Transcript Post-change material - Drug Information Association

What You Should Know When You
Make Manufacturing Changes to
Biotechnology Products
May 16-18, 2011 | Beijing, China
Mark Rosolowsky, Ph.D.
Vice President,
Global Regulatory Sciences-CMC
Bristol-Myers Squibb
Disclaimers
– The information within this presentation
represents the views of the presenter and is
based on the presenter’s expertise and
experience
2
Overview
– Comparability - key points for
consideration
– Discuss changes to biotechnology
products:
• During development
• Post-marketing
3
Why are Changes to Biotechnology
Products so Complex?
Small Molecules
– Usually synthetic, organic
compounds having well
defined structures and
chemical characteristics
– Typically produced through
chemical synthesis
– Usually micromolecules
having molecular weights of
less than 500 Daltons
– Generally very stable, and not
extremely sensitive to heat
Biotechnology Products
– Usually a protein- or
carbohydrate-based product
with complex structure
– Either composed of / or
extracted from a living
organism or produced via cell
culture
– Macromolecular by nature, and
usually have a molecular
weight greater than 500
Daltons
– Tend to be rather labile, and are
usually very heat- and sheersensitive
– Tend to be immunogenic
4
What is Comparability?
• ICHQ5E Definitions
• Comparable:
– A conclusion that products have highly similar quality
attributes before and after manufacturing process
changes and that no adverse impact on the safety or
efficacy, including immunogenicity, of the drug product
occurred. This conclusion can be based on an analysis
of product quality attributes. In some cases, nonclinical
or clinical data might contribute to the conclusion.
• Comparability Exercise:
– The activities, including study design, conduct of studies,
and evaluation of data, that are designed to investigate
whether the products are comparable.
5
Comparability Exercise Considerations
– No one right answer when deciding a
comparability package
– Decision must be made with consideration of:
•
•
•
•
•
•
Product clinical development plan
Complexity of the product
Stage of development of the product
Robustness of analytical methods
Existence of relevant animal models
Previous health authority interactions
6
What is “Highly Similar”?
– Comparability does not require quality attributes
of pre-change and post-change product to be
identical
– “Highly similar” depends upon whether:
• Existing knowledge can adequately support that
differences in quality attributes have no adverse
impact upon safety or efficacy
– Side-by-side analysis of “post-change” vs. “prechange” product is useful for contemporaneous
evaluation
7
Comparability is a Sequential Process
Quality
Non-clinical
Clinical and/or
Pharmacovigilance
If the analytical procedures used are not sufficient to discern
relevant differences, then…
Non-clinical studies may be necessary, if non-clinical studies
cannot discern relevant differences, then…
Confirmatory clinical testing may be necessary
OVERALL GOAL: Assess potential impact to safety and efficacy of the product
8
Parameters to Consider
– Production step where changes are introduced.
– Potential impact of changes to: purity , physicochemical and
biological properties
• considering complexity and degree of knowledge (e.g., impurities,
product related substances).
– Availability of suitable analytical techniques to detect potential
modifications
– Understanding of relationship between quality attributes and safety
and efficacy, based on overall nonclinical and clinical experience.
– Relevant physicochemical and biological characterization data
regarding quality attributes;
– Need for stability data, including accelerated or stress conditions,
• to provide insight into potential product differences in the
degradation pathways
9
Parameters to Consider (continued)
– Batches used for demonstration of manufacturing consistency;
– Historical data that provide insight into potential “drift” of quality
attributes
– Critical control points in the manufacturing process that affect
product characteristics,
– Impact of the process change on the quality of in-process materials
& ability of downstream steps to accommodate material from a
changed cell culture process;
– Adequacy of the in-process controls (critical control points & inprocess testing:
• In-process controls for post-change process should be confirmed,
modified, or created, as appropriate, to maintain product quality
– Nonclinical or clinical characteristics of the drug product and its
therapeutic indications
10
Risk Assessment
– Utilize prior knowledge and development studies
– Categorize risk change of process parameters
based upon potential to impact product quality
– Examples:
• High: Change to Master Cell Bank (MCB)
• Moderate: Media composition change using
established raw materials, <50% output
• Low: Step optimization (e.g. flow rate, wash volumes,
elution collection criteria)
– Provides an effective tool for internal discussion
of change & subsequent communications to
regulators regarding the assessment
11
Risk Assessment Model
High risk
Red = Stop & Reconsider
High likelihood to
Impact program
Change Type
Yellow = Proceed with Caution
Moderate likelihood to impact program
Green = Go
Unlikely to impact
program
Low risk
High risk
Phase of clinical program
Example Risk Assessment Tool
Total risk score
generated by
multiplying individual
risk factors
 Each risk factor category has built-in drop-down boxes with
potential values
 Higher values indicate greater risk
 Team discussion is critical to document thought process that
drove the scores (“no one right answer”)
13
Evaluating Changes
During Development
14
Phase-based Approach to Changes
Early Development:
– Before nonclinical studies:
• Comparability is not generally not a concern
• Subsequent nonclinical and clinical studies using the
post-change product as part of the development
process support change
– Early phases of nonclinical and clinical studies:
• Comparability testing is generally not as extensive as
for an approved product
– As knowledge and information accumulate, the
comparability exercise will generally become
more comprehensive
Phase-based Approach to Changes
• During Pivotal Clinical Studies:
– Changes are discouraged
– Sponsor should seek scientific advice from the relevant
health authorities
• If process changes are introduced in late (postpivotal studies) stages of development:
– Thorough comparability exercise is generally required:
• Physicochemical and biological in vitro studies
• Clinical pharmacokinetic and / or pharmacodynamic
comparability studies may also be required
– If comparability exercise cannot rule out impact to the
efficacy and safety profile:
• Additional clinical studies may be required
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Guidelines for Acceptance Criteria Setting for
Analytical Comparability
a
Pre Pivotal
Post Pivotal
Development Release Specification
 3SD from small number of lots

Development or Commercial Release
Specification
3SD from larger number of lots
CQA - closer to manufacture history
Release Test

Extended
Characterization a

Reported as found but summarized
by expert analyst as being comparable
or not comparable

Stability

Same requirements depending on
whether the test is a release test or
extended characterization.

Quantified acceptance criteria where possible.
 Visual equivalence should have defined criteria
the analyst uses to make the determination.
Same requirements depending on whether the
test is a release test or extended
characterization.b
 Stability CQA stress changes demonstrate
comparable rate changes c
Orthogonal support for release test or independent attribute assessment for structure-function relationship
If a stability indicating attribute is identified under recommended storage conditions
c If a forced degradation or stressed condition degradation product attribute is identified and believed relevant to
structure-function
b
Case Study Development
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Case Study Process Changes
Overview of Changes
– Drug Substance
• New MCB (higher producing subclone of current MCB)
• New DS manufacturing site (Site “A” Site “B”)
• New DS manufacturing process (cell culture and purification)
– Drug Product
• New DP manufacturing site (Site “X”  Site “Y”)
• Minor change to sterile filtration (0.1 µm0.2 µm)
Reason for Changes
– Increase drug substance yield ~4X
– Manufacturing control
– COG
Comparability Exercise
 Goal - to ensure the quality, safety and efficacy of
drug product produced by a changed
manufacturing process
 How - through collection and evaluation of the
relevant data based on process and product
knowledge
–
–
–
–
Analytical assays
Biological assays
Nonclinical data
Clinical data
Analytical Comparability
 Established at multiple points
– In-process
– Release
• Release tests
• Extended characterization tests
– Stability profile
• Recommended storage condition
• Accelerated/Stress storage conditions
– Downstream
• Drug substance changes may only be seen in the drug product
(release, stability profile)
Analytical Acceptance Criteria
 In-process
– Comparable process/product related impurity/adventitious
agent clearance
 Release tests
– Current (pre-change) specification
• Additional tests may be needed
 Extended characterization
– May need to evaluate additional pre-change batches to
establish appropriate acceptance criteria
Evaluation against historical data (i.e. clinical experience)
Side-by-side comparison of pre- and post-change product
by various analytical characterization techniques
Binding Kinetics by Surface Plasmon Resonance
RU
80
70
60
50
Association
Resp. Diff.
40
30
Dissociation
20
10
0
-10
0
100
200
300
400
Tim e
500
600
700
800
s
Electron Spray Ionization Mass Spectrometry
Post-change product
Slight increase in
one subtype observed
Reference material (pre-change)
Tryptic Peptide Maps
Overlay of pre- and post-change materials
0.26
0.24
0.22
0.20
0.18
pGlu-H1 - 52.058
0.14
0.12
0.10
0.08
0.06
H1 - 41.537
AU
0.16
0.04
0.02
0.00
34.00
36.00
38.00
40.00
42.00
44.00
46.00
48.00
Minutes
50.00
52.00
54.00
56.00
58.00
60.00
62.00
Comparison of Carbohydrate Profiles by HPAEC-PAD
Post-change material
Pre-change material
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Isoelectrically Focused
Lane 1: Reference material (pre-change)
Lanes 2 through 5: Post-change material
Cation Exchange Profiles
Gray line: Pre-change material
Black line: Post-change material
Evaluating Changes
for Marketed Products
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Changes to Marketed Products
• Changes during life-cycle are inevitable:
– Yield increases necessary to meet market
demand / address cost of goods issues
– Quality improvements are necessary to
adhere to current GMPs
– Unexpected events require corrective
action, such as process parameter changes
– Vendor / supply issues necessitate use of
alternate materials
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Hypothetical Process Evolution
Phase II
Phase III &
Process C
Process D
Process E
Commercial
Process
Step
Cell Bank
XYZ-01
XYZ-01.1
Same
Same
Same
Media
DE
CD-CHO,
eRDF &
Yeastolate
Same, Plus
Same
Same
Additional
Minerals
Production
Conditions
No temp.
shift
Two phase
temp. shift
Same
Same
Single temp. shift
Downstream
Sequence
Six
columns
Five
columns
Same
Change of one
resin
Change of one
resin
Other
Process
Changes
N/A
N/A
Centrifugation &
filtration
parameters
Filter changes
N/A
Case Study – Marketed
Product
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Case Study: Change in Media
– Quality: Media component change
resulted in minor differences to quality
attributes
– Nonclinical: Study conducted using nonhuman primate model with previously wellestablished concordance to human PK for
the product
• Model had demonstrated sensitivity to
changes in:
– Minor glycosylation alterations
– Moderate sialic acid profile shifts
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Serum Concentration [ug/mL]
Non-Human Primate Results
Time in Hours
Red line = pre-change
Blue line = post-change
FDA Feedback
– Quality attributes evaluated against historic
data alone deemed insufficient
• “…the Agency strongly encourages the use of
side-by-side analysis as the most rigorous
assessment of comparability…”
– Side-by-side comparison required:
• “Since the product approved for marketing
authorization was made using the…media...,
this product should be directly compared to the
product produced from the proposed
process…”
Regulatory Experiences with Comparability
– Comparability exercises can be successfully
used to support changes
– Most changes can be supported on Quality
attributes alone
• Specifications alone are generally NOT sufficient to
support comparability
– Additional characterization required
– Side-by-side analysis preferred by FDA
– Additional non-clinical & clinical data may be
required
– Safety & efficacy data are generally not
required
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In Summary
– Comparability is a key issue for biotech products
– There is no single, correct strategy to demonstrate
comparability
– Decision must be made with consideration of multiple factors:
•
•
•
•
•
Complexity of the product
Stage of development of the product
Process knowledge & robustness of analytical methods
Existence of relevant animal models
Previous health authority interactions
– Comparability should be approached stepwise:
• Quality
• Non-clinical
• Clinical
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Acknowledgements
Cheryl Watson
Reb Russell
Dave Peck
Charlene Craig
Gary Lazarus
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