Developing Analytical Chromatographic Methods for Pharmaceutical Stability Investigations

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1 Developing Analytical Chromatographic Methods for Pharmaceutical Stability Investigations Warren B Potts III Senior Director Americas Marketing Warren_potts@waters.com 2017 Waters Corporation 1

2 Outline Stability Indicating Methods and Pharmaceutical Stability Investigations Reverse Phase Chromatographic Method Development Considerations Instrument Considerations Case Study 2017 Waters Corporation 2

3 Outline Stability Indicating Methods and Pharmaceutical Stability Investigations Reverse Phase Chromatographic Method Development Considerations Instrument Considerations Case Study 2017 Waters Corporation 3

4 Stability Indicating Methods (SIMs) What is a Stability Indicating Method (SIM)? An analytical method capable of measuring: o Drug and degradants In the presence of excipients and additives expected to be in the formulation Such methods are usually chromatographic How are they used? Used in Long term, Intermediate and Accelerated Stability Studies o Assess ( indicate ) drug stability and visualize degradants How are they developed? The topic of this seminar o Numerous degradants Challenging method development 2017 Waters Corporation 4

5 Pharma Stability Investigations ICH Quality Guidelines, Stability Sections (ICH Q1, A-E) Apply to drug registration in the EU, Japan and the US Assess drug quality over time under various conditions Establish drug shelf life and storage conditions Stability Investigation Examples Long Term o ± 2 C / 65% ± 5% RH (ambient storage labeling) o 12 5 ± 3 C (refrigerator storage labeling) Accelerated o 6 40 ± 2 C / 75% ± 5% RH (ambient storage labeling) o 6 25 ± 2 C / 60% ± 5% RH (refrigerator storage labeling) Stress o temperature, humidity above Accelerated conditions o oxidative, photolytic, high/low ph conditions as appropriate RH = Relative Humidity International Council for Harmonization of Technical Requirements for Pharmaceuticals for Human Use 2017 Waters Corporation 5

6 Outline Stability Indicating Methods and Pharmaceutical Stability Investigations Reverse Phase Chromatographic Method Development Considerations Factors, Responses & Response Criteria used in Method Development Method Development Stages & Strategies Instrument Considerations Case Study 2017 Waters Corporation 6

7 Chromatographic Method Development: Factors Factors are inputs in method development Levers of Power that cause analyte selectivity/resolution changes Optimal Factor combinations = key to successful Method Development Some Factors have stronger effects Solvent, ph, Column Stationary Phase Others Factors have weaker effects Gradient Slope, Column Temperature Some Factors are numeric (continuously variable) Column Temperature, ph, Gradient Slope Others Factors are categorical (non-numeric, fixed) Column Stationary Phase, Solvent Must Decide: Which Factor Combinations To Examine? 2017 Waters Corporation 7

8 AU AU Effects of Solvent on Separation: Changes in Selectivity Thymine 2. Amiloride 3. Doxylamine 4. Pindolol 5. 2-Acetamidophenol 6. Acetanilide 7. Imipramine 8. Demoxepam 9. Suprofen 10. Ketoprofen 11. Hexanophenone 12. Diflunisal Acetonitrile 0.1% Formic Acid / /12 7 Methanol 0.1% Formic Acid Minutes Separation on a XSelect HSS PFP XP, 2.5 µm, 3.0 x 50 mm Bases, Acids, Neutrals 2017 Waters Corporation 8

9 Factors: ph Considerations ph vs. Retention Retention of neutral analyte not affected by ph Neutral Analyte Retention Factor (k) ph Increases Retention of Acidic Analyte ph Increases Retention of Basic Analyte 10 5 Basic Analyte Acidic Analyte ph Silica ph Range Hybrid Particle ph Range Neue et. al. American Laboratory 1999 (22) Waters Corporation 9

10 AU AU Effect of Mobile Phase ph on Separations: Changes in Selectivity Amiloride Diflunisal Thymine 2. Amiloride 3. Doxylamine 4. Pindolol 5. 2-Acetamidophenol 6. Acetanilide 7. Imipramine 8. Demoxepam 9. Suprofen 10. Ketoprofen 11. Hexanophenone 12. Diflunisal Methanol 10mM Ammonium Hydroxide Methanol 0.1% Formic Acid Minutes Separation on a XSelect CSH C 18 XP, 2.5 µm, 3.0 x 50 mm Bases, Acids, Neutrals 2017 Waters Corporation 10

11 Factors: Column Considerations Waters Particles and Chemistries 2017 Waters Corporation 11

12 Chromatographic Method Development: Responses Responses are outputs measured in method development Characterize Factor combinations Peak Properties (for specific peaks) Responses Can Be: Peak retention time, resolution, tailing, etc. Absence of co-elution Peak Aggregates (for chromatograms) Total # of peaks in a chromatogram # of peaks in a chromatogram with specific desirable result e.g. > Resolution value Must Decide: Which Responses to measure? 2017 Waters Corporation 12

13 Chromatographic Method Development: Response Criteria Response Criteria Used to compare quality of Factor combinations (method conditions) Examples For Peak Properties (specific peaks) o Retention in a specific range o Tailing > 0.9 but < 1.0 o Resolution > 1.5 For Peak Aggregates (chromatograms) o Total # of peaks in chromatogram = # of components known/believed present or maximum # found (when # known/believed present cannot be determined) Must Decide: What Target Response Criteria to use for evaluating success? 2017 Waters Corporation 13

14 Chromatographic Method Development: Stages Set Method Development Objectives o Include Strategy, Factors, Responses & Response Criteria Screen Wide range of Factor combinations o Usually with stronger effects Optimize Narrow range of Factor combinations o Often adding Factors with weaker effects Lock onto specific values for some Factors from Screening Select Final Method Conditions meeting objectives 2017 Waters Corporation 14

15 Outline Stability Indicating Methods and Pharmaceutical Stability Investigations Reverse Phase Chromatographic Method Development Considerations Instrument Considerations Case Study 2017 Waters Corporation 15

16 Instrument Used In The Case Study Column Manager CHC 30 cm 4.0 to 65.0 C 3 Column Selector Temperature Accuracy/Stability C/+ 0.3 C 2998 PDA Detector Sample Manager FTN-R Accuracy/Precision (1.0 to 4.9 ul) ul/<0.5% RSD Linearity > ( ul) Isocratic Solvent Manager QDa Makeup flow Quaternary Solvent Manager-R 9,500 PSI to 5 ml/min Solvents Lines A, B, C, D1-D6 Flow Accuracy/Precision + 1.0%/0.075% RSD Composition Accuracy/Precision + 0.5% (absolute)/+0.15% RSD AutoBlend+ (Online ph Blending) capable QDa Mass Detector Self calibrating Pre-optimized & Adjustment free +/- ESI Source MS made simple! System performance 25 µl system dispersion (Alliance = µl, H-Class = 7 µl) Ideally suited 3.0 / 4.6 mm ID columns 2.5 / 5 µm Platform extension of ACQUITY family 2017 Waters Corporation 16

17 AU Key Meth. Dev. Instrument Feature: Detecting Co-Eluting Peaks UV chromatogram of a 12 component mixture Where is the 12 th peak? Minutes 2017 Waters Corporation 17

18 Intensity Intensity AU Peak Tracking & Co-elution Detection Made Easy with the QDa Mass Detector nm 6x10 6 4x10 6 2x Acetamidophenol m/z 0 2x10 7 1x10 7 Pindolol m/z Minutes Co-eluting peaks detected by using a QDa and tracking compounds masses 2017 Waters Corporation 18

19 Outline Stability Indicating Methods and Pharmaceutical Stability Investigations Reverse Phase Chromatographic Method Development Considerations Instrument and Column Considerations Case Study Developing a SIM for Stability Studies on Amoxicillin Powder for Oral Suspension (APOS) 2017 Waters Corporation 19

20 Chromatographic Method Development: Strategies Analyst Only Method Development One Factor At a Time (OFAT) Full Factorial Screen Tiered Screen (e.g. Waters Systematic Protocol) Assisted Method Development (Analyst + Design & Model Software) Statistical Based Model Design of Experiments (DoE) / Quality by Design (QbD) o E.g. S-Matrix Fusion QbD software Structure Based Model o E.g. ACD ChromGenius software Chromatographic Theory Based Model o E.g. Molnar-Institute DryLab and ACD LC Simulator software For Many Analysts: Method Development Software is a Useful Black Box Tool. Will Use This Strategy In Case Study 2017 Waters Corporation 20

21 Amoxicillin Powder for Oral Suspension (APOS) Amoxicillin: beta-lactam antibiotic (hydrolytically unstable). Formulated: amoxicillin trihydrate with excipients Administered: aqueous amoxicillin powder oral suspension Label Shelf Life: Dry powder = 3 years Aqueous suspension = 14 days Storage: Dry powder: Room temperature (not above 25 C) Aqueous suspension: Refrigerator temperature (2 8 C) 2017 Waters Corporation 21

22 Case Study Objectives Use Stress (Forced Degradation) Sample Made by heating aqueous APOS (2 90 C) Do Method Development with Fusion QbD Software Assistance Create reverse phase liquid chromatography (LC) method to separate the API (Amoxicillin), excipients and degradants o Separate > Rs 1.5 for all peaks with an area > 1% of the API in the Stress sample except: Peaks for diasteriomers of known impurities can coelute Achieve this goal by setting appropriate o Factor combinations to test o Responses to measure o Response Criteria to use API = Active Pharmaceutical Ingredient 2017 Waters Corporation 22

23 Known Amoxicillin Degradation Pathways Polar Compounds! All have both acidic and basic groups. ph will be important! 2017 Waters Corporation 23

24 QbD Method Development Screening: Factors Used Initial Constant Factors Column Temperature = 30 C Flow Rate = ml/min Injection Volume = 4.0 ul Sample Concentration = 0.80 mg/ml aq. amoxicillin in APOS Column Geometry and Particle Size: 3x50 mm, 2.5 μm Monitor 214 nm Must Decide: The ACQUITY Arc has 3 column switching positions. Which 3 columns should we use (and why?) Hint: Amoxicillin and degradants are very polar! 2017 Waters Corporation 24

25 Waters Reversed Phase Columns: Used in the Case Study FULLY POROUS FULLY POROUS BEH Technology (XBridge) Unparalleled ph, mobile phase and temperature versatility HSS Technology (XSelect) Mechanical Stability of Pure Silica Particle Increased retention lower ligand density Good general purpose column Unique selectivity, due to lower ligand density giving better access to silanols. Improved retention for polar compounds in high aqueous mobile phases. Unique selectivity, due to embedded polar group Waters Corporation 25

26 QbD Method Development Screening: Factors Used (cont.) Initial Variable (Screen) Factors 3 Columns: XBridge BEH C18, XBridge BEH Shield RP18, XSelect HSS T3 2 Strong Solvents (SS): Acetonitrile, Methanol 5 phs: 2.31 to 6.16 (HSS T3 cannot handle high ph) o Select 20 mm aq. formic acid / 20 mm aq. ammonium formate blends to achieve ph = 2.31, 2.99, 3.75, 4.80, 6.16 (AutoBlend+ approach) 5 Gradient Times/Slopes: 5.88 / 0.90% to / 0.30% (min. / % SS/CV) o Specific Values: 5.88 min (0.90% SS/CV) 8.82 min (0.60% SS/CV) min (0.45% SS/CV) min (0.36% SS/CV) min (0.30% SS/CV) CV = Column Volume (from Waters Columns Calculator) Duration (min) 2017 Waters Corporation 26 Start %SS End %SS Gradient Slope (% SS/CV) # CV to % to 0.30% 27.7 to

27 Enter Screen Factors into Fusion QbD Software Solvents & phs - AutoBlend+ (Online ph Blending) capability ACQUITY Arc has fully automated control over mobile phase ph Blend phs confirmed by aliquot collection and ph measurement 20 mm conc. each A/D solvent line ratio controls ph 2017 Waters Corporation 27

28 Enter Screen Factors into Fusion QbD Software (cont.) Columns & Gradient Profile including Gradient Times ( Slopes) Set gradient time range Gradient Profile Example: Set columns A/D line ratio controls ph 2017 Waters Corporation 28

29 Case Study Screening: Full Factorial vs. QbD Full Factorial Screening 3 Columns X 2 Strong Solvents X 5 phs X 5 Gradient Times/Slopes o 150 Injections needed to examine all Factor combinations Fusion QbD Screening Statistical Design of Experiments (DoE) Approach: 38 Statistically selected Factor combinations (injections) o 29 Factor combinations model Full Factorial space o 9 Replicate Factor combinations assess statistical error Much faster! o Eliminate ca. 80 % of the injections required for Full Factorial Screening Less acquisition and data review time o All acquisition methods made by Fusion and run by Empower o Fusion constructs statistical Factor/Response Performance Model 2017 Waters Corporation 29

30 QbD Method Development Screening: Responses, Criteria & Model Analyst selects Responses (Response Criteria) No. of Peaks (maximize) No. of Peaks > 1.50 USP Resolution (maximize) No. of Peaks > 2.00 USP Resolution (maximize) Max Peak #1 (Amoxicillin) USP Resolution (> 1.5) Max Peak #1 (Amoxicillin) USP Tailing (= ) Fusion creates methods in Empower General separation quantity General separation quality General separation quality Specific (API) separation quality Specific (API) peak shape quality Empower runs methods & integrates chromatograms Fusion fetches results from Empower, uses Responses to calculate Performance Model 2017 Waters Corporation 30

31 QbD Method Development Screening: Best Column & Solvent Combination Responses (Response Criteria) No. of Peaks (maximize) No. of Peaks > 1.50 USP Resolution (maximize) No. of Peaks > 2.00 USP Resolution (maximize) Max Peak #1 (Amoxicillin) USP Resolution (> 1.5) Max Peak #1 (Amoxicillin) USP Tailing (= ) Fusion QbD Model Proposes BEH C18 & Acetonitrile as Best Column & Solvent combination to use. Cumulative Desirability Result (scale of 0 to 1) BEH C18 BEH Shield RP18 HSS T3 Acetonitrile Methanol Waters Corporation 31

32 Examine Target Reference Point In APR API # Pks > 1.50 Rs Lower bound Larger peaks co-elute # Pks > 2.00 Rs Lower bound ph API < 0.9 Tailing Lower bound T APR Grad. Time = 8.38 min, ph = 4.53 Peak count = 22 # Pks > 1.50 Rs = 14 # Pks > 2.00 Rs = 12 API Rs = 4.75, Tail = 1.02 API > 1.50 Rs Lower bound Gradient Time (min) API > 1.1 Tailing Upper bound Peak Count Lower bound 2017 Waters Corporation 32

33 Examine Points Outside APR The Model Is Just a Guide on Where to Focus Effort # Pks > 1.50 Rs Lower bound Larger peaks more spread out # Pks > 2.00 Rs Lower bound ph API < 0.9 Tailing Lower bound T APR Grad. Time = 8.38 min, ph = 5.17 Peak count = 22 Higher than # Pks > 1.50 Rs = 14 expected # Pks > 2.00 Rs = 12 API Rs = 0.46, Tail = 0.98 API > 1.50 Rs Lower bound Gradient Time (min) API > 1.1 Tailing Upper bound Peak Count Lower bound Lower than expected 2017 Waters Corporation 33

34 Examine Points Outside APR # Pks > 1.50 Rs Lower bound Larger peaks more spread out # Pks > 2.00 Rs Lower bound ph API < 0.9 Tailing Lower bound T APR Grad. Time = 8.38 min, ph = 3.88 Peak count = 24 # Pks > 1.50 Rs = 18 Improved # Pks > 2.00 Rs = 15 API Rs = 3.03, Tail = 1.26 API > 1.50 Rs Lower bound Gradient Time (min) API > 1.1 Tailing Upper bound Peak Count Lower bound > Waters Corporation 34

35 Optimization Region Gradient Time (refine) 6.80, 8.35, 9.90 min ph (refine) 4.01, 4.49, 5.04 Column Temperature (added) 30, 35, 40 C # Pks > 1.50 Rs Lower bound # Pks > 2.00 Rs Lower bound ph API < 0.9 Tailing Lower bound Optimization Region APR API > 1.1 Tailing Upper bound API > 1.50 Rs Lower bound Peak Count Lower bound Gradient Time (min) 2017 Waters Corporation 35

36 Optimization: Example Gradient Time 6.80 min ph 4.01 Column Temperature 30 C API Co-Elute Non-API Co-Elute M QDa Positive Apex Amoxicillin (API) MH+ = 366; 2MH+ = 731 Peak # QDa P Apex 2017 Waters Corporation 36

37 Optimization: Example Gradient Time 9.90 min ph 5.04 Column Temperature 30 C M QDa Positive Scan API Co-Elute Non-API Co-Elute Leading Apex Trailing 2017 Waters Corporation 37

38 Optimization: Example Gradient Time 8.35 min ph 4.49 Column Temperature 35 C API Co-Elute Non-API Co-Elute 2017 Waters Corporation 38

39 Optimization: Best Conditions Gradient Time 8.35 min ph 4.01 Column Temperature 35 C M QDa Positive Scan Good API Peak Purity Confirmed some components (std. inj.) Related Compounds C and D (as diasteriomers) APOS excipient component API Cmpd D diastereomers Leading Apex Trailing Cmpd C diastereomers Excipient component in APOS Objectives met 2017 Waters Corporation 39

40 Chromatographic Stability Indicating Method Conditions System: ACQUITY Arc with PDA and QDa detection, 3 column positions Column: XBridge BEH C18 XP, 2.5 µm, 3.0 x 50 mm Mobile Phase A: 20 mm Aq. Formic Acid (for AutoBlend+ / Online ph Blending) Mobile Phase B: Acetonitrile Mobile Phase D: 20 mm Aq. Ammonium Formate (for AutoBlend+ / Online ph Blending) Flow Rate: 1.10 ml/min Gradient: See Table Column Temperature: 35 C UV Detection: 214 nm Injection Volume: 4.0 µl Time (min) %A %B %D #CV Slope (%B/CV) QDa Settings: Ionization Mode: Positive Cone Voltage: 15 V Capillary Voltage: 1.5 kv Mass Range: m/z Listed Constant Mobile Phase A/D Ratio Sets ph = 4.0 CV = Column Volume (from Waters Columns Calculator) 2017 Waters Corporation 40

41 Summary Case Study: Amoxicillin Powder for Oral Suspension Screened: solvent, ph, column & gradient slope Optimized: ph, gradient slope, column temperature on best column & solvent combination Result o Fusion QbD guided efforts o Required < 20 % of the work compared to Full Factorial Far fewer injections to make and review Automated method creation Model assisted best Factor combinations to consider o Obtained optimal Factor combination Stability Indicating Method 2017 Waters Corporation 41

42 Acknowledgements Waters Corporation Thomas Swann Ken Berthelette Neil Lander Vladimir Binshtock Jean Michele Plankeele Jacob Fairchild Michael Jones Kevin Jenkins S-Matrix Corporation Richard Verseput George Cooney Bill Merkle 2017 Waters Corporation 42

43 2017 Waters Corporation 43

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