Seymour.pdf

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Continuous Processing

Christine SeymourGlobal Chemistry Manufacturing and ControlsPfizer Inc


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The details are not the details. Theymake the design.

harles Eames

Introduction


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Introduction - Examples of Pharmaceutical Continuous Processes

Continuous separation of optical isomers * (levo enantiomers of -methyldopa from the dextro species) Fluidized bed continuous crystallizer Operates in the non-equilibrium conditions Close control of supersaturation to prevent nucleation Population balance maintained by crystal fracture (sonication) Batch process could not be scaled up

Selective oxidation (Convert 4-methyl-thiazoleto corresponding nitrile) *

Adiabatic packed-bed reactor Obtained desired conversion/selectivity/quality

Pervious process was shown to work at 1-2% yield

Commercialized these process in the 1960s

* Edward Paul and Carlos Rosas, Challenges for Chemical Engineers in the Pharmaceutical Industry, Chemical Engineering Progress, December 1990


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Introduction

Traditionally the Pharmaceutical Industry has focused on batch

processing

Perhaps due to: Flexibility of multipurpose plants Large number of products Increased regulation (ICH guidelines begin implementation in1996)

Continuous process Cultural change Lack of experience Perceived regulatory

barriers Not the way it has

always been done

Graph data reference: www.fda.gov (Home>About FDA>What We Do>History)

New Molecular EntitiesNDAs Approved per Year

0

10

20

30

40

50

60

1960 1970 1980 1990 2000 2010 Year

N D A s

A p p r o v e

d


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Introduction

(2)

(1)

(3)

(2)

(1)

(3)

(2)

Continuous Process

Material continuous flowsinto and out of theequipment

Batch Process

Material flows into theequipment, processingoccurs and material isemptied form theequipment

Semi ContinuousProcess

Material flows into theequipment, materialenters or leaving duringthe processing and

material is emptied formthe equipment


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Continuous Processing - Perceived Regulatory Hurdles

Are the regulatory definitions applicable to continuousprocessing?

o ICH Q7: Good Manufacturing Practice for Active Pharmaceutical Ingredients a batch (or lot) is a specific quantity of material produced ina processes or series of processes so that it is expected to behomogeneous within specified limits. In the case of continuous or semi-continuous production , a batch may correspond to a defined fraction of

the production. The batch size can be defined either by a fixed quantityor by the amount produced in a fixed time interval.

o 21 CFR 210.3 (2): Batch means a specific quantity of a drug or othermaterial that is intended to have uniform character and quality, withinspecified limits, and is produced according to a single manufacturingorder during the same cycle of manufacture.


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Are the regulatory definitions applicable tocontinuous processing?

o Batch - A quantity of drug in dosage form, a raw material, or a packagingmaterial, homogeneous within specified limits, produced according to asingle production order and as attested by the signatories to the order.

In the case of continuous manufacture , a batch corresponds to a definedfraction of the production, that is characterized by its intended homogeneity.

It may sometimes be necessary to divide a batch into a number of sub- batches, which are later brought together to form a final homogeneous batch.(Health Canada Good Manufacturing Practices (GMP) Guidelines - 2009

Edition (GUI-0001))

o A batch is considered homogeneous when equivalent parts or materials aremanufactured and/or tested in the same manner, without interruption,typically on the same day or in the same time period , and produced by thesame person, or with the same machine/equipment set-up and fulfill the samespecifications. (EMA MEDDEV 2.5/6 Rev. 1 February 1998)


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Are the regulatory definitions applicable tocontinuous processes?

o 21 CFR 210.3 (10) Lot means a batch, or a specific identified portion of a batch, having uniform character and quality within specified limits; or, in thecase of a drug product produced by continuous process , it is a specificidentified amount produced in a unit of time or quantity in a manner thatassures its having uniform character and quality within specified limits.

o Lot - A quantity of any drug in dosage form, a raw material, or a packagingmaterial, homogeneous within specified limits, constituting all or part of asingle batch and identified by a distinctive lot number that appears on thelabel of the finished product. (Health Canada Good Manufacturing Practices(GMP) Guidelines - 2009 Edition (GUI-0001))

The regulatory definitions are applicable to continuous processing

o Appears to be no major hurdles in guidelines/laws (ICH, CFR, EMA forclinical trial or commercial applications)


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How is steady state defined?

Steady state not in current regulations. Proposed definitions

Steady state is obtained when all flows and concentrations do not changewith time

Steady state is when the processing conditions (i.e. material flow rates,temperatures, and/or pressures) are within normal processing variations

Steady state is when the process controls are at the pre-determined,desired set points (for example, a reactor temperature set point) and thereare only normal process variations.

Steady state is when the critical process parameters are within a specified

range


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Steady State On going discussions

When is steady state obtained?

How are start up and shut down handled?

How are perturbations handled?

Steady state and perturbations can be mathematically modeled

o First order reaction in a continuous stirred tank reactor can becalculated *

+1ln= k

t e steadystat

* Elements of Chemical Reaction Engineering, H Scott Fogler, 1992

Fast reactions t steadystate = 4.6/ k

Slow reactions t steadystate = 4.6


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ICH Q8, 9, 10 and 11

Are the current regulatory guidelines are applicable tocontinuous processes?

Concepts in ICH Q8, 9, 10 and 11 are applicable to continuousprocesses

o A more systematic approach to development (Quality by Design: QbD)o Multivariate interactions emphasizedo Incorporation of risko Knowledge managemento Product lifecycleo Increased assurances of qualityo May reduced post-approval regulatory burdeno Provides the flexibility to use modern manufacturing approaches


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Real Time Release

Real Time Release

All quality tests are on-line/at-line

Manufacturing flexibilityo Increased efficiencyo Control in real-timeo Process adjustments in real-time

Increased assurance of qualityo More representative of the processo More information gained

Adoption of PAT technologieso Continuous process monitoringo Feedback control


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Process Validation of Continuous Processes

Traditional three batch approach

Continuous Process Verificationo An alternative approach to process validation in which manufacturing

process performance is continuously monitored and evaluated (ICH8)o Continuous Quality Verification (CQV) is described as an approach to

process validation where manufacturing processes (or supporting utilitysystems) performance is continuously monitored, evaluated andadjusted as necessary. *

Product/ProcessUnderstanding

ProductQuality

ContinuousQuality

Monitoring

ContinuousProcess

Improvement

Process PerformanceEvaluation*ASTM E2537


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The holy grail

Continuous ProcessingTelescopedReal Time Release

Continuous Quality Verification

RTR

API

Excipients

RTR

DPRecycle

PackagedDrug ProductRaw

Materials


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Potential hurdles for continuous processing

Tractability of raw material lots and intermediate batches

Regional regulatory differences and acceptanceo Potential for additional queries and longer review periodo Some regulatory agencies have additional requirements

Steady stateo Definition of steady stateo How to handle start up/shut downo How to handle perturbations and deviations

Inventoryo Need more inventory? Need less inventory?


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Benefits of Continuous and Batch Processing


Increased control of flows,temperature and pressure

o Higher temperatures/pressurepossible

o Short material contact timebetter controlled

better for fast kinetics (i.e.reactions & crystallizations)

better for exothermic

operations

Neat processing possibleo Less waste, lower environmental

impact

Typically operated in dedicatedequipment and non stop; oftenwith less inventory

Batch Processing

More flexible operationso Slow material contact time

better for slow kinetics (i.e.

reactions & crystallizations)

Typically operated diluteo Often higher solvent load

Typically operated inmultipurpose equipment and incampaigns; often with largeinventories of intermediates/finished products


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Further processing options

Most continuous operationswould be new equipment

o small scale skids possible

Less product variabilityo No batch to bath variationo Process variations and

upsets

Batch Processing

Less processing alternatives

Most existingpharmaceutical plants aremultipurpose batch plants


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Typically lower cost at highproduction rates *

o However continuous operationstypically have increased flow andtemperature control canoperation processes that are notpossible in batch processing

o Can be a large advantage inearly development

Batch Processing

Typically lower cost at lowproduction rates *

* Douglas, Conceptual Design of Chemical Processes, 1988

Typical Trend of Continuous and Batch Cost vs Scale

1

10

100

1000

10 100 1,000 10,000

Scale

C o s

t

Continuous

Batch


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Cost Analysis is likely part of the Batch orContinuous decision

Typically process cost analysis examineso Raw Material costo Waste Costo Processing (Overhead) Costs

Other processes costs are hard to quantifyo Cost of lot failures and investigationso Cost of recalls and stock outs

o Cost of inventory (finished product, intermediate, raw materials)o Cost of analytical tests and release


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Comments about Process Costs

Analytical Release Costs Analytical release time and costs can be high examples below Real time release has potential to decrease these costs

(Graph source: G. K. Raju, M.I.T. FDA Science Board Meeting, November 16, 2001)


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Intermediate Storage

Batch processes are typically operated in campaigns with largeintermediate storage

Continuous process are typically operated non-stop with lessintermediate storage potential to decrease storage cost

Inventory Holdings

$0

$1,000

$2,000

$3,000

$4,000

$5,000

$6,000

$7,000

TKPHF AZN BMY AMGN BOE* LLY MRK ABT WYE SGP TEVA PFE JNJ SNY NVS RHHBY GSK

$ M i l l i o n s

Raw MaterialsWork in ProgressFinished Goods

Inventory holdings for 17 pharmaceutical companies based on inventories listed ineach individual companies 2008 annual report.

Chemical Engineering in the Pharmaceutical Industry R&D to Manufacturing , Edited by David J. am EndeCopyright @ 2010 John Wiley & Sons, Inc.


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Cost impact of decreasing processing time with continuous processing

What is the cost contributors of typical Pharmaceutical processes in terms ofraw material, waste and overhead costs

Case study:

8 drug substance development/commercial compounds Commercial scale basis

o equipment sizeo cost per houro raw material costs

Comprehensive modeling ofincluding mass balances,raw material amounts,unit operations, cycle time,number of batches, waste amount

Estimated commercial cost

Process Costs ContributionsPercent Raw Material, Percent Waste and Percent Overhead

0%

50%

100%

Raw Material Cost Waste Cost Overhead Cost


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Question: Cost analysis oftypical drug substancePharmaceutical processes

Observations: Raw material costs range from 30 to 75% Waste costs typically < 20% Overhead costs range from 10 to 70% Shows the potential for process improvements

o Example 1 (yellow bar) was later optimized lowering theoverhead time/cost and greatly decreasing the overall cost

o Provides impact of decreasing processing time Processes with low overhead costs might have

limit benefit converting to continuous processing

Process Costs ContributionsPercent Raw Material, Percent Waste and Percent Overhead

0%

50%

100%

Raw Material Cost Waste Cost Overhead Cost


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Question: Cost analysis oftypical drug substancePharmaceutical processes

Observations: Average raw material costs 51% Average waste cost 11% Average overhead costs 38%

Average Cost Contributions

Overhead,38%

Raw Material,51%

Waste, 11%


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Conclusions

Continuous Processes

Is established technology Have been implemented in the Pharmaceutical Industry

The current guidelines are applicable to continuous processes There are no major regulatory hurdles There are several unique regulatory aspects of continuous

processingo Steady state, startup/down, perturbations

Modern manufacturing operations (Continuous Processing, realtime release) have potential to

Decrease process costs Decrease intermediate storage and costs Decrease release costs


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Acknowledgements and References

Acknowledgments David am Ende, Tim Watson, Steve Colgan, Roger Nosal, Bob Baum (Pfizer) Ed Paul (Merck, retired) Shekhar Viswanath and Vaidyaraman Shankarraman (Eli Lilly and Co.)

References Conceptual Design of Chemical Processes, James Douglas, 1988

Elements of Chemical Reaction Engineering, H Scott Fogler, 1992

Edward Paul and Carlos Rosas, Challenges for Chemical Engineers in thePharmaceutical Industry, Chemical Engineering Progress, December 1990

Continuous Manufacturing in the Pharmaceutical Industry An FDA Perspective, MohebM Nasr, ISPE Continuous Processing Symposium, Brussels, March 30, 2009.

White Paper on Regulatory Aspects of Continuous Processing, Rick McCabe, ISPEContinuous Processing Symposium, Brussels, March 30, 2009.

A Science and Risk Based Proposal for Understanding Scale and EquipmentDependencies of Small Molecule Drug Substance Manufacturing Processes,Timothy J. N. Watson et al, Journal of Pharmaceutical Innovation, July 16, 2010.

Chemical Engineering in the Pharmaceutical Industry R&D to Manufacturing, Edited byDavid J. am Ende Copyright @ 2010 John Wiley & Sons, Inc.

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