Industry Case Study: Continued Process Verification (CPV) For A Biotech Product

INDUSTRY CASE STUDY: CONTINUED PROCESS
VERIFICATION (CPV) FOR A BIOTECH PRODUCT

OUTPUT FROM BIOPHORUM OPERATIONS GROUP (BPOG)
COLLABORATION OF BIOTECH COMPANIES
Presenting to the IFPAC Meeting (Jan 2014) on behalf of the BPOG CPV
Workstream
Outline
Background
Case Study
1.
Why write this Case Study?
2.
How has it been put together?
3.
What does the Case Study contain?
4.
What are the Key Learning Points?
Application Scenarios
CPV Benefit Estimates
Outstanding topics for further discussion
CPV Document Slide Pack V5.4
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Background
The BioPhorum Operations Group (BPOG) is an industrywide collaboration to enable networking and to share best
practice in the area of Operations.
Beginning in 2008, it now has 26 member companies with
over 600 participating representatives. The community
primarily consists of experts from biopharmaceutical drug
substance operations, who meet and work together at
face-to-face meetings in the USA and Europe, on regular
teleconferences and via web meetings.
The group has established best practice on a wide range
of quality, engineering and organizational topics
considered central to the challenge of mastering effective
biotech drug substance operations.
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1. Why Write a CPV Case Study?

New industry regulatory guidelines published by FDA in 2011
Little experience submitting new license applications under these
guidelines
Very few articles on the topic and most literature covers only
some aspects of the topic
Very few articles written by actual practitioners

Cross-functional and complex affecting several functions &
disciplines
Convenient & clear way to share perspectives across the industry

and with regulators
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Purpose
To exemplify implementation of Continued Process Verification
(CPV), third stage of process validation lifecycle as presented in
FDAs 2011 Process Validation guidance
To identify then realize the benefits of implementing CPV:
Comply with FDA guidance
Improve process control
Clarify opportunities for process improvement
Reduce operating costs
Reduce cost of goods
Increase access to products

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Concept of the Case Study

Recommendations & rationale for end-to-end illustrative plan
for Continued Process Verification (CPV)
Plan links process design to continued process verification and
its lifecycle
Initial CPV plan focus (post-PPQ completion)
Process description and development taken from industry

generated A-mAb Case Study*
Except without building on design space claims
Case study focuses on Drug Substance

Drug Product effort planned (with analogous DP Biophorum group)
Ref:A-mAb: A Case Study in Bioprocess Development, CMC Biotech Working Group. 2009
(Available free download at ispe.org)
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2. How was it assembled?

Reference to the A-mAb case study
Independent co-ordination & facilitation
Broad input & contributions from all participating member
companies
A sequence of virtual meetings
A face-to-face event
An editorial process
An approvals process
Free of charge access to full case study, once finalised
http://www.biophorum.com/page/123/BPOG-CPV-Case-Study.htm

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3. What does the Case Study contain?

Selected Outline
Descriptions of
CPV
implementation
Purpose and Scope

Roles and Responsibilities
References (as used in CPV Plan)
Product and Process Description
Development of a CPV Strategy
Embedded
elements of an
illustrative CPV
plan
Scope of Data Collection and Analysis Plans

Establishing Initial Control Limits
CPV Execution Plan

- Including Lifetime Limits & Other Monitoring
- Change control decision tree
Sampling and Data Management

- Sample Plans/Templates
Data Entry and Verification
Data Analysis Methods & Responses
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Discretionary Elements of Guidance

External references
Product and Process Description

Product and Process for CPV plan is based on A-mAb study
Product Development based on a QbD approach** applying principles
from ICH guidelines Q8, Q9, Q10 & Q11
Identification of Quality Attributes (QA) based on Quality Target Product Profile (QTPP)
Risk evaluation to identify Critical Quality Attributes (CQAs)
Upstream / Downstream process description
Risk-based approaches and analyses to classify process parameters and other variables
linked to product quality (e.g. identification of Critical Process Parameters - CPPs)
Univariate or Multivariate Approaches to define Proven Acceptable Ranges or Design
Space**
Rational approach to define Control Strategy that reflects product/process knowledge
and risk
Background used to develop presumed Process and Equipment Performance
Qualification (Stage 2) to verify established control strategy (Stage 1)
** Although A-mAb claims a design space, this case study does not address CPV
concepts associated with design space implementation
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Pre-requisites for Continued Process Verification
TPP
QTPP
CQA
CPP
Covered in A-Mab Study
PV Stage 1
Proven
Acceptable
Ranges
(Design
Space)
CPV
CPV
PPQ
EQ
PV Stage 2
Short-term
Plan
Long-term
plan
PV Stage 3
CPV plan (this work), covering PV stage 3 requirements, follows available

data from PV stage 1 (A-mAb) & assumed outcome from PV stage 2
Short-term (initial) plan created that develops into a long-term (lifetime) plan

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CPV Strategy:
Assurance of Control Strategy
Control strategy consists of quality-linked process parameters (CPPs and WCCPPs), Key Process Parameters (KPPs), Key Process Attributes (KPAs) and
IPCs.
Control strategy ensures required product quality (CQAs) and consistent /
robust process
Elements of control strategy should be monitored and improved in
accordance with ICH Q10 Sect. 3.2.i):
Pharmaceutical companies should plan and execute a system for the
monitoring of process performance and product quality to ensure a
state of control is maintained. An effective monitoring system
provides assurance of the continued capability of processes and
controls to meet product quality and to identify areas for continual
improvement.
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CPV Strategy:
Production Monitoring Considerations
Demonstration of consistent robust production within validated
parameters
Product history and knowledge
Areas of greatest risk
Frequency of production

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CPV Strategy:
Recommendations for A-mAb drug substance
Written plan to examine data that establishes process capability and control
limits that account for normal process variability
Assumes successful PQ (PPQ & EQ)
Variables to be considered for data gathering include:

Critical Quality Attributes (CQAs)
Critical Material attributes (CMAs)
Critical Process Parameters (CPPs)
In-process controls (IPCs)
Key process parameters and key process attributes (KPPs and KPAs)
Not required to include every CQA, CPP, CMA, etc. in CPV plan, but provide
justification for what is included/not included
-- Explain why included items sufficient to meet CPV plans objectives

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CPV Strategy:
Application to A-mAb Drug Substance Process
Example Step 6, Low pH treatment for reduction of adventitious viral agents (AVA)
Variable
Class
CQAs impacted
CPV recommendation & rationale
Recommended elements to include in CPV
pH (during
inactivation)
CPP
AVA, aggregates
Include, to confirm product quality
Post-inactivation
aggregates
CQA
--
Include, to establish SPC capability
Optional elements to include in CPV (supplementary)

(Inactivation) time
CPP
AVA
Optional, to augment SPC capability
Quantity of acid
added
KPP
--
Optional, to further confirm process

consistency; linked to inactivation pH
Additional justification for including/excluding other variables (e.g., KPPs and KPAs, remaining CQAs
and CPPs) based on sufficient verification during PPQ and expectations of minimal variation
Qualitative nature of measurement may also justify exclusion

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CPV Strategy:
Scope of Data Collection and Analysis Plans
Typically starts with the PPQ batches
Informed by clinical or scale up batch data
Two phases:
Initial, Short-term: Stage III-A
Prior to Statistical Process Control (SPC)
Accumulate ~30 batches to set limits based on statistical significance
Review parameters and update risks
Long-Term: Stage III-B
Introduce SPC with rules for alerts

Continue ongoing process verification
Understand variation and trends
Identify opportunities to continuously improve process

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CPV Strategy:
Establishing Initial Control Limits
Although clinical and scale up batches indicate process
performance, they may not give statistically valid basis for
establishing control limits. PPQ batches (commercial scale)
are of course relevant here
Initial control limits must not be regarded as acceptance criteria
Once sufficient data gathered and performance of process vs.

variation in attributes / parameters understood through
correlation, control limits can be confirmed
May be possible to aggregate some data sources to establish
highly sensitive multivariate performance indicators
PLS model utilized in A-mAb for production bioreactor
High level of statistical competence required to ensure

performance indicators interpreted appropriately
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CPV Execution Plan (post-PPQ timeframe)

Tables of variables selected for CPV for each process step with:
Classification of each variable (CPP, CQA, KPP, KPA, IPC, CMA)
Data treatment prior to analysis
Unadjusted, converted for standardization, combinations/data interactions
Monitoring tool options
Run chart, Control chart, EWMA (Exponentially-Weighed Moving Average), 3SD tunnel, or by
exception (trend atypical results only)
Initial baseline monitoring (Short-term)
Series of next several batches (~30) to set long term sigma for control limits
Initial baseline control limits (Short-term)
Based on PPQ limits and other data (not acceptance criteria but alert triggers linked to control
strategy content). No long-term limits during initial period.
Periodic evaluation (time/batch-based or event-based)
Every X batches, annually, or at end of campaign; aligned to raw material lot changes, etc.
(Proposed) Lifetime control limits (Long-term)
Robust SPC ranges & PpK from baseline analysis. Avoid limit updates that mask drift or special
cause variation. Track limit history in case reset needed.
For cause evaluation (change-based)
Planned process change triggers (e.g. cell bank, modified controls)
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Sampling Management
Sample plan and frequency
Routine monitoring
Non-routine monitoring
o Baseline monitoring, time-based periodic monitoring, or special event / change based
monitoring
Other sampling
o Intermediate stability/hold time, resin reuse, cleaning verification
Specific / representative sampling location and collection

Sample container and container size
Sample volume, aliquots, and retains
o Sample labelling
o Sample storage temperature and transport conditions
Follow existing SOPs and batch records for collection
Tests to be performed (including additional samples such as reference solutions)
Testing limits or ranges of expected results

Sample Plan Matrix
Sampling/Testing Template
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Sample Plan Matrix (Attributes)
Product variant
Truncated impurity
Antifoam
Methotrexate
Affinity ligand
DNA
Potency
product conc.
HCP
Aggregates
Charge Variants
Conductivity
10 mls
<-40 C
N
Y
42
Step 4: Affinity chromatography

Load post hold period
Load flow-through
Elution pool
Strip flow thru
Step 9: UFDF
Load pool post hold period
Permeate during concentration
Retentate pool post diafiltration
Step 10: Bulk filtration and Freezing
post hold period, prior to filter
Bulk sample prior to freeze
Routine test
Retain
Non-Routine test
Stability
Reuse Lifetime Performance
Cleaning Verification
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Endotoxon
U
n
it
o
p
s
Product Quality Tests
Bioburden
Sample volume
Storage temp
Testing offsite
Testing onsite
Method SOP
pH
Retain
CQA/IPCs/KPAs
A280 conc
On-floor tests QC Micro
ROUT
RETN
NROU
STBL
LFTM
CLNV
Type of test
20
Template for Sampling and Testing (Attribute)

Process Step
Step 7: Cation Exchange Chromatography
Variable
Aggregation
Classification (Quality Attribute or Process Parameter)
Assay Method
Sample Plan
Sample Frequency
Sample location
Sampling device
Sample Collection
Sample Storage
Sample Transportation
Assay Testing
Results
Container MOC
Container Size
Sample Volume
Sample Replicates
Sample Retain
Sample Handling
Sample Labeling
Temp
Location
Transport
Who
Reference/Blank
Criteria
Options for consideration
CQA
SEC
CPP
KPP
KPA
Routine Monitoring
Baseline Monitoring
Time-based Periodic
Monitoring
Special Event or change

based monitoring
Multiple times in a batch (e.g.,

every day for bioreactor)
once per batch
every X batches
automated sample valve

no sample - on-line
instrument
automated sampling device
After eluate is well-mixed at the

eluate collection tank
manual sample valve
PP tube, sterile
10 ml
5 ml
None
None
Nothing additional
Driven by SOP
Ambient
Manufacturing
Yes (per SOP)
Manufacturing
Reference
Release specifications
2
Yes
aliquoted
in-line sensor
prepared for shipping
2-8 C
QC Lab
No
-20 C
Development lab
-70 C
Sample Control
QC Dept
Blank Solution
Control limit
Development Dept
Control
Control chart rules
External Lab
None
None
Selections highlighted (in yellow)

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Data Management
Covers data collation, entry and verification
Data aggregation in usable format--preferably single digital file
Many data sources likely manually recorded
Goal: Verify data accurately transcribed from source (batch

records, assay forms) to data storage system
Database
Double Blind Data Entry / System
Data Entry / Manual Verification
Error Proofing
Database
Errors during manual data entry are unavoidable but can be minimized
Data Storage System flags out of range /out of trend values
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Discretionary Elements of Guidance

Although fundamentals clear, several discretionary elements exist
Element
Description
Guidance text
Operational or
Performance
Elements
Process performance attributes

(i.e., bioreactor titer, column
elution volumes) or input
parameters linked to process
performance attributes..
Many products are single-source or involve complicated manufacturing

processes..Validation offers assurance that a process is reasonably protected against sources
of variability that could affect production output, cause supply problems, and negatively
affect public health.
An ongoing program to collect and analyze product and process data that relate to product
quality must be established ( 211.180(e)).The information collected should verify that the
quality attributes are being appropriately controlled throughout the process.
Multivariate
Analysis (MVA)
MVA, particularly Partial least

squares (PLS) regression or
Principal component analysis
(PCA), may be used to identify
latent variables and increase
understanding
We recommend an integrated team approach to process validation that includes expertise

from a variety of disciplines (e.g., process engineering, industrial pharmacy, analytical
chemistry, microbiology, statistics, manufacturing, and quality assurance).
Column/Resin/UF
Membrane
Cleaning and
Performance
Lifetime
Verification
Full scale verification of column

and/or ultra-filtration membrane
cleaning and performance out to
established lifetime limits
The extent to which some materials, such as column resins or molecular filtration media, can
be re-used without adversely affecting product quality can be assessed in relevant laboratory
studies. The usable lifetimes of such materials should be confirmed by an ongoing PPQ
protocol during commercial manufacture.

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4. What are the Key Learning Points?

Differences in regulatory histories of biotech companies lead to different
perspectives on response(s) to regulatory guidelines
With a common purpose, differences can be recognised & accounted for,
quickly establishing a consistent position (or else clear reasons for
divergence!)
Establishing a CPV plan is complex, requiring a team with a range of
knowledge working together to be comprehensive and deliver real results
Additional monitoring, beyond what has been previously done, can be a
value-add
Simple and cost-effective IT solutions are needed to support CPV
implementation

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Utility of the CPV Case Study

Comprehensive industry mock example to illustrate CPV
program implementation
Embedded detailed available process design and process

development information from widely available prior case study
Includes perspectives from wide cross-section of biotech
industry participants
Groundwork for further useful discussion on implementation

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Scenario 1. Supplier change notification: Culture

media manufacturing change
A supplier modified their process to manufacture a cell culture
media ingredient that may alter performance of A-mAb process,
despite lack of impact on raw material specifications. Supplier
claimed that no intentional changes to composition, test
requirements or certificate of analysis were made.
Justification for the change was provided:
(1) Improved control of temperature during blending reduces potential for
degradation of the heat labile components;
(2) Equipment cleaning will use robust validated cycles to reduce ingredient
carryover risks;
(3) Equipment is located in an Animal Origin Free area to reduce cross
contamination risks.

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Scenario 1. Supplier change notification: Culture

media manufacturing change
Strategy employed to introduce revised cell culture media:
Risk-based determination of process and quality impact for the material change
through change control process
o Outcome: Verification testing needed to assess culture performance and ability to operate
within established parameters and attributes
Small scale study completed from thaw through the production bioreactor to provide
additional process characterization data
o Outcome: Minor but statistically significant differences for key process parameter normal
operating ranges and attributes (e.g. VCC, , titer and turbidity at harvest) identified
Media qualification attributes assessed in the change control evaluation to determine

if/how these attributes may be impacted
Small scale production bioreactor material purified. No structural modifications to
protein, or shifts in CQAs observed
CPV impact: Based on small scale study outcome, DS product quality at full-scale should be
evaluated to provide further verify step performance and process control ranges by examining data
before/after change. Based on this evaluation, and associated risk assessment, changes to CPV
monitoring plan can be considered.

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Scenario 2. High Protein A leachate observed in

chromatography eluate, step 5
A PPQ batch contained 123 mg of protein A/g A-mAb in Protein A
pool, which exceeded in process control limit, but not DS release
specification, for this process-related impurity.
Investigation revealed that:
Protein A ligand released from the chromatography resin (Resin A from
Supplier A) and entered process stream during product elution. R&D and
Supplier A confirmed that elevated amounts of Protein A can leach from bead
surface during an initial elution after extended resin storage-- even when
storing under recommended conditions.
Extended storage can cause increased Protein A leaching in the next use cycle.
The resin storage time of more than 12 months between last clinical
manufacturing batch and first PPQ batch was longer than previously
experienced and was not represented in small scale trials used to establish PPQ
limits.
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Scenario 2. High Protein A leachate observed in

chromatography eluate, step 5
Strategy developed:
Risk analysis of the level measured in eluate was orders of magnitude below impurity
safety limit for final drug product.
Downstream clearance of Protein A below detectable level was demonstrated for this
batch, which is consistent with small-scale observations that subsequent
chromatography steps capable of removing leached Protein A.
Additional Design of Experiments (DOE) study conducted after PPQ to determine
potential for Protein A leaching relative to storage time, resin age (use cycles) and
storage conditions.
Spiking study confirmed downstream clearance capabilities and identified new CPPs to
control clearance which then were updated in control strategy
CPV impact
For an initial period, in-process testing of Protein A content performed to assess process
capability
Newly identified CPPs monitored for a set of 3 batches, then consider addition to plan
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Benefits vs Costs of CPV

Estimates of intangible and tangible (eg, monetary) benefits highly dependent on the
product/process scenario
Data and information gained as a result of CPV is likely to:
Raise the standard of reporting at APRs;
Lead to improvements in the manufacturing process
.Enhance transparency internally and with regulators
Costs associated with CPV vary considerably based on data retrieval system
Estimate of effort required to create one CPV report for A-mAb product
For mostly manual system, working assumptions made:
o 3 CPV reports (excluding APR)
o 20 attributes/parameters trended
o Per data set: 3 hrs to retrieve; 1 hr to create control chart; 4 hrs to analyse / investigate
Indicates about 10 additional person-weeks of effort each year (~ $50 K at $200 K/person/year)
o For 3 sites each executing 5 CPV plans, manual implementation costs ~$250k/year
A multi-site integrated data management system costing ~ $1.25 MM expected to reduce

effort by ~ 50% or $125k/year
System takes ~ 3 years to pay for itself
Shorter payback if consider costs of losing one batch (~ 1 MM)

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Outstanding Topics for Further Discussion

Type & extent of supporting justification for not initially trending certain wellcontrolled variables not subject to random variation or performance drift
Additional rationale for initial decisions on what is trended and how that monitoring
accomplished considering limited commercial-scale experience
Ability to justify exclusion of qualitative measurements
Return to initial short term control limits before setting (or re-setting) lifetime
long-term control limits after implementation of changes
Extent and application of statistics, especially for non-normal data
Use of formalized acceptance criteria or limits in an approved plan that might trigger
extensive investigations (eg, control chart rule triggers)
Decision-tree for product quality impact
Risk-based monitoring of attributes/parameters related to understanding/improving

process consistency (eg, titer, yield, intermediate stream quality measures, cycle
time, etc)
Relationship of CPV plan to ongoing PPQ protocols (eg, resin / membrane reuse)
Application of CPV to licensed products with extensive manufacturing experience
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BACKUP
Some additional background slides

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Pfizer
Covers short term

Control Limits
Covers long term

Control Limits
This is an attempt to link CPV related documents (red) with corporate (orange)
and site specific (white) documentation. It is still a work in progress.
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Industry Case Study: Continued process verification (CPV) for a biotech product
Beth Junker, Merck and Co, on behalf of BPOG
Version: 1
Date: 21 Dec 2013
Continued Process Verification (CPV) encompasses a written plan for monitoring a licensed
biopharmaceutical manufacturing process, then documenting and reporting the results. CPV reporting
provides a basis from which to improve process understanding, and hence risk assessment, control
strategy, and ultimately process improvement. This presentation describes one of the first cross-company
efforts to be compiled on CPV in response to the FDAs 2011 process validation guidance. It has been
created by representatives from 20+ biopharmaceutical companies, sharing and building knowledge, with
support and facilitation from the BioPhorum Operations Group (BPOG) (www.biophorum.com). We
describe general approaches to implementing CPV and offer some specific recommendations on the
content of a CPV Protocol, along with associated rationale. These recommendations are based on a typical
cell culture production process for making a fictitious monoclonal antibody product described in the A-Mab
Case Study. Consequently, these recommendations may not apply directly to specific products or
processes, but the principles and concepts described can be considered where applicable.
In general, the nature and extent of CPV is aligned with the outcomes of Process Qualification (PQ).
Adopting a monitoring system to reveal manufacturing trends offers the ability to acquire more data over
the products lifetime. Hence, a deeper understanding of the process is acquired, along with a foundation
for enhancements to the Control Strategy (CS). CPV execution may involve examination of process control
variables to improve methods for data tracking and analysis. Monitoring process performance provides the
opportunity to identify sources of variation and hence improve process robustness. For products that are
recently commercialized, there is unlikely to be a statistically robust set of manufacturing scale data. To
practically, manage this situation, short term control criteria are set initially based on prior process
experience including at the laboratory or clinical scales. This early period of production then is used to
establish the longer term criteria.
The implementation of CPV systems likely requires significant effort, beyond what is typically prepared for
the Annual Product Review (APR), because substantial amounts of additional data are collected and
analyzed to improve understanding of process variability. The benefits of improved process management
are expected to outweigh this additional investment. Such benefits include improved information
supporting both annual products and continuous process improvements. The frequency of data analysis
and reporting depends on several factors, including: whether production is campaigned or continuous; the
extent of variability apparent in the process; if risks to product quality (and thus product disposition) and
process consistency are sufficiently mitigated, and the intended usage of the reported data.
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Background from a-mAb Step 1:

The Quality Target Product Profile (QTPP)
QTPP describes quality characteristics (attributes) of the Product to
reproducibly deliver therapeutic benefit promised in the label
Attributes in the
red box are
tested during
Drug Substance
manufacturing.
These attributes
reflect DS CQAs
relevant for CPV
monitoring.
The Criticality
Analysis was
performed using risk
ranking approaches
(per ICH Q9).
QTPP used to establish Critical Quality Attributes (CQAs)

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Background from A-mAb Step 2:

Critical Quality Attributes (CQAs)
Claimed acceptable ranges based on prior knowledge, in-vitro studies,
non-clinical studies and clinical experience.
Attribute
Claimed Acceptable Range
Rationale for Claimed Acceptable Range
Afucosylation
2-13%
2-13% afucosylation correlates with 70-130% ADCC activity. Lower end

covered by prior knowledge; upper end covered by modeled material in
animal model.
Aggregation
0-5%
5% upper range claimed based on prior clinical experience with X-Mab.
Deamidated isoforms
None claimed; measure of consistency
NA
Galactose Content
10-40%
Range is based on a combination of prior knowledge (Y-Mab experience)

and clinical experience.
HCP
0-100 ng/mg
Sialic Acid
High Mannose
0-2%
3-10%
100 ng/mg upper limit claimed based on prior clinical experience with XMab.
In vitro studies with A-Mab.
Clinical Experience with A-Mab.
Non-Glycosylated
Heavy Chain
0-3%
Clinical Experience with A-Mab.

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Background from A-mAb:

Risk Evaluation of Process Parameters
Consistency of Terminology Addressed
Parameters divided into critical

and non-critical groups. Further
differentiation
into
a
wellcontrolled section made based
on control and capability
Terminology used from A-mAb study.

Key for each company to explain individual risk evaluation approach selected
terminology. Terminology preferably based on ICH.
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Critical and Key Process Parameters (CPPs and KPPs)
Upstream process
Process Step
WCB
CPP
KPP
none
temperature, time
Step 1: Culture
expansion in
disposables
none
temperature, culture duration, initial

VCC/ split ratio
Step 2: Culture
expansion in
fixed bioreactors
none
temperature, pH, dissolved oxygen,

culture duration, initial VCC/ split
ratio
temperature, pH, dissolved CO2,

culture, duration, osmolality, remnant
glucose
antifoam concentration, time of

nutrient feed, volume of nutrient
feed, time of glucose feed, volume
of glucose feed dissolved oxygen
none
flow rate, pressure
Step 3:
Production
culture
Step 4:
Centrifugation
and filtration

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Critical and key process

parameters established for
upstream and downstream
steps.
Used as basis for

establishing control
strategy .
38

Critical and Key Process Parameters (CPPs and KPPs)
Downstream Process
Process Step
CPP
KPP
Step 5: Protein A
Chromatography
protein Load, elution buffer, pH
end collection
Step 6: Low pH
treatment
pH, time, temperature
none
Step 7: Cation
Exchange
Chromatography
protein load, load/wash, conductivity,

elution pH, elution stop collect
none
Step 8: Anion
Exchange
Chromatography
load pH, protein load, flow rate, load

conductivity
none
Step 9: Small
virus retentive
filtration
operating pressure, filtration Volume
none
Step 10:
Ultrafiltration,
diafiltration
none
none
Step 11: Final

filtration,
freezing
none
none

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Critical and key process

parameters established for
upstream and downstream
steps.
Used as basis for

establishing control
strategy .
39

Typical commercial mAb upstream manufacturing process
Thaw Working Cell Bank
Upstream
Process:
Starting Material:
Seed
Maintenance
Seed Culture Expansion

(flasks or bags)
Seed
Maintenance
Seed Culture Expansion

(tank)
- Frozen Working Cell Bank

Seed Culture Bioreaction
(3,000L)
End of Upstream Process:

- Clarified Bulk
Nutrient
Feeds
Process Flow charts used as basis for CQA/CPP evaluation
and establishment of Control strategy prior to Product &
Process Qualification (PPQ)

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Production Bioreaction
(15,000L)
Harvest Centrifugation and
Filtration
40

Typical commercial mAb downstream manufacturing process
Protein and Affinity
Chromatography
Downstream
Process:
Starting Material:
- Clarified Bulk
Low pH Incubation
Cation Exchange
Chromatography
Anion Exchange
Chromatography
End of Downstream Process:
- A-mAb drug substance
Small Virus Retentive

Filtration
Formulation Ultra-filtration
and Diafiltration
Process Flow charts used as basis for CQA/CPP

evaluation and establishment of Control strategy
prior to PPQ
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Formulation Final filtration

and freeze
41

Development of Control Strategy (upstream)
Monitoring and control ensures that process operated in consistent and

predictable manner. Control of key process parameters and attributes also
ensures commercial success criteria (such as cycle time and yield) are met.

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42

Development of Control Strategy (downstream)
From A-Mab Case Study.

4-Feb-14
43

Industry Case Study: Continued Process Verification (CPV) For A Biotech Product

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Industry Case Study: Continued Process Verification (CPV) For A Biotech Product

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INDUSTRY CASE STUDY: CONTINUED PROCESS

VERIFICATION (CPV) FOR A BIOTECH PRODUCT

Why write this Case Study?

How has it been put together?

What does the Case Study contain?

What are the Key Learning Points?

1. Why Write a CPV Case Study?

Very few articles written by actual practitioners

Convenient & clear way to share perspectives across the industry

CPV Document Slide Pack V5.4

Concept of the Case Study

Process description and development taken from industry

Case study focuses on Drug Substance

2. How was it assembled?

CPV Document Slide Pack V5.4

3. What does the Case Study contain?

Purpose and Scope

Scope of Data Collection and Analysis Plans

CPV Execution Plan

Sampling and Data Management

Discretionary Elements of Guidance

Product and Process Description

Pre-requisites for Continued Process Verification

Covered in A-Mab Study

CPV plan (this work), covering PV stage 3 requirements, follows available

CPV Document Slide Pack V5.4

CPV Document Slide Pack V5.4

Variables to be considered for data gathering include:

CPV Document Slide Pack V5.4

CPV recommendation & rationale

Recommended elements to include in CPV

Include, to confirm product quality

Include, to establish SPC capability

Optional elements to include in CPV (supplementary)

Optional, to augment SPC capability

Optional, to further confirm process

CPV Document Slide Pack V5.4

Long-Term: Stage III-B

Introduce SPC with rules for alerts

CPV Document Slide Pack V5.4

Once sufficient data gathered and performance of process vs.

High level of statistical competence required to ensure

CPV Execution Plan (post-PPQ timeframe)

CPV Document Slide Pack V5.4

Specific / representative sampling location and collection

Testing limits or ranges of expected results

Sample Plan Matrix (Attributes)

Step 4: Affinity chromatography

Product Quality Tests

On-floor tests QC Micro

Template for Sampling and Testing (Attribute)

Options for consideration

Special Event or change

Multiple times in a batch (e.g.,

once per batch

automated sample valve

automated sampling device

After eluate is well-mixed at the

prepared for shipping

Selections highlighted (in yellow)

Goal: Verify data accurately transcribed from source (batch

Double Blind Data Entry / System