醫(yī)學(xué)專(zhuān)題—報(bào)批美國(guó)FDA仿制藥研發(fā)與相關(guān)問(wèn)題探討-Final課件

1、開(kāi)發(fā)報(bào)批美國(guó)開(kāi)發(fā)報(bào)批美國(guó)FDA的仿制的仿制(fngzh)藥與相關(guān)問(wèn)題探討藥與相關(guān)問(wèn)題探討第一頁(yè)，共四十一頁(yè)。第二頁(yè)，共四十一頁(yè)。藥物制劑藥物制劑目標(biāo)目標(biāo)(mbio)主流市場(chǎng)主流市場(chǎng)第三頁(yè)，共四十一頁(yè)。第四頁(yè)，共四十一頁(yè)。第五頁(yè)，共四十一頁(yè)。第六頁(yè)，共四十一頁(yè)。仿制(fngzh)藥研發(fā)團(tuán)隊(duì)CONCEPT-1 BUILD UP A TEAMINFORMATIONFORMULATIONPRODUCTREGULATORYANALYTICALBIO-PHARMACEUTICALPROJECTLEGEL第七頁(yè)，共四十一頁(yè)。第八頁(yè)，共四十一頁(yè)。Product Development Roadmap仿制仿制(

2、fngzh)藥的藥的研發(fā)過(guò)程研發(fā)過(guò)程第九頁(yè)，共四十一頁(yè)。 Quality Acceptably low risk of failing to achieve the desired clinical attributes Pharmaceutical Quality= f drug substance, excipients, manufacturing. QbD Product and process performance characteristicsscientifically designed to meet specific objectives, not merely empir

3、ically derived from performance of test batchesWhat is QbD (?QbDQbD在制劑在制劑(zhj)(zhj)開(kāi)發(fā)中怎么體現(xiàn)？開(kāi)發(fā)中怎么體現(xiàn)？第十頁(yè)，共四十一頁(yè)。What is QbD?QbDQbD在制劑開(kāi)發(fā)在制劑開(kāi)發(fā)(kif)(kif)中怎么體現(xiàn)？中怎么體現(xiàn)？第十一頁(yè)，共四十一頁(yè)。Essential elements of QbD Definition of the quality target product profileHigh level quality aspects of the product: purity, drug

4、release (dissolution/disintegration time), pharmacokinetic profile, etc. Critical quality attributes (CQAs) for drug product Characteristics of DP which have impact on desired profile Conscious attempt to study and control Critical Process Parameters (CPPs) Identification of material properties and

5、process parameters which haveeffect on product CQAs Design Space: The multidimensional combination and interaction ofinput variables and process parameters that have been demonstrated to provide assurance of quality Identification of a control strategy for critical process parametersWhat is QbD?QbDQ

6、bD在制劑開(kāi)發(fā)中怎么在制劑開(kāi)發(fā)中怎么(zn me)(zn me)體現(xiàn)？體現(xiàn)？第十二頁(yè)，共四十一頁(yè)。Raw MaterialsEquipmentEnvironmentOperatorsVariable Inputsx“Locked” Process=Variable QualityHow Did We Work in the PastWhat is QbD?QbDQbD在制劑在制劑(zhj)(zhj)開(kāi)發(fā)中怎么體現(xiàn)？開(kāi)發(fā)中怎么體現(xiàn)？第十三頁(yè)，共四十一頁(yè)。Raw MaterialsEquipmentEnvironmentOperatorsUnderstood Variable InputsxUnd

7、erstood and Controlled Process=Predefined QualityFlexible Process Design SpaceHow Can We Work in the FutureWhat is QbD?QbDQbD在制劑開(kāi)發(fā)在制劑開(kāi)發(fā)(kif)(kif)中怎么體現(xiàn)？中怎么體現(xiàn)？第十四頁(yè)，共四十一頁(yè)。What is QbD?QbDQbD在制劑開(kāi)發(fā)中怎么在制劑開(kāi)發(fā)中怎么(zn me)(zn me)體現(xiàn)？體現(xiàn)？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressionProduct第十五頁(yè)，共四十

8、一頁(yè)。Drug SubstanceExcipientsSourceAssayImpurities LODPS What is QbD?QbDQbD在制劑開(kāi)發(fā)在制劑開(kāi)發(fā)(kif)(kif)中怎么體現(xiàn)？中怎么體現(xiàn)？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompression第十六頁(yè)，共四十一頁(yè)。WaterBinderTempSpray RateSpeedTimeP.SWhat is QbD?QbDQbD在制劑開(kāi)發(fā)在制劑開(kāi)發(fā)(kif)(kif)中怎么體現(xiàn)？中怎么體現(xiàn)？Raw MaterialsWet GranulationFluid

9、Bed DryingBlendingCompression第十七頁(yè)，共四十一頁(yè)。What is QbD?QbDQbD在制劑在制劑(zhj)(zhj)開(kāi)發(fā)中怎么體現(xiàn)？開(kāi)發(fā)中怎么體現(xiàn)？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressionAir FlowTempRHShock CycleP.S.第十八頁(yè)，共四十一頁(yè)。What is QbD?QbDQbD在制劑開(kāi)發(fā)中怎么在制劑開(kāi)發(fā)中怎么(zn me)(zn me)體現(xiàn)？體現(xiàn)？Raw MaterialsWet GranulationFluid Bed DryingBlendingC

10、ompressionFill VolumeRotation SpeedEnd Point (Time)Blend UniformityDensitiesAngle of Repose第十九頁(yè)，共四十一頁(yè)。What is QbD?QbDQbD在制劑開(kāi)發(fā)中怎么在制劑開(kāi)發(fā)中怎么(zn me)(zn me)體現(xiàn)？體現(xiàn)？Raw MaterialsWet GranulationFluid Bed DryingBlendingCompressionFeed FrameToolingPunch Penetration DepthCompression ForcePress SpeedFeeder Speed

11、第二十頁(yè)，共四十一頁(yè)。第二十一頁(yè)，共四十一頁(yè)。Examples of QbD questions under QbR Control of Drug Substance What is the drug substance specification? Does it include all the critical drug substance attributes that affect the manufacturing and quality of the drug product? (2 pages) Drug Product What attributes should the d

12、rug product possess? (1.5 pages) How were the excipients and their grades selected? How was the final formulation optimized? Manufacturing Process How are the manufacturing steps (unit operations) related to the drug product quality? How were the critical process parameters identified, monitored, an

13、d/or controlled? Pharmaceutical Development Manufacture Container Closure System第二十二頁(yè)，共四十一頁(yè)。AspectsTraditionalQbDPharmaceuticaldevelopmentEmpirical; univariateexperimentsSystematic; multivariateexperimentsManufacturingprocessFixed; validation on 3 initialfull-scale batches; focus on reproducibilityA

14、djustable within design space; continuous verification;focus on control strategyProcess controlIn-process testing for go/nogo; offline analysis w/slow responsePAT utilized for feedback &feed forward, real timeProductspecificationPrimary means of qualitycontrol; based on batch dataPart of the overall

15、 qualitycontrol strategy; based ondesired product performanceControlstrategyMainly by intermediate andend product testingRisk-based; controls shiftedupstream; real-time releaseLifecyclemanagementReactive to problems &OOS; post-approvalContinuous improvementenabled within design spaceQbDQbD小結(jié)小結(jié)(xioji

16、)(xioji)-SUMMARY-SUMMARY第二十三頁(yè)，共四十一頁(yè)。研發(fā)研發(fā)( (高難高難(o nn)(o nn) )仿制藥的一些仿制藥的一些體會(huì)體會(huì)第二十四頁(yè)，共四十一頁(yè)。第二十五頁(yè)，共四十一頁(yè)。Dissolution Profile-體外溶出曲線體外溶出曲線(qxin)第二十六頁(yè)，共四十一頁(yè)。生物等效生物等效(dn xio)(BE)結(jié)果結(jié)果AUC0-tAUC0-infCmaxFastRatio108.01%108.12%86.26%90% Geometric C.I.103.49% to 112.73%103.64% to 112.79%75.28% to 98.84%FedRatio

17、111.21%112.48%85.24%90% Geometric C.I.104.40% to 118.47%105.78% to 119.60%73.47% to 98.90%Summary of in vivo study results of Test Formulation vs. RLD第二十七頁(yè)，共四十一頁(yè)。原因原因(yunyn)調(diào)查調(diào)查第二十八頁(yè)，共四十一頁(yè)。第二十九頁(yè)，共四十一頁(yè)。第三十頁(yè)，共四十一頁(yè)。第三十一頁(yè)，共四十一頁(yè)。第三十二頁(yè)，共四十一頁(yè)。第三十三頁(yè)，共四十一頁(yè)。PRODUCT P DATA (Log Transformed Data, Fast, n-12)Rat

18、io of Geometric Means x 10090% CI of Log Transformed DataCV (%)Test A vs ReferenceAUC10690.4; 12322.0Cmax10480.1; 13436.4Test B vs ReferenceAUC133114; 15522.0Cmax129100; 16736.4第三十四頁(yè)，共四十一頁(yè)。PRODUCT P DATA (Log Transformed Data, FED, n-11)Ratio of Geometric Means x 10090% CI of Log Transformed DataCV

19、(%)Test A vs ReferenceAUC96.175.4; 12332.7Cmax10983.5; 14135.3Test B vs ReferenceAUC92.472.5; 11832.7Cmax10983.7; 14135.3第三十五頁(yè)，共四十一頁(yè)。PRODUCT P DATA (Log Transformed Data)Ratio of Geometric Means x 10090% CI of Log Transformed DataCV (%)FASTAUC10293; 11133,9Cmax10594.5; 11638.8FEDAUC98.891.6; 10726.4Cmax99.689.2; 11138.4第三十六頁(yè)，共四十一頁(yè)。案例案例(n l)研究研究-4API is Water Soluble. Prototy