Implementing Continuous Pharmaceutical Manufacturing: An FDA Perspective

Transcription

1 Implementing Continuous Pharmaceutical Manufacturing: An FDA Perspective Christina Capacci-Daniel, Ph.D. Acting Quality Assessment Lead / Consumer Safety Officer Division of Inspectional Assessment, Office of Process and Facilities Office of Pharmaceutical Quality, CDER Continuous Manufacturing Oral Solid Dosage Forms & PAT Swiss Society of Industrial Pharmacists Workshop, 09 November 2017

2 Information and views herein do not represent new Agency policy. This is reflection of the author s current thinking. 2

3 Outline Continuous Manufacturing in the Regulatory and CGMP Framework Process Validation Approach Quality Unit s Role Inspectional Considerations Quality Procedures Equipment & Computer Systems 3

4 Advantages of Continuous Pharmaceutical Processing Quality High degree of process understanding, development/commercial equipment Enhanced monitoring Facilitates lifecycle management and continuous improvement Patients Reduced production schedules; more readily respond to market needs and fewer shortages Shorter development timelines Industry Considerations Smaller equipment footprint; no need for multiple scale up sizes Less potential for operator exposure; new chemistry now feasible Reduced waste 4

5 Approved Continuous Processes Vertex s ORKAMBI (lumacaftor/ivacaftor) First NDA approval for using a CM technology for production of the Cystic Fibrosis drug (tablets) (July 2015) 1 EMA approved continuous process (Sept 2015) 2 Janssen s PREZISTA (darunavir) First NDA supplement approval for switching from batch manufacturing to CM process for an FDA-approved HIV drug (tablet) (April 2016) 1 Swissmedicapproves continuous process (May 2017) 3 EMA approves continuous process (June 2017) 3 1 = - Accessed April = WC pdf Accessed 22Oct = Accessed 22Oct2017 5

6 How did we get here? Wikimedia / BriarPress 6

7 FDA View of Continuous Pharmaceutical Processing Continuous manufacturing is consistent with FDA and International Industry Quality Initiatives ICH Q8 and Q9: Science and risk-based approach to process design and product development ICH Q10: Robust quality oversight FDA Guidance for Industry on Process Validation (Jan 2011): Control strategy and monitoring plan developed to support the entire product lifecycle Current Good Manufacturing Practices (21 CFR 210 & 211) Flexibility to support new types of operations 7

8 CM Development Considerations Equipment and automation engineering Material transformations Reliable orchestration and automation, quality oversight Process dynamics, residence time distribution State of control Traceability Process ranges, design space Monitoring In process assessment PAT, sampling frequency Process control models 8

9 Risk Assessment Mitigating incidence of disturbances with equipment design Detection of disturbances Identification and isolation of non-conforming material Alarm, alert, and statistical control limits Quality and Production procedures to react in real time 9

10 Control Strategy Implementation Layers of controls intended to support the manufacture of acceptable material Process parameter ranges Statistically based in process performance criteria Equipment monitoring and maintenance plans Quality and Production SOPs for handling events and deviations in real time Draft FDA Guidance: Established Conditions, May

11 Process Validation Process Validation The collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process of capable of consistently delivering quality products. Process Qualification Confirming that the manufacturing process as designed is capable of reproducible commercial manufacturing. FDA Guidance for Industry, Process Validation: General Principles and Practices, January

12 PV Considerations for Continuous Processes Process Dynamics Equipment Studies Process Performance Qualification Experience, Analysis, and Improvement Design of the Continuous Process Ensuring Robustness Control Strategy, Monitoring, Knowledge Management, Quality Oversight 12

13 Integration of Validation Phases Process design changes to integrate NIR cleaning and calibration Identification of PAT point to monitor blend uniformity In situ cleaning procedures to support expected commercial batch size Qualification of equipment, validation of NIR model 13

14 Integration of Validation Phases Implement range and communication alarms Loss in weight feeders used to control API and excipient addition Determine performance limits based on learnings & Quality expectations Qualification of feeder & automation 14

15 Quality Unit Oversight Expertise in continuous manufacturing throughout the organization Particularly needed in the Quality organization Involvement in Risk Assessment and all stages of process validation 15

16 Process Risk and Control Strategy Risk to Product Detect and remove non-conforming or potentially non-conforming material Risk to Process Maintaining a state of control, establish thresholds for in control Does limited control over the entire batch manufacturing period pose an indirect threat to product quality? Monitoring approach for both the Product and Process 16

17 Process Risk and Control Strategy Equipment Performance Drift; deviations vs. expected performance Process Stability Statistically justified rules Batch review and acceptance criteria Percent yield; Time in control, frequency and duration of rejections Criteria developed in advance based on Quality expectations and process understanding Examine process and variability; develop control strategy through strong process validation 17

18 Quality and Automation Continuous processes are highly automated and often time require realtime decision making. Quality decision making must be programed into the automation: Interlocks, communication checks, recipe integrity, data management 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 fundamental. QCU And QCU Wikimedia Commons 18

19 CGMPs & Continuous Manufacturing The Commissioner is keenly aware that the general CGMP regulations must apply to a wide variety of drug products. Therefore, the CGMP regulations in Part 211 are intended to be: general enough to be suitable for essentially all drug products, flexible enough to allow the use of sound judgment and permit innovation, and explicit enough to provide a clear understanding of what is required. Preamble to 21 CFR 210 & 211, March

20 CGMPs & Continuous Manufacturing CGMP s are intended to be flexible and amendable to new technology Production Instructions and Process Controls Equipment, Laboratory Controls, Records In implementing CM, the Quality Assurance Unit may appear to have the greatest challenges adapting. Compressed timeframes Immediate decision-making on in-process and finished materials New ways of thinking about old business processes (e.g. investigations, deviations) Importance of process understanding and process validation 20

21 Importance of Automation Validation 21 CFR Equipment must be suitable for intended use. User requirements include both technical and quality functionality. Installation / Operational / Performance Qualification should consider both unit component functionality as well as the entirety of the integrated system. OQ/PQ should consider the relative risk and impact to product of the automation design specifications. 21

22 Maintenance of Automation 21 CFR Equipment shall be maintained as appropriate according to procedures to prevent malfunction that would alter the drug product. Robust change control process for code improvements Design, testing, implementation, & confirmation Monitoring of automation performance QCU should be auditing the delegated responsibilities Version control, back-ups, and security 22

23 Deviation Preparation 21 CFR & 192 Failure to meet any specification shall be thoroughly investigated. Proactive Quality Control Unit Deep understanding of process is required Have identified potential failure modes Detectability: process parameters & PAT signals Clear plan of action justified and determined in advance Overall batch quality: What is acceptable control? This decision-making also feeds into QC strategy and automation design 23

24 Summary Regulatory support for continuous manufacturing Existing regulatory frame provides applicable guidance Thorough Process Validation enhances the robustness of processes designed and intended to remain in a constant state of control Quality Unit involvement throughout process development Continuous Manufacturing is compatible with CGMPs 24

25 Communication Pathways FDA Emerging Technology Team (ETT) Avenue to obtain early feedback, even before IND stage Pre-Operational Visits to discuss the process in its entirety Meetings requests can be submitted to References: Sept 2017 guidance, Advancement of Emerging Technology Applications to Modernize the Pharmaceutical Manufacturing Base March 2015 draft guidance (revision of the 2009 guidance), Formal Meetings Between the FDA and Sponsors or Applicants of PDUFA Products 25

26 Acknowledgements Mahesh Ramanadham, PharmD Sau (Larry) Lee, PhD Tara Gooen Bizjak Celia Cruz, PhD Rapti Madurawe, PhD Sharmista Chatterjee, PhD Extended members of the FDA Emerging Technology Team 26

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