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Xcellerex…speeding medicines to people …

PAT for BiologicsEnsuring Quality of Biologically

Produced Drugs

FDA Advisory Committee on Pharmaceutical Sciences April 13, 2004

Parrish Galliher and li!a"eth Fo#ler $cellere%

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Xcellerex View of PAT

& Process .no#lede ained throuh processanalytics and statistically desined processoptimi!ation studies

& Processes desined (or /uality

& Continual monitorin ensures process control

& is. "ased approach to /uality PA) providesdata

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Key Issues in Biologics

Production

& +ioloical variation in production o( material - Animal to animal variation

- Cell culture variation

& +ioloical sa(ety - un.no#n pathoens& nrelated impurities #ith un.no#n activities

More

biological

variables

Greater

need for

PAT

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Product Ris !anage"ent

Present inimal process chane allo#edProcess parameters used as surroates (orproduct /uality monitorin

elease and some in5process testin used toensure product consistency

Future eal5time monitorin provides increasedassurance o( process and product /uality

consistency

*ncreased process understandin ena"les ris.5ad6usted evaluation o( process 7 product data

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Real#Ti"e Process !onitoringBiotec$nology Drugs

Fermentation

Puri(ication

Formulation

Fill Finish

Present

Cell ro#th

Cell via"ility

eta"olic parameters8d92, p:, lucose;

Process parameters89D, p:, Flo# rate,Conductivity;

AP* concentrationnvironment

Fill volume

Future

AP* content

AP* /uality

*mpurities

+io"urden 7 viruses

AP* /ualityContent uni(ormity

%cipient uni(ormity

*mpurity levels

Sterility

AP* concentration AP* /uality

*mpurity clearance

+io"urden 7 viruses

Purpose

Controlproduct /uality

nsure"iosa(ety

Control product/uality

nsure impurityremoval

nsure "iosa(ety

nsure product

nsure uni(ormity

nsure sa(ety

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Value of PAT for Biologics

& nsure product /uality remains consistent& Assess deviation impact in real time

- Avoid costs o( processin unreleasa"le "atches

- Data 6usti(ication o( "atch release

& Continual process monitorin o"viates need (orprocess validation

& educe testin re/uirements at end o( process

& *ncrease process .no#lede

- *denti(y critical steps and parameters that impact/uality

- *mprove ris. assessment validity

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!anufacturing In%est"ent Ris

& Savins via 9n5year ?20,000,000 annual "udet, (ully loaded

?1,000,000 cost per "atch, (ully loaded @0 overall "atch success rate - 1B "atches

- Cost o( lost "atches ?2,000,000>year

Possi"le savins via on5line (ermentation"io"urden ?1,000,000>year

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Xcellerex PAT Progra"

Process De%elo&"ent ' Analytics

Proram *nitiative

& Process Development - Automation 5 :ih throuhput

screenin

- Statistical processoptimi!ation

& Process Analytics - Product =uality - microarray

lycosylation analysis

- Process control via non5invasive sensors - p:, D92,optical density, *

- 9n5line environmentalmonitorin - non5via"leparticulates

+ene(it

& 9ptimi!ed process (rom starto( clinical manu(acturin

& %amine more parameters inless time

& eal time assessment o(product /uality

& on5invasive monitorin o(process parameters

& eal5time assessment o(environmental control

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Xcellerex PAT Progra"

!anufacturing

+ene(it

& inimi!e operator errors

& arly detection o( deviations

& Protect product /uality

& apid "atch release

& inimi!e environmentalcontamination

& *ncrease (le%i"ility

& inimi!e cross5contamination

Proram *nitiative

& Automation

- lectronic "atch records

- on5invasive sensors - p:and D92

- 9n5line /uality assurance

& Controlled environmentmodules

- 9perator separation

& Disposa"les

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Knowledge !anage"ent

e(actory)

eFACTORY™ Knowledge Management•Data

•Experiments

•Methods

PD

•Data

•Protocols

•Methods

Quality

•Doc Approvals

•Doc Revisions

•Change control

QA Documentation

•Lot release

•Exceptions

•Deviations

QA Release

•Batch data

•Trending

•BPRs

Mfg

MPro!ectsec"re portal

Supply Ops

•#endors

•Mat$ %low

•&nventor

Quality Control

•Test Methods

•'ample stat"s

•Trending

Finance

•Contract

•&nvoices

•Accr"als

Proj Mgmnt

•Contract

•Phases

•(o"r pro!ect

Reg Affairs

•)DA contact

•&*D o"tlines

•'"+missions

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Fractional

Factorial Wells

Center Point

Wells

Sigma Medium

Wells

Number of

Wells

256 20 12

Average !600 0"2#1 0"$05 0"$2$

C% of !600&

avg

$"'( $"6( '"6(

A))ro*imate

Cell !ensit+ at

average !600

,MM cells-ml.

1"2 1"5 1"'

C% based on

a))ro*imate

cell densit+& MM

cells-ml

10"2( #"'( 1'"0(

Normal M/ 0"# MM

cells-ml

est condition 1"3 MMcells-ml

Cells still 34( viable

Process O&ti"i*ation +y DOE

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Auto"ation, eBatc$ Record

Purification

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-tatistical Process .ontrol

Step 1

Step 3

Step 2

Step 4

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.$allenges in A&&lying PAT to Biologics

& *nvestment in "rinin analytics on5line

& *nnovation to develop analytical tools to assesscritical attri"utes

& %tensive data accumulation needed durindevelopment to identi(y critical attri"utes andappropriate limits

& eulatory uncertainty

- ore data may reveal more variation - Strinency o( limits related to criticality o( impact

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Regulatory Ris wit$ On#line Analytics

& Data

- :o# much data is too much data

- Collection interval 5 Continuous versus intermittent

- :o# to use the data - speedin release or real5timerelease

& oise

- :o# to handle spurious spi.es in continuous on5linedata

- ay need e%tra validation to inore these

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.ontinual En%iron"ental !onitoringTotal Particulates during .$ro"atogra&$y -te&

1000

00

400

200

0

B00

2 F 5 A u , 5 0

2

1 G H 2

2 F 5 A u , 5 0

2

2 1 4 B

2 G 5 A u , 5 0

2 0 1 4 4

2 G 5 A u , 5 0

2 0 @ 3 G

2 G 5 A u , 5 0

2

0 H 4 1

2 B 5 A u , 5 0

2 0 H 1 0

2 B 5 A u , 5 0

2 0 @ 1 H

2 B 5 A u , 5 0

2

1 3 1 2

2 B 5 A u , 5 0

2

1 G 0 B

2 B 5 A u , 5 0

2 2 1 0 4

2 G 5 A u , 5 0

2

1 3 3 3

2 G 5 A u , 5 0

2 1 G 3 0

2 G 5 A u , 5 0

2 2 1 2 0

2 B 5 A u , 5 0 2

0 1 1 1

P a r t i c u l a t e s I 0 E H J

p e r ( t 3 8 % 1 0 5 3 ;

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-u""ary

I"&act of PAT

& easure product /uality in process stream

& *ncreased understand o( process - product /ualityrelationship

& Continual process monitorin o"viates need (or processvalidation

& na"les science5"ased decision ma.in in manu(acturin

& educes "atch release time, increases plant capacity

&

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O&& tunity

&& tunity

P r o c e s s K n o w l e d g e

Present

Future

Result, Better Quality ' /ower

.O0- for Entire Industry

P A

T

P A

T

fficienc!

4034oph1_01_fowler

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