Merck(Online-Blending)默克(在線混料)

1、 Pharmaceutical Process Analytics利用近紅外測定藥劑的在線混料均勻度 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 混料儀器操作和混料特征 NIR 應(yīng)用，光譜獲取 觸發(fā) vs. 連續(xù) 采樣注意事項 數(shù)據(jù)分析 移動塊, 波長相關(guān)性 重現(xiàn)性, 終端判定 應(yīng)用于處理開發(fā)和混料機尺寸增大情況 填料體積，混料機尺寸增大, 活性vs. 無效配方 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過程概述: 連續(xù)添加原料旋轉(zhuǎn)混料機設(shè)備： Bohle tote 混料機 (桶式混料機)尺寸: 試驗尺寸 (300L) & 全尺寸 (1800L)干粉末混合(API & 輔料) & 潤滑 (粉末混合，或顆粒)過程條件 填料體積、轉(zhuǎn)數(shù)和藥劑屬性 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取樣: 在離散時間點內(nèi)進行空間取樣 - 分析含量提供有差異的原料vs 時間可以區(qū)分特定地點的混料性能缺陷:時間分辨率代表性取樣需要資源是PAT的機會近紅外每次旋轉(zhuǎn)的光譜過程中進行采樣實時信息，自動化操作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 近紅外光譜儀電池供電，無線通訊直接檢測 通過藍寶石視窗檢測獲取: 1100-2300nm, 6nm 增量試驗尺寸 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連續(xù)獲取1 光譜 20% 轉(zhuǎn).光譜分離 單波長吸光度值最小影響 閾值 #包含光譜/轉(zhuǎn)數(shù)窗口直接顯示 (無)應(yīng)用于最佳觸發(fā)獲取觸發(fā)獲取觸發(fā)優(yōu)化后，S/N更適合自動化，常規(guī)應(yīng)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 需測定的配方藥 取決于配方和儀器靜態(tài) vs. 動態(tài)檢測 考慮外部- vs. 內(nèi)部- 轉(zhuǎn)數(shù)與取樣對比(實例) NIR: 10mg x 100 轉(zhuǎn) = 1g 一系列“微觀評估”，高時間分辨率 取樣: 100mg 樣品 x 10個位置 = 1 g 一轉(zhuǎn)處的微觀評估 基于單次檢測（轉(zhuǎn)數(shù)），停止混料機?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平均光譜標準偏差 無校準 光譜變異性 - 配方變異性 預(yù)處理: SNV波長相關(guān)系數(shù) 單光譜與光譜庫（點積）的相關(guān)值 光譜庫基于先前批處理的終點光譜 預(yù)處理: 二次微分123456轉(zhuǎn)數(shù)光譜 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大移動塊適當終點 基于Y軸值（1點）或圖示斜率小移動塊適當終點 基于連續(xù)的Y軸值（多點）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 相同處理條件 API 混合 移動塊尺寸= 3 移動塊尺寸= 20 Pharmaceutical Process AnalyticsWavelength Correlation profiles0.880.90.920.940.960.9811.02010203040506070RevolutionWavelength correlation 9 批 相同處理條件 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 相同處理條件 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波長相關(guān)性9 批內(nèi)閾值，基于終點可變性17-26 轉(zhuǎn)代表 10 連續(xù) “傳遞” 值與移動塊對應(yīng) 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樣和NIR方法早期時點取樣10個位置/時點的取樣數(shù)據(jù)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 填料體積 API vs. 無效配方 API/輔藥混合 潤滑 試驗尺寸 vs. 全尺寸 API/輔藥混合 潤滑 混合動力 (大填料體積) 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, 試驗尺寸填料體積，5 % 差異移動塊 波長相關(guān)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. 無效配方試驗尺寸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. 無效配方的潤滑試驗尺寸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試驗 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試驗vs. 全尺寸無效配方潤滑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 顆粒配方的潤滑 95% 填料體積 通過混料機底端添加潤滑劑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