Development and Implementation of Continuous Manufacturing Processes for API

Paul C. Collins, Ph.D., Senior DirectorSmall Molecule Design and DevelopmentEli Lilly and Company

Outline

♦ Introduction to CM API• Why do we do CM?• Why is it better for enhancing product quality?• Examples from Lilly CM API journey

♦ Future state• Possibilities• Things to ponder

What is Continuous Processing?

Continuous manufacturing (CM) is a method to manufacture, produce or process without interruption.

Constant material flow in and out of the process

While batch operations are dynamic processes (changing over time), continuous processes rely upon steady state operation (no change over time)

Smaller amounts of material “at risk” at any time is central to the concept

3

CM History in Lilly

2 Hybrid Processes in Manufacturing at

Kinsale

Continuous Unit Operation (Mfg)

IE2 SVC Facility, KinsaleUnder construction

Small Volume Continuous (SVC) Mànufacturing in Fumehood at Kinsale

Coil inside

1990’s 2017+201420132006-10

More Potent, Lower Volume Medicines

Platform & Technology

Development in R&D

Ozonolysis Quench

PumpPump

Tank 1 Tank 2

Hybrid CM Multiple Steps in CM

Realized Benefits of Continuous at Lilly

Enabling Chemistry-Extreme conditions-New options on old reactions-New SRs-Expanded toolbox

Safety

-Smaller

volumes

-↑ heat transfer

-No headspace

Quality-Natural QbDlinkage- PAT integration-Steady State control-Less at risk-↓Operational complexity

Going Green!-Less waste

-Lower energy

-Neat reactions

Cost Savings-Capital avoidance-New capabilities-Cytotoxic & HiPo capacity-↑Throughput

Early proofs of concept in Lilly Manufacturing

Project AAPI cost reduction of >50%

Robust Pd removalGreen chemistry reduces waste

Registration Stability120 kgs

Project BEliminated $20M spend on H2 bunker

Safer alternative to batchGreen chemistry

Registration Stability1800 kgs

Project CDevelopment time reduced

Tech transfer req’d half the timeGreen chemistry reduces waste

Pre-registration stability150 kgs

CM Opportunities

Pro

cess

Lilly’s Future Medicines are evolving towards more potent,

lower volume productsCurrently >70% post FHD portfolio has

projected volume of <1.5 MT/year

Forward Looking Strategy for CM

500 to 1000 mg dose 2 to 20 mg doses

Bus

ines

s

MINIMIZING VOLUMES including NEAT reactions.Containment of hazardous reagents3-15 kg/day

MAX THROUGHPUT FOR SVC

SCALEDEVELOPMENT ≡ MANUFACTURING

Leaner and faster tech transfers

Small Volume Continuous (SVC) Manufacturing Opportunities

CSTR 30 L

0.8 L PFR

300 Gal Batch reactor

Greater SECURITY OF SUPPLY due to shorter manufacturing lead times

REDUCED Processing & Turnaround TIMESDedicated/disposable equipment sets

Reduced Environmental ImpactLower volumes & number of isolations

Skids are part of a platform to support chemical unit operations in any product

• Modular to be combined into unit operations (e.g. CSTR/mixer skids combined for a counter-current extraction).

• Flexible and adaptable – simple skids with standard components (where possible)

• Plug into Distributed Control System (DCS)• Working with high end equipment e.g. gear

pumps & data management system.

SVC Facility for GMP API ManufactureFuture State

CSTR Skid

Plug Flow Reactor Skid

Feed System Skid

SVC Facility Virtual Tour

Reshaping our Manufacturing Footprint

MATERIALSBatch Definition SpecificationsMaterial Tracking / Genealogy incl. Deviation boundaries

EQUIPMENTReactors RTDCommercial skidsSingle use technology

PROCESS DESIGN including IMPURITY REJECTION

Rejection connected to unit operation

RISK ASSESSMENT

PRODUCT COLLECTION & MATERIAL DIVERSION

STATE of CONTROLincluding PROCESS MONITORING & DATA MANAGEMENTincl. Sampling | IPC | PAT | Offline testing | Modelling | MVA | Real-time analytics | Automation | Feedback Control

Product Control

Strategy*

Why CM is better for Product Quality -Control Strategy Elements

‘’Divert & Surge Strategies’’

Manufacturing process produces products of intended quality in a reproducible way

Failure modes

*Note: Elements not equally weighted

Control Strategy DiagramCase Study

Surge locations whereby material was isolated and provided complete decoupling of steps.

Step 1 Rxn Step 1 Extraction Step 1

DistillationStep 2 SNAR

Step 2 Crystallisation

Step 2 Filtration/Wash/

Dissolution

Step 3 Deprotection

Step 4Distillation

Step 4 Crystallisati

on

Nitrile SM, THFMeOH, AcOHHydrazine

DMSOWaterNa2CO3 DMSO

Pyrazine SMNEM

MeOHMTBE

Formic AcidWater

Lactic AcidWaterTHF

AcONa, Hydrazine, DeBoc, Water

MeOH, THFToluene, Water

MeOH, MTBE, DMSO, NEM*HClRegioisomersBis-PyrazinePyrazine SM & deg

HydrazoneDes-AminoNitrile SM

API*HClRegioisomersBis-PyrazineNEM*HCl API*HCl

CO2C4H8

Formic AcidWater

Formic Acid, Lactic Acid, Water, THF, t-Bu Amide, Hydrolysis imp., T-Bu Amine

API

API*HClt-Bu AmideHydrolysis Imp.t-Bu Amine

API*HClt-Bu AmideHydrolysis Imp.t-Bu Amine

MeOH

.

Surge after crystallization was a small CSTR with small tau, to dampen the 60 minute intermittent flow cycle time from the dissolve off filter.

Plug Flow Reactors (PFRs)Cleaner Reaction Profile | ‘Consumable Reactors’

Step 1 – 316L Stainless Steel PFR• 130 °C, 1 h V/q, 500 psi• Assay yields of 97–99%• Reduced hydrazine eq. versus

batch.• Faster reaction

Step 2 & Step 3 PFA PFRs• Step 2 - SnAR: ~85 °C at 3 h V/q• Step 3 - Deboc: 20–50 °C at 4 h V/q

− Mild conditions for deboc reaction. Gas-LiqPFR used to allow for gas sweeping & volatile removal

− Single use equipment

Counter-Current Extraction in Step 1Efficiently removed Hydrazine from 6000 ppm to <2 ppm

Counter-Current Extractions & DistillationImpurity Rejection

Distillation in Step 3• Distillation rate could not be replicated in

batch mode! Batch distillation times were longer which led to elevated impurity formation.

• Effective in formic acid removal to <1 equiv.

Continuous Crystallization Impurity Rejection & Safety

Automated Parallel Filters for filtration, washing, drying, and dissolution - “Isolation-Free Isolation”• Properly sized filters

achieve very consistent filtration rates and residual solvent levels, which is important for subsequent process step.

• No handling of cytotoxic product with OEL = 1 µg/m3

Mixed suspension mixed product removal (MSMPR) vessels• Crystallisation represented the

most significant element of the impurity control strategy

• The purity of the crystallized solids was in excess of 99.8 area%.

Online UPLC used in Steps 1, 2, 3:

Process MonitoringPAT data for Process Monitoring

Step 1

‘’Step 2’’

Step 2 Step 3

Offline HPLC confirmation for Step 3

PATrol Unit

0

0.1

0.2

0.3

0.4

0.5

0.6

0.7

0.8

0.9

1

95

95.5

96

96.5

97

97.5

98

98.5

99

99.5

100

Days of Sampling4 8 12 16 20 24

Product Starting Material Cis Isomer

Are

a %

Pro

duct

Area %

Starting M

aterial, Cis

Isomer

In-process Monitoring: Manufacturing

Distillation End Point (Step 3)Parametric Analysis for Process Monitoring

• First distillation performance evaluated offline by 1H NMR spectroscopy. Parametric analysis used thereafter.• Distillation performance assessed by distillate temperature (temperature, pressure, time, and mass flow)• Confidence in distillation performance and removal of formic acid.

Step 3 Distillation Temperature

Process Monitoring

Monitoring models for parameter and PAT analysis can provide traffic light signals to operators/ tech support. Multivariate capability. Feedback loop controls.

MODELS

DCSincl. ALARMS

MANUAL DATA RECORDING

SOPH

ISTI

CAT

ION

Periodic checks by operators/tech support. Data can also be entered manually into a control chart system. Resource and time intensive –not desirable!

Real time automated data analysis. No MSPC and relies on set limits and simple calculations.

PAT central to Process Monitoring

Step 2 EventIncrease in Key Impurity

Day 6 of 7, the Step 2 SNAr reaction performance changed as per online UPLC.

Area% Impurity over time

STARTING MATERIAL

PRODUCT

KEY IMPURITY Area

%

Time (h)

Root Cause:Reagent lost causing HClsalt formation that could not be rejected downstream.

Material TrackingDeviation Management

Drum 12 Collection08:35 to 20:30

12 h

Drum 13 Collection20:30 to 09:55

13.5 h

Drum 14 Collection09:55 to 00:01

14 h

Drum 15 collection00:01 to 21:16

21.25 h

τ ~ 3 h

τ ~ 2 x 1h

Cycle~ 2 x 1h

Surge time adjustable0 to 12 h

τ ~ 4h

PATr

ol

22:10Rxn stopped

02:10 Base equiv. corrected & rxn restarted

02:19Atypical

material starts collecting

19:25Start rxn &

resume typical material.

15:23Pause upstream unit op

to pump down CSTR surge to almost empty.*

Trend detected by PAT and not by parametric data.*If the level in the CSTR surge had not been pumped down then Drum #15 would have also had elevated impurity.

Divert StationsDivert & Surge Strategies for SVC

“The extent of material to be isolated and rejected depends on the duration, frequency, and severity of the disturbance and the mixing patterns of the system” FDA J. Pharma Innov. (2015) 10:191-199

DIVERT at source

Non-Conforming Material

SURGE Collect downstream

• Process Risk Assessment is key for determining appropriate strategy.• Process design, equipment robustness will be influencing factors as well as

the magnitude and duration of the disturbance.• Process monitoring, PAT, Modeling, key for managing these scenarios

effectively.

Strategy at Lilly

Data ManagementThe journey…

• PAT will be a key component of manufacturing control systems.

• Identified synTQ software platform to develop, deploy and manage data.

• PAT will communicate directly to the DCS.• Future potential: Advanced control e.g. MVA, MSPC,

Computational models for decision making, live batch tracking.

2 PATrols collect samples every

hour

Manual check by Chemist

Results exported and trended (manual)

Trended data shared with team

Repeat for duration of campaign2014 Proof of Concept:

Future CM Processes

• Approach not sustainable long term

Current control strategy status

♦ Control Strategy is a combination of Level 1 and 2 controls today

Lilly manufacturing:• 2 registration stability campaigns in 2013• 2 clinical trial campaigns in 2014• 1 validation campaign in 2015• SVC on line in 2017

External manufacturing:• 2 clinical trial campaigns in 2013• 2 validation campaigns in 2015• 3 fully continuous multi-step process in SVC format

Regulatory activity:• 1 Type C meeting with FDA in 2013• Several End of Phase 2 (EOP2) with FDA meetings since 2013• 1 NDA submission and 1 planned NDA submission with FDA for 2015• HPRA visit in 2016

Accomplishments to Date

Possible Future

♦ Demonstrated on-line monitoring gives much better view of “state of control” – robustness and productivity• In process testing done offline in traditional labs not

needed (already possible now)♦ A set of approved unit operation modules could be

deployed in an approved manufacturing site in only days/weeks – supply chain flexibility and robustness• Digitized workflows check the CM API process train is

compliant for manufacture. • An example – deployment of a second manufacturing

train in a second location would be analogous to a system suitability test to use in a second location.

• “Scale up” exits the pharmaceutical vernacular…

Possible Future

♦ Miniaturization of API manufacture allows for dedicated processing equipment – cross contamination concerns eliminated

♦ Deviations and associated cost will be reduced over ten fold – robustness and control

♦ Traditional inspection approaches could be done digitally – overall pharma oversight becomes less costly, yet more rigorous• Continuous process control data• Continuous in-process analytical data

Missing elements and gaps to full implementation

♦ Regulatory• Approaches to control strategy, technology transfer

(including site to site), validation, filing parameters (such as design space) were created on a batch paradigm

• CM API changes the meaning associated with each of these

– Equipment design and automated control more important than range definition/procedural control

– Scale and equipment differences associated with traditional batch development and manufacture are largely eliminated

• Confusion and energy barrier associated with how to fit square pegs into round holes will keep some companies out of CM API

• Geographic flexibility, response to supply chain disruptions are very possible with miniaturized, modular CM API – but regulatory flexibility does not currently match

CM API – A few questions we might ponder…♦ What is the goal of CM API from the regulatory

perspective?♦ Why would you have a control strategy if you

could actually control?♦ What was the original reason for things like

validation and why do we need them in CM?

♦ Our regulatory perspectives need to evolve to fit the capabilities now available for full implementation and utilization

Backups

Batch and Continuous Comparison

Bridge = Continuous Operation

Car Ferry = Batch Operation

3/15/2017

Batch vs Continuous Processes

3/15/2017

30 L CSTR

2 L PFR

Vessels and auxiliary equipment are smaller than batch vessels for the same throughput!

1200L Batch Tank