A

A Risk
Risk Assessment
Assessment of
of
Pre-Licensure
Pre-Licensure
Manufacturing
Manufacturing Changes
Changes
Patrick
Patrick G.
G. Swann,
Swann, Ph.D.
Ph.D.
Deputy
Deputy Director
Director
Division
Division of
of Monoclonal
Monoclonal Antibodies
Antibodies
Office
Office of
of Biotechnology
Biotechnology Products
Products
Office
Office of
of Pharmaceutical
Pharmaceutical Science
Science
FDA-CDER
FDA-CDER

2008 AAPS National Biotechnology Conference

June 22-25, 2008
Toronto, Canada

1
 Overview
Overview
• Q5e + Q9 = ?
• A Proposed Risk Assessment for Drug
Substance Manufacturing Changes during
Phase 1 for Monoclonal Antibodies and
Related Products
• Apply to examples of regulatory submissions
describing various manufacturing changes

2
Why
Why Pre-Licensure?
Pre-Licensure?

3
Scope: Protein products where manufacturing process changes
are made in development…..

4
Annex II: Potential Applications
Quality Risk Management as Part of Regulatory Operations
•To evaluate impact of proposed variations or changes

5
Q9 - Figure 1: Overview of a typical quality risk management process
6
 Q9:
Q9: Quality
Quality Risk
Risk Management
Management

• Risk Assessment
– What might go wrong?
– What is the probability it will go wrong?
– What are the consequences?
• Identification - systematic use of
information to identify hazards
• Analysis – Estimation of the risk
• Evaluation – Comparison against criteria

7
 Failure
Failure Mode
Mode and
and Effects
Effects Analysis
Analysis
(FMEA)
(FMEA)
• FMEA…provides for an evaluation of
potential failure modes for processes and
their likely effect on outcomes and/or
product performance.
• “Failure Modes” means the ways, or
modes, in which something might fail.
• “Effects Analysis” refers to studying the
consequences of those failures.

8
 Disclaimer
• The views expressed in this presentation are my
own, and do not necessarily reflect the official
views of the FDA.
• “The FMEA is a team function and cannot be
done on an individual basis”.* This is only a
proposal at this point.

*D.H. Stamatis, Failure Mode and Effect Analysis: FMEA from

Theory to Execution (Milwaukee: American Society for Quality, 2003).
9
 AA Proposed
Proposed Risk
Risk Assessment
Assessment for
for Drug
Drug
Substance
Substance Manufacturing
Manufacturing Changes
Changes during
during
Phase 11 for
Phase for Monoclonal
Monoclonal Antibodies
Antibodies and
and
Related
Related Products
Products

• Manufacturing changes are common

during the development of monoclonal
antibodies and related products under
IND.
• Can we use the FMEA method for the
assessment, communication and review
of risks associated with phase 1
manufacturing changes? 10
 The
The 10
10 Steps
Steps for
for an FMEA11
an FMEA

1. Review the process

• This proposal is based on process

FMEA with focus not on particular
products or manufacturing processes
but on changes in the drug substance
manufacturing process for monoclonal
antibodies and related products in
general.

1The Basics of FMEA; McDermott, Mikulak & Beauregard, 1996

11
 The
The 10
10 Steps
Steps …
…

2. Brainstorm potential failure modes

•• Manufacturing
Manufacturing changes
changes are
are not
not considered
considered
failures
failures as
as they
they are
are necessary
necessary for
for
continuous
continuous improvement.
improvement.

•• The
The failure
failure modes
modes assessed
assessed here
here are
are
manufacturing
manufacturing changes
changes that
that result
result in
in aa
deleterious
deleterious change
change in
in product
product quality
quality
attributes.
attributes.
12
 The
The 10
10 Steps
Steps …
…

3. List potential effects of each failure

mode

• Effects analysis references the

potential change in product’s
safety/efficacy profile.

13
 Step 4: Assign a Severity Rating
Rating Description
1 No differences have been observed and no
adverse impact on safety or efficacy (S/E)
profiles is foreseen.
2 Some differences have been observed but it can
be justified that no adverse impact on
safety/efficacy is expected.
3 Some differences have been observed but it can
be justified that no adverse impact on safety is
expected. Impact on efficacy is unknown.
4 A possible adverse impact on safety cannot be
excluded. Additional studies are needed.
5 Change results in conclusion that post-change
material is a new product. Safety and efficacy14
data with prechange material is not applicable
 Step 5 – Assign an Occurrence Rating
Rating Description

1 No known occurrence
2 Possible, but no known data
3 Documented but infrequent
4 Documented and frequent
5 Documented, almost certain

15
 Step 6 – Assign a Detectability Rating
Detectability
1 Robust CMC analytical tools sensitive to all
relevant changes and attributes
2 Critical Quality Attributes (CQA) known. WCBP with
robust CMC analytical tools sensitive to changes in
CQA.
3 Prior knowledge of potential product class CQA and
impact of process changes on some CQA
(“platform”). WCBP with robust CMC analytical tools
sensitive to potential changes.
4 CQA unknown. WCBP with robust CMC analytical
tools sensitive to potential changes.
5 CQA unknown. Not WCBP. Changes are not
detectable by CMC analytical tools. 16
Examples
Examples of
of classes
classes of
of products
products and
and
their
their detectability
detectability ratings
ratings
•• Detectability
Detectability rating
rating ## 11 can
can include
include defined
defined
molecular
molecular entities
entities (e.g.
(e.g. small
small peptides).
peptides).
•• Detectability
Detectability rating
rating ## 22 can
can include
include licensed
licensed
monoclonal
monoclonal antibodies.
antibodies.
•• Detectability
Detectability rating
rating ## 33 can
can include
include some
some
investigational
investigational IgG
IgG monoclonal
monoclonal antibodies.
antibodies.
•• Detectability
Detectability rating
rating ## 44 can
can include
include Fc-fusion
Fc-fusion
proteins.
proteins.
•• Detectability
Detectability rating
rating ## 55 can
can include
include complex
complex
biologics
biologics (e.g.
(e.g. IgM’s).
IgM’s).

17
 The
The 10
10 Steps
Steps …
…
relative risk value
7. Calculate the risk priority number for
each effect
8. Prioritize the failure modes of action
9. Take action to eliminate or reduce the
high risk failure modes.
10. Calculate the resulting RPN as the
failure modes are reduced or
eliminated.

18
 Example
Example 1-
1- New
New Cell
Cell Line
Line
•• Humanized
Humanized IgG1IgG1 monoclonal
monoclonal antibody
antibody produced
produced inin
CHO
CHO cell
cell line.
line. Prior
Prior to
to initiation
initiation of
of phase
phase 22 studies,
studies,
sponsor
sponsor generated
generated aa new
new CHO
CHO cell
cell line
line that
that produces
produces
higher
higher titers
titers of
of antibody.
antibody.

•• MCB
MCB tested
tested and
and passed.
passed. FDA
FDA reviewer
reviewer concurred
concurred that
that
analytical
analytical results
results demonstrated
demonstrated comparability.
comparability.

Factor # Description RRV

Severity 1 No differences have been observed…
Occurrence 3 Documented but infrequent 9
Detectability 3 “Platform”

19
 Example
Example 22 –– Multiple
Multiple Mfg
Mfg Changes
Changes
•• Human
Human IgG1
IgG1 monoclonal
monoclonal antibody
antibody produced
produced in
in NS0
NS0 cells.
cells.

•• Prior
Prior to
to Phase
Phase 2, 2, multiple
multiple manufacturing
manufacturing changes
changes werewere
made
made including:
including:
–– Phase
Phase 11 mfg
mfg process
process utilized
utilized aa non -clonal cell
non-clonal cell line.
line.
Clone
Clone cell
cell line.
line. New
New MCB
MCB and and WCBWCB
–– Production
Production Bioreactor
Bioreactor scaled
scaled up up
–– Change
Change inin DS DS manufacturing
manufacturing site site
–– Cell
Cell Culture
Culture process
process modifications
modifications
–– Changes
Changes to to affinity
affinity column
column resin
resin
–– Introduction
Introduction of of linear
linear gradient
gradient elution
elution for
for IEC
IEC
–– Change
Change toto aa different
different viral
viral filter
filter mfg
mfg

20
 Example
Example 22 –– Multiple
Multiple Mfg
Mfg Changes
Changes
•• Human
Human IgG1
IgG1 monoclonal
monoclonal antibody
antibody produced
produced in
in NS0
NS0 cells.
cells.

•• Reviewer
Reviewer concurred
concurred thatthat CMC
CMC safety
safety issues
issues were
were
addressed
addressed and
and in
in vitro
vitro analytical
analytical data
data supported
supported
comparability.
comparability.

Factor # Description RRV

Severity 1 No differences have been observed…
Occurrence 4 Documented and frequent 12
Detectability 3 “Platform”

21
 Example
Example 33 –– Multiple
Multiple Mfg
Mfg Changes
Changes
•• Human
Human IgG2IgG2 monoclonal
monoclonal antibody
antibody produced
produced inin NS0
NS0 cells
cells
•• Prior
Prior to
to Phase
Phase 2, 2, multiple
multiple manufacturing
manufacturing changes
changes werewere
made
made including:
including:
–– Phase
Phase 11 mfg
mfg process
process utilized
utilized aa non -clonal cell
non-clonal cell line.
line.
Clone
Clone cell
cell line.
line. New
New MCB
MCB and and WCB.
WCB.
–– Production
Production Bioreactor
Bioreactor scaled
scaled up up
–– Change
Change inin DS DS manufacturing
manufacturing site site
–– Cell
Cell Culture
Culture process
process modifications
modifications including
including removal
removal
of
of animal -derived raw
animal-derived raw materials
materials
–– Change
Change toto thethe harvest
harvest process
process
–– Changed
Changed the the order
order of
of downstream
downstream operations
operations
–– Change
Change toto aa different
different viral
viral filter
filter mfg
mfg

22
 Example
Example 33 –– Multiple
Multiple Mfg
Mfg Changes
Changes
•• Human
Human IgG2
IgG2 monoclonal
monoclonal antibody
antibody produced
produced in
in NS0
NS0 cells.
cells.
•• No
No data
data presented;
presented; only
only aa plan.
plan.
•• Plan
Plan did
did not
not provide
provide sufficiently
sufficiently detailed
detailed acceptance
acceptance
criteria.
criteria.
•• Plan
Plan did
did not
not adequately
adequately address
address Q5a
Q5a (viral
(viral safety)
safety) risks.
risks.

Factor # Description RRV

Severity 4 A possible adverse impact on safety
profiles cannot be excluded 64
Occurrence 4 Documented and frequent
Detectability 4 All CQA unknown.

23
Example
Example 44 –– Multiple
Multiple Mfg
Mfg Changes
Changes including
including
aa change
change inin amino
amino acid
acid sequence
sequence
•• Humanized
Humanized IgG1IgG1 monoclonal
monoclonal antibody
antibody produced
produced inin NS0.
NS0.
•• Prior
Prior to
to Phase
Phase 2,2, sponsor
sponsor noted
noted aa relatively
relatively high
high rate
rate of
of
immunogenicity
immunogenicity andand poor
poor cell
cell line
line productivity.
productivity.
•• Investigation
Investigation revealed
revealed that
that murine
murine sequence
sequence in in the
the light
light
chain
chain constant
constant region
region waswas inadvertently
inadvertently not not removed
removed
during
during humanization.
humanization.
•• Multiple
Multiple changes
changes proposed
proposed including:
including:
–– Substitute
Substitute human
human amino
amino acids
acids for
for murine
murine
–– Change
Change from
from NS0
NS0 to to CHO
CHO
–– Change
Change from
from roller
roller bottles
bottles to
to bioreactor
bioreactor
–– Add
Add an
an additional
additional chromatographic
chromatographic step step
–– Change
Change the
the viral
viral filter
filter

24
Example
Example 44 –– Multiple
Multiple Mfg
Mfg Changes
Changes including
including
aa change
change inin amino
amino acid
acid sequence
sequence
•• Humanized
Humanized IgG1 IgG1 monoclonal
monoclonal antibody
antibody produced
produced in in NS0.
NS0.
•• Primary
Primary sequence
sequence changes
changes indicated
indicated that
that this
this is
is aa new
new
product
product andand the
the applicability
applicability of
of previous
previous non
non--
clinical/clinical
clinical/clinical data
data toto the
the development
development of of the
the new
new
product
product waswas called
called into
into question.
question. AA consensus
consensus was was
difficult
difficult to
to reach.
reach.

Factor # Description RRV

Severity 5 Change results in conclusion that
postchange material is a new product 75
Occurrence 5 Documented almost certain
Detectability 3 “Platform”

25
 Summary Results

Example S O D RRV

1. New cell line, data 1 3 3 9

provided
2. Cloned cell line etc, data 1 4 3 12
provided
3. Cloned cell line etc, data 4 4 4 64
not provided
4. New sequence, new cell 5 5 3 75
line, etc.
26
 Summary Results

Example S O D RRV

1. New cell line, data 1 3 3 9

provided 2 2 2 8
3 3 2 18
2. Cloned cell line etc, data 1 4 3 12
provided 2 2 2 8
3 3 2 18

27
 Summary Results

Example S O D RRV

3. Cloned cell line etc, data 4 4 4 64

not provided 4 3 4 48
4 4 4 64
4. New sequence, new cell 5 5 3 75
line, etc. 4 3 3 36
5 4 4 80

28
 Summary Results

Example S O D RRV

1. New cell line, data 1 3 3 9-18

provided
2. Cloned cell line etc, data 1 4 3 8-18
θ provided
3. Cloned cell line etc, data 4 4 4 48-64
not provided
4. New sequence, new cell 5 5 3 36-80
line, etc.
29
 Moving
Moving Forward
Forward
•• Formalized
Formalized risk
risk assessments
assessments may
may be
be useful
useful in
in
planning
planning for
for and
and evaluating
evaluating manufacturing
manufacturing
changes.
changes.

•• Occurrence
Occurrence ratings
ratings would
would benefit
benefit from
from
systematically
systematically collecting
collecting the
the results
results of
of
comparability
comparability assessments.
assessments.

•• Consider
Consider weighing
weighing factors
factors based
based on
on confidence
confidence
(e.g.
(e.g. S
S >>
>> O,
O, D)
D)

•• Apply
Apply to
to other
other phases
phases of
of development?
development? Drug
Drug
Product
Product Manufacturing
Manufacturing Changes?
Changes? 30
 More
More Information
Information Needed?
Needed?

Guidance can be found at :

http://www.fda.gov/cder/guidance/index.htm

AND

Points to Consider in the Manufacture and Testing of

Monoclonal Antibody Products for Human Use

http://www.fda.gov/cber/gdlns/ptc_mab.txt

31
 Acknowledgements
Acknowledgements
•• Steven
Steven Kozlowski
Kozlowski •Ruth Cordoba
•• Kathleen
Kathleen Clouse
Clouse •Laurie Graham
•• Barry
Barry Cherney
Cherney •Sarah Kennett
•Carla Lankford
•Kurt Brorson •Jun Park
•Gerald Feldman •Ram Sihag
•David Frucht
•Chana Fuchs
•Subramanian Muthukkumar
•Barbara Rellahan
•Marjorie Shapiro
32