Developing the Control Strategy for Enhanced Testing and Continuous Monitoring

Transcription

1 Developing the Strategy for Enhanced Testing and Continuous Monitoring i Graham Tulloch, PhD Research Advisor BioProcess Research and Development

2 Outline Introduction Regulatory environment strategy t elements Process Development Continuum Analytical l Strategy t Development Parametric Strategy Development Post-PPQ Strategy Evolution Summary strategy risk assessment Enhanced testing program Reduced analytical testing Continued process verification (routine monitoring) Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 2

3 Definitions Process Validation (Annex 15): The documented evidence that the process, operated within established parameters, can perform effectively and reproducibly to produce a medicinal product meeting its predetermined specifications and quality attributes Process Validation (FDA Guidance for Industry): The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. Stage 1: Process design Stage 2: Process qualification (including process performance qualification (PPQ=PV)) Stage 3: Continued process verification Strategy (ICH Q10): A planned set of controls, derived from current product and process understanding that ensures process performance and product quality. The controls can include parameters and attributes related to drug substance and drug product materials and components, facility and equipment operating conditions, in-process controls, finished product specifications, and the associated methods and frequency of monitoring and control. Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 3

4 Regulatory Environment Process Validation Stage 1 Process Design Stage 2 Process Qualification Stage 3 Continued Building and capturing process knowledge and understanding Establishing relationship Facility design, and utility and equipment qualification Process performance qualification Process validation Process Verification Maintenance of the validated state between variable inputs (e.g. process parameters) and resulting outputs (e.g. CQAs) Establishing a strategy for process control Consistency batches Conformance batches Derived from: FDA Guidance to Industry Process Validation: General Practices and Principles Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 4

5 Strategy Elements: Assuring Quality Raw materials Parametric control In-process analytical control Specifications Raw materials Parametric control In-process analytical control Specifications Drug substance manufacturing Drug product manufacturing what what what goes in goes on comes out Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 5

6 Drug substance process development continuum FHD FRD Submission/ approval/ Pivotal CT supply campaign(s) PPQ campaign launch Commercial manufacturing Drug substance and in-process intermediate analytical data (CQA impact) Quality attribute risk assessment Integrated parametric and analytical control strategies for PPQ Process development program Post-PPQ program Process definition Process characterization Small scale validation Process improvements/ investigations Enhanced testing Routine monitoring Risk assessment: CQA*parameter FMEA: CQA*process control strategy FMEA: Process *facility Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 strategy risk assessments 6

7 Development of the Drug Substance Analytical Strategy Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 7

8 Developing the Analytical Strategy: Identifying Critical Quality Attributes FHD FRD PPQ/ Submission Quality attribute risk Quality attribute risk Quality attribute risk assessment assessment assessment CQAs Knowledge Impact risk H M L No information High Knowledge continuum Molecule specific knowledge High High High Medium Low Low Experience Severity Risk: risk of the quality attribute having a meaningful impact on the pharmacological properties of the bioproduct (biological activity, safety and toxicity, pharmacokinetics, immunogenicity, and efficacy) CQA = quality attribute with medium or high risk Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 8

9 Developing the Analytical Strategy: Evaluation of Process Performance Baseline Performance Process Points Matrix Assessment Cell culture (A) Quality Attribute Primary Point A B C D E F G H I J Primary recovery (B) Monomer Chromatography 2 Form Impact Aggregate Chromatography 2 Form Form Remove Remove Fragment Chromatography 2 Form Form Remove Viral clearance 1 (C) Charge Heterogeneity (% Main peak) Cell culture Form/ Impact Impact Chromatography 1/ viral clearance 2 (D) Viral clearance 3 (E) Charge Heterogeneity (% Acidic Variants) Charge Heterogeneity (% Basic Variants) Glycoforms Cell culture Cell culture Cell culture Form/ Form/ Form/ Impact Impact Impact Impact Chromatography 2 charge prep (F) HCP Chromatography 1 Form Remove Remove Remove Remove DNA Chromatography 1 Form Remove Remove Remove Remove Chromatography 2 G) Viral clearance 4 (H) DS concentration (I) Cell culture media Chromatography 1 Form Remove components Resin leachate Chromatography 2 Form Remove Remove Drug substance concentration DS concentration Drug substance matrix Multi BioPotency Cell culture Form/ Viral safety Multi Form Remove Remove Remove Remove DS formulation/ filling/ storage (J) Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 9

10 Evaluation of Process Performance Quality Attribute 1 Key control points: Unit operation D Unit operation G Quality Attribute 4 Key control points: Unit operation G Unit operation I Key control points: Unit operation D Unit operation F Quality Attribute 5 Key control points: Unit operation G Key control point: Unit operation G Key control points: Unit operation A Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 10

11 Process Performance Evaluation Analytical s for PPQ Purpose of each unit operation with respect to control of quality attributes Analytical testing strategy for process performance qualification Primary Specifications Quality Attribute A B C D E F G H I J Point for PPQ Quality Attribute 1 Chromatography 1 X X X Quality Attribute 2 Chromatography 1 X X X Quality Attribute 3 Chromatography 2 X X Quality Attribute 4 Chromatography 2 X X X Quality Attribute 5 Chromatography 2 X X Quality Attribute 6 Cell culture X Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 11

12 Development of Parametric Strategy Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 12

13 Platform Approach to Process Development Risk Screening Characterization ti Impact Parameter assessment DOEs DOEs assessment classification Process Parameter Characterize impact of parameter range (+ 6σ of control capability) on: Quality attributes t Business attributes Probable Risk to CQAs? No Yes evaluate in empirical study Statistical Significance? No Citi Critical Yes Practical Significance? No Not critical Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 13

14 Parameter x Quality Attribute Risk Assessment Step # Parameter(s) Inc. Rationale Equilibration buffer ph Y ph control is fundamental to the chemistry of ion exchange chromatography, therefore included in DOE to characterize CEX response to ph variation despite the high capability to control ph by buffer formulation. Equilibration ph combined with wash and elution ph as a single variable (mobile phase ph or buffer ph). Process Parameter 1 Equilibration volume Equilibration flow rate N Y Excess is used, and volume control/measurement is highly capable with gradient skid Provide flexibility for pressure/flow issues that may emerge as column ages. Equilibration flow rate combined with charge, wash and elution flow rates as a single variable. Probable Risk to CQAs? Resin bed height Y Determines total theoretical plates for impurity resolution. Can affect binding and elution isotherms. Provides flexibility to manufacturing to vary bed height for throughput and/or pressure flow control. Column load Y Manufacturing requires flexibility in load to accommodate upstream variability in titer and yield. Load may affect chromatographic separation. Charge ph Y ph control is fundamental to chemistry of ion exchange chromatography. Variability in charge ph controlled by upstream unit ops, not directly by buffer make-up, therefore included in DOE as a separate variable. 2 Charge conductivity N Within the range of conductivity expected with titration using formulated buffers, charge conductivity known to be sufficiently low to allow column loads up to 80g/L resin. Charge flow rate Y Charge flow rate may affect binding isotherm. Provide flexibility for pressure/flow issues that may emerge as column ages. Equilibration flow rate combined with charge, wash and elution flow rates as a single variable Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 14

15 Development of the Parametric Strategy: Parameter Classification Statistical Significance? No Sorted Parameter Estimates for Quality Attribute 1 Term Mobile Phase ph Load (g/l) Abs Cut (%)*End[NaCl] (mm) End[NaCl] (mm) Load (g/l)*start[nacl] (mm) End[NaCl] (mm)*mobile Phase ph Start[NaCl] (mm)*start[nacl] (mm) Mobile Phase ph*mobile Phase ph Load (g/l)*mobile Phase ph Abs Cut (%)*Mobile Phase ph Abs Cut (%)(-20,20) Start[NaCl] (mm) Estimate Std Error t Ratio Prob> t <.0001* <.0001* * * * * * * * * Critical Yes Practical Significance? No Not critical Process Parameter Column Loading: grams IgG/ L resin Linear Gradient Start [NaCl] Linear Gradient End (mm NaCl) CQAs Stat Significance (P- DOE Effect Value) Magnitude CT Variability Quality attribute 1 < % 59% Quality attribute % 108% Quality attribute 4 < % 39% Quality attribute 5 < % 50% Quality attribute % 16% Quality attribute % 59% Quality attribute % 108% Quality attribute 4 < % 39% Quality attribute % 50% Quality attribute 6 >0.1 NA NA Quality attribute % 59% Quality attribute % 108% Quality attribute 4 < % 39% Quality attribute 5 >0.1 NA NA Quality attribute 6 < % 16% Critical? Y N N Summary of Critical Parameters Parameter A B C D E F G H I J Parameter 1 X X Parameter 2 X Parameter 3 X X Parameter 4 X X X Parameter 5 Parameter 6 X X X Parameter 7 X X Parameter 8 X X Parameter 9 X X X Parameter 10 X Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 15

16 Post-PPQ PPQ Strategy Evolution Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 16

17 Strategy Risk Assessment RPN = Severity x Occurrence x Detectability Diagram From A-MAb Case Study Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 17

18 Risk Assessment Scoring Tools Seve erity Impact ris sk Knowledge continuum No information Molecule specific knowledge H High High M High High Medium L Low Low Severity Risk: risk of the quality attribute having a meaningful impact on the pharmacological properties of the bioproduct, including biological activity, safety and toxicity, pharmacokinetics, immunogenicity, and efficacy. Occu urrence Demonstrated Process Capability Meaningful Change on Stability? No Yes High Low Medium Medium Medium High Low High High Process capability = amount x variability x process understanding Occurrence Risk: risk of the manufacturing process producing material that does not meet acceptable limits it for the product quality attribute t throughout its shelf-life. De etectability Analytical Testing Strategy Method Capability Detectability Risk Score Routine testing High Low Low Medium Non-routine testing Medium No Testing High Method capability = specificity x precision Detectability Risk: risk of the analytical control strategy not detecting meaningful changes in the product quality attribute. Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 18

19 Overall Risk (RPN) Scoring Tool Severity Risk Score Occurrence Risk Score Detectability Risk Score H M L H H H H M H M H M L M H H M L H L M L L M M M L L Overall Risk M L L L L Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 19

20 Process Knowledge Assessment Large-scale manufacturing experience Low High Process ch haracteriza ation know ledge Low High Not ready for PPQ Enhanced analytical testing Routine monitoring Additional monitoring Enhanced analytical testing Reduced analytical testing Routine monitoring Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 20

21 Reduced Testing: Factors to Consider Attribute controlled to very low level (e.g. < LOQ) prior to final control point Excess process capability Attribute controlled to very low level (e.g. < LOQ) at final control point No negative impact of unit operation(s) downstream of final control point No change during drug substance storage No change during drug product manufacturing or storage Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 21

22 Hypothetical Examples Key control points: Unit operation D Unit operation F No change during DS storage or DP manufacturing and storage Unit Operation F Unit Operation G Spike 2x 5x 2x 5x Residual <LOQ <LOQ <LOQ <LOQ Remove from in-process and DS analytical testing Key control point: Unit operation G No change during DS storage or DP manufacturing and storage Unit Operation G Spike 2x 5x Residual <LOQ >LOQ Remove from in-process analytical testing Include in enhanced DS analytical testing program Key control points: Unit operation G Unit operation I Gradual increase during DS and DP storage, no change during DP manufacturing Unit Operation G Spike 2x 5x Residual <LOQ >LOQ Remove from in-process analytical testing Include in routine DS analytical testing Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 22

23 Integrated Drug Substance Strategy: Parametric, In-Process Analytical, Specifications, and Stability Example DS CQAs Process control points (unit operations) Critical process parameters In-process acceptance criteria (PPQ) DS acceptance criteria (PPQ) Include in enhanced DS testing program CQA confirmed by testing DS (routine commercial manufacturing) CQA monitored on stability Chromatography 1 -Column load (g IgG/ L resin) -Wash buffer composition & ph NMT X ppm Quality Attribute 1 NMT X ppm Yes Yes No Chromatography 2 None NMT Y ppm Quality Attribute 2 Chromatography 1 None NMT X ppm Chromatography 2 Preparation -Charge bff buffer ph NMT Y ppb NMT X ppb No No No Quality Attribute 3 Chromatography 2 None NMT X ppm NMT X ppm Yes No No Viral Clearance 3 -ph -Incubation time NMT X% Quality Attribute 4 Chromatography 2 None NMT Y% NMT X.% Yes Yes Yes DS Concentration - Maximum drug substance concentration NMT Z% Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 23

24 Summary Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 24

25 Drug substance process development continuum FHD FRD Submission/ approval/ Pivotal CT supply campaign(s) PPQ campaign launch Commercial manufacturing In-process intermediate analytical data (CQA impact) Quality attribute risk assessment Integrated parametric and analytical control strategies for PPQ Process development program Post-PPQ program Process definition Process characterization Small scale validation Process improvements/ investigations Enhanced testing Routine monitoring Risk assessment: CQA*parameter FMEA: CQA*process control strategy FMEA: Process *facility Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 strategy risk assessments 25

26 Strategy Development and Evolution Cell culture (A) Quality Attribute Point Primary A B C D E F G H I J Primary recovery (B) Monomer Aggregate Chromatograp Form Impact hy 2 Chromatograp Form Form Remov Remov hy 2 e e Process Parameter Viral clearance 1 (C) Chromatography 1/ viral clearance 2 (D) Chromatograp Fragment Form hy 2 Charge Form/ Heterogeneity Cell culture (% Main peak) Charge Heterogeneity Form/ Cell culture (% Acidic Variants) Form Impact Impact Remov e Impact Impact Probable Risk to CQAs? No Viral clearance 3 (E) Chromatography 2 charge prep (F) Charge Heterogeneity Form/ Cell culture Impact Impact (% Basic Variants) + Form/ Glycoforms Cell culture Chromatograp HCP Form Remov Remov Remov Remov hy 1 e e e e Chromatograp Remov Remov Remov Remov DNA Form hy 1 e e e e Statistical Significance? Yes evaluate in empirical study No Chromatography 2 G) Cell culture Chromatograp media Form hy 1 components Remov e Viral clearance 4 (H) DS concentration (I) Resin leachate Chromatograp hy 2 Drug substance DS concentration concentration Drug substance Multi matrix Form Remov Remov e e Critical Yes Practical Significance? No Not critical BioPotency Cell culture Form/ DS formulation/ filling/ storage (J) Viral safety Multi Form Remov Remov Remov e e e Remov e Example DS CQAs Process control points (unit operations) Critical process parameters In-process acceptance criteria (PPQ) DS acceptance criteria (PPQ) Include in enhanced testing program CQA confirmed by testing DS (routine commercial manufacturing) CQA monitored on stability Large-scale manufacturing experience Severity Risk Occurrence Detectability Risk Score Low High Quality Attribute 2 Chromatography 1 None NMT X ppm Chromatography 2 -Charge buffer ph NMT Y ppb Preparation NMT Y ppb No No No Low Not ready for PPQ Additional monitoring Score Risk Score H M L H H H H M Quality Attribute 3 Chromatography 2 None NMT X ppm NMT X ppm Yes No No Enhanced analytical testing H M H M L Viral Clearance 3 -ph -Incubation time NMT X% M H H M L Enhanced analytical testing Reduced analytical testing H L M L L Chromatography 2 None NMT Y% Quality Attribute 4 NMT 5% Yes Yes Yes High Routine monitoring Routine monitoring M M M L L DS Concentration - Maximum drug substance concentration NMT X% M L L L L Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 26

27 Acknowledgements Bryan Harmon Pete Lambooy Kristi Griffiths Jerry Gao Matt Osborne Ciaran Brady Presentation for CMC Strategy Forum, G Tulloch, Eli Lilly & Company, 01/ 13 27