Xcellerex … speeding medicines to people … PAT for Biologics Ensuring Quality of Biologically...

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 Elizabeth FowlerXcellerex


Outline

• Xcellerex View of PAT• Importance of PAT for Biologics• Value of PAT• Implementation of PAT – Xcellerex Program• Summary


Xcellerex View of PAT

• Process knowledge gained through process analytics and statistically designed process optimization studies

• Processes designed for quality

• Continual monitoring ensures process control

• Risk based approach to quality; PAT provides data


Key Issues in Biologics Production

• Biological variation in production of material– Animal to animal variation– Cell culture variation

• Biological safety – unknown pathogens

• Unrelated impurities with unknown activities

More biological variables

Greater need for

PAT


Product Risk Management

Present: Minimal process change allowed

Process parameters used as surrogates for product quality monitoring

Release and some in-process testing used to ensure product consistency

Future: Real-time monitoring provides increased assurance of process and product quality consistency

Increased process understanding enables risk-adjusted evaluation of process & product data


Real-Time Process MonitoringBiotechnology Drugs

Fermentation

Purification

FormulationFill Finish

Present

Cell growth

Cell viability

Metabolic parameters(dO2, pH, glucose)

Process parameters(OD, pH, Flow rate, Conductivity)

API concentration Environment

Fill volume

Future

API content

API quality

Impurities

Bioburden & viruses

API quality

Content uniformity

Excipient uniformity

Impurity levels

Sterility

API concentration

API quality

Impurity clearance

Bioburden & viruses

Purpose

Control product quality

Ensure biosafety

Control product quality

Ensure impurity removal

Ensure biosafety

Ensure product

Ensure uniformity

Ensure safety


Value of PAT for Biologics

• Ensure product quality remains consistent

• Assess deviation impact in real time– Avoid costs of processing unreleasable batches– Data justification of batch release

• Continual process monitoring obviates need for process validation

• Reduce testing requirements at end of process• Increase process knowledge

– Identify critical steps and parameters that impact quality

– Improve risk assessment validity


Manufacturing Investment Risk

• Savings via On-Line Bioburden QC– Assumptions:

20 batches attempted/year $20,000,000 annual budget, fully loaded $1,000,000 cost per batch, fully loaded 90% overall batch success rate – 18 batches

– Cost of lost batches: $2,000,000/year

Possible savings via on-line fermentation bioburden: $1,000,000/year


Xcellerex PAT ProgramProcess Development & Analytics

Program Initiative• Process Development

– Automation - High throughput screening

– Statistical process optimization

• Process Analytics– Product Quality – microarray

glycosylation analysis– Process control via non-

invasive sensors – pH, DO2, optical density, IR

– On-line environmental monitoring – non-viable particulates

Benefit• Optimized process from start

of clinical manufacturing• Examine more parameters in

less time

• Real time assessment of product quality

• Non-invasive monitoring of process parameters

• Real-time assessment of environmental control


Xcellerex PAT ProgramManufacturing

Benefit

• Minimize operator errors• Early detection of deviations

• Protect product quality

• Rapid batch release

• Minimize environmental contamination

• Increase flexibility

• Minimize cross-contamination

Program Initiative• Automation

– Electronic batch records– Non-invasive sensors – pH

and DO2

– On-line quality assurance

• Controlled environment modules– Operator separation

• Disposables


Knowledge Management eFactory™

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

MyProjectsecure portal

Supply Ops

•Vendors

•Mat. flow

•Inventory

Quality Control

•Test Methods

•Sample status

•Trending

Finance

•Contract

•Invoices

•Accruals

Proj. Mgmnt

•Contract

•Phases

•Your project

Reg Affairs

•FDA contact

•IND outlines

•Submissions


Figure 1. Quality Control Plot: Replicate Wells Ploted vs. Average of Wells

0.22

0.24

0.26

0.28

0.3

0.32

0.34

0.36

0.22 0.24 0.26 0.28 0.3 0.32 0.34 0.36

Average OD of Replicates

OD

of R

eplic

ates

Factorial Rep 1

Factorial Rep 2

Center Pts

Sigma Media

Fractional Factorial Wells

Center Point Wells

Sigma Medium Wells

Number of Wells

256 20 12

Average OD600 0.281 0.305 0.323

CV of OD600, avg

3.7% 3.6% 7.6%

Approximate Cell Density at average OD600 (MM cells/ml)

1.2 1.5 1.7

CV based on approximate cell density, MM cells/ml

10.2% 8.7% 17.0%

Normal MHB ~ 0.8 MM cells/ml

Best condition: 1.9 MM cells/mlCells still 94% viable!

Process Optimization by DOE


Automation: eBatch RecordPurification


Statistical Process Control

Step 1

Step 3

Step 2

Step 4


Challenges in Applying PAT to Biologics

• Investment in bringing analytics on-line

• Innovation to develop analytical tools to assess critical attributes

• Extensive data accumulation needed during development to identify critical attributes and appropriate limits

• Regulatory uncertainty– More data may reveal more variation

– Stringency of limits related to criticality of impact


Regulatory Risk with On-line Analytics

• Data– How much data is too much data – Collection interval - Continuous versus intermittent– How to use the data – speeding release or real-time

release?

• Noise– How to handle spurious spikes in continuous on-line

data – May need extra validation to ignore these

Lost productivity, lower plant output, high mfg. costs


Continual Environmental MonitoringTotal Particulates during Chromatography Step

1000

600

400

200

0

800

26-A

ug-0

2 17

:52

26-A

ug-0

2 21

:48

27-A

ug-0

2 01

:44

27-A

ug-0

2 09

:37

27-A

ug-0

2 05

:41

28-A

ug-0

2 05

:10

28-A

ug-0

2 09

:15

28-A

ug-0

2 13

:12

28-A

ug-0

2 17

:08

28-A

ug-0

2 21

:04

27-A

ug-0

2 13

:33

27-A

ug-0

2 17

:30

27-A

ug-0

2 21

:20

28-A

ug-0

2 01

:11

Par

ticul

ates

≥0.

5 µ

per

ft3 (x

10-3

)


SummaryImpact of PAT

• Measure product quality in process stream

• Increased understand of process – product quality relationship

• Continual process monitoring obviates need for process validation

• Enables science-based decision making in manufacturing

• Reduces batch release time, increases plant capacity

• Lower manufacturing risk and COGS

• Can be a very cost effective investment

OpportunityOpportunity

Pro

ces

s K

no

wle

dg

e

Present

Future

Result: Better Quality & Lower COGS for Entire Industry

PATPAT

Efficiency

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Xcellerex … speeding medicines to people … PAT for Biologics Ensuring Quality of Biologically...

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