TRACK #3: ENHANCING PRODUCT QUALITY THROUGH CONTINUOUS MANUFACTURING

Track #3: Enhancing Product Quality Through Continuous Manufacturing Session 1: Where are We Now Moderator: Stephen Tyler, AbbVie Speakers: Christine Moore (Merck), Celia Cruz (FDA), Diane Zezza (Novartis) Contributor: Nima YazdanPanah, (FDA)

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‘Where are We Now’ Presentations • Christine Moore, Ph.D., Merck, Sharp and Dohme Perspectives on Continuous Manufacturing: Where Are We Now, Where Are We Going

• Celia Cruz, Ph.D., US Food and Drug Administration Continuous Manufacturing as an Emerging Technology • Diane Zezza, Ph.D., Novartis Pharmaceuticals Continuous Manufacturing: An Industry View

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Track 3 Session 1 Key Themes • Case and benefits for Continuous Manufacturing (CM) is compelling and

supports NCE and NBE but will probably will not result in use for all products • Progress substantial, e.g. moved beyond time for batch definition but batch

definition can also be a f(business risk) • CM concepts have evolved—set the foundation, on way to broad acceptance

• With CM: QUALITY WINS! • Medicinal products predictably available to our patients • Continual process improvement enabled

• Uptake by industry is significant but not at tipping point-- • Measures include Emerging Technology Team (ETT) CM projects, applications # • Pace of uptake driven by learning, non-alignment of regulations

• Communication is critical! • FDAs Establishment of ET Team (EU PAT team, Japan’s Innovative Mfg Tech) • Everyone must learn—need to develop industry and regulatory expertise • Collaborate—more dialogue, e.g. factory tours, white papers, ICH Q&A?,

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Track 3 Session 1 Key Themes (cont’d) • Key Elements of CM Control Strategy

• Process Understanding • Characterization of Process Dynamics • State of Control moving toward Active Control ( hierarchy of control:

SQCSPCMVSPC) • Material traceability and diversion of non-conforming material • Batch Definition and considerations • Defining procedures for start-up/shut down, when product collection starts

• Regulatory Considerations • Existing Current framework supports CM • Batch and CM processes dossier content goals are the same • Dossier Content vs. GMP aspects • Adaptable batch size • Some CTD modules will differ • Global Acceptance through convergence/harmonization

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Track 3 Session 1 Key Themes (cont’d) • Technical

• Control strategy complexity • Spectrum of Implementation approaches—not just one way to implement

• Quality • Operating in a State of control • Control strategy implementation and effectiveness • Continuous monitoring and lifecycle approaches

• Process Validation • Continuous Process Verification

• Batch Release • Data integrity • Data Management: Big data • Material reconciliation including handling of non-conforming material • Metrics for determining the failure of an entire continuous run

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Session 2: API Focus Moderator: Robert Meyer, Merck & Co., Inc. Speakers: Paul Collins (Eli Lilly and Co.), Thomas O’Connor, (FDA), Aaron Côté (Merck & Co.)

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Background (Session 2)

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Continuous Synthetic API Manufacturing consists of continuous unit operations, continuous flow reactors and integrated control (end-to-end)

Scientific Considerations for Continuous API Manufacturing: Process understanding, Control strategy

Integrated process without interruption, steady state, state of control

Benefit of CM in API Manufacturing: Enabling Chemistry, Safety, Quality (QbD, PAT), Green, Economical

Drug substance and drug product processes have different control and quality approach.

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Session Summary (Session 2) Product quality expectations are the same for continuous and batch manufacturing. Differences are: • Risk assessment: hazards identified for a CM process are different than batch • Risk mitigation: control strategies may be different for CM than for batch • Risk communication: communicating residual levels of risk

Traditional inspection approaches could be done digitally

A control strategy should: • 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

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Session Summary (Session 2) Lily’s case study:

• Project A: Cost reduction of >50%, Robust Pd removal, Green chemistry • Project B: Eliminated $20M spend on H2 bunker, Safe, Green chemistry • Project C: reduced development and Tech transfer time, Green chemistry • Small volume production: 1200L batch ->30L CSTR->0.8L PFR • Skid based and modular design, Miniaturization of API manufacture

Seamless integration of DS and DP: integration strategy, potential to streamline process development

Drug Substance CQAs: Purity and Impurities, Physical characteristics of API

Diversion of Non‐Conforming Material and Surge Capacity

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Process understanding and risk assessments can lead to identification of critical material attributes and process parameters

Use the understanding of the impact of CPPs and CMAs on product CQAs

Sate of control, RTRt, PAT; CM promote the adoption of higher level controls: • Inherently data rich processes • Availability of plant wide information systems • Advancements in process modeling and simulation

Process Dynamics: The dynamics of how materials or disturbances flow through the process is a critical aspect of process understanding

Combination of input controls, reactor design and control of process parameters shapes product quality

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Takeaway Messages and Future Actions (Session 2)

Session 3: Continuous Manufacturing (CM) for Manufacturing of Drug Product

Moderator: Sharmista Chatterjee, FDA Speakers: Eleni Dokou (Vertex), Eric Sanchez and Gilfredo Navarro (Janssen), Dave Schoneker (Colorcon), Arwa El Hagrasy (FDA)

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Session Layout CM

implementation for new

molecules

Eleni Dokou, Vertex

Switching from a batch to CM

Eric Sanchez & Gilfredo

Navarro, Janssen

Excipient considerations

for CM Dave Schonekar

Scientific and regulatory

considerations

Arwa El Hagrasy, FDA

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Resonating Themes.. • Control strategy for CM has some unique considerations, that includes:

• Establishing a state of control • Understanding system dynamics (e.g. estimation of residence time distribution)

and equipment performance over proposed duration of run • Plans to detect and remove non-conforming materials

• Some special properties needed for excipients that are used for CM • Demonstrate good flow properties to allow dispensing at the desired flow rate • Need to understand variability in raw material properties (API & excipients)

when designing a CM system • Quality Systems (QS) associated with CM warrant additional considerations,

for example: • QA associated with product disposition, batch release, stability strategy, product

specification (RTRT versus traditional methods), models for release, automated controls

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Take Away Messages & Next Steps • Future goal is to move to automated control where process parameters can

be adjusted in feed-back or feed-forward manner • Models can help to optimize development of UO associated with CM • When switching from legacy batch process to CM

• Re-assess appropriateness of existing raw material specification (API & Excipient)

• Re-assess impact of critical process and equipment design parameters on process performance

• Robust PQS (Pharmaceutical Quality System) is critical for continued successful implementation of CM

• Could consider use of ‘custom excipients’ that facilitate CM implementation • Early and continued risk based communication with the regulators is pivotal

for successful CM implementation • Via meetings and on-site visits (POV and PAI)

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Nest Steps II IPEC and PQRI are currently developing a plan for a workshop in 2018 which will focus completely on the “Impact of Excipients and APIs on Continuous Manufacturing”.

Some Objectives: • To bring together both industry and regulatory experts to discuss the

impact of excipients and APIs in Continuous Manufacturing of Oral Dosage Form Pharmaceutical Products (Benefits & Challenges).

• Identify and evaluate excipient and API properties (possibly new) which could impact the continuous manufacturing process

• How to design for excipient and API variability in Continuous Manufacturing.

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Session 4: Strategies to Support Continuous Manufacturing Moderator: Linda Evans O’Connor (Lachman Consultants) Speakers: Patric Klotzbuecher (FDA), Fernando Muzzio (Rutgers), Ahmad Almaya (Eli Lilly and Co.)

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Background (session 4)

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Implementation of CM, technical and regulatory consideration

Regulatory Considerations: State of Control, Lifecycle Quality Risk Management (ICH Q10)

Technical Consideration: Material, Process, PAT, DoE/Model, RTRt, Validation, data management

Batch Vs. Continuous: change of definitions, control strategies, regulations

Operability in the qualified production environment

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Session Summary (session 4) Verify integrity of data supporting Design of Experiments

Identify CPPs and CMAs for process and formulation performance and control CPPs & nCPPs : Model based design and optimization; Adv. process control

Predictive models by DoE, PLS, first principles

Minimizing occurrence and magnitude of potential transition disturbances

Build detailed understanding of data flow; development of production recipes Information Management:

• General system architecture • Hierarchal control structure & system integration • PAT function (including method validation) & automation

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Session Summary (session 4)

CM make higher assurance quality than batch: monitoring tools (real time), risk assessment, detectability and predictively

Guardrails at the end of the process for unforeseen modes

Models and control tools (based on monitoring tools) for equipment: real time handling of disturbances (what-if scenario) for multiple CQAs

Lily’s case studies on CM, feeder, blender, and tablet press. Messages:

Learn from others, Use internal data to convince stakeholders, tailored message to audience, organizational and manufacturing harmony, innovative and creative, multidisciplinary team, intercompany discussion, refine work plans.

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Takeaway Messages and Future Actions (Session 4)

Strategy for Min time and materials and Max process understanding, issues and key concepts with CM:

• Identify system failure modes • Define metrics to predict impact of failure • Have material property data base • Predictive models for new materials and UO • Define DOEs and select PAT and control • Formulation and process optimization • Materials (API and excipient) Characterization and Prediction • Process Modeling, Control, and PAT for CM RTR • Adjustment of models based on variability • Define reject mechanisms, decision, making, tracing, and tracking • Standardization and regulatory compliance

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Session 5: Challenges to Implementing Continuous Manufacturing Moderators: Sau (Larry) Lee (FDA) and Ganapathy Mohan (Merck) Speakers: Roger Nosal (Pfizer), Rapti Madurawe (FDA), Dolores Hernán Pérez de la Ossa (EMA), Yoshihiro Matsuda (PMDA)

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Background (session 5) • Objective: To discuss challenges to implementing continuous

manufacturing from both industry and regulatory perspectives • Regulatory Challenges to Implementing Continuous Manufacturing

• Roger Nosal, Pfizer • Enabling Continuous Manufacturing: An FDA Perspective

• Rapti Madurawe, FDA • Continuous Manufacturing: Challenges and Opportunities – EMA

Perspective • Dolores Hernán Pérez de la Ossa, EMA

• PMDA’s Perspectives on Continuous Manufacturing • Yoshihiro Matsuda, PMDA

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Session Summary (session 5) Some challenges for CM implementation:

• Huge upfront investment is needed. • Regulatory uncertainties exist outside the US, EMA, and PMDA regarding the

level of regulatory support for CM. • Inconsistency in regulatory expectations (e.g., differences in specification for the

same products and definition of data integrity) still persists (not only limited to CM).

• Inconsistency of interpretation of regulations and guidance • Some key CM considerations (e.g., roles of advanced process control and PAT

monitoring, and lot traceability) need further clarification. Opportunities

• CM is a transformative technology that can modernize pharmaceutical manufacturing and enhance product quality.

• CM can be implemented under the current regulation. • CM provides a great opportunity for early global alignment as we start fresh.

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Session Summary (session 5) FDA, PMDA, and EMA all recognize the potential benefit of CM and fully support CM implementation for pharmaceutical manufacturing.

Regulatory effort exists to facilitate the adoption of CM: • FDA Emerging Technology Team (ETT). • PMDA innovative Manufacturing Technology Working Group (IMT-WG). • EMA PAT team, Innovation Task Force (ITF), SME office • FDA, PMDA, and EMA all encourage early engagement to discuss company’s

plan on implementation of CM. There is currently no CM specific regulatory guidance, but some existing guidelines (e.g., from ICH, EMA and FDA) are applicable to CM.

FDA, EMA, and PMDA ‘s thinking on CM share a lot of commonalities (e.g., defining a batch for CM, importance of process dynamics, and key aspects of control strategy)

There are interactions among FDA, EMA ,and PMDA in the CM areas.

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Takeaway Messages and Future Actions (Session 5)

The regulatory agencies strongly supports advancement of pharmaceutical manufacturing technologies, including continuous manufacturing!

Early engagement with regulatory agencies to discuss CM implementation is strongly encouraged!

More interactions and collaborations among regulatory agencies are beneficial to address industry’s concerns regarding regulatory uncertainties and move towards global alignment in the CM area!

Let’s do it together!

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Moderator: Rich Levy, PDA Speakers: Sau (Larry) Lee (FDA), Robert Meyer (Merck), Charles Cooney (Massachusetts Institute of Technology) Panelists: Yoshihiro Matsuda (PMDA), Patric Klotzbuecher (FDA)

Session 6: Where are We Heading in Continuous Manufacturing?

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Session 6: Where are We Heading in CM?

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R. Levy - What will the future be like? • More reliable and safer products

• 100% continuous process • Advanced supply chain and characterization of in-coming materials. • Automation, simplification and integration of manufacturing steps. • High frequency on-line monitoring and automated flow control (for increased

product quality assurance in real-time). • Incorporation of RTQA into continuous manufacturing drives RTR • Diversion of non-conforming materials in real time. • Decisions and future product development based on information from inherently

data rich processes. • Implement end to end, synergistic, platform Drug Substance / Drug Product

processing options to product development (which further optimizes product manufacturing)

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Session 6: Where are We Heading in CM?

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R. Levy - What will the future be like? • Decreased Scale of Manufacturing

• Smaller equipment and facilities (leading to lower manufacturing costs, possibly resulting in lower drug prices for consumers).

• Less Materials • Decreased product variability downstream

• Increased Flexibility and Responsiveness • Ability to adjust to changes in demand (potentially contributing to prevention of

drug shortages). • Uninterrupted processes lead to faster production.

• Regulatory Picture • Encouraging • Transparent

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Session 6: Where are We Heading in CM?

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• FDA CDER Perspective on the future – Larry Lee • Performance-based Approach for Control Strategy • Operational flexibility – driven by modular, portable systems - CM plug and play –

“pharmacy on demand” • Clear linkage of control points to finished product CQAs • Collaborative knowledge platform development and management – exploit prior

knowledge as well as OPQ and external collaborations • Science-based Process Models – KM and Risk Management • Efficient Cleaning approaches • End to End CM Process – integrated synthesis, purification and final dosage

formulation • Right Mindset and Culture – knowledge sharing, cooperative • Transparency – Regulators and Industry; multidisciplinary approaches to

developing dynamic guidelines

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Session 6: Where are We Heading in CM?

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• Industry Perspective 2030 – Bob Meyer, Merck • Diffusion of Innovations – Rate of innovation diffusion depend son the social

construct of industry • Lag is about 12 years or longer in our industry – obstacles, clinic, filings, etc. • The innovators and early adopters will be most likely to win the largest benefits

• Integrated Automation and Continuous • Small flexible, replicable, multiproduct in sync with customer demand • Big Data – rich data and dynamic experimentation to create design space • New Technologies drive innovation – example hot melt extrusion • Supply chain – must be integrated • Shelf-life requirements can be reduced dramatically • Changing from one product to the next in hours – true SMED • Plants built in less than a year • Virtual, risk-based inspections

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Session 6: Where are We Heading in CM?

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• Navigation the Challenges of Integrated Continuous Manufacturing – Charles Cooney, MIT • Continuous biomanufacturing is not new! We’ve chosen batch mode. • Questions to ask first:

• What is the goal?

• Sustained delivery of safe and efficacious medicine to the patient

• What are your aspirations?

• Set your process metrics

• Deploy technology to tactically deliver goals • Target process profile next • Integrated bioprocessing – continuous only one mode • Intensified operations – smaller, faster, leaner robust processes

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Session 6: Where are We Heading in CM?

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• Charles Cooney, MIT: Navigation the Challenges of Integrated CM

• Practitioners lens - Upstream and downstream desires • Criticality of in-line and at-line sensors and automation

• Business lens • Flexibility / Agility – to deliver new diversity of products, new markets and

short time to clinical trials

• Convergence of technologies is pulled by business cases

• Regulatory lens • Evolution not revolution – need collaboration to deliver

• Recognition of enabling new technologies – ETT, multiple agencies

• Implement only value added steps • QbD is right at the center of this movement

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Additional Takeaway Messages and Future Actions (Session 6) There are no major regulatory hurdles for CM implementation. Regulatory agencies support the adoption of CM for pharmaceutical production based on science and risk-based approaches.

Getting Ready: • Right Mindset and Culture

• Regulatory agencies: Willing to learn, collaborative, transparent • Industry: Be transparent and willing to share, Collaborative

• Building collaborative knowledge platform • Promote regulatory science and research • Industry working together • Academia working with industry

• Building Standards and Guidelines Together • Continued knowledge sharing – like at this PQRI/FDA meeting

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