Achieving Quality Beyond Compliance Through Continuous ...€¦ · Quality Beyond Compliance Process Transformation Batch • Mostly step based • Separation of DS & DP steps and

2nd FDA/PQRI Conference on Advancing Product Quality | October 5 to 7th, 2015 | Washington, DC

Achieving Quality Beyond Compliance Through Continuous Manufacturing

Yanxi Tan Cain, Ph.D.

Regional Head Quality Operation

Novartis Pharma


Disclaimer

This presentation is based on publicly available information. These slides are intended for the personal use of the audience. These slides are not intended for wider distribution outside the intended purpose without presenter approval. The content of this slide deck is accurate to the best of the presenter’s knowledge at the time of production.

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The Journey of Quality Beyond Compliance

Manufacturing

Strategy/ Quality

Strategy; Quality by

Design

Continuous

Improvement

Focus on our

products and “how we

make medicine”

Making Medicine

Common quality

system & standards

across all Novartis

divisions

Managing Quality

Sustainable and

reliable supply

network of high quality

products

Competitive

advantage

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Quality Culture

Quality Beyond Compliance

Cooperation

and

alignment

Quality

systems

and

tools

External

engagement

People,

organizational

capability,

training

Products,

process,

and

technology

Managing Quality and Making Medicine

Continuous Improvement, Competitive Advantage

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Supply Patients with Quality Products

Right first time and Every time, Efficiently and Safely

• Offer in depth process understanding and knowledge to manage the risks through product lifecycle

• Deliver quality product through precise systematic process control and confirmed through PAT

• Reduce complexity of the processes (less steps) and product lifecycle

• Ensue product quality at dosage level vs. batch

• Truly achieve product quality by design, rather by analysis

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Concept for Continuous Manufacturing

• All continuous unit

operations

• Total integration,

coupled end-to-end

• Systems approach

• Plant wide control

strategy

The process is the product!

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Quality Beyond Compliance Process Transformation

Batch

• Mostly step based

• Separation of DS & DP steps and sites

• Large fragmented footprint, high CAPEX

• Long lead times

Continuous

• Simultaneous inlet and outlet of materials

• Intensified processes with shortened lead times (hours vs. months)

• Increased supply chain flexibility

• Reduced plant footprint, lower CAPEX

• Quality quantum leap by higher level of process control

Reactor 1 LLE Crystallizer

Filter 1

Reactor 2 Reactor 3

Membrane

SeparatorReactor/

Crystallizer

Filter 2

Dryer 1

Extruder

Injection

Mold

Waste Waste Waste Waste

DP (Tablets)

Waste

Tablet

Coater

Dehydration Column

Ba

tch

C

ontinuous

Facility 1 & 2

Facility 3

Facility 1

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Process Transformation: Continuous Manufacturing

Continuous Manufacturing

is based on Process Intensification which allows more precise process control

• Maximized material processing in the smallest process space, for

example:

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Process Transformation: Continuous Manufacturing

10 c

m

Corning

www.corning.com

Intensification made easy with simultaneous inlet of raws

and outlet of products

Continuous conversion of materials = flow processing

= Continuous Manufacturing

Flow=Rate Control is key! Yanxi Tan Cain 9


Concept Pilot Reality

Continuous Manufacturing Plant

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End-to-End Pharmaceutical Manufacturing on the Size of a Tennis Court

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Magnitude of Technical Challenge • New process technologies for most unit operations

• New approaches for end to end integration of process technologies

• New development roadmaps for projects

• New screening tools to match projects and technologies

• New process control strategies

• New quality and regulatory pathways

• New health safety and environment (HSE) strategies

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Role of PAT in Continuous Manufacturing

• Enables one half of CM control strategy

• Faster is better: online, inline, at-line, offline

• Predictable and reliable response time is key

• Non-destructive principles

• Indirect measurements (surrogate test)

• Challenges: impurities, dissolution, micro, polymorphism

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New Quality Paradigm Lead Successful Implementation

Quality cannot be tested into the product, i.e., quality should be built in by design.“ (ICH Q8) – CM will bring us there...

• Batch definition: batch vs. lot

• Start product collection

• Material traceability

• Release decision

• Process validation

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What is a batch, lot etc? - 21 CFR 210.3

2) Batch means 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.

(10) Lot means a batch, or a specific identified portion of a batch, having 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.

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Batch Definition

• In the discrete manufacturing mode: technical capability lot size

• In the continuous manufacturing mode:

• The lot size is completely decoupled from the technical manufacturing

framework.

• The decision for the pre-defined lot size will be based on a balance of

acceptable business risk and effectiveness considerations.

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Material Traceability and Propagation 0

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Reaction Purification Crystallisation Extrusion

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Tableting

Key characteristics: - basis step response

= cumulative form

- Describes directly amounts of

material

- Includes experimental

determination and verification

- Can be based on material or

events (states)

- Characterized by minimum (e.g.

5%) and maximum (e.g. 95% of

material) propagation times

- Determines the area of impact

Pro

cess

tim

e

Area of Impact used for

reporting and flagging

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Propagation of Material • Characterize the propagation of materials and events on the basis of step

responses per unit operation.

• Propagation dynamics is the basis for a decision at the end of the train to

determine conforming vs non-conforming material

• Lot release data will be based on process data and quality attributes from

conforming material

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Handling of Non- Conformity • Non-conformity e.g. process event or OOS is electronically flagged

• Separation of conforming vs. non-conforming material based on real-

time material traceability and material flow property knowledge

• Impacted material will be diverted at the end of the process

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Material Traceability and Event Handling

Key characteristics: - State of control matters, not steady state

- Events (reach or lose state of control) will propagate through system following similar

principles like materials

- Events are basis for flagging and diversion decision

- Divert material at end of process to minimize disturbance

Release decision would be based on quality attributes AND process history with time-

stamped data

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Continuous Quality Verification (CQV) for CM

Product and process understanding

Continuous Quality Monitoring and

Control

Process Performance Evaluation

Release Decision

Continuous Process Improvement

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Integrated Drug Product Specifications

• No separate DS testing and release

• Comprise of some final product testing including traditional DP quality attributes

• Traditional DS quality attributes being evaluated in the final DP

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Batch Release Decision Based on the integrated drug product specification, i.e. on-line, at-line, off-line, in process tests and finished product testing

Start of Shelf-Life

The start (or date) of the continuous manufacturing process lot,

specifically the starting point of the collection of the specific lot.

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CM Changing the Way Medicines are Made

• Quality beyond compliance

• Ensure patients’ rapid access to breakthrough therapies

• Offer in depth process understanding and knowledge to manage the risks through product lifecycle

• Truly achieve product quality by design, rather by analysis

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Acknowledgements

Dedicated and innovative Novartis CM Technical, Quality and Regulatory scientists

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Q&A

Documents

Achieving Quality Beyond Compliance Through Continuous ...€¦ · Quality Beyond Compliance Process Transformation Batch • Mostly step based • Separation of DS & DP steps and