CMC STRATEGY FORUM JAPAN 2017
Prior Knowledge in Attribute Based Control Strategies
Michael AbernathyExecutive Director, Regulatory Affairs
Jette WypychDirector, Process DevelopmentAmgen
06 December 2017
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Disclaimer
The views expressed herein represent those of the author and do not necessarily represent the views or practices of the author’s employer or any other party.
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TODAY, WE ARE IN A BIOTECHNOLOGY ERA WHERE INNOVATION PROGRESSES RAPIDLY
Processing Manufacturing
Analytical Testing
Novel Modalities
Timely innovation is integral to our industry
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BIOLOGIC MEDICINES ARE MORE HIGHLY ENGINEERED AND DIVERSE
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Product quality drivers
Supply requirements
Financial considerations
Regional manufacturing
One size does not fit all
APPROPRIATE MANUFACTURING TECHNOLOGIES CAN BE MATCHED TO MODALITIES TO DELIVER TO THE QUALITY TARGET PRODUCT PROFILEhttps://www.amgenscience.com/the-shape-of-drugs-to-come/
EXPECTATION OF SPONSORS IS TO STAY CURRENT WITH REGULATIONS AND GUIDANCE REGULATIONS STAY CURRENT AND ALIGN WITH TECHNOLOGICAL INNOVATION
AN INDUSTRY GOVERNED BY cGMP AND REGULATORY GUIDELINES
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MANUFACTURING IS CHANGING
Conventional Flexible
Key Enabling Technologies
• High titer processes
• Single-use systems
• Modular design and construction
• Connected processing
• Online / At-line analytics
• Real-time remote monitoring
• Raw material variation control
PATIENT BASED, MODULAR AND DISTRIBUTED MANUFACTURING MAY REPRESENT OUR NEXT PARADIGM SHIFT
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• Product portfolios continue to evolve and correlated knowledge and data are growing exponentially
TODAY WE ARE AMIDST AN INDUSTRY REVOLUTION WHERE KNOWLEDGE AND DATA MANAGEMENT ARE CRITICAL
- Simple- Single defined structure- Predictable chemical /reagent reaction- Production of identical copies- Stable- Easy to fully characterize- Minimal data packet
- Large- Complex structure- Bank of living cells- Identical clones unlikely- Sensitive to environmental conditions- Correlation of structure/function elusive- Robust data packet
- Vary from small to large- Complex and unique structure- Varied modular manufacturing- Heterogenous sub-populations- Varied stability - Personalized nature difficult and costly to characterize- Limitless data packet
Small Molecules Therapeutic Proteins Novel Treatment Modalities
HOW DO WE EFFECTIVELY MANAGE THIS KNOWLEDGE AND DATA?7
KEY STEPS IN IMPLEMENTATION OF QbD FOR A BIOTECHNOLOGY PRODUCT (ICH Q8 (R2)) – AN OPPORTUNITY TO LEVERAGE PRIOR KNOWLEDGE
QTPP
Product quality attribute
assessment
Product risk assessment
Integrated control strategy
Lifecycle management
QTPP forms basis of design for the development of the product
Product quality attribute assessment ranks the risk of an attribute having a clinical impact to identify quality attributes with higher risk that need to be within an appropriate range/limit to ensure the desired product quality (critical quality attributes)
Product Risk Assessment (s) to link material attributes and process parameters to CQAs
Control Strategy designed to ensure that a product of required quality will be consistently produced
Lifecycle management and continuous improvement
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AMGEN IS APPLYING PRIOR KNOWLEDGE IN PROCESS DEFINITION
PLATFORMED
MODALITIES AND
ASSOCIATED ATTRIBUTES:
PROCESS DEFINITION AND
MANUFACTURING TECHNOLOGIES:
DRUG SUBSTANCE:
DRUG PRODUCT:
Mabs: IgG1s and IgG2s Canonical BiTEs Fc fusion ProteinsHalf-life Extension BiTEs
Batch, Perfusion, Continuous UF/DFHarvest, VI and Filtration
Affinity, CEX, HIC and Mixed Mode
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THE ULTIMATE ATTRIBUTE BASED CONTROL STRATEGIES INTEGRATE ALL ASPECTS OF PROCESS AND PRODUCT CONTROLS
Production Process
Procedural controls(process design and facility, equipment and operational controls)
Input controls(raw materials and components)
In-process testing(IPCs, process monitoring, validation)
End product testing(specifications, comparability, stability)
AN EFFECTIVE, RISK AND KNOWLEDGE BASED INTEGRATED CONTROL STRATEGY ENSURES CONSISTENT PRODUCT QUALITY
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INPUT CONTROLS: AMGEN ADOPTS THE ICH Q9 CONCEPTS PRIOR KNOWLEDGE IS APPLIED TO E&L STUDIES
Identification
• Extraction studies use a wide array of analytical methods to characterize and identify extractables (> lower limit of quantitation)
Qualification
• Toxicology assessments are conducted on identified extractables. Thresholds (e.g. TTC, PDE) are established on compounds of concern in the qualification of process and product contact materials
Action Threshold
• Thresholds (e.g. TTC, PDE) are converted to concentration limits in drug products to guide methods development in targeting the compounds of concern
• Action thresholds (≤ 10 micrograms/dose) are limits above which a quality investigation is conducted to determine potential product impact.
Threshold of Toxicological Concern (TTC): A level of exposure to a chemical below which there would be no appreciable risk to human health (FDA CFSAN 2011, Kroes et al. 2004, Patlewicz et al. 2008 )Permitted Daily Exposure (PDE): An acceptable intake of an impurity (e.g. residual solvent) in a pharmaceutical product (ICH Q3C)
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THE DATABASE IS UNIQUELY RELEVANT TO BIOTECHNOLOGY PRODUCTS
• The Amgen database has > 169 organic compounds from extractables & leachables studies:• Pre-filled syringes
• Vial stopper systems
• On-body infusion devices
• Single-use bioprocess systems and components
• Process contact materials
AMGEN IS BUILDING AN E&L DATABASE ON A WIDE VARIETY OF MATERIALS
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USE OF PRIOR KNOWLEDGE: PROCESS CHARACTERIZATION
• Prior Knowledge Assessments– Amgen has accumulated a large knowledge base on cell culture and purification performance, including the impact of
process parameters on quality attributes and process consistency– This data can be leveraged to focus design studies on higher risk areas:
• Potential critical process parameters (CPPs) are identified for further evaluation based on prior knowledge or knowledge gaps• Non-critical process parameters (nCPPs) can be identified without product specific experimentation in scenarios where the
process/product of interest is sufficiently homologous with the available prior knowledge data– Risk and knowledge based process design facilitates deeper understanding of the impact of the process on product
quality
• Cell Culture Applications– For common cell lines and media, in seed train processes where product quality is not directly impacted, parameter
ranges can be determined from early development studies without additional characterization• Culture performance is evaluated every production lot through in-process testing control, ensuring a continued well controlled
process– For the production bioreactor, potential CPPs and nCPPs can be identified for processes that apply similar cell lines and
process conditions, especially in cases where a large body of prior knowledge exists (e.g., Mabs)• Focused process characterization studies then enable a detailed understanding of the impact of process parameters on product
quality and process consistency
• Purification Applications– For downstream unit operations, potential CPPs and nCPPs can be identified for common unit operations (e.g., Protein A
chromatography, viral filtration, etc.), especially in cases where a large body of prior knowledge exists (e.g., Mabs)
A priori determination of potentially high risk process parameters
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-0.2
0
0.2
0.4
0.6
0.8Load Rate (g/L resin)
Load pHLoad cond
Load treatment
Equil pH
Equil Conductivity / concentration
Equil volume
Wash pH
Wash cond./ concentrationWash volume
Elution buffer ConcentrationElution buffer pH
Elution salt concentration/cond
Start Collect
Stop Collect
Gradient length
Flow rate
Temperature
Bed HeightResin lot / ligand density
-0.10
0.10.20.30.40.5
Load Rate (g/L resin)Load pH
Load cond
Load treatment
Equil pH
Equil Conductivity /concentration
Equil volume
Wash pH
Wash cond./ concentrationWash volumeElution buffer
Concentration
Elution buffer pH
Elution saltconcentration/cond
Start Collect
Stop Collect
Gradient length
Flow rate
Temperature
Bed Height
Impurity 2
Same process parameters impact impurities 1 and 2
EXTENSIVE PLATFORM DATA CLEARLY IDENTIFY HIGH RISK PARAMETERS (RADIAL PLOTS OF NORMALIZED IMPACT)
Impurity 1
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PLATFORMED
MODALITIES AND
ASSOCIATED ATTRIBUTES:
MEASUREMENTS, ANALYTICS,
ADVANCEMENT OF PAT:
Mabs: IgG1s and IgG2s Canonical BiTEs Fc fusion ProteinsHalf-life Extension BiTEs
PAT and MAM AdvancementANALYTICAL METHODS
AMGEN IS APPLYING PRIOR KNOWLEDGE FOR ANALYTICAL MEASUREMENTS
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PLATFORM APPROACH TO PRODUCT PURITY AND PROCESS IMPURITY METHODS
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ATTRIBUTE(S) TYPE PLATFORMEDPARAMETERS APPLICATION
Product Concentration Spectroscopy System, controls Multi-product
HMWS SE-UHPLC Chromatography system. Column, load, buffers Product specific or Universal
Post translational modifications and clips
Multi-attribute Method
LC-MS system, column, load, buffers, digestion conditions Product specific
Charge variants CEX-HPLC Chromatography system. Column, load, buffers Product specific
Clips CE-SDS CE system, capillary, sample preparations, run conditions
Product specific
DNA qPCR System, sample preparation and run conditions Multi-product
Host cell Protein ELISA System, sample preparation and run conditions Multi-product
Potency Bioassay System, sample preparation and run conditions Product Specific
Identity Raman/ELISA System, sample prep Product Specific
Using platform approaches for measurements optimizes development
PLATFORM APPROACHES TO ANALYTICS PROVIDE FIRST INTENT AND IS LARGELY BASED ON PRIOR KNOWLEDGE
• Product Quality Attribute Assessment and Quality Target Product Profile
• Molecule Assessment • Sequence Variant Analysis• Platform Release and Stability Methods√ • Impurities Testing• Testing Strategies for Process Reagents • Stability Indicating Properties of Methods • Analytical Target Profile (ATP) • Biological Characterization • Product Characterization and CMC• Higher Order Structure and Particles• Comparability • Biosimilarity• Specifications • Control Strategy • Rapid Analytics Support for Process Development
• GxP Testing • Sample Plan• Reference Standard• Stability and Expiry • Method Qualification and Validation• Method Technology Transfer• Method Remediation • Attribute Impact• Forensics • Extractables and Leachables√ • Process Analytical Technologies and Product
Attribute Control • Predictive Modeling and Digital Analytics • Hardware and Software Platform• Platform Adherence and Technical Performance
Reviews Against
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START WITH A WELL DEFINED TARGET PRODUCT PROFILE (TPP)
Patient centric life cycle management
Target Product Profile (TPP) Product Quality Attribute Assessments (PQAA)
Quality Target Product Profile (QTPP)
• Indication & use• Dosage & administration• Tolerability• Dosage forms & strength• Efficacy• Safety/side effects• Value & access
• Attribute definition• Product quality attribute
assessment • Potential impact for
safety/efficacy
• Critical quality attribute selection
• Attribute range determination
• Attribute focused molecule & process design & development
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PRODUCT QUALITY ATTRIBUTE ASSESSMENT (PQAA): IDENTIFY ATTRIBUTES AND IMPACT
CDR modificationsOxidation, Deamidation, Isomerization
(molecule specific)• Loss of potency • Low, < x %
Fc binding regions Methionine oxidation • PK and efficacy • Low, < x % ± y%
Glycan structureHigh mannose variants (IgG class) • PK and efficacy • Low, < x % ± y%
Sialylation • PK • high x- y%
Other backbone modifications and aggregated forms
Disulfide variants (IgG2, IgG4) • Potency • Depends on criticality
Truncated/clipped forms • Potency and PK due to missing functional regions • high, < x%
Host Cell Protein • Immunogenicity • xppm
Scoring impact on safety and efficacy
Target ranges Identifying Attributes
Product Quality Attribute Assessment
Quality Target Product Profile
Target Product Profile
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QTPP: PQA RANGES CAN BE DESIGNED INTO THE PRODUCT DURING DEVELOPMENT
Category DS Attributes Target Range Ranges AchievedStrength Concentration 126 – 154 mg/mL 131 – 149 mg/mL
Quality
Asp Isomerization ≤ 2% 0.1 – 0.5%
Trp Oxidation ≤ 5% 0.1%
Met Oxidation ≤ 5% 0.3 – 0.9%
Met Oxidation ≤ 5% 0.4%
Met Oxidation 1% – 7% 2.5 – 4.1%
Met Oxidation ≤ 5% 0.7 – 1.6%
High Mannose Glycans 2% – 12% 6.2 – 8.5%
Protein Dimer/Oligomers (SEC HMW) ≤ 1% 0.4 – 0.6%
Protein Fragmentation (rCE LMW+MMW) ≤ 1% < 0.6%
Glycation (LC K) ≤ 5% 0.8 – 1.5%
Hydroxylysine (HC K) ≤ 2% < 0.1%
Hydroxylysine (HC K) ≤ 2% 1.0 – 2.0%
Osmolality 250 – 350 mOsm/kg 301 – 312 mOsm/kg
Polysorbate 80 0.005% – 0.015% 0.009 – 0.013%
pH 4.9 – 5.5 5.1 – 5.2
Safety
Host Cell Protein ≤ 100 ppm 20 – 49 ppm
Residual Protein A < 6 ppm < 1 ppm
Endotoxin ≤ 0.25 EU/mg ≤ 0.0022 EU/mg
Bioburden ≤ 10 CFU/10 mL 0
Peptide modifications• Deamidation• Succinimide• Oxidation• N and C-terminal variants• Amino acid substitution• Disulfide isoforms
Glycosylation• G0, G1, G2• Core fucosylation• High mannose
Size• Truncation• Half molecules• Dimer/Multimers• Particles
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EVOLVING OUR BUSINESS PROCESS AND TECHNOLOGY PLATFORMS TO PROVIDE MEANINGFUL ATTRIBUTE FOCUSED SPECIFICATIONS
Pre-Pivotal Specification setting is based on a combination of prior knowledge ofmolecule attributes and process performance in combination with a risk basedapproach through the PQAA and QTPP to provide relevant ranges
Evolution of technology platforms for attributemeasurement enables collection of site specificattribute data to help inform relevant specifications
• MAM provides specific attribute measurement • Allows control over levels of individual molecular CQAs
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OVERALL CONTROL STRATEGY IS BASED ON CRITICAL MOLECULE ATTRIBUTES AND OURCLINICAL EXPERIENCE
IDENTIFYING QUALITY ATTRIBUTES WHERE PRIOR KNOWLEDGE APPLIED TO MONOCLONAL ANTIBODIES CAN BE USEFUL
• Methionine oxidation in Fc region• High molecular weight species• Heavy Chain C-terminal modification
– C-terminal lysine– C-terminal proline amidation
• Glycan structure in N-linked Fc region‒ Mannosylation
‒ Galactosylation
‒ Fucosylation
• Deamidation in Fc region • Tri-sulfides• Glycation in non-CDR regions
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EXAMPLE QUALITY ATTRIBUTES WITH PRIOR KNOWLEDGE FOR MABS
Attribute Immune Safety Non-Immune Safety Efficacy: PK Efficacy: Potency Prior Knowledge Sources
Fc MethionineOxidation 1 NA 3 NA
Based on general understanding of attributeimpact, not specific molecule informationGao et al., JOURNAL OF PHARMACEUTICAL SCIENCES 104:368–377, 2015Stracke et al. mAbs 6, 1229-1242, 2015Bi et al. JOURNAL OF PHARMACEUTICAL SCIENCES102, 3545-55, 2013
Aggregates 7 7 5 7
Includes aggregates that form subvisible and visible aggregatesCarpenter et al. JOURNAL OF PHARMACEUTICAL SCIENCES 98, 1201 – 1205, 2009Singh et al. JOURNAL OF PHARMACEUTICAL SCIENCES 99, 3302 - 3321, 2010
Dimer 5 NA 5 7For most Mabs immune safety is evaluated as part of clinical studies. For many Mabs, dimers have reduced potency
Heavy Chain C-terminal Lysine 1 NA 1 1
Based on general understanding of attributeimpact, not specific molecule information.Cai et al., BIOTECH BIOENG 108, 404 – 412 2011 Antes et al. J Chromatography B 852 250-6, 2007Van den Bremer et al. mAbs 7, 672-680, 2015
Heavy Chain C-terminal Proline Amidation
1 NA 1 1
Based on general understanding of attributeimpact, not specific molecule informationJohnson et al. Anal. Biochem. 360, 75 – 83 (2007).Kaschak et al. mAbs 3, 577 – 583 (2011). Tsubaki et al. International Journal of Biological Macromolecules 52, 139-147 (2013).
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mA b 1 m
o n o me r
mA b 1 o
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e d
mA b 2 m
o n o me r
mA b 2 o
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e d
mA b 1 s
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g /ml
T C E -KL H -m
A b1
1 0
1 0 0
1 0 0 0
0
2 5
5 0
7 5
1 0 0
AD
A (
sig
na
l / n
ois
e)
% A
DA
Po
sitiv
e M
ice
4 0 0 0
IL-1
0IL
-1β
MC P -1
MIP
-1α
T N F -α
1 0
1 0 0
1 0 0 0
02 55 07 51 0 0
KEY EXPERIMENTS WERE PERFORMED TO ASSESS THE IMPACT OF MET OXIDATION ON SAFETY
Conclusions:• Safety: Met oxidation does not appear to increase immunogenicity risk as shown by the in vitro cell-based assays and the in vivo Xeno-het mouse model• Clearance: Oxidation at the conserved Fc met 252 and 428 under reasonable conditions has negligible impact on FcRn binding and subsequent PK clearance (Stracke et al., mAbs, 2015 6:5, 1229-1242)
THESE RESULTS STRONGLY SUGGEST THAT OXIDATION OF MET RESIDUES IN AMGEN ANTIBODY PRODUCTS DOES NOT POSE AN INCREASED RISK OF IMMUNOGENICITY OR IMPACT ON PK
IFN - γ
IL-1
0IL
-13
IL-2
IL-7
1 0
1 0 0
02 55 07 51 0 0
2
Early Response
Late Stage Response
Stim
ulat
ion
inde
x(a
bove
mon
omer
)
% responding donors
mAb2 Oxidized
mAb2 Oxidized
In Vitro Comparative Immunogenicity Assessment (IVCIA) Assay
Xeno-het Mouse
Immunogenicity CQA team
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PRODUCT-RELATED HMW SPECIES DID NOT INDUCE A SIGNIFICANT IMMUNE RESPONSE IN MODEL SYSTEMS
0 .1 1 1 0 1 0 00
5
1 0
1 5
2 0
[ In d u c e r] (µ g /m l)
HillSlope
50EC1
minmaxmin −
+
−+=
xy
1 2 3 4 5 6 7 8 9 1 0 1 1
1 2 3 4 5 6 7 8 9 1 0 1 1
1 2 3 4 5 6 7 8 9 1 0 1 10
2 0
4 0
6 0
8 0
1 0 0
AD
A S
ign
al
Fo
ld I
nc
rea
se
(Po
st:
Pre
-In
jec
tio
n)
A n tig e n In je c tio n s
0% HMW 5% HMW 25% HMW
IL-1α
IL-1β
IL-1
rαIL
-6IL
-8IL
-10
MC P -1
MIP
-1α
MIP
-1β
T N F -α
T N F -β0
25
50
75
100
% D
on
or w
ith≥
2-F
old
Re
sp
on
se
Positive Controls
0 1 2 3 4 5 6 7 8 9 1 0 1 1
Stirred aggregatesXeno-hetMice:ADA
PBMC:Cytokine Secretion
Cell Line:PRR Activation
All HMW samples All HMW Samples All HMW Samples
0 .1 1 1 0
R a m o s -B lu e R e s p o n s e
0 .1 1 1 0
R A W -B lu e R e s p o n s e
0 .1 1 1 00 .5
1 .0
1 .5
2 .0
2 .5
T H P -1 X B lu e R e s p o n s e
Ce
ll S
ign
ali
ng
Fo
ld I
nc
rea
se
Stirred aggregates
IL-1α
IL-1β
IL-1
rαIL
-6IL
-8IL
-10
MC P 1
MIP
-1α
MIP
-1β
T N F -α
T N F -β1
10
100
1000
Re
sp
on
se
Fo
ld I
nc
rea
se
IL-1α
IL-1β
IL-1
rαIL
-6IL
-8IL
-10
MC P 1
MIP
-1α
MIP
-1β
T N F -α
T N F -βIL
-1α
IL-1β
IL-1
rαIL
-6IL
-8IL
-10
MC P 1
MIP
-1α
MIP
-1β
T N F -α
T N F -β
5% HMW 25% HMW Stirred aggregates
HMW Samples (IgG2)
HIGH LEVELS OF HMW SPECIES, WELL ABOVE THAT OBSERVED IN PRODUCTS, DO NOT POSE AN INCREASED RISK OF IMMUNOGENICITY IN MODEL SYSTEMS
1 2 3 4 5 6 7 8 9 10 110
20
40
60
80
100
• Process-related IgG1 did not induce ADA in the mini-repertoire mouse model (Bessa et al, Pharm Res, 2015 32(7); 2344-59)
TCE-KLH-mAb
Antigenic Ligands
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C-TERMINAL LYSINE, THE MOST COMMON C TERMINAL VARIANT, HAS MINIMAL IMPACT ON SAFETY AND EFFICACY
C-TERMINAL LYSINE IS NATURALLY OCCURRING AND NOT NEAR ANY KNOWN BINDING SITES MAKING IT UNLIKELY TO IMPACT SAFETY OR EFFICACY
Heavy Chain C-terminal: SLSLSPGK SLSLPG
• Minimal safety risk due to natural occurrence in humans and short exposure in circulation
• Naturally occurring, endogenous human antibodies are expressed with a C-terminal K • Rapidly cleaved by endogenous serum carboxypeptidase B (CpB) in vivo after
intravenous injection with half-life of about an hour• Minimal impact on efficacy due to spatial distance from CDR, FcRn, and Fc
gamma receptor binding regions; and short exposure in circulation• The C-terminus of the HC is not within the known binding sites of CDR, FcRn or Fc
gamma receptors • Most C-terminal Lys is clipped shortly after patient administration
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C-TERMINAL PROLINE AMIDATION : NO KNOWN IMPACT ON SAFETY OR EFFICACY
C-TERMINAL PROLINE AMIDATION IS NATURALLY OCCURRING AND NOT NEAR ANY KNOWN BINDING SITES MAKING IT UNLIKELY TO IMPACT SAFETY OR EFFICACY
Minimal safety risk due to natural occurrence in human• After HC C-terminal Lysine is processed by carboxypeptidase
to yield Glycine at the terminus, enzymatic activities of peptidylglycine-α-hydroxylating monooxygenase (PHM) and Peptidyl- α-hydroxyglycine α-midating lyase (PAL) can
• generate the proline amidated C-terminus.
Heavy Chain C-terminal: SLSLSPGK SLSLPG:
– Levels in therapeutics Mabs: < 1% for Amgen products; 0.3 – 25.9 % in 6 of 10 IgG1 Mabs; 0.8-1.2% in 2 IgG4 Mabs
Minimal impact on efficacy due to spatial distance from CDR, FcRn, and Fc gamma receptor binding regions• The C-terminus of the HC is not within the known binding
sites of CDR, FcRn or Fc gamma receptors• Preferential clearance has not been demonstrated
Johnson et al. Anal. Biochem. 360, 75 – 83 (2007). Tsubaki et al. International Journal of Biological Macromolecules 52, 139-147 (2013), Kaschak et al. mAbs 3, 577 – 583 (2011).
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USING PRIOR KNOWLEDGE TO ESTABLISH AN ATTRIBUTE FOCUSED SPECIFICATION
Prior Knowledge of Product attribute safety threshold from in vitro and animal data
Clinical exposure with highest level of impurity
TI based off of Manufacturing Experience
Attribute acceptance criteria = clinical exposure and manufacturing experience + Prior Knowledge (clinical and in vitro)
Prior Knowledge based on clinical exposure of the attribute from relevant products
HMWS Qualified Range
Adjusted Acceptance Criteria
0% 25%
0% 25%10%
ACHIEVE KNOWLEDGE AND EXPERIENCE BASED SPECIFICATION
Today: End of Process DS/DP Release
• 30+ assays overlapping DS & DP
• End point manual testing
• Complex and resource insensitive
• Instrument centric, non PQA specific
FUTURE PRODUCT TESTING PARADIGM
Tomorrow: Real Time Release
• Multi-Attribute Method (MAM)
• Online sensor technology
• Automated online/at-line testing
• PQA specific
CEX SEC rCE-SDSGlycan Peptide Mapping
UVID, Glycosylation, Oxidation, Deamidation,
Isomerization, Hydroxylysine, Clips BioAssay
ID by Raman
Aggregate
Titer
Breakloose Extrusion Osmometer
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ATTRIBUTE-BASED STRATEGY WILL ENABLE MOLECULE DIFFERENTIATION TO MEET PATIENT NEEDS
Target Candidate Profile
Molecule Screening & Design
Molecule Assessment
Attribute Understanding(PQAA, QTPP)
Differentiated Molecule/Modality
By design
• Apply ‘Quality Target Product Profile’ to meet patient needs defined within Target Product Profile
• Deliver attribute understanding, methods to test and control them, and ensure supply for patients
• Advance new attribute technologies for specific, fast and multi-attribute methods
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• Prior knowledge is applicable from molecule design, molecule selection, non-clinical toxicology testing, first in human studies and through product lifecycle
• Prior knowledge is utilized to develop a risk-based approach for control strategy including specification setting
• Prior knowledge of product attributes and the development of the associated manufacturing process creates a basis for more flexible regulatory approaches
• It is important to understand the criticality of attributes and the impact of these attributes across different therapies
PRIOR KNOWLEDGE NEXT STEPS
PRIOR KNOWLEDGE HAS POTENTIAL FOR GREATER USE IN DETERMINING A CONTROL STRATEGY31
FUTURE DIRECTIONS: INTEGRATION OF DS, DP, AND ATTRIBUTE TESTING (AT) SUPPORTED BY PRIOR KNOWLEDGE
Drug Substance
Process
Drug Product Process
Attr
ibut
e Te
stin
g
Proc
ess F
low
Integrated Bioprocessing
Current Paradigm
Vial
DevicePr
oces
s Flo
w
AT
AT
AT
AT
Future Paradigm
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LEVERAGING PRIOR KNOWLEDGE REQUIRES BALANCED INDUSTRY AND HEALTH AUTHORITY ENGAGEMENT
Industry Intentions
Use of Prior KnowledgeRegulations, guidances, data,
tools, philosophies, knowledge management, industry best
practices Regulator Acceptance
Industry Perspective
Education of and by sponsors
Education of and by regulators
Prior KnowledgeAbility to Effectively Inform, Communicate
and Implement
Timely Review Acceptance and Implementation
Agency Thinking
Some reactions: “too risky”
Some reactions: “too slow”
NewApproach
Range of Potential Perceptions
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ACKNOWLEDGEMENTS
• Darrin Cowley
• Tom Monica
• Marisa Joubert
• Andrew Lennard
• Rohini Deshpande
• Izydor Apostol
• Nina Cauchon
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QUESTIONS?
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