FDA Perspective on Continuous Manufacturing

Transcription

1 FDA Perspective on Continuous Manufacturing Sau (Larry) Lee, Ph.D. Director & Emerging Technology Team Chair Office of Testing and Research Office of Pharmaceutical Quality US FDA Center for Drug Evaluation and Research Consortium on Continuous Pharmaceutical Manufacturing December 13, 2018 Tokyo, Japan

2 The Desired State The Vision A maximally efficient, agile, flexible pharmaceutical manufacturing sector that reliably produces high quality drugs without extensive regulatory oversight. 2 2

3 Office of Pharmaceutical Quality Office of Biotechnology Products 3

4 OPQ Strategic Priorities: COLLABORATE: Strengthen OPQ s collaborative organization Leverage a collaborative culture, an engaged and empowered workforce, streamlined processes, and effective teaming to ensure an efficient, high performing, innovative, and results oriented organization 2. INNOVATE: Promote availability of better medicines Minimize barriers to encourage innovation within FDA and in the manufacturing sector through sensible oversight, research, risk based decision making, and continuous process improvement 3. COMMUNICATE: Elevate awareness and commitment to the importance of pharmaceutical quality Effectively communicate the importance of quality and that the American public can trust their drugs 4. ENGAGE: Strengthen partnerships and engage stakeholders Build productive relationships with business partners within and outside FDA and jointly foster effective stakeholder engagement to meet the needs of the American public 4 4

5 Emerging Technologies Key to Addressing Pharmaceutical Manufacturing Challenges Address the underlying causes of product recalls and drug shortages Two thirds of drug shortages resulted from product specific quality failures or general manufacturing facility issues Product recalls has surged over the past couple of years Facilitate new clinical development precision medicines Enable a wider range of novel dosage forms, a wider range of doses without extensive alterations of the process, and convenient fixed combination dosage forms Improve manufacturing efficiency Increase process robustness Lower manufacturing costs for pharmaceutical products Increase supply chain flexibility 5

6 Emerging Technology Program Mission Encourage and support the adoption of innovative technology to modernize pharmaceutical development and manufacturing through close collaboration with industry and other relevant stakeholders ONDP OPPQ OBP OC OLDP OPF ETT ORA OTR A small cross functional Emerging Technology Team (ETT) with representation from all relevant FDA quality review and inspection programs (OPQ/CDER & ORA) 6

7 Program Objectives 1. To serve as a centralized location for external inquiries on novel technologies 2. To provide a forum for firms to engage in early dialog with FDA to support innovation 3. To ensure consistency, continuity, and predictability in review and inspection 4. To identify and evaluate potential roadblocks relating to existing guidance, policy, or practice 5. To help establish scientific standards and policy, as needed 6. To facilitate knowledge transfer to relevant CDER and ORA review and inspection programs 7. To engage international regulatory agencies to share learnings and approaches Contact us: CDER ETT@fda.hhs.gov 7

8 Why CM? FDA has identified CM as an emerging technology FDA recognizes that CM has the potential to increase the efficiency, flexibility, agility, and robustness of pharmaceutical manufacturing Integrated processing with fewer steps No manual handling, increased safety Shorter processing times Smaller equipment and facilities More flexible operation Lower capital costs, less work in progress materials Reduced environmental foot print Feasible to manufacture small batch sizes On line monitoring and control for increased product quality assurance in real time Amenable to Real Time Release Testing approaches Benefits to both patients, and industry 8

9 CDER Progress Over 30 requests accepted to the Emerging Technology Program since the launch of the program in late 2014 Over 60 ETT industry interactions (including both t con and face toface meetings) and ~50% of these interactions related to CM ProductsandTobacco/CDER/ucm htm FDA approvals of applications utilizing continuous manufacturing (CM) Vertex ORKAMBI (lumacaftor/ivacaftor) Janssen Prezista (darunavir) Eli Lilly Verzenio (abemaciclib) Vertex Symdeko (tezacaftor/ivacaftor and ivacaftor) Pfizer Daurismo (glasdegib) 9

10 CDER Current Experience CM processes for drug product Direct compression, dry and wet granulation; CM models for solid orals; modular CM processing system CM processes for drug substance Continuous drug synthesis (flow reaction) plus batch or continuous crystallization End to end CM processes Integrated synthesis, purification, and final dosage formation Pharmacy on Demand Miniaturized, flexible manufacturing platforms using CM technologies Continuous bioprocesses Continuous purification platform for monoclonal antibody (e.g., continuous chromatography and viral filtration) Control Strategy Increasing use of active process control, PAT tools, RTRT, process models for material traceability, non conforming material diversion, and blend uniformity 10

11 CM Elements Discussed Between CDER and Industry System dynamics, RTD and transient disturbances Raw material control Sampling strategy Material traceability Start up and shut down PATs, models and RTRT Product collection and material diversion Process monitoring and control Control Strategy Examples Facility and Process Validation Model maintenance and update System integration, data processing and management Equipment qualification, maintenance and cleaning Process performance qualification Continued process verification Minor formulation changes Comparability and bioequivalence Stability data package Bridging Batch to Continuous Manufacturing Batch and Lot definition Batch size flow rate and run time Scale up run time increase Primary stability batch size Mass balance or yield 11

12 Quality Assessment Focus Evaluation of the proposed attributes and specifications of raw materials Impact of variations in material properties on the performance of CM and product quality Characterization of process dynamics for critical steps and integrated system Understanding of the feeder dynamics, residence time distribution (RTD), and system response to transient disturbances Process monitoring and control strategy Monitor and detect transient disturbances and process deviation PAT and active process controls Material collection and diversion Start up and shutdown Strategy to identify, isolate and divert non conforming materials Real time release testing PAT tools for assay and content uniformity Models for product release (e.g., dissolution) 12

13 Process Understanding Use the understanding of the impact of process parameters and material attributes on product quality to: Establish design space based on the design of the experiments Build predictive models and simulation tools (ICH Q8) Inform alarm and action limits and an approach to manage process deviations (e.g., adjustments) Establish criteria for incoming and in process materials Boukouvala F et. al. Comput. Chem. Eng. 2012;42;

14 Process Dynamics Evaluate back mixing of the system over time to predict the propagation of disturbances and materials through the system Obtain an understanding of process dynamics by characterizing the Residence Time Distribution (RTD) Identify typical failure modes or deviations (long term vs. short term) (e.g., feeder variability) Aditya and Muzzio. Powder Technology 2011; 208, Evaluate response to set point changes (e.g., change in line rates) Assess the impact of Startup and Shutdown on material quality 14

15 Control Strategy State of Control A control strategy should: Be appropriate for each individual process and product based on the risks to product quality Consistently provide assurance of process performance and quality Be designed to mitigate product quality risks in response to potential variations over time for CM Level 1 Active or real time automatic control Level 2 Appropriate end product testing + Material attributes and process parameters within the established design space Level 3 End product testing + tightly controlled material attributes and process parameters For CM, this can include integration of process parameter limits (set points and alarms), in process monitoring (including PAT), process controls (feedback and feed forward), material diversion, and Real Time Release Testing (RTRT) Many continuous manufacturing systems promote the adoption of higher level controls, although a hybrid approach combining the different levels of control is viable for some continuous manufacturing process designs S.L. Lee et al., J Pharm Innov. 2015; DOI /s

16 Raw Material Control Considerations Use of multiple raw material lots in a batch Establish traceability of different lots to finished products Characterization of input materials Evaluate raw material attributes (e.g., particle size distribution and density) affecting the formulation flow behavior, segregation potential, etc. Appropriate material specifications blends conditions Operating Conditions (Z) [k x j] properties materials Measured properties of individual materials (X) [m x n] Blend Ratios (R) [k x n] properties Measured properties of blends (Y) [k x l] Impact of drug substance or excipient lot to lot variations on feeding If legacy product, appropriateness of the existing drug substance specifications for CM Appropriateness of the compendial specification for excipients S. G. Munoz et al. (2014) Chemometrics and Intelligent Laboratory Systems. 133,

17 Process Monitoring and Control Specify the role of PAT and Models Provide process understanding during development; process monitoring during production; process control; and/or real time release testing (RTRT) method Consider instrument aspects Interference due to flow; time of acquisition vs. flow rate; probes number, location, probe failure, probe maintenance, etc. Feeding: a critical operation for CM Demonstrate that acceptable quality material is manufactured near the upper and lower limits to support feeding limits Evaluate impact of operational variations (e.g., switching from gravimetric to volumetric flow during feeder refill) Assess impact of feeding variations of excipients on product performance (e.g., dissolution) Feeder Monitoring Engisch W. and Muzzio F.. J Pharm Innov. 2015; DOI /s

18 Diversion of Non Conforming Material The ability to isolate and reject nonconforming material can be one of the key aspects of a CM control strategy Planned process start ups and shutdowns Temporary process disturbances or upsets The evaluation and understanding of propagation of a disturbance in the system are important to justify the amount of material at risk Models of process dynamics are being assessed as part of the control strategy to detect and track non conforming material due to upstream disturbances 18

19 Scientific Considerations for Model Based Material Diversion Develop models using scientifically sound principles and conditions that reflect routine commercial production Validate performance for high impact models Capability of the model to trace the identified non conforming material segment through the system to the rejection point ICH Q8, Q9, & Q10 Questions and Answers Appendix: Q&As from Training Sessions (Q8, Q9, & Q10 Points to Consider) Understand model assumption and risks to validity of model predictions Model parameter uncertainty Expected variations in process parameters and material attributes (e.g., line rate) Product quality risks resulting from potential transient disturbances Process failure modes that may not be identified by or included in the model Include model maintenance approaches within the quality system as part of a lifecycle approach Routine monitoring to verify performance Model updates 19

20 RTRT Considerations Establish a valid combination of assessed material attributes and associated process controls in relation to the final product quality Evaluate ability of the sampling scheme(s) to detect non conforming materials or products Assess quality of a batch (i.e., % confidence, % coverage, and target range) Monitor or assess system dynamics (i.e., disturbances) during the continuous operation Determine whether the process is in a state of control during start up, shut down, and after restarts If the on line PAT methods are submitted as routine methods (without alternatives), describe what actions will be taken when analyzer is not available 20

21 Batch Definition 21 CFR defines a batch as a specific quantity of a drug or other material that is intended to have uniform character and quality, within specified limits and is produced according to a single manufacturing order during the same cycle of manufacture. Additionally, a lot is defined as a batch, or a specific identified portion of a batch, that has uniform character and quality within specified limits; or, in the case of a drug product produced by continuous process, it is a specific identified amount produced in a unit of time or quantity in a manner that assures its having uniform character and quality within specified limits. Definitions for both batch and lot are applicable to continuous processes 21

22 Batch Definition Considerations Regulatory expectation that: Product has uniform character and quality within specified limits and is therefore closely linked to the control strategy that is designed to ensure the process under a state of control Potential batch definitions based on: Production time period; amount of material processed; production variation (e.g. different lots of feedstock); amount of product produced; and others Established prior to initiation of manufacturing, not after the fact Other considerations Ensure material traceability to verify a complete history of the manufacture, processing, packing, holding, and distribution of a batch/lot of the product and other materials (excipients); Especially in cases of OOS/OOT investigations, consumer complaints, product recalls, or any other situations that may have public health impact Define procedures for start up/shutdown, and establishing a priori acceptance criteria for determining when product collection starts Material reconciliation including handling of non conforming materials 22

23 Facility Considerations Adjustments to existing facility pharmaceutical quality system (PQS) Updates to Quality and production procedures Quality oversight of automated controls, process data, RTRT, and electronic batch records Quality evaluation when material is diverted and quarantined Level of investigation, root cause analysis, corrective and preventive action, understanding diversion event (common vs. unexpected) for continuous improvement, etc. Process Validation, readiness for commercial manufacturing, and knowledge management Demonstration of robustness, process monitoring, and broader control strategy Assessment of change controls for total impact Integrated equipment train Knowledge gained from equipment qualification to support the proposed batch size or run time Cleaning validation, maintenance, and performance monitoring to support commercial lifecycle and multiproduct manufacturing Additional controls for incoming raw materials 23

24 Paradigm Shift for PQS Discrete unit operations In process materials are collected/tested at the end of each unit operation Hold time studies allow for investigation Quality Control Unit needs to adapt its function to CM requirements Knowledge & Quality Risk Management Integrated unit operations Material is constantly generated and moving Data rich manufacturing environment QC oversight must be built into process decision making Continuous Process Verification S. Lee et al., J. Pharm. Innov., 2015 US FDA Guidance to Industry: Process Validation: General Principles and Practices, ICH Q10 24

25 Process Validation Consult process validation guidance and verify performance of the process using the intended control strategy Demonstrate robustness of the process including the ability to remain in a state of control and make quality decisions in real time Process Qualification To examine a run time or manufacturing period that should be representative of the intended commercial run time for the initial product launch Continuous process verification Use in line, on line, or at line monitoring or controls to verify process performance on an on going basis Evaluate trending for further process understanding and improvement Provide the advantage of enhanced assurance of intra batch uniformity, fundamental to the objectives of process validation Expect retrospective data/trending analysis as part of the process validation guidance and lifecycle management Comparability protocol to increase the batch size post approval 25

26 Quality Control Unit and Automation Quality decision making must be programed Interlocks, communication checks, recipe integrity, data collection frequency Monitoring, alert & alarm limits, segregation points, automatic stops Start up sequence, restart, material collection criteria, and shut down processes Some oversight is delegated to the automation but the QCU is ultimately responsible for the product Design, validation, and qualification of automation with equipment is critical Maintenance of Automation Control System Robust change control process for code improvements Monitoring of ACS performance Version control, back ups, and security 26

27 Knowledge Management Documentation: development reports, technology transfer activities, process validation protocols and reports, batch records Establish programs to collect, analyze, and maintain data related to product quality Design a monitoring plan: attributes/metrics, frequency of trending/analysis, statistical approach(es) Intra batch and inter batch comparisons Long term assessment of impact of raw material attributes on system dynamics and process Equipment performance indicators over time PAT Model maintenance activities Monitor and improve process capability 27

28 Future Topics for Collaborations CM and performance based approach Promote the use of PATs for high frequency measurements of critical quality attributes Promote active controls and process improvement Can this performance based approach be applied to the entire integrated continuous manufacturing line? CM and parametric based approach Require comprehensive understanding of quantitative, multivariate relationships among material attributes, process conditions, and critical quality attributes Big data set to develop and validate multivariate models Complexity increases dramatically with increasing number of parameters Monitor the health of a process to make quality decision Combination of both performance and parametric approaches Materials Performance based approach Parametric based approach Process 28

29 Future Topics for Collaborations Model development, validation, maintenance and update Regulatory standards for model validation currently lacking Mostly considered as a high impact (e.g., PAT chemometric and dissolution models) What does industry want? Consistency among regulatory agencies for reporting requirements for model maintenance and update Most updates or changes managed under the company s PQS (e.g., post approval change management plan) Continuous bioprocessing Emerging hot topic that should be one of the main focus in the near future Lag behind small molecule CM in many aspects Need some breakthrough in PAT areas 29

30 Future Topics for Collaborations Data management and storage Large size of process and quality data due to high frequency measurements All raw data be strictly managed according to CFR ? Technological advance needed for data storage Data transformation or reconstruction Areas related to data transformation needed to be addressed Loss of information and hinder investigation in the event of a product recall or adverse event Loss of information for trending analysis and continuous improvement Data integrity Cloud computing and AI 30

31 Concluding Remarks No regulatory hurdles for implementing CM Both the Agency and industry are gaining experience Recommend early and frequent discussion with the Agency during CM development Emerging Technology Program should be utilized for early FDA Industry interactions even before the drug molecule is identified Process understanding is key to identifying product quality risks and developing a robust control strategy A robust control strategy for a CM process can include a combination of different scientific approaches FDA supports the implementation of CM technologies using science and risk based approaches 31

32 Thank You!