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    Add as FriendCase Studies in Quality by Design with Design of Experiments From Pharmaceutical Technology

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    1 : 19 August 2008 1 Case Studies in Quality by Design with Design of Experiments From Pharmaceutical Technology Lynn Torbeck 19 August 2008
    2 : 19 August 2008 2 Overview A little, very little, history 3 types of controlled experiments Key literature and dates Today’s driving force behind QbD “Show me an example in my area of interest” Case Studies from Pharm Tech
    3 : 19 August 2008 3
    4 : 19 August 2008 4 A Short Bit of History Sir Ronald A. Fisher Born 1890, England Died 1962, Australia Graduated college in 1913, math, genetics 1919 joined Rothamsted Experimental Station in Harpenden, England The right person in the right place.
    5 : 19 August 2008 5 Three Controlled Experiments John S. Mill, System of Logic, 1843 1. Success / Failure One run, no factors varied, one outcome, yes/no Easy to design, easy to analyze Lack of comparison, inefficient 2. OFAT, One-Factor-at-a-Time We all learned this in school Several runs, one factor varied, two outcomes Easy to Design, has comparison of outcomes Can’t find interactions and is inefficient
    6 : 19 August 2008 6 Fisher’s Experiments Multiple runs, multiple factors varied Multiple outcomes Will find interactions Is much more efficient Comparison of outcomes
    7 : 19 August 2008 7 Key Literature 1926, “The Arrangements of Field Experiments.” Journal of the Ministry of Agriculture of Great Britain. Fisher. 1935, The Design of Experiments, Oliver & Boyd, London. Fisher. 1951, “On the Experimental Attainment of Optimum Conditions,” Box and Wilson. The original source for QbD !
    8 : 19 August 2008 8 Today’s Driving Force FDA / PAT guidance ICH Q8 – Quality by Design ICH Q8 _ Annex with DOE example The freedom of Design Space Ability to change within Design Space Economics and cost savings Product / Process Knowledge
    9 : 19 August 2008 9 State of the Topic While there is more to Quality by Design than DOE, it seems to be the part that most people have the most trouble with. Chemometrics is many times more complicated than DOE but yet it seems to be more readily accepted than DOE.
    10 : 19 August 2008 10 Show Me an Example Many people have taken a DOE class at some time, but still have difficulty in getting started. The most common request is for examples in specific areas. Examples here show that it is not all that difficult to get started. QbD was being done before ICH Q8
    11 : 19 August 2008 11 Six Steps to Designing Do your homework Define the measured responses (CQA) Brainstorm factors (CPP) Select 2-7 factors to be treatments Select levels or values for treatments Select a design
    12 : 19 August 2008 12 A Short List of Designs
    13 : 19 August 2008 13 Pharm Tech Yearbook, 1999 “Functionality Testing of a Co-processed Diluent Containing Lactose and Microcrystalline Cellulose” Gohel, M., et all Pre-formulation development of excipients
    14 : 19 August 2008 14 Objective “The objective of the present study was to prepare the directly compressible adjuvant by using a simpler process that could be adopted by any pharmaceutical company. Product is a tablet
    15 : 19 August 2008 15 Treatments A: Ratio of lactose to MCC 75:25, 85:15 Binding Agent Dextrin, HPMC % binding agent 1.0%, 1.5%
    16 : 19 August 2008 16 Held Constant Stirring speed at 35 rpm Stirring time at 90 minutes
    17 : 19 August 2008 17 Agglomerate Responses Bulk Density, Tapped Density Angle of Repose, Flow Rate Hausner ratio Carr’s Index Friability Index Moisture uptake
    18 : 19 August 2008 18 Statistical Design Three treatments Each at two levels Eight sets of conditions or runs A 23 full factorial design
    19 : 19 August 2008 19 Results This is a complicated set of data with many two factor interactions, but it can be understood by looking at a geometric presentation of the factors and the responses for flow rate. Ratio is on the horizontal, A, axis Agent is on the vertical, B, axis Percent is on the third, C, axis
    20 : 19 August 2008 20
    21 : 19 August 2008 21 Observations for Flow Rate Within these bounds, flow is 14.0 to 19.0 g/s Slowest is 85/15, HPMC, 1.5%. Fastest is 75/25, HPMC, 1.5% Fast is 85/15, Dextrin, 1.0%
    22 : 19 August 2008 22 Pharm Tech, November 1999 This is a related example. “An Investigation of the Direct-Compression Characteristics of Co-processed Lactose-Microcrystalline Cellulose Using Statistical Design.” Gohel, M., and Jogami, P.
    23 : 19 August 2008 23 Pharm Tech, June, 1993 A bottle packaging example. “The Effect of Rayon Coiler on the Dissolution of Hard-Shell Gelatin Capsules. Hartauer, K.; Bucko, J.; Cooke, G; Mayer, R.; Schwier, J. and Sullivan, G.
    24 : 19 August 2008 24 BioPharm, October 1997 “Demonstrating Process Robustness for Chromatographic Purification of a Recombinant Protein.” Kelly, B.; Jennings, P.; Wright, R. and Briasco, C.
    25 : 19 August 2008 25 Objective “Control is achieved by setting operating ranges for manipulated process variables. Those ranges should ensure that a process does not fail within the multidimensional operating space defined by those limits.” That is, the Design Space !
    26 : 19 August 2008 26 Treatments Load Mass 2.4 – 15.5 Load Conductivity 2.5 – 4.2 % Cleavage 63 – 75 Wash pH 9.4 – 9.6 Wash volume 9.7 – 11.6 Elution pH 9.4 – 9.6 Elution conductivity 8.6 – 14.4
    27 : 19 August 2008 27 Responses Recovery % Purity % rhIL-11 mass Product pool volume Elution pool concentration
    28 : 19 August 2008 28 Statistical Design Wash pH / Wash volume confounded Elution pH / Elution conductivity confounded Five factors each at two levels 16 runs will still find the two factor interactions Design is a 25-1 fractional factorial
    29 : 19 August 2008 29
    30 : 19 August 2008 30 Design Space Independent Factor Space ? Dependent Response Space
    31 : 19 August 2008 31 Conceptual Design Space Uncertain space Region of operability Operation Space Opt Region of Interest
    32 : 19 August 2008 32 Statistical Design Space “The mathematically and statistically defined combination of Factor Space and Response Space that results in a system, product or process that consistently meets its quality characteristics, SSQuIP, with a high degree of assurance.” LDT
    33 : 19 August 2008 33 Analysis Analysis is done by fitting a mathematical model to the factors (CPP) and the responses (CQA) that includes the factor main effects and the significant two factor interactions The model is then used to find contour plots for recovery and purity.
    34 : 19 August 2008 34
    35 : 19 August 2008 35
    36 : 19 August 2008 36
    37 : 19 August 2008 37 Pharm Tech, February 1999 “Blow-Fill-Seal Technology: Part II, Design Optimization of a Particulate Control System.” Price, J.
    38 : 19 August 2008 38 Objectives Optimize the particulate control system Find cause and effect relationships Alter the system settings to improve performance Find interactions between factors
    39 : 19 August 2008 39 Treatments HEPA flow rate % 20 50 80 Damper % open 30 55 80 Chimney air ft/min 300 550 800 HEPA height in 0 0.375 Isolation plate Slotted – Hole Knife cut Double Single
    40 : 19 August 2008 40 Response Particulate level. Three measurements at each of the 24 conditions
    41 : 19 August 2008 41 Statistical Design Six factors Three at two levels Three at three levels 16 combinations 8 center points Design is a 26-2 fractional factorial Design is resolution IV
    42 : 19 August 2008 42 Analysis Analysis of Variance, ANOVA, was used. 15 effects were included 5 were statistically significant Damper HEPA height Knife cur Isolation plate HEPA flow * HEPA height OR {damper*knife cut}
    43 : 19 August 2008 43 Conclusions “The study met the design objective of minimizing the particulate levels while the particulate control system operated in the dynamic state. … a more thorough understanding of the cause and effect relationships between the critical input factors and the particulate levels was obtained using the DOE.”
    44 : 19 August 2008 44 Pharm Tech, Analytical Validation, 1999 Robustness Testing of an HPLC Method Using Experimental Design.” Peters, P. and Paino, T.
    45 : 19 August 2008 45 Objective “This article describes an experimental design that challenged an analytical method that assays two components in a solid dosage drug product.” Confirm the robustness of an HPLC method.
    46 : 19 August 2008 46 Treatments HPLC system A, B HPLC column Y, X Wavelength A 270, 290 B 215, 235 Flow rate 0.7, 1.3
    47 : 19 August 2008 47 Treatments Injection volume 10, 30 Column temp Ambient, 30 Mobile phase TFA 85, 75 MeCN 15, 25
    48 : 19 August 2008 48 Responses Resolution of component A and B Theoretical plates for A and B Tailing factor for A and B %RSD of the peaks for A and B
    49 : 19 August 2008 49 Statistical Design 7 factors each at two levels Wavelength A and B are confounded Mobile phase TFA and MeCN are confounded 8 runs done in triplicate for 24 total Design is a 27-4 fractional factorial Design is resolution III.
    50 : 19 August 2008 50 Analysis and Results Visual inspection of an overlay of the 8 chromatograms shows that the method is robust within the tolerance limits of the parameters tested. They have acceptable resolution and peak shape.
    51 : 19 August 2008 51 Compare Chromatograms
    52 : 19 August 2008 52 Pharm Tech, May 1998 “A Systematic Formulation Optimization Process for a Generic Pharmaceutical Tablet.” Hwang, R.; Gemoules, M; Ramlose, D. and Thomasson, C.
    53 : 19 August 2008 53 Objective “ … optimizing an immediate release tablet formulation for a generic pharmaceutical product.” Develop a generic tablet with a disintegration time of 6-12 minutes, 5 minute dissolution of 40-60% and 45 minute dissolution of greater than 90%.
    54 : 19 August 2008 54 Treatments API particle size small large API % 5% 10% Lactose MCC ratio 1:3 3:1 MCC particle size small large MCC density low high
    55 : 19 August 2008 55 Treatments Disintegrant cornstarch, glycolate Disintegrant % 1% 5% Talc 0 5% Mag Sterate 0.5% 1%
    56 : 19 August 2008 56 Responses Blend homogeneity Compression force %RSD Ejection force Tablet weight %RSD Tablet hardness
    57 : 19 August 2008 57 Responses Tablet friability Tablet disintegration time Tablet dissolution at 5 minutes Tablet dissolution at 45 minutes
    58 : 19 August 2008 58 Statistical Design 9 factors each at two levels 16 runs Design is a 29-5 fractional factorial Resolution III
    59 : 19 August 2008 59 The best formulation: API 7.14% Fast-Flo lactose 60.74% Avicel PH-302 30.37% Talc 1% Mag Stearate 0.75%
    60 : 19 August 2008 60 Conclusion “The formulation was successfully scaled up to a 120 kg batch size and the manufacturability and product quality were confirmed.” “This study has demonstrated the efficiency and effectiveness of using a systematic formulation optimization process … “
    61 : 19 August 2008 61 Pharm Tech, March 1994 “Evaluation of a Cartridge and a Bag Filer System in Fluid-Bed Drying. Bolyard, K. and McCurdy, V.
    62 : 19 August 2008 62 Pharm Tech Europe, April 2000 “Response Surface Methodology Applied to Fluid Bed Granulation.” Wehrle, P. et all
    63 : 19 August 2008 63 Pharm TechMarch 1992 and May 1992 “A Compaction Study of Directly Compressible Vitamin Preparations for the Development of a Chewable Tablet, Parts I and II. Konkel, P. and Mielck, B.
    64 : 19 August 2008 64 Pharm Tech, March 1994 “Computer Assisted Experimental Design in Pharmaceutical Formulation.” Dobberstein, R. et all.
    65 : 19 August 2008 65 Pharm Tech, April 1998 “A Unique Application of Extrusion for the Preparation of Water Soluble Tablets.” Murphy, M. and Hollenbeck, R.
    66 : 19 August 2008 66 Pharm Tech, June 2000 “Artificial Neural Network and Simplex Optimization for Mixing of Aqueous Coated Beads to Obtain Controlled Release Formulations.” Vaithiyalingam, S. et all.
    67 : 19 August 2008 67 Summary Looked at 13 Case studies Shown 3 types of analysis Shown several areas of application Illustrated how to get started Shown that Q8 QbD has a precedent DOE has been used for a long time
    68 : 19 August 2008 68 Acknowledgements The University of Adelaide Library is the owner of the image of Sir R. A. Fisher. Pharmaceutical Technology holds the copyright for the journal articles used in this presentation. Opinions in this presentation are that of Lynn Torbeck alone.

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