validated release and stability assays Continuous characterization Specification setting Final Mf scale Stability Viral Clearance Final analytical and functional similarity studies Specification setting Stability

79 New Biological vs Biosimilar Product Development Define target Process development Characterization & Comparability Biologics Comparability : to previous clinical DS 2-step development (early and late-phase) more time to gain experience with cell line / product Biosimilar Quality : Safety, Efficacy Performance : low COGs, robustness, facility-fit Start from platform process, rational DoE Extensive product quality analytics Comparability : to originator 1-step development Most efficient capacity use Increased challenge : rarely platform process useable, tight quality targets to combine with high yield Extensive set of state-of-the-art analytical methods : phys. Chem., biol. Pre-clinics- PhI PhII - PhIII Need to know structure-function relations better than originator Pre-clinics- PhI PhIII No PhII, but comparative PhI/III studies

80 New Biological vs Biosimilar Product Development

81 New Biological vs Biosimilar Product Development QTPP is a key concept for targeted and prioritized development of biopharmaceutical, e.g. biosimilars QTPP and CQAs are applicable to both biosimilars and novel Biopharmaceutical Quality targets for biosimilars can take advantage of originator quality ranges No difference in the application of ICH Q8 QbD to biosimilars and novel biopharmaceuticals Same standards and requirements for Process development Quality risk management Design space Control strategy Product life cycle management and continual improvement Product quality of biopharmaceuticals can be targeted to biosimilarity through QbD cell line and process development. Managing DS variability is essential!

82 New Biological vs Biosimilar Product Development Gather prior knowledge Create Quality Target Product Profile (QTPP) document Link QTPP specifications to Quality attributes Rank Quality Attributes Define CQA ranges Link Process Parameters to CQAs Rank Process Parameters Define CPP ranges Design of Experiments for Process characterization Biosimilars Business idea (TPP) Market forecast Originator quality profile Patent expiration Guidelines for biosimilars Number of competitororiginator clinical performance RA QTPP RA CQAs RA CPPs DoE design Literature data Process understanding Enhanced product knowledge Original biologics Patient number Existing therapies Possible indicatations Literature data In vitro studies Preclinical studies Mechanism of action Literature data Platform knowledge Undisclosed process Zalai et al., PDA J Pharm Sci and Tech 2013,

83 New Biological vs Biosimilar Product Development Screening cell lines, pools and clones to meet quality target Target defined as comparability range Generate and use diversity Choose the right stage to target a quality attribute: Cell line USP DSP Drug Product Cell line, process and product understanding is key Charge-variants can be adjusted via USP process parameters, e.g. ph media components Glycosylation can be adjusted via USP media components

84 New Biological vs Biosimilar Product Development Cell Banks Upstream Process Downstream Process Drug Substance Drug Product Thaw Working cell bank Seed Culture Expansion Production Bioreactor Harvest And Clarify Affinity chromatography Low ph incubation Cation Exchange chromatography Anion Exchange chromatography Virus Retentive Filtration Formulation and UF/DF Drug Substance (API) Fill & Finish

85 New Biological vs Biosimilar Product Development QTPP is a key concept for targeted and prioritized development of biopharmaceutical, e.g. biosimilars QTPP and CQAs are applicable to both biosimilars and novel Biopharmaceutical Quality targets for biosimilars can take advantage of originator quality ranges No difference in the application of ICH Q8 QbD to biosimilars and novel biopharmaceuticals Same standards and requirements for Process development Quality risk management Design space Control strategy Product life cycle management and continual improvement Product quality of biopharmaceuticals can be targeted to biosimilarity through QbD cell line and process development. Managing DS variability is essential!

86 QTPP Quality Target Product Profile (QTPP) identifies the desired performance characteristics of the product related to the patient s needs. Linkage from patient to product to process is described as follows: Patient : Clinical outcome Product : CQAs (Critical Quality Attributes) Process : Material attributes and process parameters QTPP components Dosage Form Route of administration Strength Weight Pharmacokinetics Appearance Identity Assay Impurities Content uniformity Friability Dissolution Residual solvents QTPP CQA CPP DS CT QTPP : 제품품질목표의약품의안전성과유효성을 감안하여, 원하는품질을보장하기위해달성해야할의약품의 예측적품질특성요약으로 다음을포함 ; - 예정된임상적용도, 투여경로, 제형, 전달시스템 - 함량 - 용기밀폐시스템 - 치료성분의방출또는전달과약동학적특성 - 제품과관련된의약품품질기준 ( 예, 무균, 순도, 안정성, 약물방출 ) CQAs Assay (efficacy) Impurities (safety) C.U. (efficacy) Dissolution (efficacy)

87 QTPP QTPP CQA CPP DS CS 제품별 QTPP 적용 - QbD 접근방식의적용은개발목표에따라 신규 (BLA, NDA), 바이오시밀러및기존판매중바이오의약품으로나누어질수있으며이에따라적용하는기준이달라진다. - 신규의약품은기준이되는제품이없음으로원칙적인 QbD 접근방법에따라 - 바이오시밀러나기존제품은 QTPP 설정시에기준이되는물질이존재함으로이를 바탕으로출발하기에좀더용이하다고볼수있다. EBE 는바이오시밀러개발에대한단계적접근에서 QTPP 의역할강화를권장 바이오시밀러의 QTPP 는충분한수의대조의약품로트분석및기타해당정보로부터유래되어야하며 ( 해당되는경우 ) 정량적이어야한다 QTPP 는세포주및공정개발단계에정보를제공하기위하여개발초기에확립되어야한다. 궁극적으로, QTPP 는단계적인생물동등성실행을위해 목표허용기준 에연결되어야한다. 목표허용기준 과 QTPP 사이의관계에대한투명성이요구된다. 정량적이고유의미한기준을설정하는것은통계적방법에대해제안된문서에서보다상세히논의되어야할가치가있는기술적이고복잡한주제이다. 시판중제품 설계공간을위해서 QTPP 는승인된 DS 나 DP 의규격을바탕으로설정할수있다. 위험평가는이미공정변수의중요도가확립되어있고 full-scale batch 에대한많은경험을가지고있다는것이장점으로작용할수있다. 이렇게출시된의약품의설계공간을확립하고자할때도신규의약품의설계공간개발시에사용했던같은원칙이적용되며 여기에는검증된 small-scale model 과 DOE 와같은실험적접근이포함된다.

88 QTPP Table Quality target product profile for A-Mab1 (CMC working group, 2009) Product attribute Dosage form Protein content per vial Dose Concentration Mode of administration Viscosity Container Target (A-Mab) Shelf life 2 years at 2-8 Compatibility with manufacturing processes Biocompatibility Degradants and impurities Pharmacopoeial compliance Aggregate 0-5% Fucose content 2-13% Glactosylation (%G1+%G2) Host cell protein Liquid, single use 500 mg 10 mg/kg 25 mg/ml IV, diluted with isotonic saline or dextrose Acceptable for manufacturing, storage, and delivery without the use of special devices (for example, less than 10 cp at room temperature) 20R type 1 borosilicate glass vials, fluoro-resin laminated stopper Minimum 14 days at 25 and subsequent 2 years at 2-8, soluble at higher concentrations during UF/DF Acceptable toleration on infusion Below safety threshold, or qualified Meets pharmacopoeial requirements for parenteral dosage forms, colorless to slightly yellow, practically free of visible particles and meets USP criteria for sub-visible particles 10-40% ng/mg Product attribute Dosage form Dose/PFs Concentration Administration mode Viscosity Container Target Liquid, single dose 100 mg 100 mg/ml Subcutaneous, thigh or abdomen <10 cp at room temperature 20R Type 1 borosilicate glass syringe, fluoro-resin laminated plunger, staked needle 27G Shelf life NLT 2 years at 2-8 Compatibility with manufacturing process Ergonomics Biocompatibility Degradants and impurities Pharmacopoeia compliance Aggregates 0-5% Fucose content 2-13% Galactosylation (%G1+G2) Host cell protein QTPP CQA CPP DS CS QTTP for a prefilled syringe/antibody combination product for Mockestuzumab (Daniella K., 2010) Soluble at high concentration at UF/DF Easy to use by arthritic patients Acceptable tolerance on injection Below safety threshold or qualified Meets pharmacopoeia requirements for parenterals, colorless to slightly yellow, practically free of visible particles and meets USP criteria for subvisible particles 10-40% ng/mg

89 Identification and RA of Quality Attributes QTPP CQA CPP DS CT CQA 는제품수명전체에걸쳐관리 제품개발도중잠재적 CQAs (pcqas) 가확인된다 pcqas 및위험점수목록은다양한제품개발단계를통해제품지식이증가하면서수정된다. QTPP 에대한변경이이루어질경우, 평가를반드시실시하여 pcqas 에대한영향을평가해야한다. 승인을위해제출할때, 잠재적 CQAs 가 CQAs 가된다. CQAs 는반드시기술, 정당화및기록되어야한다. 허가후품질특성에대하여더많은지식이얻어질경우이들특성의투명성이변화 ( 증가또는감소 ) 할수있으며 CQAs 를갱신해야한다. CQA 에변경이있을때필요한경우설계공간및관리전략에대한영향을평가해야한다. CQA 확인과제 많은다양한위험순위전략 검출가능성은이평가의일부가아님 허용기준 검출한계근처또는이하수준 안전성, 효능, PK, 면역원성에대한기여도의적절한고려 각 QA 의중요성을실제수준또는 QA 를관리하는공정능력과는독립적으로평가 나중에관리전략개발및승인후수명관리계획중공정능력을고려해야한다.

90 QTPP CQA CPP DS CS Identification and RA of Quality Attributes Quality Target Product Profile Pertuzumab 은신청자의플랫폼단일클론항체공정에기반하여만들어진 IgG1 항체로서신청자가허가받았던여러항체의약품생산에적용된기술들이었던 IgG1 프레임, 배양세포주, 공정환경, 운전전략및정제단위공정등을활용하여생산기타관련공정개발지식과함께공정및제품플랫폼에대한경험에서나온지식과 pertuzumab 에대한이해 ( 선행지식을기반으로제품의특성분석 ) 그리고관련과학적자료들은 RRF 평가를통하여 QTPP 와 CQAs 의확인및공정특성연구의설계 Quality Attributes 품질특성의평가는다음두가지평가카테고리로구분 품질특성은제품의변형체와공정관련불순물, 조성과용량, 외인성물질및그밖의필수 CQAs, 원료물질, 유출물질들로분류 품질특성을다음과같은카테고리로구분 : product variants process-related impurities composition and strength adventitious agents other obligatory CQAs raw materials and leachables

91 Identification and RA of Quality Attributes Product-Related Substances and Impurities 제품관련성분및불순물 Desired Product 원하는제품 (1) 예상되는구조의단백질또는 (2) DNA 서열및예상되는번역후수정 (glycoform 포함 ) 및활성생물학적분자를생산하는의도된정제공정으로부터예상되는단백질 Product-Related Substances 제품관련성분활성이거나의약품의안전성과효능에대하여나쁜영향이없는제조및 / 또는저장도중형성된원하는제품의분자변형. 이들변형은원하는제품과동등한특성을가지며불순물로간주되지않는다. Product-Related Impurities 제품 - 관련불순물활성, 효능및안전성과관련하여원하는제품과동등한특성을가지지않는원하는제품의분자변형 (e.g., 전구체, 제조및 / 또는저장도중발생하는특정분해산물 ) QTPP CQA CPP DS CS Product-related Impurities/Substances 분해산물 원하는제품또는제품관련물질에서의변화로부터얻어지는분자변형이시간경과에따라발생 빛, 온도, ph, 물의작용또는부형제및 / 또는즉각적인용기 / 밀폐시스템과의반응에의한작용에의해 제조및 / 또는저장의결과로변화가발생할수있다 (e.g., 탈아미드화, 이성질화, 산화, 응집, 단백질분해 안정성연구 ( 출하 vs. 유효기간 )

92 바이오의약품에의적용 제품의복잡성 바이오제품은 - 일반적으로소량의제품을필요로함 - 가능한제품의형태가다수임 - 신약의목표다양성이큼 그결과로의약품의제조는 - 제조의주기가짧음 - 제품과공정의다양 - 작은볼륨의제품으로가는경향 Tech. Transfer 의복잡성발생 QTPP CQA CPP DS CS 바이오제품은왜다른가? 1. 제각기다른 CQAs 2. 더많은 CPPs 3. 확실하지않는원료물질 (RMs) 4. 더큰변동성 5. 매단계마다공정밸리데이션이필요 6. 긴생산시간 7. 바이오시밀러의경우는동등성의이슈가복잡함

93 바이오의약품에의적용 QTPP CQA CPP DS CS pyro-e O O pyro-e Pyro-Glu (2) D O D D O D Deamidation (3 x 2) Methionine oxidation (2 x 2) G G Glycation (2 x 2) D D High mannose, G0, G1, G1, G2 (5) Sialylation (5) G G C-term Lys (2) 2 x 6 x 4 x 4 x 5 x 5 x 2 = 9600 K K Protein modifications impact different proteins differently e.g., Methionine oxidation inhibits activity of some proteins but not others e.g., Deamidation may increase immunogenicity in one protein but not another Combine physicochemical data with functional studies: case-by-case evaluation of potential clinical impact (safety and efficacy)

94 바이오의약품에의적용 QTPP CQA CPP DS CS Non-human glycan structures in available glycoprotein expression systems.

95 바이오의약품에의적용 QTPP CQA CPP DS CS Functionality of terminal residues of N-glycans on IgG

96 바이오의약품에의적용 QTPP CQA CPP DS CS The effect of the various culture parameters on various enzymes and sugar- nucleotide precursors in the glycosylation pathway of mammalian cells. Culture parameters considered include (1) Temperature, (2) Glutamine, (3) Dissolved oxygen, (4) Glucose levels, (5) Ammonia, (6) Cell lines (wild-type or engineered), (7) Cell viability, (8) Manganese, (9) Sodium butyrate, (10) Nucleotide sugar, (11) DMSO, and (12) ph. Jyoti B. Biotechnol. Prog., 2016, Vol. 32, 1092~1102

97 바이오의약품에의적용 QTPP CQA CPP DS CS Structural heterogeneity of the glycan molecule attached at Asn297 position of the immunoglobulin molecule. Acceptable Limit for mab Glycosylation (A-Mab) S.N. Attribute Acceptable Range 1. High mannose 3 10% 2. Afucosylation 2 13% 3. Galactosylation 10 40% 4. Sialic acid 0 2%

98 Identification and RA of Quality Attributes QTPP CQA CPP DS CS Finkler C. Biologicals 44 (2016)

99 QTPP CQA CPP DS CS Identification and RA of Quality Attributes Product variants Product variants 와공정관련불순물의 Criticality 는 RRF(Risk Ranking & Filtering) 로결정 CQA 에대한허용기준확립 CQA RRF 접근은영향도와불확실성을적용 to each quality attribute. - 영향도 (Impact Scores) 는 4 가지 (bioactivity, pharmacokinetics (PK), immunogenicity, and safety) 에대한영향의심각성에따라결정. - 불확실성은지식의수준에따라결정 제품 variants 는제품특이성에기초하여평가함 to account for the unique modifications, mechanism of action, route of administration, non clinical and clinical experience, in vitro studies and other factors that influence potential risk to patients. Prior knowledge was applied as applicable, in part to assess risk for process-related impurities in products manufactured using this same platform process. Risk score for product variants and process related impurities is obtained by multiplying impact rating with uncertainty (Table 4). Perjeta CHMP assessment report Rev04.12 Page 22/129

100 Identification and RA of Quality Attributes 규제기관으로부터의권고로생물제약사들이 QAs 의중요성을평가하기위해위험등급및분류 (RRF, Risk Ranking & Filtering) 의사용을채택 (Martin-Moe et al. 2011) 두가지요인 : 영향및그영향의불확실성. 영향은변형또는불순물이환자안전성및제품효능에대하여가질수있는잠재적영향이다 ( 이들은함께 유해성 을구성할수있음 ). 불확실성은영향이 QA에올바르게지정되는신뢰성정도와연관된다. 영향및불확실성등급은두요인의상대적중요성을반영하기위하여 - 영향을불확실성보다높은수준으로하여다양한규모를가질수있다 위험점수에대한 cut-offs 형태의필터를사용하여고위험 (CQAs 로분류 ) 및저위험 ( 비 -CQAs 로분류 ) 으로특성을확인한다 중요성점수 = f ( 영향, 불확실성 ) QTPP CQA CPP DS CS 중요성점수안전성및효능에대한특성의영향을정량적측정 임상안전성및효능에대한가능한최상의대용인자를사용 영향다음을고려한안전성및효능에대한알려지거나잠재적인결과 : 생물학적활성 PK/PD 면역원성 안전성 ( 독성 ) 불확실성정보타당성 e.g. 문헌사전지식 In vitro 전임상, 임상또는조합정보 제조사의누적된경험, 해당정보, 데이터 e.g. 문헌, 사전 & 플랫폼지식, 전임상및임상배치, in vitro 연구, 구조 - 기능관계

101 Identification and RA of Quality Attributes 제품변형체와공정관련불순물 제품변형체와공정유래불순물에대한중요성 (Criticality) 은 RRF로평가하였고, CQAs에대한허용기준범위역시 RRF를통해설정 RRF를이용해 CQA 기준을설정할때에영향력에관한요소와불확실성에대한점수를각각의품질특성에대해평가하여적용 영향력에대한평가의 4 가지요소 - 생리활성, - PK/PD - 면역원성 - 안전성에대한효과의크기나강도에따라점수를부여. QTPP CQA CPP DS CS

102 Identification and RA of Quality Attributes 제품변형체와공정관련불순물 QTPP CQA CPP DS CS 불확실성에대한점수는특정품질특성에대한지식수준을기반으로이를점수화제품변형체와공정관련불순물에대한위험점수는영향력과불확실성에대한수치를곱하여얻어짐

103 Identification and RA of Quality Attributes QTPP CQA CPP DS CS 의무적 CQA 규제요구조건은구성 / 강도및외인성물질범주의특정한특성은반드시항상관리되어야한다고규정한다. 따라서이들특성은의무적 CQAs 로정의하고상세한평가대상이되지않는다. 이들특성에대하여, 적절한공정및분석관리가실시되었다. 원료물질공정중제거가없다고가정하거나일일섭취허용량 ( 그림 2) 와비교하여원료를일일섭취추정량에의한잠재적독성으로평가이러한접근은이들물질의존재와관련하여환자에대한이론적위험을평가하고표현하는수단으로여겨진다. 실제로, 이들물질은지속적으로공정에의해제거된다. 많은경우원료는신청자의플랫폼 CHO 항체공정에공통적이다. Leachables CQAs 로서특성 leachable 의확인을위한접근은특성화합물이검출될수있는지여부에달려있다. 특정 leachable 이수용가능안전수준을초과하는경우이이화합물은 CQA 로지정될수있다. Is EDI 0 < ADI? No 공정중풀시험. ( 분석민감도가제한적인경우스파이킹연구수행 ) Is EDI actual <ADI? No Yes Yes 관리전략정의 : 관리된전략은임상경험, 공정능력 / 견고성및시험옵션에서의인자를고려한다. 시험또는제거연구가필요없음. 관리전략에영향없음 더이상의연구필요없음. 관리전략에대한영향없음.

104 Identification and RA of Quality Attributes QTPP CQA CPP DS CT Risk score defined by impact and uncertainty. Finkler C. Biologicals 44 (2016)

105 Process Characterization QTPP CQA CPP DS CS pcqas 가확인되면 QbD 공정에서다음주요단계는 CPPs 와설계공간을정의하는것이다. 이작업은 CQAs 의확인및특성분석과병행하여이루어진다. CPPs와설계공간의개념은제조공정변수및제조조건에대한허용범위를정의하는제조공정개발연구에사용된다 (Jameel and Khan 2009; Martin-Moe et al. 2011). 공정특성분석및밸리데이션연구는 CPPs 및설계공간을확립하기위한최종단계이다. 공정특성분석의목적은주요운전및성능변수의확인, 핵심변수에대한허용가능한범위확립, 공정견고성제시등이다 (Li et al. 2006). CPP 와설계공간확립에있어주요단계는다음을포함 1. 연구해야하는공정변수식별을위한위험평가실시 2. 모델설계 3. 연구실시 4. 공정변수의중요도와설계공간 결정을위한결과분석

106 Process Characterization QTPP CQA CPP DS CS CPP : 중요공정변수 Critical Process Parameter (CPP): A process parameter whose 영향을주므로공정이원하는 variability has an impact on a critical quality attribute and therefore 품질을생산하도록하기위해 should be monitored or controlled to ensure the process produces the desired quality. 변수 변동이발생하면중요품질특성에 모니터링또는관리해야하는공정 Material Attributes: Raw material or component factors that impact CQAs Process: The sequence of activities, people, and systems involves in carrying out some business or achieving some desired results or products. x 1 x 2 x q 제어가능인자 ( 입력변수, Process Parameter) Input (Raw Material) Unit Operation Unit Operation Output (y 1, y 2,..) (Response, Attributes ) n 1 n 2 n q 제어불가능인자 ( 잡음변수 )

107 Process Characterization : Parameter vs Attribute QTPP CQA CPP DS CS Process Parameter (PP) = Input, x Machines, materials, measurements, processes, people, and environments. CPPs 1 CPPs 2 CMAs 1 Input Materials Unit Operation 1 CMAs 2 Output Materials Unit Operation 2 CQAs Product Attribute (A) = Output, y Physical, chemical or microbiological property or characteristic of a material (or process) 각단위공정에는투입및결과변수가포함된다. 공정변수 (parameter) : 직접관리가가능한, 이론적으로 CAQ 에영향을미칠수있는공정투입물을의미한다. 특성 (attribute) : 직접제어할수없는공정결과물은특성이된다. CQA : 해당특성이제품품질을보장하면, 이는 CQA 가된다. Attributes evaluated includes both product quality attributes (QA) process performance attributes (PPA)

108 Process Characterization QTPP CQA CPP DS CS 공정변수평가의목적은관리전략과함께공정에따른 CQAs 의변화에얼마나영향을미치는지결정하는것이다. 원료특성은재료출하결과이다. 중요한원료특성 (CMA) 은영향을미치는공정변수로서 CPPs 와함께고려해야한다. 장비규모, 장비설치, 사전프로그램레시피등고정된변수는기록되어야하지만낮거나중요하지않은것으로평가된다. 멸균공정과세척공정에대한변수와공정중간물질조제가일차공정평가에포함될수있다. 대신에이들은자체공정변수, 품질특성, 중대성평가및공정입증으로독립적인공정으로처리될수있다. 장비및기구에대한보정및표준화설정은보통공정변수로포함되지않는다. 조제레시피는고정된변수로간주될수있다 ( 낮거나중요하지않음 ); 이들변수는일반적으로상대적으로타이트한한계를가지며, 이는조제개발중정당성이입증된다. 이러한변수는변하지않으며, 공정변동성에영향을미칠수없다. 이러한규칙에대한예외는운영자가반드시생물학적활성등의변수입력을기초로분량을계산해야하는경우이며 ; 이러한변이성공정변수는공정일탈로이어질수있다. 가공이진행되지않는보관 / 저장시간및조건은제품에대한영향을보이지않는것은입증해야한다. 이들은기록되어야하며이들인자가공정변수로포함되는경우낮거나중요하지않는것으로간주된다. 보관중또는공정중환경조건 ( 실온, 습도 ) 은설정한계를가지므로공정에영향이적거나없다. 클린룸, 콜드룸및드라이룸등공정특이적환경조건은제품품질을보장하기위하여감시되기때문에공정변수로포함된다.

109 Process Characterization QTPP CQA CPP DS CS Description of the (QbD) approach applied to the drug substance manufacturing process of an Fc fusion protein. JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 101, NO. 10, OCTOBER 2012

110 Preliminary Risk Analysis This cause-and-effect analysis breaks the process into its unit operations and conveys its impact on the CQAs Critical quality attribute (risk level): Preculture & expansion Main Culture and harvest Centrifugation Unit operations Cation exchange chromatography Cause-and-effect matrix Viral filtration Anion exchange chromatography Concentration & diafiltration Vial filling Appearance (M) Low Low Medium No No Low Low Low Impurities (H) Medium High Medium High High Medium Low Low Protein content (H) Low High Medium Medium Medium Low Medium No Immunoreactivity (H) Low Medium Low Low Low Low Low No Purity (H) Low Low Low Medium Medium Medium Low No ph and ionic strength (M) Low Low No Low Low Low Medium No Amino acid content/ratio (H) Medium Low No Low Low No No No Bioburden (H) Low Low No High High Medium Medium Low In-process controls QTPP CQA CPP DS CS Fill weight check (M) No No No No No No No High Visual inspection (M, L) No No Medium No No Low Low Medium In addition to the matrix, it is important to document the justification for these decisions as part of this analysis For example, the parameters of the cation- and anion-exchange chromatography processes are expected to have a high impact on impurities because they are designed to remove impurities of different ionic charge than the desired product. unit operation to parameter

111 Process Characterization QTPP CQA CPP DS CS 생산바이오리액터의초기위험분석 제품의품질특성요소에유의미한위험이될수있는설비디자인, 관리변수, 공정조건, 출발물질을파악할목적으로, 생산바이오리액터와 N-1 시드배양단계를대상으로일차 RA 를실시하여어골도기법으로이모든변수를분석 그림 3.3 생산및 N-1 바이오리액터의 RA 분석대상변수를나타낸어골도

112 Process Characterization QTPP CQA CPP DS CS Multi-level Ishikawa diagram depicting the connection between process parameters, critical quality attributes, and the targeted quality profile. Dataset of a selected QTPP specification (glycosylation pattern) and a selected CQA (galactosylation) is shown as an example. Dashed lines represent the logical linkage between consecutive stages of process development, condensed in Risk Questions. Q T P P PRODUCT UNDERSTANDING (CQAs) PROCESS UNDERSTANDING (CPPs) Glycosylation pattern (Originator quality profile) Fucosylation GlcNac Sialylation High Mannose Galactosylation Process parameters Mechanical/ Physicochemical Physiological state at inoculation SEED CULTURE PRODUCTION BIOREACTOR Viability Redox Potential Substrate Uptake rates Process mode PRODUCTION BIOREACTOR Control parameters Metabolites Transition condition leachables (metal ions) KPIs TOXIC AGENTS P r o c e s s i n g P h y s i o l o g y Risk Question: How critical is the effect of a possible deviation from the originator s quality profile with respect to safety and efficacy? Risk Question: How critical is the effect of the process parameter or process variable on the CQA? Zalai et al., PDA J Pharm Sci and Tech 2013,

113 Process Characterization QTPP CQA CPP DS CS - 이미허가받은항체 (X-MAb, Y-MAb, Z-MAb) 제품의개발과정에서확보한선행지식을바탕으로 Upstream 공정을설계 - 이들 MAb 의공정지식을 A-Mab 에적용 : CHO 숙주세포주, 발현시스템, 세포배양공정을포함한 공정단계 공정기반 (Platform) 이동일하기때문 - 품질특성의일부만을개발의분석에서고려 : 응집체, 당화, 탈푸코오스화, 탈아미드화, HCP 실제로는모든관련제품품질특성과물품특성을대상으로평가해야함 A-Mab 업스트림플랫폼공정에관한선행지식을활용하여초기 RA 를실시했다. 생산바이오리액터가제품품질에의미있는리스크가되는유일한업스트림공정 다른공정단계 (Seed expansion 및 Harvest) 는제품품질에영향을미칠리스크가낮았다. 모든공정단계는 KPA(Key Process Attributes) 와의관계를통해공정성능과일관성에 영향을미칠리스크가높은것으로파악되었다. 제품품질특성에 영향을미칠위험 주요공정특성에 영향을미칠위험 1 Seed Culture expansion in disposable shake flasks and/or bags Low High 2 Seed Culture expansion in bioreactors Low High 3 Production bioreactor High High 4 Harvest: centrifugation and depth filtration Low High Note: 간편히하기위하여원료물질과배지조성에관한 RA 는고려하지않았으나실제로는공정성능과제품품질에관한 RA 를수행하여야한다.

114 Process Characterization QTPP CQA CPP DS CS Initial Risk Assessment 공정단계 제품품질특성에 영향을미칠리스크 주요공정특성에 영향을미칠리스크 1 Seed Culture expansion in disposable shake flasks and/or bags Low High 2 Seed Culture expansion in bioreactors Low High 3 Production bioreactor High High 4 Harvest: centrifugation and depth filtration Low High Risk Assessment Results Seed 배양단계제품축적 제품품질에영향을 미칠리스크 Seed expansion in spinner or shake flasks Negligible Low Seed expansion in wave bag bioreactor Negligible Low Seed expansion in fixed bioreactor Negligible Low Seed bioreactor do not impact product quality Established process control strategies (Platform) Not need to be included in the design space

115 PC : Initial Risk Assessment QTPP CQA CPP DS CS Once each unit operation is related to CQAs and the process parameters and attributes are documented, an initial risk assessment to determine the potential impact of each process parameter is performed Process parameters Inoculum in-vitro cell age Initial risk assessment Low Justification Separate end of production studies have justified limit of cell age. Osmolality Medium Can affect impurities and cell viability. Keep constant in scale-up. Antifoam concentration No Knowledge from previous studies have defined acceptable range to have no impact to quality. Keep constant in scale-up. Nutrient concentration Medium Must be sufficient to maintain cell viability. Keep constant in scale-up. Medium storage time and Knowledge of medium storage from previous studies. No temperature No effect when kept within pre-established limits. Medium expiration (age) No No effect when kept within pre-established limits. Volume of feed addition Medium Related to component concentration. Scale by fermentor volume. Component concentration in feed Amount of glucose Dissolved oxygen Medium Low High Yield impact and impacts cell viability. Related to volume of feed addition. Keep constant in scale-up. Glucose fed as needed to maintain cell viability. leading to different cell concentrations. Scale by fermentor volume. Must be sufficient to maintain cell viability. Impacts yield by low cell growth. Controlled by rate of aeration. Scale to large scale by pre-defined model. Temperature High Impacts cell growth and viability. Keep constant on scale up. ph High Impacts cell growth and viability. Keep constant on scale up. Agitation rate Low Speed set by previous process experience. Scale to large scale by pre-defined models. Culture duration (days) High Related to nutrient concentration for cell viability.

116 PC : Initial Risk Assessment QTPP CQA CPP DS CS 변수 Initial Cell Density Temperature, ph Dissolved Oxygen 요약 피크생존세포농도 (VCC), VCC 수준, 최종역가, 배양기간에영향을준다. 품질영향과위험 : 제품품질에영향을주지않으므로 Low Risk VCC 수준, 최종역가, 배양기간, 성장속도, 생산성, 포도당소비및젖산생산에영향또한영양소투입시점, 포도당및베이스소비량에도영향을준다. 품질영향과위험 : 온도및 ph 는 Afucosylation 과 Galactosylation 수준, charge heterogeneity, HCP 수준, aggregate 형성에영향을줄수있으므로 High Risk 넓은범위에걸쳐제품품질이나공정성능에영향을주지않는다. 제품품질과공정성능에영향이없도록하려면, 최소 DO 수준이상을유지해야한다. 품질영향과위험 : 제품품질에영향을주는경우가보이기도했으므로, 공정관리및모니터링수행능력근거하여 Medium Risk 상대적으로넓은범위에걸쳐공정성능과제품품질에영향을주지않는다. pco pco 2 가허용범위를넘어서면, 공정성능 ( 피크생존세포농도 (VCC), VCC 수준, 최종역가, 2 배양기간, 성장속도, 생산성, 포도당소비량 / 젖산생산량 ) 에영향을줄수있다. 품질영향과위험 : 제품품질에영향을주는경우가관찰되기도했기때문에 Medium Risk Mixing and gassing Feeding Strategy Culture Duration 엔지니어링특성분석결과를바탕으로, 여러공정스케일과바이오리액터구성을대상으로다양한공정조건이존재한다. 품질영향과위험 : 제품품질에영향을주는경우가관찰되기도했기때문에 Medium Risk 공급농도, 볼륨그리고첨가시기는넓은범위에있어서제품품질에영향을주지않는다. 투입전략은공정성능 ( 피크생존세포농도 (VCC), VCC 수준, 최종역가, 배양기간, 성장속도, 생산성, 포도당소비량 / 젖산생산량 ) 에영향을줄수있다. 품질영향과위험 : 제품품질에영향을주지않으므로 Low Risk 배양기간이늘어나면제품품질이영향을받을수있다.. 품질영향과위험 : 제품품질에영향을주는것으로관찰되었으므로 High Risk. 또한배양기간은세포가제거된배양액중의 HCP 와 DNA 농도에영향을준다.

117 PC : Initial Risk Assessment QTPP CQA CPP DS CS 생산바이오리액터의초기위험분석 그림 3.3 의공정파라미터를대상으로공정특성요소 (Harvest 시점의탁도와제품수율이나세포활성 ) 또는지정 CQA( 용해성응집, 탈푸코오스와, 갈락토오스와, 탈아미드화 HPC, DNA) 에미칠영향을리스크랭킹방법으로평가 녹색표시는공정성능에유의미하게영향을줄수있는파라미터를의미한다. 황색과적색표시는 CQA 에영향을줄가능성이있는파라미터를의미한다. 황색은해당파라미터의관리능력이견고하고효과적임을의미한다. 예를들어배지와투입물의양과및성분농도를엄격하게관리한다면, CQA 에미칠리스크수준은낮다. 적색은 CQA 에영향을주는해당파라미터의범위가관리능력에가깝다는의미이다.( 예, ph).

118 Process Characterization QTPP CQA CPP DS CS 공정에대한 RA 결과 ㆍ Temperature ㆍ CO2 ㆍ ph ㆍ Osmolality ㆍ Culture duration ㆍ DO ㆍ Medium concentration ㆍ Feed 1 volume (% of WV) ㆍ icc (MM/mL) 등 Impact Description and Corresponding Ranking Experimental Design Strategies Based on Severity Score Severity Scoring 리스크경감활동 DOE: 공정변수와 CQA 사이의관계를확인하기위한다변량실험 DOE-indirect: DOE 실험을하며변수를간접적으로다르게했다. 예, 세포활성을유지하는데필요한수준으로포도당을공급그에따라시점별로공급량이달랐고농도프로파일도달랐다. 연계실험 (linkage study): seed 단계 - 생산바이오리액터실험 EOPC(End of production Cell): 체외세포연령한계를정하기위한 EOPC 실험. 배지보관실험 (medium hold study): 배지와 Feed 유지시간의타당성을제시하기위한실험 불필요 (Not required): 특별한리스크경감대책을수행하지않았음을의미한다. 이들파라미터를관리하고기록했으며, 데이터를회고적으로분석하여상관성을평가했다.

119 Process Characterization QTPP CQA CPP DS CS N-1 Bioreactor Process Characterization full-factorial DOE in 2L bioreactors, ph, DO, 온도가피크 VCC, 계대별세포활성, 계대배양기준에도달할때까지의 N-1 단계배양기간에미칠영향 이실험에서확보한배양액을생산바이오리액터단계로넘겨배양 - 결과 : N-1 seed 바이오리액터의운전파라미터가운데생산바이오리액터단계에서제품품질에영향을주는것은없다고판단 또한 N-1 바이오리액터 ph와온도는공정특성요소 ( 피크 VCC, 세포활성, 배양기간 ) 에영향을주기때문에 KPP(Key process parameters) 로정했다. 그러므로설계공간정의에포함시킬필요가없다고평가된다.

120 Process Characterization QTPP CQA CPP DS CS INITIAL SCREENING STUDY 위험분석에서 High 또는 Medium 으로분류된공정변수를대상으로 DOE 방법에따라공정특성분석실시 DOE 실험으로조사한변수와범위는 Table (a resolution IV fractional factorial experimental design augmented with four center points) - 중심점조건은목표공정조건과연계 - 배양 15 일, 17 일, 19 일째에샘플을분석하여배양기간의영향을평가 - 분석 : 탈푸코오스화, 갈락토오스화 (CE-LIF 이용 ), 응집체 (asec), HCP(ELISA 이용 ), DNA(qPCR 이용 ), 산성변형체 (acex 이용 )( 탈아미드화의지표 ) 결과 : ph, CO 2, 온도, 삼투농도, 배양기간이 CQA 에가장큰영향을줌 Table 3.14 설계공간설정실험 : 변수와범위 Process Parameter Low Middle High Temperature ( C) DO (%) CO2 (mm Hg) ph (% sat) Medium concentration (X) Osmolality (mosm) Feed 1 volume (% of WV) icc (MM/mL) Culture duration (days)

121 Process Characterization QTPP CQA CPP DS CS Temperature, CO 2, ph, osmolality and culture duration : largest influence on the levels of CQAs

122 Process Characterization QTPP CQA CPP DS CS 표면반응모델 (RSM) 개발을위한추가 DOE 실험 보강 DOE 연구를통해변수사이의상호작용을파악하고, 생산용바이오리액터의완전반응표면모델 (Full Response Surface Model) 을개발 8회실험을실시하여 (full factorial 4 parameters, 8 axial points) 그에따라온도, CO 2, ph, 삼투농도, 배양기간사이의모든상호작용을추정하고, 추가실험 (fractional factorial CCD in 4 parameter with 4 center points) 을통하여반응의굴곡을위한 (main effect, two-way interaction and quadratic(2 nd order)) 영향을추정결합데이터세트결과 ( 표3.16) -CQA ( 응집체, 산성변형체, 갈락토오스화, 탈푸코오스화, HCP, DNA) 의반응표면모델을위한모든유의한변수추정치를제공 - 통계적유의성평가 (P- 값 ) - 주영향, 양방향상호작용, 이차다항에대한모든추정치정리 - 이모델은여기에포함된공정변수의범위에서 CQA 의평균수준을예측하는데적합

123 Process Characterization 설계공간규정 (DS) : 표 3.16 의반응표면모델과표 3.17 의 CQA 레벨 (Acceptance Criteria) 을적용하여생산용바이오리액터의설계공간을규정모든 CQA 가한도기준이내에있을것임을보증하는공정변수의다변량조합 Table CQA Level Lower Higher CQA Limit Limit Afucosylation (%) 2 13 Galactosylation (%) Acidic Variants (%)* Soluble Aggregates (%) 0 3 중요도평가결과에따라변형체는 CQA 로간주되지않는다. 공정일관성을확인하는차원에서모델에포함 QTPP CQA CPP DS CS DOE 실험에서발견된비선형동태와상호작용때문에단위작업의설계공간은상당히복잡 음영처리된부분은 CQA 의평균수준이허용기준또는규격범위를벗어나는곳임 DOE 실험범위안에서는산성변형체와응집체는한도기준을벗어나지않았다.

124 Process Characterization Design space :Provides high assurance all CQA QTPP CQA CPP DS CS CQA Lower Limit Higher Limit Afucosylation (%) 2 13 Galactosylation (%) Acidic Variants (%)* Soluble Aggregates (%) 0 3 두 CQA 기준을만족시키는 배양기간 (15,17,19), 온도 (34,35,36), ph(6.6,6.85,7.1) CO 2 (40,100,160) Osm(360,400,440) 범위 각패널은다른회수일자또는배양기간 패널마다 3 개삼투농도 3 개 CO 2 농도의조합에따른 9 개그림 각각의그림은온도와 ph 변화에따라기준을충족하는영역표시 음영처리된부분은 CQA 의평균수준이허용기준또는규격범위를벗어나는곳임

125 Process Characterization QTPP CQA CPP DS CS RSM 은평균값을기준으로표시하기때문에경계선의공정신뢰도는대략 50% 임. 불확실성을고려한신뢰도예측을위한 Bayesian Statistical approach 방법을사용한결과 암적색으로표시된지역은 > 99% 의신뢰도로 CQA 기준을충족한다.

126 Process Characterization QTPP CQA CPP DS CS Upstream 공정의설계공간범위는 생산용바이오리액터의공정변수가운데 CQA 에영향을주는공정변수 (WC-CPP) 를중심으로 다른 Upstream 공정단계 (Seed Expansion 배양및회수 ) 는 CQA 에영향을주지않았으므로, 설계공간에서제외 one equation for the limit of each CQA that constrains the design space 생산용바이오리액터의설계공간 ( 그림 3.8) 은아주복잡하며다차원적이고이설계공간은공정신뢰성을바탕으로하므로, 그림 3.6 의반응표면모델을반드시따르지는않는다. 설계공간의범위를명확히규정하기위하여그림 3.8 의설계공간을따르는공식을개발 - 설계공간을제한하는각각의 CQA 에대하여한개의공식 (model) 으로개발 - 실험했던범위내에서공정을운영했을때갈락토오스와탈푸코오스와의경우상한, 하한기준을이탈하는경우가있었으며 - 따라서, EOF(Edges of Failure) 가규정되었고다차원적입방체형태의지식공간내한도기준을정함 이에따라다음부등식의합에따라 ph, 온도, CO2 삼투농도, 배양기간의조합으로설계공간의범위를규정했다

127 Process Characterization QTPP CQA CPP DS CS where, ph, T, CO2, Osm, and CD refer to ph, temperature, dissolved CO2, osmolality and culture duration. For the models in inequalities 1 to 4, these process parameters were normalized according to the following Equations:

128 Process Characterization QTPP CQA CPP DS CS Example of Spreadsheet-based template Paremeters Normalized Parameters CD CO2 Osm ph T CD CO2 Osm ph T afuc Limit of CQA Equation (should be 4.6) afuc Gal GAL <13% >2% <40% >10% High limit medium limit low limit (2.82) (5.01) Low (CD, CO2, Osm, ph) (7.89) Low (CD, CO2, Osm) Low (CD, CO2) Low (CD) Low (T) Low (ph) Low(Osm) Low(CO2) Low(CD) High (T) High (ph) High(Osm) High(CO2) High(CD) T failure (5.58) ph failure (2.45) Osm failure (6.70) CO2 failure CD failure

129 Design Space Design Space (DS): QTPP CQA CPP DS CS DS : 설계공간 품질보증과의연관성이증명된공정변수와투입변수 ( 예, 물품특성요소 ) 의다차원적조합과상호작용. The multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. (ICH Q8) - Design Space 안에서의작업은변경으로 - Working within the design space is not considered as a change. 간주되지않는다. - Movement out of the design space is considered to be a change and would normally initiate a regulatory post approval 에변경신청을 change 해야 process. 한다. - DS 를벗어나는것은일반적으로규제기관 - DS 는신청하는제약업체가제안하며규제기관의평가와승인을받는다. Knowledge Space : A summary of all process knowledge obtained during product development. [33] The batch process/control parameters are NOT registered and, hence, moving them within the Design Space is NOT a change

130 Application of the Approach to the Cell Culture Process resulting in Design Space QTPP CQA CPP DS CS Figure Cause-and-effect diagram identifying the process steps and associated process parameters Production step DoE study Critical FMEA for the Production Culture Step JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 102, , 2013

131 Application of the Approach to the Cell Culture Process resulting in Design Space QTPP CQA CPP DS CS IVCD, ph, and temperature a two-level full factorial design to evaluate culture duration Multivariate regression analysis for main peak in CEX. (a)distribution of main peaks in CEX. (b)correlation between actual values and predicted values from the multivariate regression model. (c)residual analysis for the multivariate regression model. (d)significant factors affecting main peak in CEX. Normal distribution Potential CPP adj. R 2 =0.914, P value of lack of fit Residual scatter plot JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 102, , 2013

132 Application of the Approach to the Cell Culture Process resulting in Design Space QTPP CQA CPP DS CS Design Space for the Production Culture Step DS CS KS Design space in terms of contour plots CQA-AC Minimum values of main peak in CEX : 79.69% Titer : 94.02% H 2 L 2 : 87.03% maximum value of high-mannose : 7.30% which were all within the acceptable criteria. These results indicate that the production culture step in the cell culture process was robust JOURNAL OF PHARMACEUTICAL SCIENCES, VOL. 102, , 2013

133 PAR/MAR(DS) QTPP CQA CPP DS CS PAR 는공정변수에대해특성분석된범위로써다른변수들을고정시킨채이범위안에서어떤공정을수행하게되면이제품과관련된품질기준에적합한제품을생산할수있음을의미 MAR 은신청자에의해제시된품질을만족하는제품을생산할수있는변수의범위로써, 시험가능한모든공정변수들의범위를교차시켜공통적으로만족하는범위를의미 검증된허용범위 (PAR, Proven acceptable range) 와설계공간 (ICH Q8 규정 ) - 검증된허용범위들의조합이설계공간이되지는않는다. 하지만단변량실험에근거한증명된허용범위는공정에관한유용한지식을제공할수있다.

134 PAR/MAR(DS) QTPP CQA CPP DS CS Q&A : Improving the understanding of NORs, PARs, DSp and normal variability of process parameters Item Definition Result Flexibility NORs* Normal Operating Range PARs Proven Acceptable Range DSp Design Space a region around the target operating conditions that contain common operational variability (variability that can t always be controlled) defined as a characterized range of a process parameter for which operation within this range, while keeping other parameters constant, will result in producing a material meeting relevant quality criteria (ICH Q8 R2) defined by the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. NOR does not represent deliberate adaptation of the process A PAR allows deliberate change in one parameter without changing the others outside their NOR/ target Working within the approved design space is not considered as a change use of NORs alone is not intended to introduce flexibility in the conditions for manufacturing Working within the approved PAR is not considered as a change to the MA dossier A DSp can be restricted by ranges of process parameters only, input material attributes only, or a combination of process parameters and input material attributes. Presentation & justification should be presented in marketing authorisations as what is practically achievable. proposed by the applicant and are subject to regulatory assessment and approval. should be adequately justified Design space is proposed by the applicant and is subject to regulatory assessment and approval (ICH Q8 R2). * NOR is not an established ICH term 6 June 2017 EMA/CHMP/CVMP/QWP/354895/2017

135 관리전략 QTPP CQA CPP DS CS 의사결정체계에서의핵심적인질문 어떤특성이중요한가? 각특성의적절한한계는? 임상또는공정에기초해야하는가아니면둘다? 공정이품질특성을제어할수있는가? 이특성은안정한가? 어떤것이 test 되어야하는가? 특성과공정을보증하기위하여미래에어떻게관리할것인가? Finkler C. Biologicals 44 (2016)

136 관리전략 QTPP CQA CPP DS CS 전반적인관리전략은다음과같이다양한구성요소로이루어져있다. 환경관리 원료물질관리 공정관리 ( 절차, 공정변수 ) 시험관리 ( 규격, 공정중 ) 지속적공정검증 관리전략의주요요소 1. 물질특성관리 : MAs 의품질이제품품질에매우중요 2. 공정변수관리 : CPPs 에의한공정성능관리 3. 공정시험 : 공정을감시 / 조정하기위한최종제품시험대신에 CQAs 시험 4. 중간물질시험 : 제품풀 규격 & 저장시간 5. 절차관리 : QMS 및 cgmp 의일환으로 SOPs (non-cpp & 시설장비 ) 6. 출하시험에의한최종제품관리 : 사전정의된 AC 를이용한방법의정의된세트 7. 안정성모니터링 : 안정성시험에의해제품유효기간결정 8. 전주기관리 : 관리전략은최근얻어진지식, 제조성능및모든공정변경을기초로정기적으로재평가된다 (e.g. 연간제품품질평가, 승인후전주기계획, 동등성평가등 ).

137 관리전략 QTPP CQA CPP DS CS

138 CQA Acceptance Criteria QTPP CQA CPP DS CS CQA-ACs / CQA-TR 제조공정이 CQA-ACs 를만족하는제품을계속생산할수있다는것을추가적으로보장하기위해, 공정특성분석의결과를더욱보수적으로범위를제한한 CQA-TR (CQA 의목표범위 ) 설정 CQA-TR 은 CQA-AC 의범위를더욱좁혀서만들어지는데 scale-down( 소규모 ) 시스템이나통계적모델링과연관된불확실성요소들을반영한것이다.

139 Process Parameter 분류 QTPP CQA CPP DS CS 공정평균값 (Process Mean) 이란공정을설정목표 (Set point) 에맞춰수행할경우에얻어진평균 CQA 반응값을의미하고, MAR Result 란공정변수가 MAR 의경계기준에맞춰수행할때의예상되는 CQA 반응값을의미한다. Impact Ratio ( 영향비 ) 의분자값은공정변수를목표값에서 MAR 의경계값으로이동시킬때에 CQA 에미치는효과를나타낸것이다. 이것은선형회귀분석의 Estimate(β) 에서유래한것이다. 분모의경우는공정이목표조건하에서운영된다고할때 CQA 평균값과 CQA-TR 경계값과의절대차를나타낸다. 변수들을다음기준에따라구분. Impact Ratio > 0.33: high-impact 0.33 Impact Ratio 0.10: low-impact 0.10 > Impact Ratio: non-impact 0.33 과 0.10 이라는 cut-off 수치는최악의조건상황에서다양한공정변수들이동시에작동할가능성을기초로하여선정.

140 Process Parameter 분류 Process Parameter QTPP CQA CPP DS CS 공정변수의중요성평가 : 임상시료 (CT Lots) 와비교및유의성여부확인 Critical (CPP/CIPC) Yes Probable Risk to CQAs? Statistical Significance? Practical Significance? Risk Assessment/ Prior knowledge No- Do not evaluate in empirical study Yes or unknown evaluate in empirical study (DOE) Yes No No Not Critical (OPP/IPC) 임상제조의경험과연계 개발과정중데이터 (5 L to 500 L) 를임상규모의경험과비교 CQA 에대한영향은 변수의 CQA 에대한영향이통계적으로유의미한가 (P<0.05)? 그렇다면, 실험실규모의 DOE 실험결과와대규모임상롯트의 CQA data 를비교하여제조공정범위에서의 CQA 예상치가임상경험을초과할것으로평가하여. If so, then CPP. If not, then OPP. 접근방법은임상제조경험의합리적인양 ( 횟수 ) 의필요성에의존하거나제한된다. Daniela Kasulke., Boehringer Ingelheim Pharma GmbH & Co

141 관리전략 Knowledge of pcqas is used to Design & Characterize Each Unit Operation identifying CPPs & CMAs QTPP CQA CPP DS CS CQAs, CPPs and their Allowed Ranges Create an Overall Commercial Control Strategy CQAs Identify CQAs Determine the levels for each CQA at each step Input : Process Parameter Output : Product Attribute Characterize Characterize the process the process (CPPs/CMAs) Perform small scale experiments for each unit operation Monitor all relevant CQAs Define site and scale independent PP impacts CPPs CMAs Acceptance Range CQAs Acceptance Criteria Confirm a Design Space Process Validation Perform small scale DOE or worst-case studies for each unit operation Monitor all relevant CQAs Define site and scale independent PP impacts Confirms consistency of process at scale in the commercial manufacturing site Confirms site and scale dependent validation Note: Multivariate (DOE) data are expected unless otherwise justified Design Space CPPs & Non-CPP Controls + Specified CQAs CQAs Monitoring Attribute Testing Strategy

142 Life Cycle Management QTPP CQA CPP DS CS Post-approval lifecycle management (PALM) plan 은판매승인후 QbD 기반안에서제품을어떻게관리할것인지를설명하는공식적인문서이다. 규제기관은 QbD 방식으로개발한제품은공식적인전주기관리계획과지식관리프로그램을포함할것으로기대한다.. Product Knowledge CQA Management Control Strategy Management Lifecycle Management Plan Process & Product Monitoring Scale-Down & Design Space Verification Knowledge Management Program CPP/non-CPP Management Design Space Management Process Knowledge Components of the lifecycle management plan(palm)

143 Overall Process of Product Development TPP to QTPP QTPP to CQAs Unit Operations with Risk to Unit Operations Factor/Responses Marketing DS/DP Regulation Factor/Responses to Operational Ranges and DOE Design DOE Results to Scaled Estimates (Effect Size) and Design Space CQAs to Analytical Methods and Requirements (Spec Limits) Analytical Methods and CQAs to Unit Operations with Development Risk Design Space and Profilers to Optimal Recipe Scaled Estimates to Critical Process Parameters, Critical Material Attributes Critical Process and Material Parameters to Controls Design Space and Control to Method Validation and Process Validation Controls to OOS and Release Testing