Physical Appearance Determination Of A Drug Substance .

Physical Appearance Determination of a Drug Substance Utilizing aCommercially Available Color Guideby Jennifer Alligood, Kimberly Lupo, Joe Cobb, Lauren McNeil, Ashley Dunning, LaurenBrock, Ken Jones, Credle Harris, Marjorie Misiura, David Nelson, Kym RispressOBJECTIVETo develop a robust method to determine the physical color appearance of drug substance Xthat eliminates the subjective human bias for color selection.GENERAL BACKGROUNDPhysical appearance testing can be the most subjective but important tests performed ondrug substances. The polymorphous form can provide information regarding the solid state ofthe material. The color can be an indication of purity and a means to identify contaminationthat occurred during the synthesis process. Typical testing involves viewing the materialagainst a white background under specified lighting and reporting the color and form. Due tohuman bias observed during physical appearance testing of drug substance X, a commerciallyavailable color guide was utilized to develop a robust method to determine the physicalappearance of said material.METHODOLOGYMaterialsActive Pharmaceutical Ingredient (API) X, Form A, Micronized, Supplied by ClientActive Pharmaceutical Ingredient (API) X, Form B, Non-Micronized, Supplied by ClientActive Pharmaceutical Ingredient (API) X, Form B, Micronized, Supplied by ClientPantone Formula Guide, Solid Uncoated, Product Code GP1201White Computer PaperAnalytical EquipmentLight Booth, Byko-Spectra, Part No. CG-6050Olympus Model C2020Z Digital CameraVisual MethodThe following data were collected on several different lots and type of API X by three analystsusing the visual method. The visual method consisted of viewing approximately 50 mg of APIX placed on a white sheet of paper under laboratory lighting. The color of the API wasrecorded by each analyst without the knowledge of what the other analyst had recorded.There was some variability within each sample tested.Page 1

Table 1 – Visual Method ResultsAPI XLotAPI X DescriptionVisual Method ResultsPrecisionAnalyst 1Analyst 2Analyst 3PercentageAForm B,NonmicronizedOff-WhiteLight OrangeOff-white67BForm B, MicronizedLight OrangeLight Orangeto Light PinkLight Orangeto Light Pink67CForm B, MicronizedLight BrownLight BrownLight Orange67DForm A, MicronizedEForm A, MicronizedOff-white w/purple tintOff-white w/purple tintGray w/purple tintGray w/purple tintOff-white w/purple tintOff-white w/purple tintFForm B,NonmicronizedBrownDark BrownBrownGForm B, MicronizedOff-whiteLight OrangeOff-white67676767Pantone Formula GuideThe Pantone Formula Guide (Solid uncoated) is a commercially available compilation of colorswatches. Each color swatch contains seven color shades represented by a numerical code(i.e. Color shade:4685U, Color swatch 55.5U). Refer to Figure 1 for a picture representation ofthe terms color shade and color shade. The color guide includes hundreds of color shades.Therefore, it was desirable to eliminate the color shades from the guide that was not neededfor testing purposes but would give the analyst realistic color standards to compare thesample to.Page 2

Figure 1. Description of Terms UsedColor ShadeColor SwatchAll of the samples that were tested per the visual method were compared to the all of colorswatches contained in the Pantone Formula Guide Solid Uncoated by two analysts. Twoadditional samples were also compared. The results shown below are reported as a colorshade number followed by a color swatch code in parenthesis.Page 3

Table 2 – Initial Pantone Method ResultsAPI X LotAPI X DescriptionPantone Initial ResultsAnalyst 1Analyst 2AForm B, Nonmicronized4685U (55.5U)4685U (55.5U)BForm B, Micronized489U (58U)489U (58U)CForm B, Micronized4665U (55.5U)4675U (55.5U)DForm A, Micronized434U (51U)4755U (56.5U)EForm A, Micronized434U (51U)4755U (56.5U)FForm B, Nonmicronized4645U (55.5U)465U (55.5U)GForm B, Micronized4685U (55.5U)4685U (55.5U)HForm B, Micronized4755U (56.5U)4665U (55.5U)IForm B, Micronized465U (55U)4645U (55.5U)The color swatches that the analyst reported results from along with the color swatches thatwere in between the reported color swatches were cut into approximately 50 individual colorshades. These shades were grouped into the following color categories by 6 analysts (3 thatwork with API X regularly and 3 that had never worked with API X):Off-WhiteLight OrangeOrangeLight PinkPinkLight PurpleLight BrownBrownFurther CategorizationEach analyst assigned the color shades to the corresponding color that they thought was themost representative of that shade. Each color category consisted of 7 to 10 shades. Due topractical use of the method, the number of shades in each category was decreased to no morethan 5 shades. Each analyst categorized the 5 color shades to a corresponding color category.Using the Light Orange color category Figure 2 shows the progression of the colorcategorization.Page 4

Figure 2. Progression of Color Categorization for Light-OrangeHundreds of Color ShadesPage 5

The 3 color shades shown above are the 3 color shades that provide the widest range of the“Light Orange” color shades. The analyst will use these 3 color shades as a guide whendetermining if the reported color for API X is light orange.The following is a list of all of the color shades that were chosen for each color category. Eachset of Pantone color shades are used as a guide to assist the analyst in determining the colorof the API X. The Pantone Color Code is not reported.Table 3 – Pantone Color Categories as determined by Color Categorization ProcessColor CategoryOrangeLight OrangeBrownLight BrownPurpleLight PurplePinkLight PinkOff WhitePantone 5U5035U502U496U4755U481U4685UThe same API X samples as in Table 1 were then compared to the above Pantone ColorCategories to determine the reported color. As shown in Table 3, the results are much lesssubjective and show less variability than the visual method.Page 6

Table 4 – Pantone Appearance Results using the Color CategoriesAPI XLotABCDEFGPantone MethodAnalyst 1Off-white(4685U)Light ite(4755U)Brown(465U)Off-white(4685U)Analyst 2Off-white(4685U)Light ite(4755U)Light Brown(464U)Off-white(4685U)Analyst 3Off-white(4685U)Light ite(4755U)Light Brown(465U)Off-white(4685U)PrecisionAnalyst 4Light Brown(467U)Light te(4755U)Light Brown(465U)Light Brown(467U)Analyst 5Light Orange(475U)Light 4755U)Light 8080CONCLUSIONSThe use of the developed Pantone Method for appearance testing of API X increased theprecision of the method from 67% to 80 - 100%, and is thus considered to be more robust.The method variability decreased significantly.Page 7

set of Pantone color shades are used as a guide to assist the analyst in determining the color of the API X. The Pantone Color Code is not reported. Table 3 – Pantone Color Categories as determined by Color Categorization Process Color Category Pantone Code Orange 471U 473U 486U Light Orange 475U 488U 489U Brown 478U 4695U 464U 4645U