Merck(Online-Blending)默克(在线混料)

1、 Pharmaceutical Process Analytics利用近红外测定药剂的在线混料均匀度 Pharmaceutical Process Analytics Background blending unit operation & characterization of blends NIR implementation, acquisition of spectra triggered vs. continuous sampling considerations Data analysis moving block, wavelength correlation Repro

2、ducibility, endpoint determination Apply to processing development & scale-up Fill volume, scale-up, active vs. blank formulation Pharmaceutical Process Analytics 背景 混料仪器操作和混料特征 NIR 应用，光谱获取 触发 vs. 连续 采样注意事项 数据分析 移动块, 波长相关性 重现性, 终端判定 应用于处理开发和混料机尺寸增大情况 填料体积，混料机尺寸增大, 活性vs. 无效配方 Pharmaceutical Proce

3、ss AnalyticsProcess overview: Sequential addition of materials Spin blenderEquipment: Bohle tote blenders (bin blenders)Scale: Pilot (300L) & Full-scale (1800L)Dry powder blending (API & excipients) & lubrication (of powder blends, or granules)Process conditions fill volume, RPMs, &

4、formulation attributes Pharmaceutical Process Analytics过程概述: 连续添加原料旋转混料机设备： Bohle tote 混料机 (桶式混料机)尺寸: 试验尺寸 (300L) & 全尺寸 (1800L)干粉末混合(API & 辅料) & 润滑 (粉末混合，或颗粒)过程条件 填料体积、转数和药剂属性 Pharmaceutical Process AnalyticsSample thieving: spatial sampling at discrete timepoints - analytical assay Prov

5、ides variability of material vs. timeCan identify location-specific blend performanceDrawbacks:Time resolutionRepresentative samplingResources requiredAn opportunity for PATNear-IRSpectra at each revolutionSample provided by processReal-time information; automationTimeRSDTimeRSDRSD x x x x x x x x x

6、 x Pharmaceutical Process Analytics取样: 在离散时间点内进行空间取样 - 分析含量提供有差异的原料vs 时间可以区分特定地点的混料性能缺陷:时间分辨率代表性取样需要资源是PAT的机会近红外每次旋转的光谱过程中进行采样实时信息，自动化操作TimeRSDTimeRSDRSD x x x x x x x x x x Pharmaceutical Process Analytics Brimrose Luminar Near-IR spectrometer Battery-powered, wireless communication Interfaced to l

7、id measurement through sapphire window Acquisition: 1100-2300nm, 6nm incrementPilot scale Full-scale Pharmaceutical Process Analytics Brimrose Luminar 近红外光谱仪电池供电，无线通讯直接检测 通过蓝宝石视窗检测获取: 1100-2300nm, 6nm 增量试验尺寸 全尺寸 Pharmaceutical Process AnalyticsContinuous acquisition1 spectrum 20% Rev.Separation of s

8、pectra Single wavelength absorbance valueMinimal impact Threshold value # spectra / revolution includedDirect indication of window fouling (lack of)Apply toward optimizing triggered acquisitionTriggered acquisitionS/N if trigger optimizedMore amenable to automation, routine useTote upright and stati

9、onarySpectra of formulationSpectra of airChanges in blender directionBlending stopped. Tote upright and stationarySpectra of air + formulation Pharmaceutical Process Analytics连续获取1 光谱 20% 转.光谱分离 单波长吸光度值最小影响 阈值 #包含光谱/转数窗口直接显示 (无)应用于最佳触发获取触发获取触发优化后，S/N更适合自动化，常规应用Tote upright and stationarySpectra of f

10、ormulationSpectra of airChanges in blender directionBlending stopped. Tote upright and stationarySpectra of air + formulation Pharmaceutical Process Analytics 10 mg formulation interrogated formulation & instrument dependentStationary vs. dynamic measurement Consider intra- vs. inter- revolution

11、sComparison with sample thief (example) NIR: 10mg x 100 revolutions = 1g A series of “micro-assessments” with high time resolution Thief: 100mg sample x 10 locations = 1 g Macro-assessment at one revolution Stop blender based on a single measurement (revolution)?00.0050.010.0150.020.0250.03032649612

12、8Revolutionmean spectral standard deviationIntra-revolutionInter-revolution Pharmaceutical Process Analytics 10 mg 需测定的配方药 取决于配方和仪器静态 vs. 动态检测 考虑外部- vs. 内部- 转数与取样对比(实例) NIR: 10mg x 100 转 = 1g 一系列“微观评估”，高时间分辨率 取样: 100mg 样品 x 10个位置 = 1 g 一转处的微观评估 基于单次检测（转数），停止混料机?00.0050.010.0150.020.0250.030326496128

13、Revolutionmean spectral standard deviationIntra-revolutionInter-revolution Pharmaceutical Process AnalyticsMean spectral standard deviation No calibration Spectral variability - formulation variability Pre-processing: SNVWavelength correlation Correlation value of individual spectra to library (dot

14、product) Library based on end-point spectra from previous batches Pre-processing: 2nd derivative123456Revolution NumberSpectra Pharmaceutical Process Analytics平均光谱标准偏差 无校准 光谱变异性 - 配方变异性 预处理: SNV波长相关系数 单光谱与光谱库（点积）的相关值 光谱库基于先前批处理的终点光谱 预处理: 二次微分123456转数光谱 Pharmaceutical Process AnalyticsLarge block siz

15、e Suitable endpoint based on y-axis value (1 point) or profile slopeSmall block size Suitable endpoint based on consecutive y-axis values (multiple points) by minimal profile variabilityMoving block blend profiles using different block sizes00.020.040.060.080.10.120.140.160.180.2010203040506070Revol

16、utions (block number)mean spectral standard deviationblock = 3block = 20 Pharmaceutical Process Analytics大移动块适当终点 基于Y轴值（1点）或图示斜率小移动块适当终点 基于连续的Y轴值（多点）by minimal profile variabilityMoving block blend profiles using different block sizes00.020.040.060.080.10.120.140.160.180.2010203040506070Revolutions

17、(block number)mean spectral standard deviationblock = 3block = 20 Pharmaceutical Process Analyticsm o v in g b lo c k b le n d p r o f ile s ( b lo c k = 3 )00 . 0 50 . 10 . 1 50 . 20 . 2 501 02 03 04 05 06 07 0r e v o lu t io n ( b lo c k n u m b e r )meand spectral standard deviationM o v in g b l

18、o c k b le n d p r o f ile s ( b lo c k = 2 0 )00 .0 20 .0 40 .0 60 .0 80 .10 .1 20 .1 401 02 03 04 05 06 07 0r e v o lu t io n ( b lo c k n u m b e r )mean spectral standard deviation 9 batches Same processing conditions API blending Block size = 3 Block size = 20 Pharmaceutical Process Analyticsm

19、o v in g b lo c k b le n d p r o f ile s ( b lo c k = 3 )00 . 0 50 . 10 . 1 50 . 20 . 2 501 02 03 04 05 06 07 0r e v o lu t io n ( b lo c k n u m b e r )meand spectral standard deviationM o v in g b lo c k b le n d p r o f ile s ( b lo c k = 2 0 )00 .0 20 .0 40 .0 60 .0 80 .10 .1 20 .1 401 02 03 04

20、05 06 07 0r e v o lu t io n ( b lo c k n u m b e r )mean spectral standard deviation 9 批 相同处理条件 API 混合 移动块尺寸= 3 移动块尺寸= 20 Pharmaceutical Process AnalyticsWavelength Correlation profiles0.880.90.920.940.960.9811.02010203040506070RevolutionWavelength correlation 9 批 相同处理条件 API 混合Each profile value rep

21、resents a single revolutionEndpoint multiple profile points Pharmaceutical Process AnalyticsWavelength Correlation profiles0.880.90.920.940.960.9811.02010203040506070RevolutionWavelength correlation 9 批 相同处理条件 API 混合Each profile value represents a single revolutionEndpoint multiple profile points Ph

22、armaceutical Process AnalyticsWavelength Correlation0.880.90.920.940.960.9811.020102030405060RevolutionCorrelation coeff17 rev 26 revMoving block (n=20)00.020.040.060.080.10.120.1401020304050Block number spectral standard deviation17 rev 26 revWavelength correlationThreshold based on endpoint variab

23、ility across 9 batches17-26 Rev represents 10 consecutive “passing” valuesCorrespondence to moving blockprofile value Pharmaceutical Process AnalyticsWavelength Correlation0.880.90.920.940.960.9811.020102030405060RevolutionCorrelation coeff17 rev 26 revMoving block (n=20)00.020.040.060.080.10.120.14

24、01020304050Block number spectral standard deviation17 rev 26 rev波长相关性9 批内阈值，基于终点可变性17-26 转代表 10 连续 “传递” 值与移动块对应 Pharmaceutical Process AnalyticsSample thief and NIR applied to same batchEarly timepoint sample thievingThief data based on 10 locations / timepointMoving block blend profile (block=20)00

25、.010.020.030.040.050.060.0701020304050Revolution (block number)mean spectral standard deviationSample thieving: Rev %RSD12 21.624 6.332 2.7 Pharmaceutical Process Analytics在相同批次中使用取样和NIR方法早期时点取样10个位置/时点的取样数据Moving block blend profile (block=20)00.010.020.030.040.050.060.0701020304050Revolution (bloc

26、k number)mean spectral standard deviationSample thieving: Rev %RSD12 21.624 6.332 2.7 Pharmaceutical Process Analytics Fill volume API vs. blank formulation API/excipient blending Lubrication Pilot vs. full-scale API/excipient blending Lubrication Blend dynamics (large fill volume) Pharmaceutical Pr

27、ocess Analytics 填料体积 API vs. 无效配方 API/辅药混合 润滑 试验尺寸 vs. 全尺寸 API/辅药混合 润滑 混合动力 (大填料体积) Pharmaceutical Process AnalyticsAPI blending, pilot scale5 % difference in fill volumeMoving block Wavelength correlation00.020.040.060.080.10.120evolution (block number)mean spectral standard deviation0

28、.880.90.920.940.960.9811.020510152025303540Re v olutionWavelength correlation Pharmaceutical Process AnalyticsAPI 混料, 试验尺寸填料体积，5 % 差异移动块 波长相关性00.020.040.060.080.10.120evolution (block number)mean spectral standard deviation0.880.90.920.940.960.9811.020510152025303540Re v olutionWaveleng

29、th correlation Pharmaceutical Process AnalyticsActive vs. blank formulationPilot scaleMoving block blend profile (block=20)00.020.040.060.080.10.120evolution (block number)mean spectral standard deviationAPI Blank Pharmaceutical Process Analytics活性vs. 无效配方试验尺寸Moving block blend profile

30、(block=20)00.020.040.060.080.10.120evolution (block number)mean spectral standard deviationAPI Blank Pharmaceutical Process AnalyticsLubrication of active vs. blank formulationPilot scale00.050.10.150.20.250.30.350.40.450.50326496128160192224256Revolution (block number)mean spectral sta

31、ndard deviationAPIBlank Pharmaceutical Process Analytics活性 vs. 无效配方的润滑试验尺寸00.050.10.150.20.250.30.350.40.450.50326496128160192224256Revolution (block number)mean spectral standard deviationAPIBlank Pharmaceutical Process Analytics00.0050.010.0150.020.0250.030.0350.040.0450326496128Revolution (block

32、number)mean spectral standard deviationPilot ScaleFull Scale Pilot vs. full-scale Same formulation Pharmaceutical Process Analytics00.0050.010.0150.020.0250.030.0350.040.0450326496128Revolution (block number)mean spectral standard deviationPilot ScaleFull Scale试验 vs. 全尺寸相同配方 Pharmaceutical Process A

33、nalyticsPilot vs. full scaleLubrication of blank formulation 00.050.10.150.20.250.30.350.40326496128160192224256Revolution (block number)Mean spectral standard deviationPilot ScaleFull Scale Pharmaceutical Process Analytics试验vs. 全尺寸无效配方润滑00.050.10.150.20.250.30.350.40326496128160192224256Revolution

34、(block number)Mean spectral standard deviationPilot ScaleFull Scale Pharmaceutical Process Analytics Lubrication of granule formulation 95% fill volume Lubricant added through bottom of blenderMoving block blend profile00.050.10.150.20.2501224364860728496Revolution (block number)Mean spectral standa

35、rd deviationBlock size = 20Block size = 3 Pharmaceutical Process Analytics 颗粒配方的润滑 95% 填料体积 通过混料机底端添加润滑剂Moving block blend profile00.050.10.150.20.2501224364860728496Revolution (block number)Mean spectral standard deviationBlock size = 20Block size = 3 Pharmaceutical Process AnalyticsA rapid, non-invasive, & information-rich approach to blend uniformity has been applied toward process development, scale-up, & monitoringTwo data analysis approaches considered: Moving block Calibration-free Each point corresponds to multiple revolutions Wavelength correlation Requires