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Pfizer BioTherapeutics Pharmaceutical Sciences
Laura Bass, Katherine Arch-Douglas, Michele Bailey Piatchek, Stephanie Ferrari, Parag
Kolhe, Sue Leander, Khurram Sunasara, Roberto Rodriguez, Lavinia Lewis
Pfizer BioTherapeutics Pharmaceutical Sciences
Analytical Research and Development
St. Louis, MO
At the crossroads of comparability and characterization:
The case study for Trumenba® –
A vaccine for invasive meningococcal disease
WCBP 2015
1
Outline
• Introducing Trumenba®
• Process changes triggering the comparability study
• Characterization studies performed to enhance product/process
understanding
• Components of the comparability strategy
• Lot selection
• Testing Strategy
• Approach to assessing comparability
• Lessons Learned
2
Label Category Target
INDICATIONS AND
USAGE
Vaccine indicated for active immunization to prevent invasive
meningococcal disease caused by Neisseria meningitidis
serogroup B expressing either subfamily A or subfamily B fHBP
in persons 10-25 yrs of age
DISEASE PROFILE
AND INCIDENCE
Meningococcal disease can progress from initial symptoms to
death within 24 hours. Symptoms are similar to the common cold.
Despite the availability of antibiotic treatment, between 10-15% of
patients with meningococcal disease die and 11-19% of those
who survive are afflicted with long-term disabilities, such as
brain damage, hearing loss, learning disabilities or limb
amputations
Meningitis due to Neisseria meningitidis serogroup B accounts for
~ 40 percent of all cases of meningococcal disease
DOSAGE FORMS 0.5 ml of 60 µg of each Subfamily A and Subfamily B lipoprotein,
Histidine buffered saline, Polysorbate 80, aluminum phosphate,
pH=6, in a pre-filled syringe
DOSAGE REGIMEN 3-dose schedule of 0,2,6 months.
3
Trumenba®; Bivalent rLP2086 Vaccine
Mechanism of Action • fHBP/LP2086 binds human factor H &
protects bacteria from complement attack
• Anti-LP2086 antibodies generated by
vaccine protect through inhibition of factor H binding allowing for complement bactericidal action
Drug Substance • Two rLP2086 lipoproteins (~28 kDa)
manufactured as separate drug substance
• Formulation includes PS80 which likely results in micellar formation and an apparent MW of ~600-700 kDa
Madico et al., 2006; Schneider et al., 2006;
Mascioni et al., 2009; Seib et al., 2009;
Ala’Aldeen et al., 2010; McNeil et al., 2009;
Jacobsson, Mölling & Olcen, 2009
Drug Product • Manufactured by mixing and diluting the
two rLP2086 proteins (subfamily A & B)
with stabilizer (aluminum phosphate)
4
Drug Substance and Drug Product Process Changes
Change Phase 1/2 Phase 2/3
Scale
DS: 120 L
DP: 4L, 10 L or 19 L
(glass vessels)
DS: 2400 L
DP: 150 L
(stainless steel tanks)
Manufacturing
Site
DS: 2 Pilot scale
DP: 2 Pilot Scale
DS: 1 Commercial scale
DP: 2 Commercial scale
DS Storage
250 mL polypropylene (PP) bottle stored
at –70 ± 10°C
5-liter ethylene vinyl acetate
(EVA) bag stored at -55 ± 8°C
DP
Formulation
Succinate Histidine
NaCl NaCl
PS80 PS80 (decreased conc)
AlPO4 AlPO4 (increased conc)
pH 6.0 pH 6.0
Histidine
NaCl
PS80
AlPO4
pH 6.0
DP container
Vial Pre-filled syringe
Pre-filled syringe
5
DS Comparability Strategy Overview
Assess risk to product quality/consistency/potency
Lipid isoforms were identified early in development as a source of molecular
heterogeneity
Literature data indicated O-acyl-linked lipids were critical to potency
Product and Process Characterization • Leverage heightened product
characterization data to assess risk
associated with process changes
• Example #1: structure/function
characterization of lipids
• Understand impact of process changes on
quality attributes
• Example #2: bioreactor conditions
and purity / lipid isoform profile
Comparability Study • Testing Strategy
• Lot selection
• Strategy for evaluation of
comparability
6
DS Characterization Invest early in product understanding Example#1; Heightened characterization of lipoproteins
Assess function
of proteins In Vitro Relative Antigenicity
In Vivo Potency
Native &
Degraded
Assess function
of lipids
In Vivo Potency
TLR2 Receptor Assay
Native &
De-O-Acylated
Confirm Primary
Structure of
lipoprotein and
Identify the major
and minor product
isoforms
Peptide level: Non-reduced peptide
mapping of Lys-C proteolytic fragments
by RP-UHPLC/UHR-ESI-Orbitrap MS
Intact level: Molecular mass
determination for intact molecule by
RP-UHPLC/UHR-ESI-QTOF MS
Confirm structure
of lipids
GC/MS of released derivatized fatty acids
LC-MS of lipase digested lipoprotein
7
DS Process Characterization; Invest Early in Process Understanding Example #2: Impact of bioreactor conditions on Lipid Isoform Profile
Challenges:
Very tight lipid profile observed for clinical lots
manufactured early in development
Bioreactor conditions modified during scale up
Resolution:
Define operating space for lipid isoform profile
Execute multifactor fermentation DOE using qualified scale down
models and monitor lipid profiles as an output.
Define process parameter ranges to consistently achieve desired
lipid peak ratio as monitored by RP-HPLC
Early process development data indicated potential link between
bioreactor conditions and lipid isoform profile
Consistency of lipid isoform profile is critical to potency
8
Lipid Profile RP-HPLC for lipid isoform profile
3 Major, 5 Minor
overlay_TS
Project Name: H210_SHARE_PHARMSCIReported by User: Tanya Shang (TShang)
Report Method: overlay_TS Printed 4:17:42 PM 2/4/2011
Sample Name: 17Nov10_A_A1002; Date Acquired: 11/17/2010 5:29:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_A1003; Date Acquired: 11/17/2010 6:30:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B302; Date Acquired: 11/17/2010 7:31:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B303; Date Acquired: 11/17/2010 8:32:10 PM; Injection Volume 17.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B304; Date Acquired: 11/17/2010 9:33:10 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MS
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
Minutes
5.00 10.00 15.00 20.00 25.00 30.00 35.00
4MnB2086A-1002
Degradants De-O-Acylated
AB C
D E
1
23
AB C
D E
AB C
D E
AB C D E
AB C
D E
1
23
1
23
1
23
1
23
4MnB2086A-1003
G10700B302
G10700B303
G10700B304
overlay_TS
Project Name: H210_SHARE_PHARMSCIReported by User: Tanya Shang (TShang)
Report Method: overlay_TS Printed 4:17:42 PM 2/4/2011
Sample Name: 17Nov10_A_A1002; Date Acquired: 11/17/2010 5:29:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_A1003; Date Acquired: 11/17/2010 6:30:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B302; Date Acquired: 11/17/2010 7:31:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B303; Date Acquired: 11/17/2010 8:32:10 PM; Injection Volume 17.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B304; Date Acquired: 11/17/2010 9:33:10 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MS
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
Minutes
5.00 10.00 15.00 20.00 25.00 30.00 35.00
4MnB2086A-1002
Degradants De-O-Acylated
AB C
D E
1
23
AB C
D E
AB C
D E
AB C D E
AB C
D E
1
23
1
23
1
23
1
23
4MnB2086A-1003
G10700B302
G10700B303
G10700B304
Site 2 pilot
Pilot Scale batch#1
Pilot Scale batch#2
Commercial Scale batch#1
Commercial Scale batch#2
Commercial Scale batch#3
9
DS Process Characterization Lipid Peak Ratio: Peak 3 [C16:0, C18:1, C16:0]
• Manufacturing batches run at center points
• Fermentation DOE data were used to define operating ranges at
manufacturing scale to deliver consistent lipid profiles
0.40
0.50
0.60
0.70
0.80
0.90
1.00
1.10
1.20
1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 16 17
No
rmalized
Valu
e
Batch Number
Lipid Peak 3 Process Control
peak 3
Pk3 Prcs Cap: high
Pk3 Prcs Cap: low
10
DS Comparability Lot Selection
• Lot selection included planned use of the DS materials
• Key CMC milestones; PV, Stability, Reference Std
• Key Clinical milestones: Ph1, Ph2, Ph3
Batch Scale Manufacture Site Batch Use
10 L Site#1 Phase 1, Non-clinical Toxicology
120 L Site#1 Phase 2, Non-clinical Toxicology
120 L (2 batches) Site#1 Phase 2 Clinical
2400 L (6 batches) Site#2/Commercial Demonstration
2400 L Site#2/Commercial Process Validation
2400 L Site#2/Commercial Process Validation, Primary Stability
2400 L Site#2/Commercial Process Validation, Primary Stability,
Reference Material
2400 L Site#2/Commercial Process Validation, Primary Stability
2400 L
(2 batches)
Site#2/Commercial Phase 2 and Phase 3 Clinical, Stability
2400 L Site#2/Commercial Phase 3 Clinical, Stability
2400 L (3 batches) Site#2/Commercial Stability
11
DS Comparability Testing Strategy
Type of Testing Data Provided
Release
Tabulated data for CQA’s in 3.2.S.2.6
Tabulated data for all attributes in
3.2.S.4.4
Stability
Tabulated data for all attributes in
3.2.S.7.3
Characterization
Tabulated data and overlays of profiles
provided in 3.2.S.2.6
12
DS Comparability Testing Strategy; Characterization Testing
Test Executed Information Provided
Intact Molecular Mass by
RP-HPLC/UHR-ESI-QTOF MS
Confirm primary structure and post-
translational modifications at the
intact protein level
Non-reduced peptide mapping by
RP-HPLC/UHR-ESI-QTOF MS
Confirm primary structure and identify
post-translational modifications at the
peptide level
Lipidated N-terminal peptide
profiling by organic SE-HPLC/UHR-
ESI-QTOF MS
Identify structures of N-terminal
lipopeptide isoforms
GC/MS of released fatty acids
Confirm fatty acid composition
Far-UV CD
Assess secondary structure
Near-UV CD
Assess tertiary structure
13
DS Comparability Assessment Characterization Testing; Peptide Map Profiles
overlay_TS
Project Name: H210_SHARE_PHARMSCIReported by User: Tanya Shang (TShang)
Report Method: overlay_TS Printed 6:19:52 PM 11/16/2010
Sample Name: 15Nov10_A_A1002; Date Acquired: 11/16/2010 3:03:48 PM; Acq Method Set rLP2086_map_Hclass
Sample Name: 15Nov10_A_A1003; Date Acquired: 11/16/2010 10:53:16 AM; Acq Method Set rLP2086_map_Hclass
Sample Name: 15Nov10_A_B302; Date Acquired: 11/16/2010 11:55:38 AM; Acq Method Set rLP2086_map_Hclass
Sample Name: 15Nov10_A_B303; Date Acquired: 11/16/2010 4:06:28 PM; Acq Method Set rLP2086_map_Hclass
Sample Name: 15Nov10_A_B304; Date Acquired: 11/16/2010 2:01:41 PM; Acq Method Set rLP2086_map_Hclass
AU
0.00
0.20
0.40
0.60
0.80A
U
0.00
0.20
0.40
0.60
0.80
AU
0.00
0.20
0.40
0.60
0.80
AU
0.00
0.20
0.40
0.60
0.80
AU
0.00
0.20
0.40
0.60
0.80
Minutes
5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00
4MnB2086A-1002
4MnB2086A-1003
G10700B302
G10700B303
G10700B304
overlay_TS
Project Name: H210_SHARE_PHARMSCIReported by User: Tanya Shang (TShang)
Report Method: overlay_TS Printed 6:19:52 PM 11/16/2010
Sample Name: 15Nov10_A_A1002; Date Acquired: 11/16/2010 3:03:48 PM; Acq Method Set rLP2086_map_Hclass
Sample Name: 15Nov10_A_A1003; Date Acquired: 11/16/2010 10:53:16 AM; Acq Method Set rLP2086_map_Hclass
Sample Name: 15Nov10_A_B302; Date Acquired: 11/16/2010 11:55:38 AM; Acq Method Set rLP2086_map_Hclass
Sample Name: 15Nov10_A_B303; Date Acquired: 11/16/2010 4:06:28 PM; Acq Method Set rLP2086_map_Hclass
Sample Name: 15Nov10_A_B304; Date Acquired: 11/16/2010 2:01:41 PM; Acq Method Set rLP2086_map_Hclass
AU
0.00
0.20
0.40
0.60
0.80A
U
0.00
0.20
0.40
0.60
0.80
AU
0.00
0.20
0.40
0.60
0.80
AU
0.00
0.20
0.40
0.60
0.80
AU
0.00
0.20
0.40
0.60
0.80
Minutes
5.00 10.00 15.00 20.00 25.00 30.00 35.00 40.00 45.00
4MnB2086A-1002
4MnB2086A-1003
G10700B302
G10700B303
G10700B304
14
DS Comparability Assessment Release Testing; RP-HPLC for purity, lipid isoform profile and degradants
overlay_TS
Project Name: H210_SHARE_PHARMSCIReported by User: Tanya Shang (TShang)
Report Method: overlay_TS Printed 4:17:42 PM 2/4/2011
Sample Name: 17Nov10_A_A1002; Date Acquired: 11/17/2010 5:29:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_A1003; Date Acquired: 11/17/2010 6:30:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B302; Date Acquired: 11/17/2010 7:31:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B303; Date Acquired: 11/17/2010 8:32:10 PM; Injection Volume 17.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B304; Date Acquired: 11/17/2010 9:33:10 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MS
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
Minutes
5.00 10.00 15.00 20.00 25.00 30.00 35.00
4MnB2086A-1002
Degradants De-O-Acylated
AB C
D E
1
23
AB C
D E
AB C
D E
AB C D E
AB C
D E
1
23
1
23
1
23
1
23
4MnB2086A-1003
G10700B302
G10700B303
G10700B304
overlay_TS
Project Name: H210_SHARE_PHARMSCIReported by User: Tanya Shang (TShang)
Report Method: overlay_TS Printed 4:17:42 PM 2/4/2011
Sample Name: 17Nov10_A_A1002; Date Acquired: 11/17/2010 5:29:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_A1003; Date Acquired: 11/17/2010 6:30:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B302; Date Acquired: 11/17/2010 7:31:00 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B303; Date Acquired: 11/17/2010 8:32:10 PM; Injection Volume 17.00; Acq Method Set rLP2086_RP_STM7187_MSSample Name: 17Nov10_A_B304; Date Acquired: 11/17/2010 9:33:10 PM; Injection Volume 10.00; Acq Method Set rLP2086_RP_STM7187_MS
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
AU
0.00
0.20
Minutes
5.00 10.00 15.00 20.00 25.00 30.00 35.00
4MnB2086A-1002
Degradants De-O-Acylated
AB C
D E
1
23
AB C
D E
AB C
D E
AB C D E
AB C
D E
1
23
1
23
1
23
1
23
4MnB2086A-1003
G10700B302
G10700B303
G10700B304
Site 2 pilot
Commercial Scale batch#3
Commercial Scale batch#2
Commercial Scale batch#1
Pilot Scale batch#2
Pilot Scale batch#1
15
DS Comparability Assessment Conclusions
Type of Testing Assessment of Comparability
Release
• All results met specification acceptance criteria
and no data trends observed across lots tested.
• Results were comparable across batches.
Stability
• All results met specification acceptance criteria
and no data trends observed across lots tested.
• Results were comparable across batches.
Characterization
• Qualitative assessment confirms comparability of
profiles and tabulated data for each individual
attribute tested.
16
DP Process Changes
Change Phase 1/2 Phase 2/3
Scale
DP: 4L, 10 L or 19 L
(glass vessels)
DP: 150 L
(stainless steel tanks)
Manufacturing
Site
DP: Site#1, Site#2
DP: Site#1, Site#2
DP
Formulation
Succinate Histidine
NaCl NaCl
PS80 PS80 (decreased conc)
AlPO4 AlPO4 (increased conc)
pH 6.0 pH 6.0
Histidine
NaCl
PS80
AlPO4
pH 6.0
DP container
Vial Pre-filled syringe
Pre-filled syringe
17
DP Comparability Process Characterization Well-controlled and characterized process delivers consistent product
“Building in” Comparability During Site Change
• DeRisk impact of changes via “at scale” process characterization studies and strategic process fitting
• Execute process at commercial site and scale at high & low end of NOR (process charact.)
• “Fit” process into new site using same scale and equipment allowing for identical target ranges
Low end
High end
Target
Normal Operating Range (NOR)
70
80
90
100
110
120
130
140
150
0 0.5 1 1.5 2 2.5 3 3.5
Pro
tein
Co
nc
(ug/
mL)
Sub A- Low Range
Sub B- Low Range
Sub A- High Range
Sub B- High Range
80
85
90
95
100
105
110
115
120
0 0.5 1 1.5 2 2.5 3 3.5
Bo
un
d P
rote
in (
%)
Sub A- Low Range
Sub B- Low Range
Sub A- High Range
Sub B- HIgh Range
Beginning Middle End Beginning Middle End
Low Spec
High Spec
Spec
18
DP Comparability Lot selection and Testing Strategy
• Lot Selection • Scale: Pilot and Commercial
• Site: Site#2 Pilot, Site#3 Commercial, Site#4 Commercial
• Use: Ph2, Ph3 (lot consistency), PV, Primary Stability
• Testing Strategy:
Type of
Testing
Lots tested Data Provided
Release
All release/stability
lots included in
comparability
assessment
n=5 Site#2
n=7 Site#3
n=9 Site#4
Link to 3.2.P.5.4 Batch analysis
Tabulated data for CQA’s in
3.2.P.2.3
Graphs of CQA results for
holistic data comparison in
3.2.P.2.3
Stability
Link to 3.2.P.8.3 Stability
19
DP Comparability DP Release Data
Pfizer, Pearl River Vetter, Germany Pfizer, Ireland
Pfizer, Pearl River Vetter, Germany Pfizer, Ireland
Site#2 Pilot Site#1
Commercial Site#2
Commercial
Site#1
Commercial
Site#2
Commercial Site#2 Pilot
1.7x
1x
2x
1x
20
DP Comparability Data DP Stability Data
Site#1
Commercial Site#2
Commercial
1.7X
1X
2X
1X
21
DP Comparability Assessment Conclusions
Type of Testing Assessment of Comparability
Release
• All results met commercial acceptance criteria and
no data trends observed across lots tested
• Results were comparable across batches
Stability
• All results met commercial acceptance criteria and
no data trends observed across lots tested
• Results were comparable across batches
22
Comparability Strategy Lessons Learned
Invest early in process characterization Highlight understanding of link between process parameters and key quality
attributes
Invest early in heightened product characterization Provide clear summary of product understanding with a focus on CQA’s
Go beyond tabulation of data
Leverage process/product characterization data to design comparability
strategy
Be Strategic in lot selection
23
Comparability Strategy Lessons Learned
• Have Frequent and open dialogue with the regulatory authorities!
Robust CMC package supported 18 month acceleration of BLA after FDA
granted Breakthrough Therapy Designation
BLA Planning started ~3 yrs prior to targeted filing date
BLA Authoring started ~2 yrs prior to targeted filing date
CMC sections of BLA submitted 5 mos after BTD granted
FDA feedback on initial comparability package:
Does the Agency agree that Pfizer has demonstrated the
comparability of pilot scale materials and commercial scale
materials for drug substance and drug product?
“No, there is insufficient commercial scale lot information” **
FDA feedback on comparability package submitted in BLA briefing pkg:
CBER agrees that, pending the potency results and a thorough review, the
comparability data among vaccine lots prepared using the commercial
manufacturing scale may support an “Accelerated Approval” submission
24
Acknowledgements
• Herb Runnels
• Dave Cooper
• Arthur Duffy,
• Zhaowei Jin
• Willy Tan
• Rob Dufield
• Tanya Shang
• John Whittemore
• Marja van Zeijl
• Elisabeth Crandall
• Claire Roche
• Marta Czupryn
• Sriram Srinivasan
• Jean Crinean
• John Cundy
• Kathrin Jansen
• Emilio Emini
25
26
Abstract
• Although the frequently cited paradigm “the process is the product” is often applied rigorously
for vaccines, application of an extensive analytical toolkit is required to gain an in-depth
understanding of the process and the product (and ultimately to demonstrate
comparability). During vaccine development the goal is to minimize process changes to
ensure delivery of a product with a consistent quality and safety profile. The driver for
minimizing process changes is often due to the limitations of the analytical tools available and
difficulty associated with assessing the impact of process changes on vaccine product quality
attributes and associated clinical outcomes (an appropriate clinical surrogate is often not
available). While the goal for vaccine development is to lock the process early, changes are
often inevitable and therefore comparability studies are unavoidable. If characterization
investments are not ramped up until the later stages of development, you may encounter a
crossroad where the analytical toolkit used for process/product understanding is inadequate
for establishing comparability.
• This presentation provides, as a case study, the comparability strategy executed for a
bivalent meningococcal serogroup B (MnB) vaccine. The MnB vaccine development
example will illustrate how, consistent with quality by design principles, the application of an
extensive analytical toolkit facilitated the in-depth characterization of both the process and
product. In addition, this case study will highlight how delivery of a robust comparability
package enabled the project to advance to Phase 3 and ultimately enabled the accelerated
approval of this vaccine.