Process Development of Therapeutic

The Process Development of Therapeutic
Monoclonal Antibody Products by QbD

Kaisong Zhou, PhD
Agenda
1 Process Development of Therapeutic Monoclonal Antibody
2 Overview of Process Characterization Strategies
3 Upstream Process Characterization
4 Downstream Process Characterization
5 Drug Product
Copyright© 2019 Innovent Biologics 1

Biologics Are Not Chemical Drugs
⚫ The three major differences between biologics and chemical drugs
− Use of living source materials to produce the biologic
− Increased complexity of biologic manufacturing processes-’Process is Product’
− Increased complexity of the biologic molecules themselves
Fig.1 Illustration of a the Comparative Complexity of The Most Popular Small Molecule Drug (aspirin) and Monoclonal Antibody
Clinical and Process Development Flowchart
Clinical Development Phases

Toxicology Phase I Phase II Phase III Filing Manufacture
Product and Process Development Stages

Process Process BLA Process
Process Development
Characterization Qualification Preparation Monitoring
1 2 3 4 5 6 7 8 9
1 Target product profile (TPP) identification 6 Design space definition

2 Quality target product profile (QTPP) definition 7 Control strategy risk assessment
3 Critical quality attribute (CQA) risk assessment 8 Control strategy definition
4 Initial process risk assessment 9 Ongoing improvement and support
• Bioprocess International 2018, 16 (6) E3
5 Process risk assessment 2

Upstream Process Platform-1KL
N
1000L Production Bioreactor
WCB vial
N-1
N-2 200L Bioreactor
50L Bioreactor
Shake flasks N-3
20L Wave

Down-stream Process Platform
Cell Culture
Cell Culture
UF （1-2）+DF

Excipients used in Monoclonal Antibody Product Formulation
⚫ Osmolality Control
⚫ Cryoprotectants (such as sucrose or trehalose, mannitol, and certain amino acids

such as histidine)
⚫ Lyoprotectants and Bulking Agents (mannitol, disaccharides, and amino acids such
as glycine, histidine and arginine)
⚫ Surfactants (tween 20 and Tween 80)
⚫ Chelating Agents (EDTA)
⚫ Preservatives
⚫ Other Excipients

Fill/Finish Manufacturing Process Flow Diagram
• A-Mab: a Case Study in Bioprocess Development, Version 2.1. CMC Biotech Working Group, 2009

Agenda
5 Drug Product

Flow Chart of Quality by Design (QbD)
Step 1 Step 2
Target Product Profile Process Parameters Lists
Quality Target Product Profile Risk Assessment
Quality Risk Management Potential CPPs/KPPs
Critical Quality Attributes Process Characterization Studies Scale-down Model Qualification
CPPs/KPPs and Their Design Space

Step 3
Input Material Controls
Process Parameter Controls

Process Controls
Control Strategy
Procedural Controls
In-Process Testing Analytical Science
Process Development
Specifications
Testing QC&QA
Characterization and Comparability
Testing Manufacture
Process Monitoring QC

ICH Guidelines Provide the Framework for QbD
ICH Q8(R2): Pharmaceutical Development - This document provides guidelines for drug product development. ICH Q8
defines QbD as, “a systematic approach to development that begins with predefined objectives and emphasizes product
and process understanding and process control, based on sound science and quality risk management.”12 This guideline
outlines the principles for potentially achieving increased regulatory flexibility.
ICH Q9: Quality Risk Management - This guideline provides principles and examples of tools for quality risk management
that can be applied to all aspects of pharmaceutical quality including development, manufacturing, distribution, and
inspection and submission/review.20 This document states that: risk assessment should be based on sound scientific
knowledge; and the level of risk assessment activities should be a function of the level of risk.4,20
ICH Q10: Pharmaceutical Quality System - This document applies to pharmaceutical drug substances and drug
products throughout their lifecycles and provides a comprehensive model for pharmaceutical quality based on ISO
standards. It is intended to promote innovation and continual improvement in pharmaceutical manufacturing.8 It outlines
a pharmaceutical company’s responsibilities and ICH expectations. 4 This guideline introduces the concept of “phase
appropriate” development.
ICH Q11: Development and Manufacture of Drug Substances - This guidance covers the development and manufacturing process of
drug substances.5It providesan explanation of what should be included in the Common Technical Document submission.

Process Characterization Strategies and Methodology
Step 1 Acceptable Ranges for the Quality Attributes
Risk Assessment Used to Plan

Step 2 Process Characterization Studies
Step 3 Scale-Down Model Qualification
Step 4 Univariate /Multivariate DOE
Process Parameter Classification and Ranges /Design Space

Step 5
Step 6 Process Parameters Controls Strategies

Agenda
5 Drug Product

Step 1. Quality Attribute Assessment
⚫ Critical Quality Attribute

A physical, chemical, biological or microbiological property or characteristic that should be within
an appropriate limit, range, or distribution to ensure the desired product quality
⚫ Quality Attribute Assessment Tools

#1、Criticality (Risk Score) = Impact × Uncertainty
#2、Criticality (Risk Priority Number [RPN]) = Severity × Likelihood
#3、ISF = LD50 ÷ Level in Product Dose

Quality Attribute Assessment
- Acceptable Ranges for the Quality Attributes Discussed in a Mab Case Study
Claimed
Non-clinical Clinical Rationale for Claimed
Attribute Prior Knowledge In-vitro Studies Acceptabl e
Studies Experience Acceptable Range
Range
1-11%; Clinical experience with A-Mab with 2-13% Animal model available; 2-13% afucosylation correlates with 70-
5-10%;
X-Mab and Y-Mab; both X-Mab afucosylation tested in modeled material (15%) 130% ADCC activity. Lower end covered
Afucosylation Phase II and
and Y-Mab have ADCC as part ADCC assay; linear shows no significant 2-13% by prior knowledge; upper end covered
Phase III
of MOA correlation; 70-130% difference from 5% by modeled material in animal model.
1-5% aggregate (at end of SL) in
clinical studies and commercial Purified A-Mab dimer has
Animal models typically not 5% upper range claimed based on prior
Aggregation production with X-Mab; similar biological activity to 1-3%
relevant 0-5% clinical experience with X-Mab.
minimal ATAs with no effect on monomer aggregate
efficacy; no SAE
Stressed material (25-
None
77%) tested in potency
Deamidated Literature data reports that claimed;
assay; no effect; Serum 18-24% NA
isoforms deamidation is a common No animal studies measure of
studies showed rapid
occurrence consistency
deamidation
Clinical experience of 10- 40%
G0 for Y-Mab, another 0-100% has statistical
Range is based on a combination of
Galactose Content antibody with CDC activity as correlation with CDC 10-30%
No animal studies 10-40% prior knowledge (Y-Mab experience)
part of MOA; no negative activity with A-Mab
and clinical experience.
impact on clinical outcome;
Up to 3600 ng/kg in X-Mab 100 ng/mg upper limit claimed based
0-100
HCP Phase I trial (corresponds to NA NA 5-20 ng/mg ng/mg on prior clinical experience with X-
120 ng/mg HCP level) Mab.
Level of 0-2% on A-
Literature data show sialylated Mab shows no 0-0.2%;
Sialic Acid NA 0-2% In vitro studies with A-Mab.
forms can impact PK and ADCC statistical correlation Phase II and II
to ADCC
Literature data show
High
afucosylated forms impact NA NA 3-10%; 3-10% Clinical Experience with A-Mab.
Mannose
ADCC
Non- Literature data show that non-
Glycosylated glycosylated forms impact NA NA 0-3% 0-3% Clinical Experience with A-Mab.
Heavy Chain ADCC
Upstream Process Platform-1KL
N
1000L Production Bioreactor
WCB vial N-3 N-2 N-1
20L Wave 50L Bioreactor 200L Bioreactor
Shake flasks
Step 1 Cell thaw
Step 2 Cell expansion
Step 3 20 L wave
Step 4 50 L bioreactor
Step 5 200 L bioreactor
Step 6 1000 L fed-batch
Step 7 Harvest

Step 2. Risk Assessment Used to Plan Process
Characterization Studies
Fig.1 Ishikawa Diagram Indicating the Process Parameters Analyzed in the Risk Assessment of the Production and the N-1 Bioreactors

Risk Assessment (RA) to Establish the
Criticality of Process Parameters
3
Process improvement rating

25.0
22.5 2.5
20.0
17.5 2 2 2
15.0 Process improvement threshold
RPN
1.5
12.5
10.0 1 1 1
8.6
1 1 1 1 1
6.8
7.5 RPN threshold 5.4
5.0 3.0 3.6 3.2
3.9 0.5
2.3 2.1 2.1
2.5 0.6 0.9
0.0 0
Temperature
Cell age
pH
Phosphate Feed
Glucose Feed
pCO2 (total gas

Cell density at
Antifoam volume
Inoculum cell
DO
Stirring
Culture duration
flow sparged)
seeding
density
RPN and PIR scored based on the failure mode and effect analysis (FMEA) . RPN (Risk Priority Number) scores are in bars, and PIR (Process
Improvement Rating) scores are in diamonds. Any process parameter above the RPN threshold of 5 was considered as potentially critical. Any
process parameter below the RPN threshold of 5 but above the PIR threshold of 1.5 was considered as a potential key process parameter.
• European Journal of Pharmaceutics and Biopharmaceutics,
2012,81,426
Risk Assessment Results for Process Parameters
in the Production Bioreactor
Process
Quality Attributes
Attributes
Process Parameter in
Galactosylation
Risk Mitigation
aFucosylation
Product Yield
Deamidation
Production Bioreactor
Turbidity at
Aggregate
Viability at
Harvest
harvest
HCP
DNA
Inoculum Viable Cell DOE
Concen.
Inoculum Viability Linkage Studies
Inoculum In Vitro Cell Age EOPC Study
N-1 Bioreactor pH Linkage Studies
N-1 Bioreactor Temperature Linkage Studies
Osmolality DOE
Antifoam Concentration Not Required
Nutrient Concentration in DOE
medium
Medium storage temperature Medium Hold Studies
Medium hold time before Medium Hold Studies
filtration
Medium Filtration Medium Hold Studies
Medium Age Medium Hold Studies
Timing of Feed addition Not Required
Volume of Feed addition DOE
Component Conc. in Feed DOE
Timing of glucose feed DOE-Indirect
addition
Amount of Glucose fed DOE-Indirect
Dissolved Oxygen DOE
Dissolved Carbon Dioxide DOE
Temperature DOE
pH DOE
Culture Duration (days) DOE
CPP = Parameter impacts a Quality Attribute - Must be controlled tightly, limited robustness
WC-CPP = Parameter impacts a Quality Attribute - Well controlled, robust operation
KPP = Parameter impacts Process Attribute
Non-KPP = Parameter does not impact a QA or PA • A-Mab: a Case Study in Bioprocess Development, Version 2.1.
Copyright© 2019 Innovent Biologics CMC Biotech Working Group, 2009 18
Scale-up Criteria
⚫ The scale-up considerations used for A-Mab include the following:

− Bioreactor Design
➢ Aspect Ratio (height to diameter ratio)
➢ Impellers and agitation
➢ Sparger Element Design and Location
➢ Addition port design and location
− Mixing regime: Specific energy dissipation rates and mixing time
P/V=P0ρN3D5/V
where: P=Power (W), Po = Power number, impeller dependent (--), ρ= density of the liquid (kg/m3),
N = agitation speed (s-1), D= impeller diameter (m), and V= Volume of liquid in bioreactor.
− Oxygen and CO2 mass transfer: superficial gas velocity, kLa, gas hold-up volume, pCO2 stripping
Kla=k(P/V)a(vs)β
Where, P/V= energy dissipation rate, vs = superficial gas velocity, k, α and β = constants that depend on
bioreactor system configuration and medium composition.

Step 3. Scale-Down Model Qualification
Fig.1 The comparison of viable cell density (a), viability (b), dissolved CO2 (pCO2) © , normalized titer (d) between 2-L (n=6) and
2000-L (n=4) scales
Notes：Two-One-Side Test (TOST) is used to determine the equivalency between the scale-down model and the large-scale process performance. The
scale equivalency is defined as –Ө＜µS- µL＜ Ө，where µS and µL are performance parameter mean values at the small and large scale, respectively.
demonstrated. Variations within (3 standard deviations of the mean (3 Ө) were considered acceptable, and the range was set as [-3 Ө, 3 Ө] based on
the 2000-L process data. Using JMP software,
• Biotechnol. Prog.,2006,22,696
Step 4. Univariate /Multivariate DOE
Fig.1 Models for quality attributes. For graphs 1 (HCP), 2(DNA), 3(HMW species), 4 (Clipped forms), and 6 (Bioactivity), actual factors are VCD at
seeding= 1.40X106 vcs/mL and DO=50%. For graph 5 (G0), actual factor DO=50%. Black design points: points above predicted value; white design points:
below predicted value. Not all data points are shown. The projections shown enable to see control runs (with the DO at the center point (50%). Control
runs were measure at day 8 and 12 in addition to the center point at day 10. • European Journal of Pharmaceutics and
Biopharmaceutics, 2012,81,426
Step 5. Process Parameter Classification and Ranges
/ Design Space
Running duration: 10 days Running duration: 9 days
A G1
B G2
HCP
G0
G1
DNA
DNA
HMW
G0
NOR
MOR
MOR
G0
G0
Titer
Titer
G1 G1
• European Journal of Pharmaceutics and

Biopharmaceutics, 2012,81,426
Fig.1 Design space limits

Copyright© 2019for theBiologics
Innovent bioreactor cell culture process 22
Step 6. Overview of Control Strategy for
Upstream Manufacturing Process
Quality-linked Key Process
Process Parameters Parameters Key Process In-Process
(WC-CPPs) (KPPs) Attributes Quality Attributes
Temperature Viable Cell Concentration

Time
Working Cell Bank
Viability
Step 1
Temperature
Seed Culture Expansion Viable Cell Concentration
Culture Duration
in Disposable Shake Viability
Initial VCC/Split Ratio
Flasks and/or bags
Temperature Step 2
pH Viable Cell Concentration
Seed Culture Expansion
Dissolved Oxygen
in Fixed Stirred Tank Viability
Culture Duration
Initial VCC/Split Ratio Bioreactors
Temperature Antifoam Concentration Bioburden

pH Time of Nutrient Feed MMV
Product Yield
Dissolved CO2 Volume of Nutrient Feed Step 3 Mycoplama
Viability at Harvest
Culture Duration Time of Glucose Feed Production Culture Adventitious Virus
Turbity at Harvest
Osmolality Volume of Glucose Feed
Remnant Glucose Dissolved Oxygen
Step 4
Flow Rate Centrifugation and Depth Product Yield
Pressure Turbidity
Filtration
Controlled within the
Design Space to Assay results part
ensure consistent Controlled within acceptable of batch release
product quality and Clarified Bulk limits to ensure consistent specifications
process performance process performance
• Product quality and safety are ensured by controlling all quality-linked process parameters (CPP and WC-CPP) within the limits of
the design space. Process consistency is ensured by controlling key process parameters (KPPs) within established limits and by
monitoring relevant process attributes.

Agenda
5 Drug Product

Downstream Process Flow Diagram
Clarification
Step 1
Affinity chromatography
Step 2
Low pH inactivation
Step 3
Absorb depth filtration

Step 4
Cation exchange chromatography

Step 5
Anion exchange chromatography

Step 6
Step 7 Nano filtration
Ultrafiltration/Diafiltration
Step 8
DS
Fig.4. Downstream Process Flow Diagram

Risk Ranking for Protein A Chromatography Step
Highest
Highest
Main
Main Effect Main Effect Interaction Interaction Interaction Severity
Phase Parameter Effect
(CQA)a (PA)b (CQA)a (PA)b Score (MxI)
Score
All phases Column Bed Height (cm) 1 1 1 4 2 4 4
Load (HCCF) Flow Rate (CV/hr) 4 2 4 2 2 2 8

Load (HCCF) Operating Temperature (oC) 4 1 4 4 1 4 16
Load (HCCF) Protein Load (g/L) 4 4 4 4 4 4 16
Load (HCCF) Load Concentration (g/L) 1 1 1 1 1 1 1
Equil & Wash Buffer pH 1 1 1 1 1 1 1

Equil & Wash Buffer Molarity (mM Tris) 1 1 1 4 1 4 4
Equil & Wash Buffer Molarity (mM NaCl) 1 1 1 4 1 4 4
Equil & Wash Buffer Molarity (mM EDTA) 1 1 1 1 1 1 1
Equil & Wash Flow Rate (CV/hr) 4 2 4 4 1 4 16
Equil & Wash Operating Temperature (oC) 1 1 1 1 1 1 1
Equil & Wash Volume (phase duration) 1 1 1 4 1 4 4
Elution Buffer Molarity/pH (mM Acetic acid) 4 1 4 4 1 4 16

Elution Flow Rate (CV/hr) 1 2 2 1 1 1 2
Elution Operating Temperature (oC) 1 1 1 1 1 1 1
Elution Start Pool Collection (OD) 1 1 1 1 1 1 1
Elution End Pool Collection (CV) 1 1 1 8 1 8 8
Scale-Down Model of Chromatography
⚫ A scale-down laboratory system was qualified as a model of the manufacturing-scale

process
⚫ The model was designed based on well-established principles of chromatography

scaling, maintaining the same bed height, linear flow velocities, load, wash and elution
volumes (normalized to column volumes), and column efficiency based on plate count
and peak asymmetry
⚫ The model qualification used triplicate runs of the lab-scale system, with statistical
comparisons of the mean values of the performance parameters for lab, pilot- and
manufacturing-scale, product yield, peak volume, impurity removal (e.g. HCP, DNA, and
insulin), and levels of leached Protein A

Scale-Down Model Qualification
Table 1. CEX Process Performance and Multiple Scales
Scale up Step yield Elution pool % acidic

factor (%) volume (CV) Aggregate (%) HCP (ng/mg) species
Load material 1.8 ± 0.4 7000 ± 750 10 ± 2
Scale-down model (N=55) 1 90 ± 7 4.0 ± 0.4 0.7 ± 0.2 99 ± 22 9±2
Pilot scale 500 L (N=2) 2000 89 ± 4 4.1 ± 0.2 0.6 ± 0.1 100 ± 30 8±2
Pilot scale 5000 L (N=5) 8000 90 ± 5 4.2 ± 0.4 0.8 ± 0.2 105 ± 15 9± 2
Commercial scale 15000 L

(N=2) 33,000 89 ± 5 4.2 ± 0.5 0.7 ± 0.1 90 ± 20 10 ± 2
Clearance factors 2-3x 50-100x 0x

Design of Experiment (DoE) by JMP
Table 1. Process Parameters and Ranges evaluated in DOEs for CEX
Parameter Low Mid High
Protein load (g/L resin) 10 25 40
Elution flow rate (cm/hr) 100 200 300
Elution stop collect (OD) 0.5 1.0 1.5
Elution buffer pH 5.8 6.0 6.2
Wash conductivity (mS/cm) 3.0 5.0 7.0
Load HCP (ng/mg) 3000 7500 12000
Aggregate 2.4 2.7 3.0

Process Characterization (DOE) Results for CEX Step:
Prediction Profile based on Statistical Models
Prediction Profiler
200
±1.480463
84.78271
150
HCP
100
50
0
3
Aggregate
±0.109468
0.770113
2
0
0
0
4
0
0
0
6
0
0
0
8
0
0
0
1
Step Yield
90.71774
±0.92095
95
90
85
80
3
4
5
6
7
10
15
20
25
30
0.4
0.8
1.2
1.6
5.8
5.9
6.0
6.1
6.2
100
150
200
250
300
20 1 5 2.7
Protein 200 Stop 6 Load Wash 7500 Aggregate
Load Flow Rate Collect pH Conductivity HCP Input Input

Process Parameter Ranges / Design Space
Figure 1.Predicted Protein A HCP (ppm) concentration as a function of Protein Load and Elution pH in Protein A chromatography step
Downstream Process Design Space
Control
Parameter Range Justification Classification
Strategy
Protein A Chromatography
Batch
10-50 g protein/L resin,
Protein load Multivariate Study procedures, WC-CPP
constrained by Equation 7
Skid control
3.2-3.9, constrained Batch
Elution buffer pH Multivariate Study WC-CPP
by procedures
Equation 7 Low pH Inactivation
Aggregation and viral Batch
pH 3.2- 4.0 CPP
inactivation considerations procedures
Time 60-180 min WC-CPP
Temperature 15-25 WC-CPP
Cation Exchange Chromatography
Batch
10-30 g/L resin. constrained by
Protein load Multivariate Study procedures, WC-CPP
Equation 7
Skid control
Load / wash 3-7 mS/cm, constrained by Batch
Multivariate Study WC-CPP
conductivity Equation 7 procedures
Batch
Elution pH 6.0 ± 0.2 Multivariate Study WC-CPP
procedures
Elution stop collect 1.0 ± 0.5 OD descending Multivariate Study Skid control WC-CPP
Anion Exchange Chromatography
Equilibration / Wash 1.6-3.6 mS/cm, constrained by Batch
Multivariate Study WC-CPP
conductivity Equation 7 procedures
Multivariate Study,
7.2-7.8, constrained by Batch
Load pH Generic and Modular WC-CPP
Equation 7 procedures
Viral Clearance
Generic and Modular Batch
Load conductivity 3.0 – 8.0 mS/cm WC-CPP
Viral Clearance Studya procedures
Protein load  300 g/L resin WC-CPP
Viral Clearance procedures
Flow rate  450 cm/hr
WC-CPP
• A-Mab: a Case Study in
Viral Clearance procedures
Small Virus Retentive Filtration Bioprocess Development,
Pressure Filter Specific WC-CPP
Viral Clearance procedures Version 2.1. CMC Biotech
Filtration volume Filter Specific WC-CPP
Viral Clearance procedure
Generic and Modular Filter integrity Procedural
Working Group, 2009
Integrity test Pass
Viral Clearance test Control
a Range constrained by multivariate study. Acceptable
Copyright© 2019
range for Innovent
viral is conductivity  15 mS/cm and pH ≥ 7.0.
Biologics
clearance 32
Agenda
5 Drug Product

Formulation Composition Risk Assessment
Weight factor 10 10 5
Quality attribute Purity: Purity:
Purity: Weighted
visible subvisible
Parameter aggregation score
particles particles
pH 10 10 10 250
A-mAb concentration 10 10 10 250

Formulation Composition
Polysorbate 20 concentration 5 10 10 200
Fill Volume 5 7 7 155
Acetate concentration 5 5 5 125
Primary container DS 5 5 5 125
Raw material impurities 5 5 5 125
Sucrose concentration 5 1 1 65
20R DP primary container 1 1 1 25

Formulation Characterization Studies

Formulation Design Space
Design Space Design Space

Lower Limit Upper Limit Target
pH 4.7 5.6 5.3

Drug Substance
Acetic acid/Acetate (mM) 10 30 20
Sucrose (% w/vol) 5 13 9
Polysorbate 20 (% w/vol) 0.005 0.02 0.01
A-Mab concentration (mg/ml) 65 85 75
pH 4.7 5.6 5.3

Drug Product
Acetic acid/ Acetate (mM) 10 30 20
Sucrose (% w/vol) 5 13 9
Polysorbate 20 (% w/vol) 0.005 0.02 0.01
A-Mab concentration (mg/ml) 20 30 25

Risk Ranking Study for the Rotary Piston Filler
Process Parameters on Protein Aggregation
Proposed Main Inter- Potential Recommended

Process
Design Space Effect Rationale for (M) action Rationale for (I) Severity Score Interaction Characterization
Parameter
Range Score Score Parameters Studies
Low High (M) Main Effect (I) Interaction Effect (M x I)
Multivariate study with fill

Shear effects and foaming Other parameters Temperature, Fill
Pump Speed/ head temperature, nozzle
10 40 8 due to air interaction may 4 may exacerbate 32 volume, nozzle
(vpm) diameter, and nozzle
cause aggregation foaming effects position
position
Fill Temperature A-Mab has good May have additive

2 20 2 4 8 Pump speed See pump speed study
(°C) stability even at RT effect
Diameter affects
Nozzle Diameter May have additive
1 2 4 jetting of solution 4 16 Pump speed See pump speed study
(mm) effect
leaving nozzle
Height affects
Nozzle Position May have additive Pump speed,
0.5 2.5 4 amount of air 4 16 See pump speed study
(mm) effect nozzle diameter
interaction
Volume affects
number of pump
strokes. Product in Multivariate study with
May have additive
Fill Volume (L) 40 2000 8 between piston and 4 32 Pump speed pump speed and number
effect
wall may be over of strokes per pump head
stressed leading to
aggregation

Filling Study DOE
Nozzle ID Size Pump Speed
Number Pattern Temperature (°C) Nozzle Position (mm)
(mm) (Unit / min)
1 ++−− 20 2 0.5 10
2 +−0− 20 1 1.5 10
3 ++−0 20 2 0.5 25
4 −−−− 5 1 0.5 10
5 ++00 20 2 1.5 25
6 −+−0 5 2 0.5 25
7 −−00 5 1 1.5 25
8 −−++ 5 1 2.5 40
9 −+−+ 5 2 0.5 40
10 −++− 5 2 2.5 10
11 +−+0 20 1 2.5 25
12 ++++ 20 2 2.5 40
13 −+0− 5 2 1.5 10
14 −++0 5 2 2.5 25
15 +−−+ 20 1 0.5 40
16 ++0+ 20 2 1.5 40
17 −+0+ 5 2 1.5 40
18 +++− 20 2 2.5 10
+ represents the higher limit within a specific range

- represents the lower
limit within a specific
range 0 represents the
mid-point within a • A-Mab: a Case Study in Bioprocess Development, Version 2.1. CMC Biotech Working Group, 2009
specific range

Knowledge Space Matrix from A-Mab Filling Study

Summary of Overall Drug Product Process Control Strategy

Control Strategy Element for A-Mab
Control Element Description

These are controls pertaining to raw materials, excipients, components etc. used in manufacturing operations, including supplier
Input Material Controls quality management, raw material qualification and raw material specifications. The case study does not address risk assessment
or control strategy supporting input material controls.
Process Control Elements
A comprehensive set of facility, equipment and quality system controls which result in robust and reproducible operations
Procedural Controls supporting the production of product of the appropriate quality. These controls are supported by a quality risk management
system.
Process parameters that are linked to Critical Quality Attributes (CQAs) and include Critical Process Parameters (CPPs) or Well
Process Parameter Controlled Critical Process Parameters (WC- CPPs) that must be controlled within the limits of the design space to ensure product
Controls quality. Process parameters linked to process performance (KPPs and GPPs) that must be controlled to ensure process
consistency.
Testing Control Elements
Measurements typically conducted using analytical test methods or functionality tests to ensure that selected manufacturing
In-process Testing
operations are performing satisfactorily to achieve the intended product quality. In-process tests include acceptance criteria.
Tests with associated acceptance criteria conducted at final lot release on a set of quality attributes to confirm quality of drug
Specification (Lot
substance for forward processing and drug product for distribution. Certain attributes will also be monitored as part of the
Release Testing)
stability program.
Characterization and/or Testing of certain attributes outside of lot release testing for the purposes of intermittent process monitoring or demonstration
Comparability Testing of comparability. A specific testing plan would be developed based on risk to product quality.
Testing or evaluation of selected attributes and/or parameters to trend product quality or process performance within the design
Process Monitoring space and/or to enhance confidence in an attribute‘s normal distribution. The frequency of monitoring is periodically reviewed
and adjusted based on trends. The process monitoring program may include limits for evaluating data trends.

Summary
⚫ Historically, product quality has been assured either with end-product testing or with
strict and narrow control of manufacturing processes without a comprehensive
understanding of how process parameters link to product quality attributes
⚫ The quality by destin (QbD) modernized approach to pharmaceutical development is

intended to provide regulatory flexibility, increased development and manufacturing
efficiency, and greater room to innovate as well as improve manufacturing efficiency,
and greater room to innovate as well as improve manufacturing processes within
defined ranges without obtaining regulatory approval first
⚫ Science- and risk-based foundation tools: Knowledge management; risk assessment

and management; process analytical technology; raw material management; statistical
design and analysis
⚫ “不懂 DOE(试验设计)的工程师只能算是半个工程师...”
-田口玄一

Contact
Tel: (86) 0512-69566088

Fax: (86) 0512-69566088-8348
Web: www.innoventbio.com
E-mail: info@innoventbio.com
Address: 168 Dongping Street, Suzhou Industrial Park, China 215123

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Process Development of Therapeutic

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The Process Development of Therapeutic

Monoclonal Antibody Products by QbD

1 Process Development of Therapeutic Monoclonal Antibody

2 Overview of Process Characterization Strategies

3 Upstream Process Characterization

4 Downstream Process Characterization

Copyright© 2019 Innovent Biologics 1

− Use of living source materials to produce the biologic

− Increased complexity of biologic manufacturing processes-’Process is Product’

− Increased complexity of the biologic molecules themselves

Clinical Development Phases

Product and Process Development Stages

1 Target product profile (TPP) identification 6 Design space definition

Copyright© 2019 Innovent Biologics 3

Copyright© 2019 Innovent Biologics 4

Copyright© 2019 Innovent Biologics 5

⚫ Cryoprotectants (such as sucrose or trehalose, mannitol, and certain amino acids

⚫ Surfactants (tween 20 and Tween 80)

⚫ Chelating Agents (EDTA)

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1 Process Development of Therapeutic Monoclonal Antibody

2 Overview of Process Characterization Strategies

3 Upstream Process Characterization

4 Downstream Process Characterization

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Quality Target Product Profile Risk Assessment

Quality Risk Management Potential CPPs/KPPs

Critical Quality Attributes Process Characterization Studies Scale-down Model Qualification

CPPs/KPPs and Their Design Space

Process Parameter Controls

In-Process Testing Analytical Science

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Step 1 Acceptable Ranges for the Quality Attributes

Risk Assessment Used to Plan

Step 3 Scale-Down Model Qualification

Step 4 Univariate /Multivariate DOE

Process Parameter Classification and Ranges /Design Space

Step 6 Process Parameters Controls Strategies

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1 Process Development of Therapeutic Monoclonal Antibody

2 Overview of Process Characterization Strategies

3 Upstream Process Characterization

4 Downstream Process Characterization

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⚫ Critical Quality Attribute

⚫ Quality Attribute Assessment Tools

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Step 1 Cell thaw

Step 2 Cell expansion

Step 5 200 L bioreactor

Step 6 1000 L fed-batch

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Process improvement rating

pCO2 (total gas

⚫ The scale-up considerations used for A-Mab include the following:

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• European Journal of Pharmaceutics and

Fig.1 Design space limits

Temperature Viable Cell Concentration

Temperature Antifoam Concentration Bioburden

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