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1、浅谈质量源于设计 -Quality by Design (QbD)重庆药友制药有限责任公司张彦,自我介绍,2004年 毕业于四川大学药学院，获得博士学位2005年加入重庆药友，负责公司研发工作2006年获得“全国优秀博士学位论文”2010年，注射用前列地尔干乳剂上市，第一个ANDA向美国FDA递交申请“注射用前列地尔纳米冻干乳剂”获得国家十一五重大新药创制资助作为牵头单位承担国家十二五重大新药创制专项“辅料关键技术研究”,2,什么是“质量源于设计”,3,质量源于设计（Quality by Design，QbD) 1992年由著名的美国质量专家Joseph M. Juran 提出来。 Juran
2、相信可以通过合理的计划和设计获得优秀的产品质量。许多产品质量问题都与产品最初的设计蓝图息息相关。 QbD概念已经运用到每一个行业，尤其是自动化程度高的行业。,QbD在制药行业的应用,4,QbD被美国FDA采纳，并希望这一概念运用到新药发现、开发及商业化生产中。This FDA imperative is best outlined in its report “Pharmaceutical Quality for the 21st Century: A Risk-Based Approach.”,QbD: CMC先期计划,5,2005年6月 FDA ONDQA 宣布启动一项CMC先期计划:为制
3、药企业提供如何进行CMC的展示(i) QbD 的应用原则 (ii) 产品和生产工艺的理解使FDA有能力评价那些基于QbD 理念进行开发的新药申请。在FDA重新起草制药行业质量评估系统时寻求到更多的公众资源和信息。截止2010年底, 共有21项NDAs, 18 INDs, 9 Suppls,QbD: 仿制药,6,2005年8月, FDA仿制药审评办公室公开了一个仿制药的审评要求QbR-QoS模板作为21世纪GMP的启动;2008年1月, QbR-QoS 开始启用;2011年12月, FDA仿制药审评办公室发布了一个缓释片的QbD 模板。2013年1月，所有仿制药申请都必须基于QbD理念 。,Qb
4、D:配方和工艺开发 ICH Q8,7,定义：质量源于设计QbD是通过系统性的设计和研究开发产品。在开发过程中通过完善的科学研究和全面的质量风险管理，通过全面的过程控制手段，努力实现既定的产品质量目标。,8,设计产品以满足患者需求和满足使用需求；设计过程和工艺以稳定地生产出符合产品关键属性的好产品；通过研究，深刻理解起始物料质量与生产工艺参数对产品质量的影响；持续评估生产工艺，确保始终如一的产品质量；明确和控制引起工艺参数变动的关键原因；制定合理的控制策略。,QbD:配方和工艺开发 ICH Q8,Significance of Quality by Design,9,10, 目标产品质量(QTP
5、P) 产品的关键质量属性(CQAs) 产品设计和对产品的充分理解，包括:对原料、辅料、包材的CQAs的界定 工艺设计和对工艺的充分理解，包括：界定关键工艺参数和中间体属性 对控制策略的合理性给予充分解释例如：PAT，实时放行，设计空间，试验设计，风险评估，统计分析,QbD: FDA的期望,关键质量属性,关键质量属性 Critical Quality Attribute (CQA)：作为高质量药品应具备的理化性质、生物学特性、微生物特性，这些特性都是在一定范围内可控制的。e.g.乳粒粒径分布、溶出行为、无菌、含量均匀度、混合均匀度、流动性 Identification of a CQA is b
6、ased on the severity of harm to a patient (safety and efficacy) resulting from failure to meet that quality attribute.,11,关键物料属性,关键物料属性 Critical Material Attribute (CMA)：作为物料的理化性质、生物学特性、微生物特性，这些特性都是在一定范围内可控制的。 e.g.杂质水平、含量、残留溶剂、粒径、细菌内毒素,12,关键工艺参数,关键工艺参数 Critical Process Parameter (CPP)：影响产品关键质量属性的工艺参
7、数。对这些参数应检测和控制，以确保高质量的产品。e.g.混合时间/速率、升温速率、反应温度、喷液速率、压片力、灌装速率、进风温度,13,14,建立CMAs, CPPs和CQAs的关系,控制策略,15,基于对现有产品和工艺的理解，为了保障成功的生产过程和产品质量而制定的一系列控制手段。 包括：工艺参数，影响产品质量的物料属性，设备，中间控制，成品质量标准，检测方法，检测频率，等等。 (ICH Q10),设计空间,16,KnowledgeSpace,Design Space,Control Space,Unexplored Space,ICH Q8,设计空间-经过试验和验证确认可以保证产品质量的各
8、种变量（例如：物料属性、工艺参数）的允许范围。在设计空间之内的变化不应被视为真正的变化。设计空间之外的变化则必须要经过正式的研究并需要获得药政部门的批准才能使用。设计空间是由产品开发者提出并经过药政部门充分评估、批准后才能运用。,QbD各元素之间的关联Lionberger R. et al AAPS J. 10(2):268, 2008,17,18,QbD :配方和工艺开发 ICH Q8,19,20,I. 目标产品质量(QTPP),定义: 为实现产品说明书中描述的安全性和功效，产品所必须具备的质量谱制定产品QTPP的三个步骤:明确质量属性-了解已上市对照药确定关键质量属性并解释其合理性(Jus
9、tification)汇总、制定目标产品质量,21,22,常见的目标产品质量属性表,23,CQA,常见的目标产品质量属性表（续）,建立仿制药的QTPP第一步：了解已上市对照药,24,25,普通制剂QTPP案例: Acetriptan片,26,普通制剂QTPP案例: Acetriptan片,普通制剂QTPP案例: Acetriptan片,27,28,Make a new Table for CQA,普通制剂QTPP案例: Acetriptan片,列出所有质量属性: 物理性质、鉴别、含量、含量均匀性、溶出度、降解产物、残留溶剂、水分、微生物限度等等。质量属性分为关键和非关键属性。关键质量属性是根据
10、对产品安全性和有效性影响的严重程度来界定的。在产品开发过程中，只有那些受产品配方和工艺参数变化影响大的关键质量参数才会被研究。某些关键质量属性（例如：鉴别）并不会因配方或工艺参数的变化而变化，因此它并不是我们要重点研究的质量属性。,29,建立仿制药的QTPP第二步：确定关键质量属性,30,建立仿制药的QTPP第二步：确定关键质量属性,31,案例：普通制剂的关键质量属性,32,案例：普通制剂的关键质量属性,II. 充分理解你的产品,目标: 开发出一个在整个货架期之内都能保持稳定质量的优秀产品。影响因素:原料药：理化性质、生物学性质辅料选择: 种类、型号、规格(e.g.PC,lactose,HPM
11、C)配方优化：确定关键物料属性原辅料属性中间体属性.,33,原料药性质,34,35,辅料性质,36,原辅料相容性,37,配方优化,38,配方优化,39,.充分理解你的工艺,步骤1：确定工艺步骤工具: 工艺路径图(缓释制剂QbD 案例),40,步骤1：确定工艺步骤寻找关键物料属性、关键工艺参数与关键质量属性的关系,41,摘自FDA 缓释制剂QbD 模板,42,步骤2：确定潜在的高风险参数工具: 风险评估和专业知识,43,步骤2：确定潜在的高风险参数工具: 风险评估和专业知识,44,步骤2：确定潜在的高风险参数工具: 风险评估和专业知识,FDA QbD MR Example,45,步骤2：确定潜在
12、的高风险参数工具: 风险评估和专业知识,可以从相似的工艺和公开信息获取相关经验：产品开发过程作用机理构效关系技术转移数据包工艺验证内部研究和审计供应商信息原辅料检测数据,46,步骤3：确定工艺参数范围工具: 专业知识和生产经验,根据预定的设计系统地试验，去揭示输入变量和结果的关系。评估实际试验结果和预测结果的差异当DOE运用到配方优化或工艺优化时，输入的变量可以包括物料的属性（例如：粒径），工艺参数（例如：压片速度或喷液速率；而结果则可以选择产品或中间体的关键物料属性（例如：混合均匀度、含量、释放曲线）。DOE可以帮助我们确定最优条件、关键物料属性、关键工艺参数，从而最终找到设计空间。,47,
13、步骤4：设计并完成试验工具: 实验设计(DOE),48,Updated Process Risk Assessment Example after the Analysis,步骤5：分析试验数据工具: 统计分析(ANOVA,数学模型),摘自FDA 缓释制剂QbD 模板,49,摘自FDA 缓释制剂QbD 模板,步骤5：分析试验数据充分解释实验数据,Step 6: Develop Control Strategy (Example),50,步骤6：确定控制策略,摘自FDA 缓释制剂QbD 模板,51,评估什么:原料、辅料配方变量工艺参数变量如何评估：从对各变量的分析开始风险评估实验数据分析更新对各
14、变量的分析去控制或减少产品风险,IV.风险评估工具: ICH Q9,质量风险管理,52,质量风险评估应基于专业知识和对患者的保护意识不同级别的风险因素应给予不同的关注和监测,质量风险管理的原则,53,1)质量风险评估应该建立在专业知识的充分理解和对患者的足够保护基础之上。2) 对不同等级的风险，应该投入不同程度的关注和精力。,风险评估：原辅料属性,54,摘自FDA 普通制剂QbD 模板,55,风险评估：合理性解释,摘自FDA 普通制剂QbD 模板,风险转移,56,对制剂的关键质量属性而言，原料属性属于高风险因素原料属性 制剂属性 风险转移固态 溶出度 QC粒径分布 含量均匀度和溶出 QC和工艺
15、开发部溶解度 溶出度 配方开发和工艺开发化学稳定性 含量和降解 配方开发和工艺开发流动性 含量均匀度 工艺开发,摘自FDA 普通制剂QbD 模板,57,风险评估：配方变量,需要做的实验,58,原辅料相容性试验两两混合配方所有成分的混合物 配方开发试验第一轮DOE：原料 的粒径分布、颗粒内乳糖用量、MCC用量、CMS用量对产品关键质量属性的影响。第二轮DOE ：颗粒外乳糖、滑石粉、硬脂酸镁对产品关键质量属性的影响。,及时更新风险评估,59,原料属性的控制策略,60,QbD是一个系统思考、计划和试验的过程，基于对产品质量和工艺的深刻理解；通过揭示物料属性、工艺步骤对产品质量的影响，从而找到产品质量
16、的关键控制点；利用一系列监测手段和风险控制手段去保障产品质量。,61,总结,Q&A,GDUFA,The Generic Drug User Fee Act (GDUFA) calls for the generic drug industry to pay $299 million annually in user fees for the next five years, beginning October 1, 2012. This funding is supplemental to what Congress appropriates to FDA each year and will
17、 enable the FDAs Office of Generic Drugs to hire the scientific resources needed to provide timely approval of generic medicines. The new fees also will provide increased funding for generic manufacturer facility inspections, which are required before new generics can be approved.,Type of Fees Will
18、be Paid Under GDUFA,One time backlog fee for ANDAs pending on Oct 1, 2012. A notice of amount of fees will be published by 10/31/12 (50MM/#ANDAs). Fee due date in 30 calendar days.DMF fee (same above)ANDA and prior approval supplement filing fee (75% refund if ANDA is not considered to be received).
19、An annual fee for facility to manufacture API or Generics.Amount of fee published 60 days before each fiscal yearFee due date within 45 days after notification.299MM: 6% DMF; 24% ANDA; 56% Generic facility; 14% API facility (2013-2017) charged from Generic Pharma.,Type of Fees Will be Paid Under GDU
20、FA,Facility fee (annual): 100K 125KANDA: 60K 90KPAS: 30K 45KBacklog one time fee: 15K-20KDMF: 15K-20KThis is not official information. Final fees information is available in Oct 2012 IF the Act is passed.,New Paradigm of DMF Review,FDA DMF Team,Team dedicated to drug substance review (Type II DMFs)
21、Started as a pilot program in the Fall of 2010 with 3 chemists supporting 2 ANDA review teams Mission: Perform review of Type II DMFs for Drug Substances in support of original ANDAs Currently has 10 dedicated chemists and a Project Manager Supporting review activity in 9 of the 16 ANDA Teams for or
22、iginal ANDAs,67,Review Process,Previously, DMF was reviewed with the ANDA by the assigned reviewer Review of the DMF starts before the ANDA is assigned by the DMF Team Often the DMF is adequate before the first cycle ANDA review is complete,68,Question Based Review for DMFs,Most of the questions fro
23、m 2.3.S section of the original QbR-QOS for ANDAs remain in the DMF QbR Additional questions are asked regarding the starting materials, manufacturing process and controls Questions are also asked regarding process development and control strategies assuring the quality of the drug substance The que
24、stions will be made available on our website along with additional information to help DMF holders meet expectations Like QbR for ANDAs it will be phased in over time,69,Question Based Review for DMFs,A DMF QbR Associated Document will be published which will provide the agencys expectations regardi
25、ng the responses and supporting documents in the Module 3 Most of the agencys expectations are being provided based on the available FDA and ICH Guidances and also draft ICH Q11 This document is very similar the ANDA QbR FAQ and will be useful for the industry in providing information and help revie
26、wers in making decisions.,70,Proposed Implementation Timeline,Post QbR questions document with expectations on OGD website Fall 2012 Post additional material (if needed) Spring 2013 Encourage DMF holders to submit a QoS in QbR format for new DMFs Summer 2013 Strongly Encourage DMF holders to submit
27、a QoS in QbR format for new DMFs Beginning 2014 For maximum benefit DMFs should be in electronic CTD format,71,Expectation for Process Dev & Process Scale-up Information,Summarize development information in a report (similar to a Pharmaceutical Development Report) Current information in 3.2.S.2.6 (m
28、anufacturing process development) is inadequate Typically we currently get a paragraph or two on development that provides no context for the final process and control strategy Summarize results from lab scale and pilot scale batches Link knowledge gained to final process and control/specification c
29、hoices for the finished drug substance Cite prior knowledge when appropriate QbR questions will be helpful in providing a useful PD report for drug substances Development report should provide context to choices made for: Finished commercial scale process Control strategy (specifications, in-process
30、 controls) Tell us how the process design and control strategy ensure quality,72,Proposed Draft QbR Questions,73,Proposed Draft QbR Questions,74,Proposed Draft QbR Questions,75,76,Completeness Assessments (“filing review”) for DMFs,Consistent with language in GDUFADifferent than the administrative “
31、filing” review performed by the Central Document Room Avoid confusion with the ANDA Filing Review process,77,Why a Completeness Assessment or “Filing Review” for Type II DMFs?,New requirement in the proposed GDUFA legislation Drug substance (Type II) DMFs must be deemed “available for reference” by
32、the HHS Secretary to be referenced by an ANDA Two things must happen for the DMF to be considered “available for reference” 1. DMF Fee must be paid 2. DMF must pass a “completeness assessment” ANDAs can only be filed by OGD if all DMFs for the drug substance(s) are “available for reference”,78,Which
33、 Fee is associated with the Completeness Assessment?,Drug Master File Fee paid by the DMF Holder Not to be confused with the facility fee related to the drug substance manufacturing facility One-time Fee paid once in the DMF lifecycle Fee is due upon the first reference by an ANDA submission under G
34、DUFA Payment of this fee triggers the Completeness Assessment process in OGD,79,What are the responsibilities for the Completeness Assessment under GDUFA?,DMF holder Pay the DMF Fee allowing sufficient time for the completeness Assessment to occur Provide a high quality DMF submission Respond to com
35、ments in letters and teleconferences quickly Office of Generic Drugs Perform a timely Completeness Assessment Issue comments for DMFs found “Incomplete” Communicate comments by teleconference when possible Publish a list of DMFs found “available for reference” (fee paid and complete) on an FDA websi
36、te Publish our criteria for the Completeness Assessment,80,Initial OGD Goals for the Process,Should be comprehensive and provide useful feedback to the DMF holder Improve quality of the submission Improve the efficiency of the scientific review Should be performed exclusively by the DMF Team Should
37、be performed by a chemist Enhance efficiency Leverage expertise Should not be a huge workload burden Complete in 2 to 3 hours Should not cross the line into Scientific Review Comments are information requests Reviewer training,81,Work Flow 1,82,Work Flow 2,What can DMF holders do to ensure success?,
38、Provide high quality submissions Plan ahead and pay DMF Fees early Increase communication between DMF holders and ANDA sponsors Use the resources available from OGD Respond to Information Requests in letters and T-cons completely and promptly Submit DMFs in electronic format,83,Stability Expectation
39、 For Generic Drugs,Proposed Stability Guidance,FDA is proposing to formalize its stability policies for ANDAs by adopting the recommendations in the ICH Q1 Stability Guidances Although the ICH stability guidances were intended to define what stability information should be provided in NDAs for a new
40、 drug substance or drug products, OGD believes the recommendations provided on stability testing are also appropriate for ANDAs,85,ICH Stability Guidances,Q1A (R2) Stability Testing of New Drug Substances and Products (November 2003) Q1B Photostability Testing of New Drug Substances and Products (No
41、vember 1996) Q1C Stability Testing for New Dosage Forms (November 1996) Q1D Bracketing and Matrixing Designs for Stability Testing of New Drug Substances and Products (January 2003) Q1E Evaluation of Stability Data (June 2004),86,ICH Q1A Requirements: General Case (2.2.7.1),87,If significant change
42、occurs during 6 months testing at the accelerated condition, additional testing at the intermediate condition required Initial application should include a minimum of 6 months data from a 12-month study at the intermediate storage.,ICH Q1A Requirement: Selection of Batches (2.2.3),88,Stability studi
43、es data should be provided on at least three primary batches of the drug product. Two of the three batches should be at least pilot scale batches, and the third one can be smaller if justified. Stability studies should be performed on each individual strength and container size of the drug product u
44、nless bracketing or matrixing is applied.,ICH Q1A : Batch Definitions,89,Primary batch: A batch of a drug substance or drug product used in a formal stability study, from which stability data are submitted in a registration application for the purpose of establishing a retest period or shelf life, r
45、espectively. A primary batch may be a production batch. Production batch: A batch of a drug substance or drug product manufactured at production scale by using production equipment in a production facility as specified in the application It is proposed that one of the three batches be an exhibit bat
46、ch on which ANDA holder has conducted bioequivalence studies comparing to a Reference Listed Drug, where applicable.,Guidance Status,90,The draft Stability Guidance (ANDAs: Stability Testing of Drug Substances and Products) is currently obtaining clearance for posting OGD has met with Generic Indust
47、ry representatives during guidance development Industry will have the opportunity to provide comments After evaluation of comments and revision as appropriate, the guidance will be posted,ICH Q8关于QbD的三个主要元素,91,“知识管理”structured requirements flow down and cause effect overview “ quality function deplo
48、yment,过程理解structured experiments and data collection (e.g. DoE and modeling) to provide an understanding of cause and effect and interaction.,质量风险管理Using the assessment of the risk associated with the cause and effect to remove or control the risk to an adequate level -PAT, Control Strategy,92,CQA Final Tally = 4 quality attributesAssayContent uniformityDissolutionDegradation productsStep 3: how do the drug substance, excipients, process etc impact these critical quality attributes?,案例：普通制剂的关键质量属性,QbD: FDA的期望,93,
