Determine Phase Appropriate Activities A Lifecycle Approach for Analytical Procedures and Methods Validation Xiande (Andy) Wang, Ph.D. Analytical Development Janssen Pharmaceutical Companies of Johnson & Johnson IVT Analytical Procedures and Validation, December 2015, Philadelphia
Outline I. Life Cycle of Analytical Methods II. Method Development/Validation at Early Stage (IND) III. Method Development/Validation at Late Stage (NDA) a. Notes on FDA Guideline b. Systematic method development c. Case studies of robust method development IV. Analytical methods for post-marketing support VII. Summary
Full Life Cycle of Pharmaceutical Products Supply Chain/ Operations CMC/R&D
Full Life Cycle of Pharmaceutical Products NME NEW SYNTHESIS/ FORMULATION Supply Chain/ Operations STABILITY MONITORING IND CMC/R&D NDA TECH TRANSFER LAUNCH
Phase Appropriate Activities NME: Identification; isolation; purity profile IND: Method development/validation (abbreviated) NDA: Method development/validation (thorough) LAUNCH: Primary method transfer; stability studies TECH TRANSFER: Secondary method transfer STABILIY MONITORING: Continuous stability studies Method re-evaluation Gap assessment (methods, validation, specifications) Method gap validation/re-development/re-validation New Synthesis/formulation Method development/validation/approval/transfer
IND
Method Development to Support Early Formulation Development The chemistry, manufacturing and controls (CMC) aspect of drug development is focused on producing medicines suitable for human use with specified quality, safety and efficacy characteristics The drug development program is geared towards thorough understanding of the drug product s performance identification of drug product s critical characteristics demonstration of drug s safety and efficacy ultimately leads to the review and approval of the drug Formulation development Proper API characterization (particle size, polymorph, bulk density) Solubility (intrinsic, ph dependent, saturation) Hygroscopicity study Impurity profile Drug excipient compatibility studies Probe stability studies
Validation at IND Vs. NDA IND NDA
Method Development to Support Late Formulation Development Support the following studies: Use of overages Use of excipients, approved colors Adequate optimization study data on process controls Dissolution profile Stability studies Adequate batch size and number of batches Chamber temperature and humidity condition appropriate to the target market Adequate data at the time of submission Photo stability study Proper container orientation (specially for liquid products) Adequate stability study on bulk shipment pack (if intended to ship it for repackaging) Adequate parameters covered under stability protocol (e.g.: microbial testing)
Method Development in Formulation Development: Building-in Quality through Adequate Analytical Testing/Methods Meeting Pharmacopoeial requirement / ICH guidelines Second identification test Adequate impurities & residual solvent specification Testing for preservatives, anti-oxidants wherever used Test for breakability / content uniformity Test for establishing polymorphic conversions Test for water content in solid dosage form Analytical methods: Validated (e.g.: LOD, LOQ in RS method) Stability indicating (for stability studies) Forced degradation studies performed Method development report (adequate justification for choice / selection of method and conditions)
Notes on New Guidance Supersedes 2000 draft guidance on Analytical Procedures and Methods Validation Will replace 1987 FDA guidance for industry on Submitting Samples and Analytical Data for Methods Validation Applies to DS and DP in NDA, ANDA, BLA and DMF. Not address: IND biological and immunochemical assays revalidation of existing analytical methods
Notes on New Guidance: Method Robustness during Method Development During method development, parameters may be evaluated: specificity, linearity, LOD, LOQ, range, accuracy and precision. During early stage of method development, method robustness should be evaluated. Development data should be submitted if they support method validation. A systematic approach (e.g. DOE) should be used for method robustness evaluation.
Notes on New Guidance: Details on Chemicals/Materials
Notes on New Guidance: Combination of Challenges to Demonstrate Specificity
Notes on New Guidance: Notification to FDA; Robustness Data Required
Notes on New Guidance: Compendial Methods
Notes on New Guidance: Statistical Analysis and Models
Notes on New Guidance: Life Cycle Management of Methods
Notes on New Guidance: Changes to Methods
Notes on New Guidance: Revalidation
Notes on New Guidance: Method Comparability Study (1)
Notes on New Guidance: Method Comparability Study (2)
Notes on New Guidance: Method Comparability Study (3)
Notes on New Guidance: Method Transfer
Notes on New Guidance: Report Post-marketing Changes
Analytical Techniques/Methods Titration HPLC GC CE AAS Loss on Drying Karl-Fisher UV-VIS Sulfate ash Heavy metals Insoluble matter Color and clarity Dissolution Appearance IR DSC Optical rotation Melting point/melting profile NMR MS
Stability-indicating Method A stability-indicating assay is a validated quantitative analytical procedure that can detect the changes with time in the pertinent properties of the drug substance and drug product. A stability-indicating assay accurately measures the active ingredients, without interference from degradation products, process impurities, excipients, or other potential impurities Key characteristics of a stability-indicting method: Accuracy Precision Sensitivity (LOD/LOQ) Specificity Peak purity Mass balance Resolution Forced degradation Orthogonal method
Systematic Method Development Process Samples are stressed under different conditions Stressed samples are analyzed with a generic method Representative stressed samples are chosen Process impurities and/or excipients are obtained The methods are optimized A primary method and an orthogonal secondary method are identified Method screening is conducted with selected samples Stressed samples are analyzed with optimized methods The primary method is ready for further optimization / validation
Stressing of API Purposes: To facilitate method development/validation To aid in development of the first API specification To understand the degradation pathways of the API to facilitate rational product development To screen for possible formation of potential genotoxins Provides a control baseline for excipient compatibility studies Target 5-15% degradation with secondary degradation minimized Typical conditions for API might be: Solid under light or heat/humidity In acid, base or buffered media of ph 1-10 with peroxide (and/or free radical initiator) With water under light or heat
Stressing of Formulations Purposes: To facilitate method development/validation Pre-formulation investigations To confirm the mass balance Solid state degradation and stability assessment Role of excipients in API instability Typical conditions might be: Solid under light or heat/humidity In acid, base or buffered media of ph 1-10 with peroxide (and/or free radical initiator) With water under light or heat Different grade/source of excipients
A Generic HPLC Method Column: Endcapped C18, 15x0.46cm, 3.5um (or 1.7 um) Mobile phase A: 0.05%TFA in H 2 O Mobile phase B: 0.05% TFA in MeCN 10/90, A/B Flow rate: 1.2mL/min 20min Run time: 25 min 90/10,A/B 5min Ref: X Wang, Generic HPLC Methods for Pharmaceuticals, Nov 14, 2006, EAS, Somerset, New Jersey. 32
Representative Stressed Samples Deploy the right technique LC-MS or LC/MS/MS Establish the appropriate threshold 0.01% or 0.03% Preparation of degradants Purchase Preparative separation Organic synthesis 33
HPLC Column Screen Set: An Example Orthogonal Screening Columns Stationary Phase Column ph Range a Manufacturer Part Number C18 Twin Technology Gemini C18, 5 m, 110A, 4.6 x 150 mm 1-12 Phenomenex 00F-4435-E0 Phenyl with Hexyl (C6) linker, Luna Phenyl-Hexyl, 3 m, 4.6 x 150 mm 1.5-10 Phenomenex 00F-4256-E0 endcapped C18-20% C loading Discovery HS-C18, 3 m, 4.6 x 150 mm 2-8 Supelco 569252-U C18 polar embedded, hybrid particle with Shield Technology XTerra RP18, 3.5 m, 4.6 x 150 mm 1-12 Waters 186000442 C18 silica Sunfire C18, 3.5 m, 4.6 x 150 mm 2-8 Waters 186002554 Pentafluorophenyl Curosil PFP, 3 m, 4.6 x 150 mm 2-7.5 Phenomenex 00F-4122-E0 a Columns were screened only against mobiles phases within their compatible ph range.
HPLC Screening Conditions: An Example Orthogonal Screening Method Description Time (min) %Water %Acetonitrile % Modifier a Flow Rate (ml/min) 0 85 10 5 1.0 40 10 85 5 1.0 45 10 85 5 1.0 45.10 85 10 5 1.0 60 85 10 5 1.0 Injection Volume 5 L Detection 280 nm; DAD (190 400 nm) Column Temperature Ambient Sample Temperature 5 o C a Modifier stock solutions are prepared at a concentration 20 times higher than the desired mobile phase concentration since mobile phases are prepared at time of use with the HPLC quaternary pump. Modifier Mobile Phase Approximate ph Concentration Trifluoroacetic Acid (TFA) 0.05% 2 Formic Acid 0.1% 2.8 Ammonium Acetate + Acetic Acid 8 mm + 0.1% 4 Ammonium Acetate 8 mm 7 Ammonium Acetate + Ammonium 8 mm + 0.05% 10.2 Hydroxide Ammonium Hydroxide 0.05% 10.8
Method Optimization Examples of optimization parameters: Organic modifier Gradient slope ph Buffer (type, concentration) Flow rate Colum temperature Gel lots of column Sample solvent Injection volume Typically monitored characteristics: Retention time Resolution Tailing factor General approaches: One factor at a time Design of experiments (DOE)
Example of Primary and Secondary Method mau 175 150 Active HPLC method YMC Pro C18 ph 2.5 125 100 75 50 25 0 mau 175 150 6 8 10 12 14 16 18 20 Orthogonal HPLC method XTerra RP 18 C18 ph 7 min 125 100 75 50 25 0 6 8 10 12 14 16 18 20 min Ref. H. Rasmussen et al, HPLC method development, in S. Ahuja and M.W. Dong, ed, 37Handbook of Pharmaceutical Analysis by HPLC, Elsevier, Amsterdam, 2005, Chapter 6.
Approaches to Maximize Method Orthogonality Separation mode Reversed phase (RP) o o Different stationary phase Buffer/pH Normal phase (RP) Hydrophilic interaction Chromatography (HILIC) Detection Different UV wavelength Mass spectrometry Charged aerosol detector (CAD)
AU D Case #1. Complementary Selectivity of Different Separation Modes: Reversed Phase at -Low PH 0.75 0.50 0.25 0.00 A B C 0.0 10.0 20.0 30.0 40.0 50.0 Minutes Col: 250 3mm 5 m Nucleosil 100-5 Protect-1; MPA: 0.3% H 3 PO 4 ; MPB: MeCN; Gradient: Time(min) MPA(%) MPB(%) 0 100 0 26 100 0 35 20 80 40 20 80 41 100 0 Flow-rate: 0.3 ml/min; Column temp: 40 C
Case #1. Reversed Phase at High ph Col: 250 4.6mm 5 m Gemini C18; MPA: 0.3% Triethylamine; MPB: MeOH; Gradient: Time(min) MPA(%) MPB(%) 0 50 50 5 50 50 20 10 90 21 50 50 Flow-rate: 1.0 ml/min; Column temp: 40 C
Case #1. Normal Phase Col: 250 4.6mm 5 m YMC- Pack SIL; MPA: EtOH; MPB: Hexane; Gradient: Time(min) MPA(%) MPB(%) 0 10 90 25 55 45 26 10 90 Flow-rate: 1.5 ml/min; Column temp: 30 C
Case #1. Hydrophilic Interaction Chromatography (HILIC) Col: 250 4.6mm 5 m YMC-Pack DIOL; MP: 94/6, MeCN/50mM NH4OAc; Flow-rate: 1.5 ml/min; Column temp: 30 C
Case #1. Complementary Selectivity of Different Separation Modes Method Elution Order Observations Run time (min) Reversed phase Low ph A, B, C, D Difficult to resolve A & B on most columns 55 Reversed phase High ph B, C, A, D Limited selection of columns at ph ~12 Higher risk of interference Normal Phase D, A, B, C Low peak efficiency Challenging sample preparation HILIC D, B, A, C Short run time, better peak shape and efficiency 30 35 10
Case #2. Complementary Selectivity of Different Separation Modes (RP vs. HILIC) Compd Functional Groups 1 Aromatic, -NH 2, -OH 2(API) Aromatic, -NH 2, -O-CONH 2 3 Aromatic, -OH, -NH-CONH 2 4 Aromatic, -O-CONH- Ref: X. Wang, W. Li, H. Rasmussen, J. Chromatogr. A, 1083 (2005), 58.
Case# 2: HILIC Method Validation Summary Category Specificity Accuracy Limit of Quantitation Linearity Precision Results All peaks of interest are separated. The peaks are free of co-elution as demonstrated by RP-HPLC orthogonal method and peak purity analysis on the UV spectra. The recovery from multiple sample preparation is within the range of 99.2% to 100.6%. 3.75 ng; or 0.05% of standard concentration (0.75mg/mL, 10 L injection, S/N =10) In the range of 0.05% to 120% of standard concentration (0.75mg/mL), the curve composed of 7 data points is linear (R 2 =0.9999). 5 injections of the same standard solution (0.75mg/mL) have a relative standard deviation of 0.4%; 3 individual sample preparations at different concentration levels have a relative standard deviation of 0.8%. 45
Summary of Phase Appropriate Method Development Systematic method development process Stressed sample Method screen Primary/secondary method Method optimization Method validation Approaches to enhance method orthogonality Separation mechanism (HILIC vs. RS for R331333) Detection (UV vs. CAD for paclitaxel and gentamicin/proclin) Phase appropriate development and validation Build up knowledge base for DS/DP in early phase Establish robustness (define design space) in late phase
Triggers of Post-market Method Changes New submission (renewal) to worldwide markets Compendial updates New Guidelines Development of new formulations (combination products) / new API synthetic route Change of manufacturing process Change of source/chemistry of raw materials/intermediates Method transfer to different sites New analytical techniques/improved methods Inspections Events/Observations: stability monitoring; complaints; counterfeits Periodic review/monitor
Analytical Method Transfer Types of method transfer: Comparative testing Co-validation between two laboratories Method validation/re-validation Transfer waiver Steps towards successful method transfer: Discussions initiated Method and validation reviewed Laboratory evaluated Transfer protocol written and approved Experimental data generated Transfer report written and approved
Method Change Triggered by Periodic Monitor/ Review of Methods in Testing Labs Is the method inadequate by today s scientific standard or regulatory requirement? Is sufficient data available to permit simplification of the method? Does monitoring of laboratory deviation suggest a need for method improvement? Do newer method for similar products significantly outperform? Is the volume of testing justify further method optimization or automation?
Life Cycle of Post-approval Analytical Methods Assessment Id gap Open Change Control Method development Report to authority Transfer Validation Implementation Close change control Periodic review monitoring
Change Control Process Flow Pre-CoC meeting Open CoC Site/funtional assessment Authority approval QA/Board approval Site/functional approval Site/functional Implementation Close change control
Change Control Request for change Change control No. Date Type/category of change Change related to product/document/system/facility Concerned documents with number Description of change Reason for change Impact of change Assessment of Impacted sites/functions Proposed methodology for Implementation Closure
Why Is Change Control Critical? Compliance risks due to no/ineffective change control o o o o o o o o o o o Method not aligned with Local regulatory filing Local regulatory filing not consistent with global regulatory filing Global regulatory filing not consistent with latest version of methods Translation to local language is not accurate Wrong version of test method is used at different sites Methods not validated Method not validated according to today s standard Missing information Calculation error Inappropriate system suitability Compendial changes in each country Effective change control system provides evidence of compliance to FDA. It is invaluable to maintain a history of the lifecycle of all change requests.
Summary Analytical methods are essential part of product life cycle Method development/validation activities should be phase appropriate: IND, NDA, post approval New FDA guideline on analytical methods reflects current thinking of agencies and industry trend: to proactively address method issues Robust method development is the best investment in life cycle of analytical methods It is important to manage post-market changes to analytical methods