Automated Method Development With UPLC and Fusion Software A Quality by Design-based Tool Jean-Michel Plankeele May Waters Corporation 1

Transcription

1 Automated Method Development With UPLC and Fusion Software A Quality by Design-based Tool Jean-Michel Plankeele May Waters Corporation 1

2 Agenda LC method development and Quality-by-Design guidelines Definition of key words: QbD, DOE, Design Space Waters consistent approach for efficient method development FusionMD for method development How it works, what it does Summary & conclusions 2012 Waters Corporation 2

3 Quality By Design Published Guidelines QbD approach has been there since decades in all types of industry More recently implemented in pharmaceutical area (early 2000) Guidelines are published by ICH* Everything about QbD, design of experiment can be found in ICH Q8 (R2) QbD, DoE, design space, graphical tools Additional details in ICH Q9 & Q10 *ICH: International Conference on Harmonisation 2012 Waters Corporation 3

4 Some Definitions What Is Quality By Design? Quality by Design: A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management ICH Q8(R2) Guidelines QbD is a systematic approach to development No speculation or a priori statements about results that begins with predefined objectives Defining criteria (response factors) to be used to measure the quality of the method sound science and quality risk management Statistical treatment of data to provide quantitative values to goals and limits of response factors QbD approach is implemented with an experimental design 2012 Waters Corporation 4

5 ICH Q8 (R2) guidelines for Design Of Experiment (DoE) Formal Experimental Design: A structured, organized method for determining the relationship between factors affecting a process and the output of that process. Also known as Design of Experiments. ICH Q8(R2) Guidelines A structured and organized method of gathering empirical knowledge DoE are represented as a multi-dimensional spaces (matrix) Selectivity parameters (study variables) are the dimensions of this space Z (Organic Solvent) Best method Number of experiments is optimized using an appropriate study design (full factorial design & partial factorial design) X (ph) Y (Gradient Time) 2012 Waters Corporation 5

6 What Is a Design? Full Factorial, Partial With a full factorial design, all elements (experiments) of the matrix are sampled In an incomplete factorial design the multidimensional space is sampled evenly and efficiently Factor levels are chosen randomly and then balanced to achieve uniform sampling Three variable full factorial design Three variable partial factorial design 2012 Waters Corporation 6

7 ICH Q8 (R2) guidelines Design Space Design Space: the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality. Working within the design space is not considered as a change ICH Q8(R2) Guidelines Around the best method, there is a space where the method achieves the predifined objectives This is the area of robustness Z optimum Z Operating Space Each method (combination of parameters) within the design space meets the requirements Working within the design space is not considered as a change No need for revalidation within the design space Y optimum Y (Gradient Time) X (ph) X optimum 2012 Waters Corporation 7

8 ICH Q8 (R2) Recommandations For Depiction Of Interactions And Design Space Response graphs: 3 D plots for viewing effects (linear effects, combined effects, interactions ) 3 D plots for evaluating the performances Contour plots (or 2 D plots) for evaluating the robustness 2012 Waters Corporation 8

9 How Does It Translate When Developping LC Methods? Quality by design Chromatographers must consider all selectivity parameters The impact of parameters (range/effect) must be evaluated Chromatographers must work with preset objectives o Cleaning validation o Impurity profiling o Quality control Speed Resolution Speed, specificity Experiment design, design of experiment (DoE) Definition of experimental region, selection of study variables with their ranges Primary selectivity parameters Stationnary phase, ph & solvent Secondary selectivity parameters Temperature, flow rate, slope, gradient time, 2012 Waters Corporation 10

10 Agenda LC method development and Quality-by-Design guidelines Definition of key words QbD DOE, Design Space FusionMD for method development What is it, What it does, how it works Summary, conclusions 2012 Waters Corporation 11

11 What Is Fusion - What It Does Fusion works in cooperation with Empower I, II & III From workstation to network Fusion supports all UPLC configurations ACQUITY UPLC and H-CLASS All optical detectors Solvent switching valves (external/uplc or internal/ssv) Column managers (temperature control and column switching) Fusion supports all Empower controlled configurations Alliance, Automatically builds methods, method sets and sample sets 2012 Waters Corporation 12

12 Fusion Alignment With [Q b D] Approach [1] Define Experimental Region Select study variables Define study ranges Screening/scouting of all selectivity parameters Supports RP, NP, IEX, SEC, HILIC, Controls all UPLC configurations All options (detectors, valves, ovens) [2] Develop Knowledge Space Applies the DoE approach Structured, optimized set of experiments Conduct experimental design Analyze results and study variable effects Full factorial and partial factorial designs Automatically creates and exports all methods [3] Establish Design Space Builds the models of variable effects Finds the best method Define optimum conditions Define robust operating space Incorporates robustness modeling in the MD process 2012 Waters Corporation 13

13 Fusion Workflow In A Few Simple Steps 1. User selects the experimental parameters (study factors or study variables): Columns, temp, solvents, ph, slope, Quality by Design: A systematic approach to development that begins with predefined objectives and emphasizes product and process understanding and process control, based on sound science and quality risk management ICH Q8(R2) Guidelines 2012 Waters Corporation 14

14 Step 1 Define The Variables And Their Ranges Flow rate Gradient shape (time, slope, hold, wash, ) Gradient curve Column temp. ph Buffer strength Organic solvent Column type Injection volume Wavelength 2012 Waters Corporation 15

15 Fusion Workflow In A Few Simple Steps 1. User selects the experimental parameters (study factors or study variables): Columns, temp, solvents, ph, slope, 2. Fusion generates all required methods and creates the experiment design in Empower Formal Experimental Design: A structured, organized method for determining the relationship between factors affecting a process and the output of that process. Also known as Design of Experiments. ICH Q8(R2) Guidelines 2012 Waters Corporation 16

16 Step 2 Create & Export The Design To Empower Fusion automatically selects the most statistically appropriate design type and generates the experiment Minimizes the number of runs Creates instrument methods and method sets within Empower Automatically reconstructs experimental design within Empower The newly created sample set can be edited/customised 2012 Waters Corporation 17

17 Fusion Workflow In A Few Simple Steps 1. User selects the experimental parameters (study factors or study variables): Columns, temp, solvents, ph, slope, 2. Fusion generates all required methods and creates the experiment design in Empower 3. The methods defined above are run on the system Few hours with UPLC vs days with HPLC 2012 Waters Corporation 18

18 Fusion Workflow In A Few Simple Steps 1. User selects the experimental parameters (study factors or study variables): Columns, temp, solvents, ph, slope, 2. Fusion generates all required methods and creates the experiment design in Empower 3. The methods defined above are run on the system 4. Fusion imports results from Empower and builds the models 2012 Waters Corporation 19

19 Step 4 Process Results 2 Develop Knowledge Space* Conduct formal experimental design Analyze results, build equations Run and Process KNOWLEDGE SPACE The information and knowledge gained from pharmaceutical development studies and manufacturing experience to support the establishment of the design space, specifications, and manufacturing controls. [ ICHQ8(R1)] R s = β o + β 1 (X 1 ) + β 11 (X 1 ) 2 + β 2 (X 2 ) + β 22 (X 2 ) 2 + β 12 (X 1 *X 2 ) Linear Effect (main effects term) Curvature Effect (simple curvilinear effects) Interaction Effect (two-way effects) 2012 Waters Corporation 20

20 Fusion Workflow In A Few Simple Steps 1. User selects the experimental parameters (study factors or study variables): Columns, Temp, solvents, ph, slope, 2. Fusion generates all required methods and creates the experiment design in Empower 3. The methods defined above are run on the system 4. Fusion imports results from Empower and builds the models 5. Fusion combines the mathematical models to predict the optimum method 2012 Waters Corporation 21

21 Step 5 Automated Numerical Search for Optimum User enters chromatographic performance goals: Any calculated result can be selected Result fields: No. of peaks, No. of peaks > n%, Peak fields: Rs of max peak, RT of last peak, purity index of max peak, Custom fields can also be selected Fusion MD identifies study parameters of best method performance 2012 Waters Corporation 22

22 Step 5 Numerical Solution Search, Best Conditions Fusion MD identifies study parameters of best method performance 2012 Waters Corporation 23

23 Graphical Tools Visualize factor effects with overlay graphs Define performance goals (No. of peaks > 8) Visualize effects Shaded region indicates Final % and Gradient Time combinations that do not meet performance requirements Waters Corporation 24

24 Add effects to build the Design Space Define performance goals (No. of peaks > 8, RT < 3 min) Visualize effects 2 performance goals Shaded regions indicate Final % and Gradient Time combinations that do not meet performance requirements Waters Corporation 25

25 Combine All Performance Goals Establish the Design Space Design Space Mean Performance Operating space = + Robustness 2012 Waters Corporation 26

26 Next Phase Of Method Development Option 1: Confirm optimised settings Run the sample with predicted settings Automatically built methods and sample set Method is ready to be validated Option 2: Optimise these predicted settings Select best column, best solvent Fine tune secondary parameters o Slope, flow rate, column temperature 2012 Waters Corporation 27

27 Summary & Conclusions FusionMD is a tool for developing LC methods according to Quality-by-Design (QbD) guidelines Automates the entire process of method development Saves time by determining the minimum number of experiments needed for valid results Provides tools to vizualise the impact of chromatographic parameters Integrates robustness during development FusionMD is a part of a System Solution Empower UPLC chemistry UPLC hardware 2012 Waters Corporation 28

28 Need More Information? Waters Corporation 29