Transcript Lessons Learned - Drug Information Association

Perspectives on Comparability of
Biotechnology Derived Protein
Products
Barry Cherney, Ph.D., Deputy Director
DTP/OBP/CDER/ FDA
www.diahome.org
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Overview
• High Level Concepts
• General Observations &
Misconceptions
• Recent Trends in Comparability
Determinations
• Lessons Learned
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Concepts
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Defining Comparability
• A determination that a product is “Comparable”
indicates that products are highly similar before and
after a manufacturing change and that no adverse
impact on the quality, safety or efficacy of the drug
product occurred
- Does not mean pre and post-change products
are identical
- However, knowledge is sufficiently predictive
to ensure any differences in quality attributes
have no adverse impact on safety or efficacy
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Categories of Testing
• Quality Studies (partial or
comprehensive)
Higher
– Physicochemical Tests
– Functional Assays (Bioassays)
• Animal Studies
– PK/PD/Biodistribution
– Toxicity
• Clinical Studies
Lower
– PK/PD
– S&E
Sensitivity to
Detect changes
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Product Life Cycle & Comparability
Toxicology Studies
Short term
Long term
Pre-IND Phase 1
Dose
Ranging
S
Manufacturing
Phase 2
Dose
Ranging
S&E
Pre-Approval Post Approval
S&E
Scale/Facility Continuous
Change
Improvement
Process
Changes
Information Transfer
Low
Phase 3
Full data
set
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General Observations
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General Observations
• The approaches to comparability have been
very successful since formal implementation
of this policy with the 1996 FDA Guidance
document on comparability and ICH
Guidance Q5E in 2005
– Most post-marketing manufacturing changes are
approved based on quality criteria alone
– Sometimes evaluation of bioavailability is
performed or animal PD studies
– Rarely clinical S or E (but is becoming more
common)
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Misconceptions
1.
“The product is comparable because it
meets specifications”
a. Relevant tests may not be in specifications
─ Are the specifications sufficient indicators
of product quality – you may need
additional product characterization
b. “Results within limits but outside historical
data may suggest important differences that
warrant additional study”
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Hypothetical Example
Clinical lots
60
Potency units/ml
50
40
30
20
Marketed
10
Manufacturing Change
0
0
5
10
15
Lot number
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20
25
30
Historical Limits versus Specs
• Polyethylene gylcolated (PEG) protein
• Supplier of PEG was changed prior to licensure
• Requested PK study showed Pharmacokinetics
•
•
changed significantly
Lot chosen was out of trend in the distribution of
Peg at site 1 (12% versus 15-17% historical
range but was within spec 11%)
Successful PK study was performed with a lot
that was within historical limits
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Misconceptions
2. Outcomes of Quality Evaluations
When a product is determined not to be
comparable by quality criteria……..
A.
It’s a different, i.e., a new product or
B. You need to perform non clinical and/or clinical
testing to determine if the product is comparable
Answer: A
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Outcomes of Quality Evaluations
• Comparability is ultimately a clinical
determination i.e., no impact on S & E
• According to Q5E Quality studies can
tell you:
1. The products are comparable
2. There is insufficient info to make a
determination
3. The pre and post-change products are not
comparable i.e., they are not
interchangeable
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Trends in Comparability Studies
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1. Greater Knowledge
• Knowledge in understanding what are the
critical quality attributes changes the risk
profile
– Understanding the importance of tri and tetra
antennary species in the interaction with the
asialoglycoprotein receptor places more emphasis
on similarity for these attributes and less on bi
antennary species or total sialic acid content
• Better utilization of information obtained from
clinical studies for establishing target ranges
for comparability
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Mining Clinical Data
Clinical lots
60
Potency units/ml
50
40
30
20
10
How was this lot used?
Manufacturing Change
0
0
5
10
15
Lot number
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20
25
30
2. Better Analytics
• MS applications particularly regarding
carbohydrate structures
• AUC and FFF for protein aggregation
• CE instead of SDS PAGE
• Light scattering esp. couple to
separation techniques
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3.
Evaluation of Lot Selected for Non clinical
or Clinical Studies
• FDA is evaluating lots chosen for NC/C studies
to ensure that they provide meaningful
information on any observed differences in
CQAs
– Are differences in critical quality attributes
appropriately addressed in non
clinical/clinical comparability studies
– Picking lots that are most similar to the pre
changed product may not be useful
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“Cherry Picking”
60
Lots for PK Study
Upper
limit
% tetra antennary
50
40
30
Lower
limit
20
10
Manufacturing Change
0
0
5
10
15
Lot number
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20
25
30
4.
More Extensive Manufacturing Changes
• Changes in cell substrate and fermentation
processes have become much more frequent
• Significant changes in the master cell banks or
fermentation processes have historically required
some clinical data including on occasion, clinical
safety and/or efficacy data
• The need for clinical data in large part has been
dependent on the inability to predict with a high
degree of confidence that observed differences in
critical quality attributes or bioavailability have no
adverse impact upon safety or efficacy of the product
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Clinical Comparability Outcomes
• Several different outcomes from clinical
comparability studies have been observed:
─ Significant differences in clinical characteristics
that adversely impact clinical performance
─ Differences in clinical characteristics that are
unlikely to adversely impact clinical performance
─ Differences in clinical characteristics that show a
benefit (decreased immunogenicity)
─ Insufficient information to conclude the product is
comparable (Small clinical studies may not be
informative, PD markers may have questionable
relationship to efficacy)
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5. Use of Comparative Stress Studies
• For comprehensive quality determinations the
Agency has asked for stress studies
comparing the rates of degradation for the
pre and post-change product
• Typically, more then one stress condition
• Measurable rate of degradation that allows a
meaningful comparison
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Hypothetical Example
120
Potency units/ml
100
Pre-Change
Product 45 °C
80
60
Post-Change
Product 45 °C
40
20
Pre-Change
Product 60 °C
0
1
2
3
4
Time (in days)
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5
6
6. Global Harmonization
Engagement with other regulatory authorities regarding
reasons for the different regulatory outcomes is increasing.
For example:
A pre-licensed comparability study resulted in 3 distinct regulatory
decisions from 3 regions
• One region only approved a small scale process based on
differences in the API
• One region only approved a large scale process based on
differences in impurities
• One region approved both
FDA discussed with each group, with the sponsor’s permission,
why the specific approach was taken.
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Lessons Learned
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Lessons Learned
•
Protein products can be exquisitely sensitive to minor
impurities and seemingly minor process changes
•
Changes within specification but out of trend with
historical data may impact clinical performance
•
Undetected differences in product attributes may
have a potential impact on clinical parameters
•
•
If you know what to look for you can find it, if it’s there
•
Site or scale changes have been less problematic
when other process changes are not included in the
site or scale change
Upstream process changes (i.e., impacting
fermentation) have a greater risk to product quality
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Lessons Learned
•
Don’t make major process changes between the
pivotal clinical studies and a marketing application –
end of phase 2 is perhaps the best time
•
When fixing a quality issue, implement the least
significant change possible
•
A different formulation is automatically different so
the risk to product quality may be higher and could
require higher categories of testing
•
Physicochemical/biological characterizations are not
a reliable predictor of immunological properties of a
product
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