PAT for Biologics

Ensuring Quality of Biologically

Produced Drugs

FDA Advisory Committee on Pharmaceutical Sciences

April 13, 2004
Parrish Galliher and Elizabeth Fowler
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Outline

Xcellerex View of PAT

Importance of PAT for Biologics
Value of PAT
Implementation of PAT Xcellerex Program
Summary

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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

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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
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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 riskadjusted evaluation of process & product data

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Real-Time Process Monitoring

Biotechnology Drugs

Fermentation

Purification

Formulation
Fill Finish
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Purpose

Present

Future

Control
product quality

Cell growth
Cell viability
Metabolic parameters
(dO2, pH, glucose)

API content
API quality
Impurities
Bioburden & viruses

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

API concentration
API quality
Impurity clearance
Bioburden & viruses

API concentration
Environment
Fill volume

API quality
Content uniformity
Excipient uniformity
Impurity levels
Sterility

Ensure
biosafety
Control product
quality
Ensure impurity
removal
Ensure biosafety

Ensure product
Ensure uniformity
Ensure safety

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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
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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
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Xcellerex PAT Program

Process Development & Analytics
Program Initiative
Process Development
Automation - High throughput
screening
Statistical process
optimization

Benefit
Optimized process from start
of clinical manufacturing
Examine more parameters in
less time

Process Analytics
Product Quality microarray
glycosylation analysis
Process control via noninvasive sensors pH, DO2,
optical density, IR
On-line environmental
monitoring non-viable
particulates

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Real time assessment of

product quality

Non-invasive monitoring of
process parameters

Real-time assessment of
environmental control

Xcellerex PAT Program

Manufacturing
Program Initiative
Automation
Electronic batch records
Non-invasive sensors pH
and DO2
On-line quality assurance

Benefit

Minimize operator errors

Early detection of deviations

Protect product quality

Rapid batch release

Controlled environment
modules
Operator separation

Minimize environmental
contamination
Increase flexibility

Disposables

Minimize cross-contamination

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Knowledge Management
eFactory
MyProject
secure portal
Proj. Mgmnt

Supply Ops

Quality Control

Finance

Reg Affairs

Contract

Vendors

Test Methods

Contract

FDA contact

Phases

Mat. flow

Sample status

Invoices

IND outlines

Your project

Inventory

Trending

Accruals

Submissions

eFACTORY Knowledge Management

Data

Batch data

Doc Approvals

Data

Lot release

Experiments

Trending

Doc Revisions

Protocols

Exceptions

Methods

BPRs

Change control

Methods

Deviations

PD

Mfg

QA Documentation

Quality

QA Release

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Process Optimization by DOE

Bestcondition:1.9MM
cells/ml
Cellsstill94%viable!

Fractional
FactorialWells

CenterPoint
Wells

SigmaMedium
Wells

256

20

12

AverageOD600

0.281

0.305

0.323

CVofOD600,
avg

3.7%

3.6%

7.6%

Approximate
CellDensityat
averageOD600
(MMcells/ml)

1.2

1.5

1.7

CVbasedon
approximate
celldensity,MM
cells/ml

10.2%

8.7%

17.0%

Numberof
Wells

NormalMHB~0.8MM
cells/ml
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Automation: eBatch Record

Purification

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Statistical Process Control

Step 1

Step 2

Step 3

Step 4

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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
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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
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Xcellerex

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28-Aug-02 21:04

28-Aug-02 17:08

28-Aug-02 13:12

28-Aug-02 09:15

28-Aug-02 05:10

28-Aug-02 01:11

27-Aug-02 21:20

27-Aug-02 17:30

27-Aug-02 13:33

27-Aug-02 09:37

27-Aug-02 05:41

27-Aug-02 01:44

26-Aug-02 21:48

26-Aug-02 17:52

Particulates 0.5 per ft3 (x 10-3)

Continual Environmental Monitoring

Total Particulates during Chromatography Step

1000

800

600

400

200

Summary
Impact 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
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Opportunity

PA

Process Knowledge

Future

Present

Efficiency

Result: Better Quality & Lower

COGS for Entire Industry