CONTINUED PROCESS

VERIFICATION: AN INDUSTRY
POSITION PAPER WITH
EXAMPLE PLAN
 SUMMARY

CPV PAPER LEADING EXECUTIVE SUMMARY

CONTRIBUTORS This paper is a response to US Food and Drug Administration (FDA) 2011 process validation
guidance on Stage 3, ‘Process Validation: General Principles and Practices’[5]. It describes the
approach commonly referred to as ‘Continued Process Verification’ (CPV). As one might expect,
The following people were lead contributors to the content of this document, writing sections, manufacturers in the biopharmaceutical sector all wish to respond to this guidance appropriately.
editing and liaising with colleagues to ensure that the messages it contains are representative A group of 20+ companies felt it would be valuable to work on this topic together, using the
of current thinking across the biopharmaceutical industry. This document is a consensus view facilitation services of the BioPhorum Operations Group (BPOG) (www.biophorum.com). This
of a model CPV Plan, but it does not represent fully, the internal policies of the contributing paper is one of the results of the collaborative effort. It is written as a consensus view of an
companies. acceptable CPV program, but it does not fully represent the internal policies of the contributing
companies. It is a basis upon which to build and share knowledge further across the industry.
Cynthia Ball (AstraZeneca), Joerg Gampfer (Baxter), John Grunkemeier (Bayer), Madeline Roche (Gallus), Lada Laenan (Genzyme), The authors believe this is one of the first comprehensive papers on this topic.
Dan Baker (GSK), Rajesh Beri (Lonza), Julia O’Neill (Merck), Abe Germansderfer (Novartis), Jeff Fleming (Pfizer), Jenny McNay
(Regeneron). The paper seeks to provide practical developments on the It encompasses a written plan for monitoring a licensed
themes: what is CPV, why is it important, and how might it biopharmaceutical manufacturing process, as well as regular
Additionally, excellent editorial support and constructive criticism was provided by: be implemented. It offers some specific recommendations on reporting and actions based on the results of monitoring
the content of a CPV Plan, along with associated rationale. the process. CPV reporting provides a basis from which to
Ranjit Deschmukh (AstraZeneca), Mark Smith (Genentech/Roche), Beth Junker (Merck), Christelle Pradines (Novartis) These recommendations are based on a typical cell culture improve process understanding, risk assessment, the control
Eric Hamann (Pfizer), Paul McCormac (Pfizer), Rajesh Ahuja (Regeneron), Bert Frohlich (Shire). production process for making a fictitious monoclonal strategy (CS) [9], and ultimately the process itself. In general,
antibody product, described in the ‘A-Mab Case Study’ [3]. the nature and extent of CPV is aligned with the outcomes
The work was facilitated by Darren Whitman and Robin Payne of the BioPhorum Operations Group (BPOG). Consequently, not all of the details contained in this paper of process qualification. Whilst a CPV Plan is likely to include
are going to apply directly to actual products or processes. data related to Batch Release (BR), and so may be useful in
Though this paper is issued under copyright, © 2014, BPOG - Biophorum Operations Group, it is intended to be readily The authors recognize that the A-Mab Case Study represents supporting BR decisions, CPV operates independently from
accessed across the industry, free of charge and can be accessed from the BioPhorum website at the following address: only one industry archetype, and that there are a number the BR process and is not expected to have any impact on
of others that are important. However, the concepts and batches that have been previously released.
www.biophorum.com/Page/123/BPOG-CPV-Case-Study.htm principles upon which the content of this paper was derived
should help with CPV implementation for a real product. Adopting or building on an existing system of monitoring
When citing this paper, please use the following form: Some of the complications of implementation are addressed, manufacturing process performance means more data will
with recommended approaches, but the issue of information be collected over the lifetime of the product. CPV execution
BPOG, 2014, Continued Process Verification: An Industry Position Paper with Example Plan, technology (IT) systems is not dealt with directly here. The may involve examination of existing process control
© 2014, BPOG - Biophorum Operations Group case for IT systems, their design and introduction, is the measurements and improved methods for data tracking
subject of other collaborative efforts facilitated by BPOG and analysis. Enhanced monitoring of process performance
and some of the results of that work may be published in provides the opportunity to identify and control sources of
the future. variation and hence improve process robustness, offering
the major benefit of reliable supply to the market.
CPV is fundamentally a formal means by which a commercial
manufacturing process is monitored to ensure product quality.

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One of the main technical issues to resolve when
implementing CPV relates to the quantity of data required
before product commercialization. In a sense, CPV
complements the ‘Quality by Design’ (QbD) framework that
manufacturers have developed to license and commercialize
the product, though a CPV Plan may be constrained to data
available in manufacturing. It should be noted that not all
products will have a QbD framework but all need a CPV Plan.
Also, at the time of commercial product introduction, there
is unlikely to be a statistically robust set of data at the scale
of commercial manufacture. To manage this situation in
practice, it is recommended that short term control criteria
are set initially, based on prior process experience and
including data acquired at the laboratory and clinical scales
of manufacture. This initial period of production would
then be used to establish longer term criteria that are more
statistically appropriate.
The implementation and ongoing execution of a CPV Plan
is likely to require additional effort, beyond what is typically
needed to prepare for the Annual Product Review (APR),
because significant amounts of additional data are collected
and analyzed to improve understanding of process variability.
However, it is likely that the benefits accruing from the
Page 4 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
improved information available for process improvement will
outweigh any additional costs. The actual additional cost
depends on the amount of data to be analysed which in turn
depends on the outcomes of quality risk assessments that
define data collection scope and frequency. The frequency
of collection depends on several factors, including: whether
production is campaigned or continuous; the extent
of variability apparent in the process; whether risks to
product quality (and thus product disposition) and process
consistency are sufficiently mitigated, and the intended
use of the reported data (for example, use in continuous
improvement may mean collecting and analyzing certain
data on a daily basis).
Given the importance of CPV in both compliance and process
improvement terms, the authors encourage executives
to read and share this paper with their colleagues. The
authors also welcome any comments or questions arising
which can be submitted via the following email address:
cpv@biophorum.com.
TABLE OF CONTENTS
1.0 PURPOSE..............................................................................................................................................................................................................................7
2.0 SCOPE .................................................................................................................................................................................................................................9
3.0 ROLES AND RESPONSIBILITIES................................................................................................................................................................................. 10
4.0 CPV PLAN REFERENCES .............................................................................................................................................................................................12
5.0 PRODUCT AND PROCESS DESCRIPTION ..............................................................................................................................................................13
5.1 BRIEF DESCRIPTION OF THE GENERAL APPROACH USED IN THE A-MAB CASE STUDY...................................................14
5.2 PARAMETERS TO BE INCLUDED IN CPV................................................................................................................................................15
5.3 UPSTREAM PROCESS OVERVIEW ...........................................................................................................................................................16
5.4 DOWNSTREAM PROCESS OVERVIEW ...................................................................................................................................................17
5.5 IDENTIFICATION OF CQAS AND ACCEPTANCE RANGES.................................................................................................................18
5.6 PROCESS PARAMETER CHARACTERIZATION .....................................................................................................................................20
5.7 CONTROL STRATEGY CQAS AND CPPS..................................................................................................................................................22
6.0 DEVELOPING A MONITORING STRATEGY ............................................................................................................................................................23
6.1 RATIONALE AND BACKGROUND............................................................................................................................................................23
6.2 HYPOTHETICAL SCENARIOS AND PLANNED PROCESS CHANGES.............................................................................................24
7.0 CPV PLAN RECOMMENDATIONS FOR THE A-MAB PROCESS .....................................................................................................................28
7.1 STEP 1, SEED CULTURE EXPANSION IN DISPOSABLE VESSELS – CPV RECOMMENDATIONS..........................................29
7.2 STEP 2, SEED CULTURE EXPANSION IN BIOREACTORS – CPV RECOMMENDATIONS.........................................................30
7.3 STEP 3, PRODUCTION CULTURE BIOREACTOR – CPV RECOMMENDATIONS......................................................................... 31
7.4 STEP 4, CLARIFICATION (CENTRIFUGATION AND DEPTH FILTRATION) – CPV RECOMMENDATIONS............................35
7.5 STEP 5, PROTEIN A CHROMATOGRAPHY – CPV RECOMMENDATIONS....................................................................................36
7.6 STEP 6, LOW PH TREATMENT – CPV RECOMMENDATIONS..........................................................................................................37
7.7 STEP 7, CATION EXCHANGE CHROMATOGRAPHY (CEX) – CPV RECOMMENDATIONS......................................................39
7.8 STEP 8, ANION EXCHANGE CHROMATOGRAPHY (AEX) – CPV RECOMMENDATIONS.......................................................40
7.9 STEP 9, SMALL VIRUS RETENTIVE FILTRATION (SVRF) – CPV RECOMMENDATIONS...........................................................42
7.10 STEP 10, ULTRAFILTRATION AND DIAFILTRATION (UF/DF) – CPV RECOMMENDATIONS...................................................43
7.11 STEP 11, FINAL FILTRATION AND FREEZING OF BDS – CPV RECOMMENDATIONS .............................................................45
7.12 BULK DRUG SUBSTANCE LOT DATA – CPV RECOMMENDATIONS.............................................................................................47
8.0 FREQUENCY AND SCOPE OF CPV ANALYSIS ......................................................................................................................................................49
8.1 SCOPE OF CPV ANALYSIS .........................................................................................................................................................................49
8.2 FREQUENCY OF ANALYSIS..........................................................................................................................................................................50
9.0 ESTABLISHING CONTROL LIMITS ........................................................................................................................................................................... 51
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 5
 SECTION 1.0

1.0 PURPOSE
10.0 EXAMPLE CPV EXECUTION PLAN FOR DRUG SUBSTANCE ...........................................................................................................................53
10.1 STEP 1, SEED CULTURE EXPANSION IN DISPOSABLE VESSELS – CPV VARIABLES...............................................................57
10.2 S TEP 2, SEED CULTURE EXPANSION IN BIOREACTORS – CPV VARIABLES................................................................................58
10.3 STEP 3, PRODUCTION CULTURE BIOREACTOR – CPV VARIABLES..............................................................................................59 This document is written with the aim of providing a technical, non-binding, industry consensus
10.4 STEP 4, CENTRIFUGATION AND DEPTH FILTRATION – CPV VARIABLES....................................................................................62 response to regulatory guidance. It is not in itself guidance. The objective of this paper is to provide:
10.5 STEP 5, PROTEIN A CHROMATOGRAPHY – CPV VARIABLES.........................................................................................................63
(1) an example of key portions of a Continued Process Verification (CPV) plan for a biologics
10.6 STEP 6, LOW PH TREATMENT – CPV VARIABLES ..............................................................................................................................64 process; (2) relevant industry thinking on CPV plan development and implementation.
10.7 STEP 7, CATION EXCHANGE CHROMATOGRAPHY – CPV VARIABLES.......................................................................................65
This document is different from others on this subject [1, 2] because it is specific to a biologics
10.8 STEP 8, ANION EXCHANGE CHROMATOGRAPHY – CPV VARIABLES........................................................................................66
manufacturing process and provides a comprehensive case-study lifecycle view that leverages
10.9 STEP 9, SMALL VIRUS RETENTIVE FILTRATION – CPV VARIABLES..............................................................................................68 antibody manufacturing process development, as described in the A-Mab Quality-by-Design
10.10 STEP 10, ULTRAFILTRATION AND DIAFILTRATION – CPV VARIABLES........................................................................................68 case study [3]. It is worth the reader being familiar with the A-Mab case study and perhaps
having a copy available for reference. It should be recognised that the monoclonal antibody
10.11 STEP 11, FINAL FILTRATION/BULK FILL AND FREEZING OF BDS – CPV VARIABLES.............................................................. 70
process is just one archetype in the industry, though it is a useful one upon which to demonstrate
10.12 CPV MONITORING OF BULK DRUG SUBSTANCE LOT DATA ......................................................................................................... 71 principles, as it is known to many.
11.0 CPV SAMPLING PLAN .................................................................................................................................................................................................73
The example of a CPV plan shown in this paper describes in process monitoring for monoclonal antibody and similar
11.1 TEMPLATE FOR SPECIFIC PROCESS STEPS ........................................................................................................................................76 how to meet expectations [5] for routine monitoring of manufacturing processes.
12.1 IDENTIFYING SOFTWARE ...........................................................................................................................................................................................80 critical process parameters (CPPs), critical quality attributes
(CQAs), key process attributes (KPAs) and key process Furthermore, this document describes the thought processes
12.2 DESCRIPTION OF TOOLS TO TREND AND EVALUATE DATA ........................................................................................................... 81 parameters (KPPs) to demonstrate the state of control over that determine the content for a CPV plan. The plan serves as
the manufacturing process. N.B. at the time of writing, the procedure governing document for the implementation
12.3 PROCESS CAPABILITY INDEX.....................................................................................................................................................................82
the European Medicines Agency (EMA) draft guidance and maintenance of CPV for a licensed manufacturing
12.4 CONTROL CHARTS.........................................................................................................................................................................................84 on Process Validation is out for consultation, referring to process. Various parts of the plan are described in the
KPAs as 'performance indicators'. The thought processes following sections of the document, as noted in Table 1.1
12.5 MULTIVARIATE DATA ANALYSIS...............................................................................................................................................................86
and examples presented in this document are backed by overleaf:
12.6 RESPONSES TO SHIFTS AND TRENDS....................................................................................................................................................87 biotech industry experience with, subject matter expertise
12.7 ESTABLISHING INITIAL LIMITS..................................................................................................................................................................88
12.8 ESTABLISHING LONG-TERM LIMITS.......................................................................................................................................................88 GENERAL TOPIC SECTION SECTION DESCRIPTION
NUMBER/
12.9 FINDING SIGNALS OF SPECIAL CAUSE VARIATION..........................................................................................................................89 TITLE

13.0 CHANGE MANAGEMENT ...........................................................................................................................................................................................90 Manufacturing Process Summary of the A-Mab manufacturing process and the A-Mab product description.
5
14.0 DATA VERIFICATION .....................................................................................................................................................................................................93
6 Selection of the process monitoring sampling plan backed by the process validation
15.0 DISCRETIONARY ELEMENTS OF A CPV PROGRAM ..........................................................................................................................................95 Phase I and II data and the updated risk assessment.

7 The rationale for classification of quality-linked process parameters summarized in

16.0 TECHNICAL REFERENCES ...........................................................................................................................................................................................96 the A-Mab case study is reviewed and summarized in the table that presents process
performance consistency and robustness. Rationale for what to include in CPV is
17.0 GLOSSARY.........................................................................................................................................................................................................................97 provided, based on a review and analysis of quality-linked process parameters from the
A-Mab case study that affect process performance, consistency and robustness.

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Table 1.1. Plan parts referenced by Section Number:
GENERAL TOPIC SECTION
Verification process
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SECTION DESCRIPTION
NUMBER/
TITLE
8 The frequency of CPV data analysis and trend review is discussed. The concept of an
initial or short-term CPV phase is introduced, where sufficient process experience
is collected to establish the manufacturing control limits for the process attributes
identified during validation. A subsequent phase of CPV implementation; that of steady
state or long-term process monitoring is also discussed.
9 Statistical and general methods for establishing CPV trend limits are presented.
10 The summary of the monitored attributes and parameters within the scope of the CPV
program are presented. The monitoring method and periodicity associated with specific
attributes and parameters are also specified.
11 The sampling plan derivation with tabulated examples.
Aspects of data analysis and evaluation of results are discussed in this section. The
12
emphasis is on the possible outcomes of routine monitoring.
Change management and the impact of CPV on this process.
13
14 The specific need for data verification.
15 Elements of CPV that are considered discretionary.
SECTION 2.0
2.0 SCOPE
Consistent with the FDA’s 2011 Process Validation guidance document [5] describing three
stages of the product lifecycle, CPV implementation discussed in this paper is limited to Stage
3, commercial manufacture of a drug substance, following process design (Stage 1) and process
qualification and qualification of the equipment and the facility (PQ, Stage 2, see FDA 2011
Guidance Stage 2 [4]) [12].
Note: Whilst this paper focuses on the drug substance manufacturing process, CPV should be applied all areas of Operations
including formulation, fill and finish.
The application of the principles discussed in this document The BPOG is initiating collaborative work, specifically focused
for new products relies on product and process development on CPV for established, licensed (or legacy) products and the
and characterization studies (Stage 1) to define the scope resulting recommendations may be published in the future.
of the CPV program. This document is based on the CS An ISPE group produced an article covering this broadened
presented in the A-Mab bioprocess development case scope in 2012 [24]; here we believe we address a reduced
study and is primarily focused on the commercialization of scope in greater detail, providing deeper development of a
a new product. However, the proposed approach for CPV model CPV Plan.
implementation is also applicable to legacy products where
quality attributes and parameters for monitoring can be
determined based on a combination of process knowledge
and historical performance data.
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 9
SECTION 3.0

3.0 ROLES AND FUNCTIONAL AREA RESPONSIBILITY

RESPONSIBILITIES
Operations / Manufacturing • Own the manufacturing process and take responsibility to ensure that it is maintained in a
Science and Technology state of control throughout the product lifecycle in manufacturing.
• Ensure that all required production and process data are collected as part of executing the
(N.B. It is not unusual for a CPV plan for the product.
Manufacturing Science and • Performs continued process monitoring activities, including collecting, entering, verifying,
Technology function to be
The roles and responsibilities suggested here as examples, are based upon a typical organizational independent of Operations
reviewing and analyzing process data.
• Generate control charts and document CPV analysis for process data.
structure of a biopharmaceutical manufacturing company (Table 3.1.). and Quality organisations. An
• Regularly participate in cross-functional teams in order to review production and QC data
alternative arrangement may be
reporting into Process Sciences.) as part of the CPV program.
Several primary functional areas have important responsibilities Outputs of the CPV program can be used by the Regulatory • Maintain the process commercial master batch production and control records up to date,
required to successfully execute the CPV program. These areas Affairs and Quality organizations for annual agency updates, capturing continuous improvements resulting from CPV in documentation as necessary.
are: Development, Validation, Operations, Quality Control, such as the Annual Product Review (APR) and Product Quality
Quality Engineering and Quality Assurance. Operations, a Review (PQR). Terminology for each function may vary by Quality Control • Perform quality control testing and document results that are used in CPV evaluations.
function which may also be known as Technical Operations, is organization. • Perform continued process monitoring activities, including collecting, entering, verifying,
assumed to contain Manufacturing as well as Manufacturing reviewing and analyzing QC data.
Science and Technology personnel. Mathematical sciences or Note: The responsibilities for continued process monitoring • Generate control charts and document CPV analysis for QC data.
non-clinical statistics support is of paramount importance in should be clearly defined within the organization and • Participate in cross-functional teams to review production and QC data as part of the CPV
achieving sound data interpretation. Each functional area recorded in the CPV Plan. Responsibilities can be tailored to a program.
has responsibility for specific activities, as shown in Table 3.1. specific organizational structure, given its maturity and size.
Quality Engineering / • Provide internal advice on statistical analyses needed to successfully complete CPV activities.
Mathematical Sciences / Non- • Act as a Subject Matter Expert (SME) and train personnel in other groups on statistical data
Clinical Statistics analysis techniques used in CPV.
Table 3.1. Roles and Responsibilities for a CPV Program: • Provide internal advice on how to develop the data collection plan and help select suitable
statistical methods and procedures that are used to measure and evaluate the process
stability and capability.
FUNCTIONAL AREA RESPONSIBILITY
• Generate procedures that define the way statistical tools and approaches are to be used in
routine process monitoring.
• Provide guidance on how to set control limits and define and interpret signal criteria.
Management • Ensure that adequate resources are available to carry out the CPV program and to regularly
perform a review of CPV plan summaries or reports.
Quality Assurance • Review and approve CPV plans and reports.
Development • Provide documentation that defines current process knowledge, quality attributes, process
parameters and elements of the overall CS that forms the basis for the CPV program. • Review and approve the list of attributes and parameters to be monitored, and control chart
• Provide documented scientific justification for parameters, limits, ranges and elements of the CS, limits.
based upon development studies or other prior knowledge. • Participate in cross-functional data review to review production and QC data as part of the
• Provide technical input to develop response actions, including input in prioritization of CPV program.
continuous improvement activities. • Review CPV reports and establish where signals require formal non-conformance
• Consider application of CPV outcomes to new processes in development. investigations.
• Coordinate assembly of CPV program reports.
Validation/ Quality functions • Provide internal advice on current validation principles and ensure that validation protocols,
interim and final reports meet applicable standards.
• Participate in cross-functional teams to review production and QC data as part of the CPV
program.
• Review the data, pursue appropriate investigations and make decisions on how to proceed.
• May generate CPV plans and summary reports.
• Review and approve CPV plan, CPV reports and any changes to the CPV plan.

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SECTION 4.0 SECTION 5.0

4.0 CPV PLAN 5.0 PRODUCT AND

REFERENCES PROCESS DESCRIPTION
The following references are expected to be created in the quality management system and are The A-Mab case study describes a model Quality by Design (QbD) approach for development of
important when constructing a CPV plan, providing background and critical internal interpretation a monoclonal antibody (A-Mab) [3, 6]. Considering the FDA process validation guideline [5],
of regulatory guidance. They should be referenced accurately in a CPV Plan document. Note, the case study includes work covered during Stage 1 (Process Design) but does not include
a CPV Plan is expected to be product and process specific. It may be advantageous to develop information on Stage 2, Process Performance Qualification (PPQ) [5].
corporate policies and this forms the basis for some of the list of references that follows.
In preparing this CPV example plan, it is assumed that Stage 2, Note: Whilst a QbD approach could be said to provide
• Quality Policy, Manual or Master Plan on CPV • Control Strategy for the process (version number) was completed successfully for the A-Mab process. The plan advantages in terms of process understanding, it is not an
• Company Standard/Guideline for CPV (requirements for • Process risk assessment (version number) described applies to Stage 3 of the process validation lifecycle. approach that has to be applied. However, it is necessary to
CPV, for e.g. timing, relationship to APRs, etc) • Applicable Risk assessment(s) (version number) have a CPV Plan for each product, even if a QbD approach has
• SOP on CPV (Definitions, Abbreviations, responses to providing basis for rationale of CPV monitoring selection not been applied.
deviations, report generation, etc) • Previous annual product report(s) if available, otherwise
• SOP on Statistical Methods for trending, statistical consider evidence for a similar product*.
analysis and identifying special cause variations
• Template for CPV Plan Technical references relevant to the detailed sections of this paper
• Template for CPV Charts & Graphs are provided in section 16. References 1 to 9 are recommended
• Template for CPV Report as initial texts when creating or updating a CPV plan.
• Manufacturing process description

* The authors recognize that the plan illustrated in this paper is written largely with CPV for new products in mind and that there
would not be APRs available at the point of product licensure. This bullet point is included as a reminder that historic APRs
would provide data for the creation of a CPV plan where established, licensed or legacy products are concerned.

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5.1
BRIEF DESCRIPTION OF THE GENERAL APPROACH USED IN THE
A-MAB CASE STUDY All types of parameters should be considered for inclusion
Principles outlined in the ICH guidelines Q8, Q9, Q10 and Q11
[7-9, 22] provide the basis for the methodology used for this
case study, even though Q11 was published after the A-Mab
case study.
One principle of a QbD approach is to develop a Target
Product Profile (TPP). As a natural extension of a TPP, a
Quality Target Product Profile (QTPP) is built to describe
quality characteristics (attributes) of the drug product.
The process of systematic development follows a general
roadmap that includes the following steps:
• Identification of Quality Attributes (QA) based on a
QTPP;
• Risk Evaluation to identify CQAs;
• Upstream/ downstream/ drug substance and product
development;
• Risk based approaches and potentially, multivariate
analyses [25] (see Section 12.5 for a description of
multivariate analysis), to classify process parameters
and other variables linked to product quality (e.g.
identification of Critical Process Parameters, CPPs);
Figure 5.1.2. Process flow of a QbD based product development according to ICH Q8, 9, 10, 11 and FDA PV guideline January 2011.
Covered in A-Map Study
Proven
Acceptable
TTP QTTP CQA CCP Ranges
(Design Space)
Development of Control Strategy
PV Stage 1
Page 14 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
• Univariate and multivariate approaches to define
Proven Acceptable Range (PARs) or limits;
• Rational approach to define a CS that reflects product/
process knowledge and risk mitigation;
• Process (and Equipment) Performance Qualification to
verify the CS established in Stage 1 of development.
• Facility design qualification of Stage 2 [5].
In creating this CPV plan it is assumed that all deliverables up
to establishment of a CS and PQ are available based on the
work described in the A-Mab study (see Figure 5.1.2 /green
boxes). For the A-Mab process, it is assumed that PPQ was
completed successfully, after investigating and resolving
deviations.
PPQ and Equipment Qualification (EQ) are part of Stage 2
and are therefore presumed to have been completed before
Stage 3 where CPV guidance applies. They are a pre-requisite
for Stage 3 CPV. See guidance for Industry [5].
PPQ CPV CPV
Short-term Long-term
EQ Plan Plan
PV Stage 2 PV Stage 3
5.2
PARAMETERS TO BE INCLUDED IN CPV
in CPV. Typically those included will be weighted more in
favor of CPPs and WC-CPPs because of their importance
to the control strategy, but non-critical “key” and general
parameters should not be overlooked if they are indicative
of process performance and/or measurably impact process
variation. Parameters to be included should be based on the
current understanding of the manufacturing process and
may be subject to change over time.
Parameter types described in A-Mab study are as follows:
(1) Critical Process Parameter (CPP) and (2) Well-
Controlled Critical Process Parameter (WC-CPP): CPPs
and WC-CPPs are process parameters whose variability
impact a critical quality attribute and should be monitored
or controlled to ensure the process achieves the required
product quality.
• A WC-CPP has a lower risk of falling outside the
specified limits.
• A CPP has a higher risk of falling outside the specified
limits.
The assessment of risk is based on a combination of factors
that include severity of impact to quality, equipment design
considerations, process control capability and complexity,
the size and reliability of the proven acceptable range and/
or design space, ability to detect/measure a parameter
deviation, etc.
(3) Key Process Parameter (KPP): An adjustable parameter
(variable) of the process that ensures operational reliability
when maintained within a narrow range. A key process
parameter does not affect critical product quality attributes
but rather impacts process consistency.
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 15
(4) General Process Parameter (GPP): An adjustable
parameter (variable) of the process that does not have
a meaningful impact on product quality or process
performance.
Typically the parameters included in CPV will be weighted
more in favor of CPP and WC-CPP because of their
importance to the control strategy. But, non-critical “key” and
general parameters should not be overlooked as they may be
indicative of process performance and/or measurably impact
process variation. Definitions of A-Mab terms used to define
categories of process parameter are provided in a Glossary at
the end of this document.
Note: Throughout this paper the A-Mab classification of
process parameters is used for consistency with the structure
of that case study, but it must be recognised this is not the
only scheme used in the industry; a situation arising in part
no standard approach is recommended by the regulators.
Consistency with ICH Q8 and Q11, where definitions exist
seems prudent. A recent informal communication by FDA/
EMA counseled against using “key parameter” for describing
lower levels of criticality in formal submissions and stated
that: ‘all parameters potentially impacting product quality
should be classified as critical process parameters’ [23]. The
use of KPPs in internal systems and documentation seems
not to contravene this statement.
In general, it is the responsibility of the biopharm company
to establish a categorization and nomenclature fitting
with their development approach and risk evaluation tools.
The company’s approach should be clearly explained and
followed over the life cycle of the product.
5.3 5.4
UPSTREAM PROCESS OVERVIEW DOWNSTREAM PROCESS OVERVIEW
The upstream commercial manufacturing process for A-Mab comprises 4 steps and is summarized below and in Figure 5.4. The downstream manufacturing process for A-Mab comprises 7 steps which are summarized in Figure 5.5.

The A-Mab cell culture process uses a proprietary, chemically defined, basal medium formulation. The medium is essentially The downstream process captures A-Mab from the clarified bulk and purifies the antibody by a combination of chromatography
protein free with recombinant human insulin (1 mg/mL) being the only protein component added. The growth medium also unit operations [11]. Also included in the process are two orthogonal steps dedicated to virus inactivation and removal. The antibody
contains 1 g/L pluronic and 50 nM methotrexate, which are added up to the N-2 seed bioreactor. The N-1 and production is formulated through an Ultra-Filtration/Dia-Filtration (UF/DF) step to a composition and concentration suitable for drug product
bioreactor steps do not contain methotrexate. manufacturing. The formulated product is 0.2 μm filtered, filled into the appropriate storage containers and stored frozen.

Figure 5.4. Upstream process flow diagram. [Adapted from A-Mab case study, Page 62 (Figure 3.1)] Figure 5.5. Downstream process flow diagram. [Adapted from A-Mab case study, Pages 113 (Figure 4.1) and 114 (Table 4.1)]

Thaw Purpose of step

Working Cell Bank
Clarified Purpose
Step 1
Seed cultures are expanded through multiple passages
Seed Seed Culture Expansion by increasing the volume and/or number of disposable • Capture monoclonal antibody from
maintenance in disposable shake flasks culture vessels. Seed cultures may be maintained for Step 5 clarified harvest liquid
and/or bags additional culture passages or used to generate Protein A Affinity Chromatography • Removal of process-related impurities
(HCP, DNA and small molecules)
additional inoculums trains.

Step 2
Additional seed expansion in fixed stirred tank • Inactivate enveloped viruses that are
Seed Step 6 potentially present in therapeutic
Seed Culture Expansion bioreactors. Cultures obtained from Step 1 are
maintenance Low pH Incubation protein products derived from
in fixed stirred tank reactors expanded to increase the volume of culture to meet the
mammalian cell culture
target initial cell density for the production bioreactor.

• Reduce aggregate to acceptable levels

for drug substance
Step 7
N-1 Seed Culture Bioreactor • Reduce HCP to acceptable levels for
Cation Exchange Chromatography
3000L WV subsequent processing by AEX
chromatography

Step 3 • Remove HCP, DNA, Protein A and

Step 8 endotoxins to levels that meet drug
Production bioreactor is inoculated with the seed Anion Exchange Chromatography substance acceptance criteria
Nutrient feed
Production Bioreactor culture prepared in Step 2 to achieve an initial Viable • Virus removal
15,000 L WV Cell Concentration (VCC) and is cultivated at
Glucose feeds controlled conditions for temperature, pH and • Removal of small parvoviruses such as
dissolved oxygen (DO). A bolus addition of nutrient Step 9 minute virus of mice (MVM) and larger
feed (NF-1) and multiple discrete glucose feeds are Small Virus Retentive Filtration viruses such as murine leukemia virus
used to maintain the glucose concentration at > 1.0 (MuLV), potentially present in product
derived from mammalian cell culture
g/L. Antifoam solution is used for foam control of
the agitated mixture. VCC, culture viability and
Step 10 • Formulation and concentration of mAb
residual glucose concentration are monitored
Formulation: to drug substance specifications (e.g.
periodically. The fermentation reaction produces a 75 g A-Mab/L)
Ultrafiltration and Diafiltration A
mixture containing the A-Mab drug substance.
Step 4
Cultures are clarified by a primary continuous Step 11 • Sterilize filtration and dispensing for
Harvest Final Filtration, Fill and Freeze drug substance storage
Centrifugation & Depth Filtration
centrifugation step using a disk-stack centrifuge to
remove the bulk of suspended cells and cell debris.
A secondary clarification using a depth filtration
system removes remnant solids and smaller debris to A-Mab drug substance
Clarified bulk provide a clarified bulk solution of A-Mab.

Page 16 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 17
 The product quality attributes and the points where they are impacted in the A-Mab drug substance process are summarized
5.5 in the Table 5.6.2 below.

IDENTIFICATION OF CQAS AND ACCEPTANCE RANGES Table 5.6.2. A-Mab drug substance Product Quality Attributes and the points where they are impacted in the process (see A-Mab
Case Study (3), Section 2.3.2, Page 29). BDS is Bulk Drug Substance, DP Drug Product and IPC in-process control.
Table 5.6.1 provides the QTPP of the A-Mab drug product, as defined in the A-Mab case study. The QTPP describes quality
characteristics (attributes) that the drug product should possess in order to reproducibly deliver the therapeutic benefit promised

non-routine
non-routine

non-routine

BDS release
step 3 IPC,
in the label. Attributes in the red box are determined during Drug Substance (DS) manufacturing. Therefore, these attributes BDS OR DP TESTING

BDS, DP

BDS, DP
BDS, DP

BDS, DP
BDS, DP
BDS, DP

BDS, DP
DP IPC

DP IPC
DP IPC
guide determination of DS CQAs [22] relevant for establishing a CPV strategy. FOR THIS CQA?

DP

DP

DP

DP
Table 5.6.1. QTPP for A-Mab (reference 3, Page 180). DS relevant product attributes are marked with a red box. STEP 11: FINAL

Remove

Remove
FILTRATION AND

Form
Alter

Alter
FREEZING

PRODUCT ATTRIBUTE TARGET

STEP 10: ULTRA-

Introduce
Introduce

entry test or prep control=

Remove
FILTRATION (UF/DF)

Form
Alter

Alter

Alter
Alter
Dosage Form Liquid, single use
Protein content per vial 500mg STEP 9: NANO-

Remove
FILTRATION (SVRF)

Form
Dose 10mg/kg
Concentration 25mg/mL
STEP 8: AEX

Introduce
Introduce
Remove

Remove
Remove
Remove

Remove

Remove
Remove
Remove

Remove
Mode of administration IV, diluted with isotonic saline or dextrose CHROMATOGRAPHY

Alter

Alter
Viscosity Acceptable for manufacturing, storage and delivery without the use of special devices (for
example, less than 10 cP at room temperature STEP 7: CEX

Introduce
Introduce

no key impact claimed=

Remove

Remove
Remove
Remove

Remove

Remove
Remove
Container 20R type 1 borosilicate glass vials, fluro-resin laminated stopper CHROMATOGRAPHY

Alter

Alter
Shelf life ≥ 2 years at 2–8°C

Inactivation
STEP 6: LOW PH

Introduce
Compatibility with manufacturing Minimum 14 days at 25°C and subsequent 2 years at 2–8°C, soluble at higher concentration

Remove
Remove
TREATMENT

Form

Alter
process during UF/DF
Biocompatibility Acceptable toleration on infusion
STEP 5: PROTEIN A

Introduce

Introduce
Introduce
Remove

Remove
Remove
Remove

Remove
Remove

Remove
Remove
Degradants and impurites Below safety threshold, or qualified CHROMATOGRAPHY

Alter

Alter

Alter
Pharmacopeial compliance Meets pharmacopoeial requirements for parental dosage forms, colorless to slightly yellow,

impacted by KPP=
practically free of visible particles and meets USP criteria for STEP 4:

Introduce
Introduce
sub-visiable particles

Remove
CENTRIFUGATION

Alter
AND CLARIFICATION
Aggregate 0–5%
Fucose conent 2–13% STEP3: PRODUCTION

Introduce

Introduce
Introduce

Introduce
Galactosylation (%G1+%G2) 10–40% BIOREACTOR

Form
Form
Form
Form
Form

Form
Form
Form

Form

Form

Form
Form
HCP 0-100 ng/mg
STEPS 1 & 2: SEED

Introduce

Introduce
Introduce

Introduce

impacted by WC-CPP=
CULTURE EXPANSION

Form

Form
Form
The DS QAs related to the QTPP are identified as summarized in Table 5.6.2. Criticality Analysis was performed using a risk
ranking approach (as in ICH Q9 [8]) and CQAs were identified as attributes of high or very high risk regarding their potential RAW MATERIAL

Introduce

Introduce

Introduce
Introduce
Introduce

Introduce
Introduce

Introduce
impact on patient safety. CONTROLS

GALACTOSYLATED GLYCANS”

NON-GLYCOSYLATED HEAVY
“GLYCOSYLATION RELATED:
PROTEIN CONCENTRATION

HOST CELL PROTEIN (HCP)

AFUCOSYLATED GLYCANS
OTHER ACIDIC VARIANTS
DEAMIDATED ISOFORMS
CLARITY & SUB-VISIBLE

SIALIC ACID CONTENT,

“OLIGOSACCHARIDES:

“ADVENTITIOUS VIRAL
MANNOSE CONTENT,
“PRODUCT QUALITY

CHARGE VARIANTS

PROTEIN A LIGAND

impacted by CPP=
SEC AGGREGATES

METHOTREXATE
SEC MONOMER

AGENTS (AVA)”
ADCC ACTIVITY

OSMOLALITY

ANTIFOAM C
ATTRIBUTES”

BIOBURDEN
ENDOTOXIN
PARTICLES
IDENTITY

CHAIN”
COLOR

DNA
PH
Page 18 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 19
 PROCESS STEP CRITICAL PROCESS IN-PROCESS CONTROLS KEY PROCESS KEY PROCESS ATTRIBUTES
5.6 PARAMETERS PARAMETERS

PROCESS PARAMETER CHARACTERIZATION Step 5: Protein Protein load ratio, Bioburden, End collection, Step yield
A Affinity Elution buffer pH Endotoxin Step duration
In reviewing the A-Mab process information while preparing the CPV plan, members of the BPOG team questioned the Chromatography
completeness of the CPPs, KPPs and Key Process Attributes (KPAs) identified in the case study. Specifically, it was felt two steps Step 6: Low pH pH, Bioburden, Quantity of acid
of the downstream process (step 10 UF/DF, and step 11 final filtration and freezing of the Bulk Drug Substance, BDS) were not Incubation Time, Endotoxin added
addressed in sufficient detail in the case study for the purpose of developing a CPV Plan, so typical characterization outcomes Temperature
for these steps were assumed and CPPs, KPPs and KPAs were identified based on that characterization [10]. In addition, two
more KPPs and KPAs were identified for process steps 3 and 7, based on typical outcomes for similar monoclonal antibody Step 7: Cation Protein load ratio, Bioburden, Step duration Step yield,
processes. The following table summarizes all CPPs, in-process quality attributes (IPQAs), KPPs and KPAs identified for the Exchange Wash conductivity, Endotoxin Eluate volume
Chromatography Elution pH,
process in preparation for CPV. Elution stop collect

Step 8: Anion Exchange Equilibration/ Wash1 Bioburden, Step duration Step yield
Table 5.7. Critical and key process parameters and key process attributes identified during process characterization. Lists were Chromatography buffer conductivity, Endotoxin
amended during planning for CPV (bold entries) Protein load ratio,
Load conductivity,
Load pH,
PROCESS STEP CRITICAL PROCESS IN-PROCESS CONTROLS KEY PROCESS KEY PROCESS ATTRIBUTES
PARAMETERS PARAMETERS
Flow rate

Step 1: Seed Culture None None Temperature, VCC (viable cell conc), Step 9: Small Virus Operating pressure, Bioburden, None Step yield
Expansion in disposable Culture duration, Culture viability Retentive Filtration Filtration volume Endotoxin
shake flasks and/ or bags Initial VCC/ split ratio

Step 2: Seed Culture None None Temperature, VCC, Step 10: Formulation: Number of Bioburden, Protein conc. prior to Step yield,
Expansion in fixed stirred pH, Dissolved oxygen, Culture viability Ultrafiltration and dia-volumes, Endotoxin Diafiltration, Permeate flow rate
tank reactors Culture duration, Diafiltraion pH, Recirculation flow
Initial VCC/ split ratio Step processing time, rate
Protein conc. prior
to fill
Step 3: Production Temperature, Bioburden, Antifoam conc., Product yield (titer),
Bioreactor 15,000L WV pH, Mycoplasma, Time of nutrient feed, Viability at harvest,
Max partial pressure of MMV and AVA Volume of nutrient feed, Turbidity at harvest, Step 11: Final None Bioburden, Filtration volume, Bulk fill step yield
CO2 (pCO2), (murine minute virus and Time of glucose feed, Peak VCC, Remnant Filtration, Fill and Freeze Endotoxin Filtration time,
Culture duration, adventitious viral agents) Volume of glucose feed, glucose concentration Maximum (inlet)
Medium Osmolality Dissolved oxygen pressure

Step 4: Harvest None None Flow rate, Pressure, Step yield,

Centrifugation & Depth Duration of clarification Turbidity
Filtration

Page 20 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 21

5.7
CONTROL STRATEGY CQAS AND CPPS
Risk-based criticality assessment, along with process
characterization studies, allows a CS to be established which
is subsequently verified during PPQ. Table 5.7 summarizes
the CS established for the A-Mab upstream and downstream
process steps for A-Mab production. The CS consists of CPPs
and WC-CPPs, KPPs, KPAs and IPQAs. The CS should ensure
required product quality and a consistent and robust process.
Here, CPPs must be controlled within limits and in-process
controls (specifically microbial and viral safety) must be
within specified ranges to ensure drug safety and efficacy.
Although KPPs and KPAs have been shown not to impact
Page 22 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
product quality, they are included in the CS because their
monitoring and control ensures that the process is operated
in a consistent and predictable manner. The control of KPPs
and KPAs also ensures that commercial success criteria such
as cycle time and yield are met.
Product quality and safety are ensured by controlling
all quality-linked process parameters (CPPs and WC-
CPPs) within the limits. Process consistency is ensured by
controlling KPPs within established limits and by monitoring
relevant process attributes.
SECTION 6.0
6.0 DEVELOPING A MONITORING
STRATEGY
6.1
RATIONALE AND BACKGROUND
CPV is a formal activity enabling the detection of variation in the manufacturing process that
might have an impact on the product quality or process consistency. CPV should evaluate whether
the process consistently delivers product with acceptable QAs and continues to operate robustly,
within the validated state. It should also identify any new sources of variability in the process
that may have arisen since the initial Stage 2 PQ was performed. For this case study it has been
determined that PPQ batches will be included in CPV data collection and analysis; indeed, all
appropriate batches should be considered. CPV efforts should, where appropriate, also focus on
areas that have proved challenging or may have shifted since the initial validation. A risk based
approach to process monitoring should be used to direct these efforts. For products with a legacy
history, a defined time period or number of batches should be set to determine how much of the
historical experience will be considered. The assessment interval chosen should be sufficient to
establish a solid production history and also reflect the frequency of production. For example
a product that is produced frequently may permit a shorter time period to be used relative to a
product that is produced infrequently.
In general, the points in the process to be monitored during be quite different to those anticipated from the early stage
CPV should be comparable to, but not necessarily include development environment.
all of those selected during the initial validation. If limited
data results are available at the time of PPQ completion, (3) The control strategy should be updated as necessary and
prior to execution of the CPV plan, a short term sampling hence the CPV Plan.
plan may be established to continue sampling based on
the PPQ protocol until sufficient data results are gathered The selection of points in the manufacturing process that are
in preparation for CPV. Additional considerations that to be monitored for CPV purposes may be either a subset of
influence the determination of which points in the process those selected during PPQ or include additional monitoring
are monitored during a CPV exercise are summarized below. points beyond those included in the initial PPQ to reflect new
learning obtained since the initial validation was conducted.
(1) The final classification of attributes should be revisited. This includes but is not limited to:
• New CS elements
(2) The process risk assessment, which is typically performed • Process elements that have proved challenging but
prior to the initial PPQ, should be revisited and updated to may not have been covered during the initial process
develop the CPV plan. The revised risk assessment should validation
reflect learning obtained during PPQ, any additional • Changed or additional analytical capabilities, including
laboratory process characterization information, and key the availability of online data collection systems and
findings from historical manufacturing experience. In improvements in assay or instrument capabilities
revisiting the process risk assessment prior to commercial • If a parameter has been shown to have good control and
manufacture, late stage clinical manufacturing knowledge consistency, it may not be necessary to continue monitoring
is particularly important. Levels of risk, and indeed the range this parameter in subsequent CPV evaluations.
of risks, that apply in the manufacturing environment might
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 23
(4) CPPs, WC-CPPs, KPPs and GPPs should be clearly specified. (6) Appropriate regulatory reporting of CPV outcomes, such • Determining process and quality impact for the Scenario 2: High Protein A leachate observed
These parameters and established release specifications, as inclusion in the Annual Product Review (APR), must be material change through the change control process in chromatography eluate, Step 5.
additional product characterization testing, and KPAs should made for any conclusions related to process assessment was electively agreed to by process experts and quality
be appropriately considered during CPV. Any changes since conducted during CPV. The CPV reports should be consistent representatives via verification testing of culture A PPQ batch contained 123 mg of protein A/g A-Mab in the
the initial validation should be explained and justified. with regulatory reporting standards, so that CPV charts may performance and the ability to operate within the Protein A pool, which exceeded the control limit for this
be copied and pasted directly into the regulatory submissions established parameters and attributes; process-related impurity. Investigation revealed that:
(5) All changes implemented should be assessed in the or included as an attachment. The regulatory submissions • A study was thus completed in the small-scale model
context of potential impact on process validation. Process then provide context and unify the information presented in from thaw through the production bioreactor to • Protein A ligand released from the chromatography resin
changes which may have occurred after the PPQ, such as the attached CPV reports. provide additional process characterization data and (‘Resin A’ from Supplier A) and entered the process stream
vendor initiated change in a raw material, should be handled establish confidence in expectations of process control during product elution. R&D and Supplier A confirmed
a change control process including but not limited to data (7) Other elements of Good Manufacturing Practice (GMP) when the new material lot is introduced into the that elevated amounts of Protein A can leach from the
trending and risk assessments, to determine if the change applicable to biopharmaceutical production operations commercial scale process; bead surface during an initial elution after extended
has any impact on process performance and/ or product are assumed to be handled by appropriate quality systems • Minor but statistically significant differences for KPPs resin storage, even when storing under recommended
quality. These changes may potentially require additional and are therefore outside the scope of this document, normal operating ranges and attributes (e.g. VCC, conditions;
testing beyond that performed as part of PPQ to ensure and will not be discussed further in the context of process and cell density, titer and turbidity at the end of the • Extended storage can cause increased Protein A leaching
full characterization. Such testing may be incorporated validation. In particular, acceptable microbial control is a bioreactor production) were identified at small scale; in the next use cycle. The resin storage time of more
as part of CPV or may be handled separately as part of the critical element for any biopharmaceutical process and is • Medium qualification attributes should be assessed in than 12 months between the last clinical manufacturing
company’s change control process, depending on the nature typically demonstrated via initial validation efforts and then the change control evaluation to determine if/ how batch and first PPQ batch was longer than previously
of the change and the potential for product impact. monitored as part of routine operations. these attributes may be impacted. The supplier was experienced and was not represented in small scale trials
requested to demonstrate if a detectable mean shift used to establish PPQ limits;
in any of their output tests could be identified with • In-process testing of the Protein A clearance will be
respect to their change. performed to further demonstrate downstream process
capability of control of this product quality attribute
Small scale production bioreactor material was purified (AEX Table 7.8, 10.8);
6.2 downstream. No structural modifications to the protein, • The level measured in the Protein A step eluate for the
or shifts in CQAs were observed. Based on the outcome of
HYPOTHETICAL SCENARIOS AND PLANNED PROCESS CHANGES the small scale studies, a comparison should be made to
batch implicated by this scenario was orders of magnitude
below the impurity safety limit for final drug product.
evaluate the product quality obtained at full scale, to verify Also, at full scale in the affected PPQ batch, downstream
Five hypothetical scenarios and planned changes are provided below to illustrate how the CPV that no unexpected quality change has occurred and to clearance of Protein A below the detectable level was
monitoring plan might be affected by events encountered during commercialization of a product provide further verification of process control ranges and demonstrated which is consistent with small-scale
such as A-Mab. In this example it is assumed that the PPQ campaign proceeded smoothly performance outcomes. observations that the subsequent chromatography steps
and that the expected results were achieved. In particular, CPPs, WC-CPPs, KPPs and GPP are are capable of removing Protein A (The possibility that
A CPV plan is expected to take account of this type of
defined and achievable and the process CS is appropriately established. The process CS is limits or controls on extended storage time, conditions,
scenario, providing the internal policies and procedures and/ or resin treatments may need to be considered if
assumed to include input raw material controls, procedural controls, process parameter controls upon which decisions related to changes in process data indicates the clearance capability of the process is
and monitoring, in-process testing, and product specification testing (see Figure 5.1.1). These verification should be based. The change described in this not sufficiently high enough for the reader’s situation).
scenarios are accounted for in the CPV plan: scenario can be addressed through the change management
system and does not require additional sampling in the CPV An additional Design of Experiments (DOE) study was
Scenario 1: Supplier change notification - (1) Improved control of temperature during blending reduces plan, as routine sampling is already in place to monitor the conducted after PPQ to determine the potential for Protein
culture medium change. potential for degradation of the heat labile components; upstream cell growth impact of this scenario (Tables 7.1, A leaching relative to storage time, resin age (use cycles) and
(2) Equipment cleaning will use robust validated cycles to 7.2, 7.3 and 10.1, 10.2, 10.3). Potential downstream impact storage conditions. Spiking study confirmation of clearance
A supplier converted to a new process to manufacture a cell reduce ingredient carryover risks; could be included in the monitoring plan, e.g. the KPAs of capabilities in the downstream process steps was achieved
culture medium ingredient that may alter its performance (3) Equipment is located in an Animal Origin Free area to inlet pressure to depth filters and duration of the broth and is discussed in the amended CS revision completed after
in the A-Mab process without impacting the material reduce cross contamination risks. clarification, which are suggested as optional items for CPV the PPQ experience, where the new CPPs to control clearance
procurement specifications. No intentional changes to in Tables 7.4, 10.4. are clearly identified. Within CPV, results will be monitored to
composition, test requirements or certificate of analysis The following strategy was employed to introduce the detect any departures from the expected behavior observed
were made. The following justification for the change was revised cell culture medium: Note: Attributes should only be considered optional after during development; monitoring tools such as ‘tool wear
provided: their impact on the process has been risk assessed and any charts’ or ‘residuals charts’ may be useful, and consultation
lack of monitoring fully justified. with a statistician is recommended. These tools are mentioned
again in Section 12.4.

Page 24 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 25
Scenario 3: High elution volume from CEX,
Step 7.
Because of resin capacity limitations, elution of the product
stream through the CEX resin requires processing a batch in
multiple portions (sub-batches). The column eluate streams
are then pooled. With one PPQ batch, an unexpected
additional volume of buffer solution was required to complete
the elution of A-Mab from the CEX column resin for one
sub-batch. The prior wash of process impurities from Cation
Exchange (CEX) Chromatography resin proceeded without
incident but there was a delay while the additional elution
buffer was prepared (during which the product loaded column
was idle) before proceeding to complete the product elution
operation to recover all the A-Mab from the resin.
• No impact on A-Mab quality was detected, which
involved a deviation for a KPA (elution buffer volume);
• The investigation did not reveal a definitive root cause.
Performance of the flow meter was not implicated as a
cause of the unusual observation from review of GPPs
and instrument calibration checks;
• Flow channeling through the resin was the initial
suspected cause, but no similar observation was made
during earlier or later PPQ sub-batches;
• Delay in starting the elution operation may have played
a role, but this could not be confirmed because it had
not been specifically studied, nor did delays after load
prior to elution occur in historical small-scale studies;
• Similar incidents have not been observed with other
A-Mab batches at any scale studied; A change in the
buffer (e.g. conductivity which is not a CPP, or pH
which is a CPP) as a result of the delay has not been
conclusively eliminated as a cause, but no deviation
associated with the buffer was apparent from careful
scrutiny of the batch record (BRc) and interview with
process operators.
Investigation of elution buffer stability data is also
suggested. If insufficient hold time and buffer attribute
data exists to determine the potential for buffer stability
to be a contributing cause, this may be pursued as an
independent study, rather than including buffer chemical
stability in the CPV Plan. Tracking of buffer volume used to
elute A-Mab from the CEX column is included in the CPV
recommendations for this step (see Tables 7.7, 10.7) because
it has demonstrated variability and there is a theoretical
potential for increased aggregates with extended processing
time (not observed in any studies as of yet) that may result
from the need for additional elution to recover A-Mab from
the CEX resin.
PAGE 26 – BPOG CONTINUED PROCESS VERIFICATION: AN INDUSTRY POSITION PAPER WITH EXAMPLE PLAN
Scenario 4: UF/DF measurements exceeded
action limits.
During preparation of one PPQ batch, the starting UF/DF
concentration measurements did not meet the PPQ control
limits and step yield was above the expected PPQ range. The
starting UF/DF concentration has not been classified as a
KPA in the A-Mab case study.
• A change prior to PPQ revised the in-process UV
absorbance (A280) test method, which led to an
apparent upward shift in yield results. While a bridging
study was conducted to determine the suitability of the
revised test method, evaluation of the change did not
consider the impact to the limits used during PPQ that
were calculated based on earlier experience. Limits in
place during PPQ were based on measurements from
the previous version of the method used for in-process
monitoring.
• Change control improved the accuracy of the
measurement and also removed a bias error when
compared to the final bulk drug substance concentration
which uses a different method performed in the QC
release testing laboratory.
• The implemented change in the test method involved
improvements to both the precision and accuracy of
the in-process measurement system; there has been no
change to the UF/DF process. Analytical SME’s decided
it would be inappropriate to compare new results to a
set of limits based on data measured using a different/
altered procedure, or simply adjust previous results for
a fixed bias correction (due to potential proportional
variance, see section 12.4).
• The corrective action being implemented will supersede
the original PPQ limits with new CPV limits calculated
using data from the revised test method procedure.
No monitoring recommendations for CPV are proposed as a
result of this scenario. Care should be taken not to include
data generated prior to the method change in calculating
long-term limits.
Scenario 5: Environmental monitoring during
Bulk Drug Substance (BDS) fill, Step 11.
During environmentally controlled open system filling
of one BDS batch, the routine sentinel plates indicated
environmental monitoring (EM) bioburden was above the
PPQ action limits. Investigation determined that:
• Based on organism identification, the likely source was
skin flora shed by an operator who conducted the final
filtration and filling of the BDS;
• The bioburden samples of each post-filtration product
container (for the PPQ) met the acceptance criteria
with results of 0 CFU/ 10 mL. This confirmed that the
0.2 μ m filtered BDS was not impacted and the routine
criteria were met for batch release (BR);
• Following the filling operation, BDS is frozen within 24
hrs, and once thawed, the material is pooled, mixed,
and sampled for bioburden prior to sterile filtration
when initiating drug product manufacturing;
• Corrective and preventive actions have been
implemented, including a review of personnel practices,
skills and training, and changes to operating procedures
to alert operators to use appropriate practices when
working in the controlled filling environment.
No additional monitoring recommendations for CPV
are proposed as a result of this scenario because, even
with this incident, no impact to the BDS was found and
corrective actions have been implemented to prevent its
recurrence. Routine monitoring is sufficient. No addition
to the enhanced monitoring plan is needed because it is
not reasonable to expect from a single incident that there
will be variability in bioburden results due to the processing
of this step. Note: Whilst attributes and parameters that
are included in a CPV Plan are likely to include some that
are relevant to BR, a CPV program is expected to operate
independently of BR processes and procedures. Analysis of
data within the CPV program is not expected to have an
impact on product that has been previously released. The
release of batches compares batch quality and performance
to a specific set of pre-determined specifications and other
measures. In contrast, the focus of CPV is to reveal trends
and sources of variation in batch quality and performance
that already fall within the predetermined criteria for BR.
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 27
SECTION 7.0

7.0 CPV PLAN 7.1

STEP 1, SEED CULTURE EXPANSION IN DISPOSABLE VESSELS –
RECOMMENDATIONS FOR THE CPV RECOMMENDATIONS
The process risk assessment established that steps 1 and 2 seed expansion steps are routinely monitored and operated

A-MAB PROCESS of the A-Mab process do not entail risk of impact to product
quality in the production bioreactor because no product is
accumulated at these stages. Specifications for raw materials,
within established limits. Therefore, monitoring of non-
critical parameters in this step such as temperature, pH, and
dissolved oxygen need not be included in the CPV plan. This
such as cell banks and media components, assure use of the is shown in Table 7.1 below.
This section describes, for each of the A-Mab process steps, what to include in the CPV plan and intended genetic cell line to produce A-Mab and control
the justification for its conclusion. This justification is primarily based on process knowledge introduction of endotoxins which could affect cell metabolism. Environmental Monitoring (EM) is routinely performed for
and process experience. A table is provided for each step to summarize the recommendations for open (under appropriate ISO classified conditions) process
CPV. Discretionary items are also included that may be needed in a CPV program depending on CPV for this step should focus on process consistency and manipulations (including use of Rodac and settling plates)
obtaining sufficient data to calculate long-term control to demonstrate microbial control and the existing QC
the assurance of process understanding or that provide additional depth to the monitoring plan.
limits (see Sections 9.0 and 10 for further discussion and laboratory program is established for reporting results and
examples of control limits, and Section 12 for information assessing trends. Therefore inclusion of this EM monitoring
No recommendation for including in-process product pool tested as routine in-process controls. The nature of test
on the statistical basis for control limits. which account plan in the CPV plan is unnecessary. As noted previously,
hold times in CPV is proposed, because the hold times were results in this case (approximately 0 cfu/ sample, and ≤
for normal process variability. As stated in the A-Mab case these systems need to connect as it would be best practice
validated as part of the basis for controls within the Master Limit of Quantification, LOQ, respectively) do not permit
study and demonstrated in the PPQ, BR procedures, SOPs, to ensure deviations are present in CPV Reports.
BRc. In the event that a hold time is exceeded this one-off meaningful Statistical Process Control (SPC) analysis in CPV.
automated process controls and use of alarms all ensure the
event would trigger a deviation within the Quality System, QC microbiology laboratory review of these results against
under which impact to product quality would be determined. action and alert limits will provide appropriate monitoring
for drift in microbial control of the process and management Table 7.1. Step 1 CPV recommendations
In the steps with elution of product from resin beds (i.e. steps of deviations, so monitoring, data analysis and any response
5 and 7), several resin loading/ elution cycles are used to to bioburden and endotoxin results are not included under VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/
IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH
process each batch. No controls have been identified for this CPV plan.
resin regeneration operations in either of these steps. For
VCC KPA – Include, to verify process Routine batch Discrete value,
these steps, concurrent validation of the resin use lifetime Note: It could be seen as best practice that the quality (each passage end) consistency documentation for each univariate
includes periodic sample testing of appropriate quality system for bioburden and endotoxin monitoring and the passage.
attributes for continued verification of packed resin CPV system are connected, so that any deviations would be OPTIONAL ELEMENTS TO INCLUDE IN CPV
effectiveness during its use lifetime. Effectiveness of resin reflected in CPV Reports.
Initial VCC/split ratio KPP – Optional, to verify process Calculation from routine Discrete value, multivariate
regeneration conditions is included in the ongoing resin use (each passage) consistency batch documentation for
validations. Therefore monitoring of CQAs for this purpose Statistical criteria that may be applied to analyses of data each passage, ratio of
need not be included in the CPV plan. Continued monitoring, are discussed in section 12. passage ending cell density
and further verification of effective process controls, should over initial cell density of
next passage.
be considered for CPV when resin use lifetime monitoring The A-Mab case study did not identify any critical raw
ceases, if further data are needed for understanding of materials or address CS or risk assessment for input material Culture duration KPP – Optional, to verify process Routine batch Discrete value,
(each passage) consistency documentation for each univariate
impurity clearance. controls. However, as a result of a hypothetical culture
passage.
No recommendation for including in-process hold times in medium change described in section 6, one monitoring
CPV is proposed because ongoing study of hold times during recommendation related to material variability is provided as Culture viability KPA – Optional, to verify process Routine batch Discrete value, multivariate
commercial manufacturing is conducted using a separate a recommendation for the CPV plan. Additional monitoring (each passage end) consistency documentation for each
hold time qualification study. of materials used in the bulk drug formulation is also passage.
included as an option.
Steps that have in-process quality attributes related to
microbial control (bioburden, endotoxin) are sampled and

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7.2 7.3
STEP 2, SEED CULTURE EXPANSION IN BIOREACTORS – STEP 3, PRODUCTION CULTURE BIOREACTOR –
CPV RECOMMENDATIONS CPV RECOMMENDATIONS
As noted in section 7.1 for step 1, cell growth is complex and it is difficult to comprehensively define or predict all sources of The process risk assessment established the BDS CQAs that timing of nutrient feed does not provide value because they
variability. Expansion culture conditions may impact cell biology which in turn can impact product quality during product may be impacted by this step. As stated in the A-Mab case are not subject to random variation. Harvest attributes of
expression. CPV for this step should focus on process consistency and obtaining sufficient data to resolve long-term control study and demonstrated in PPQ, BR procedures, other SOPs, titer, viability, and culture duration are also included for trend
limits which account for normal process variability. automated controls, and an alarm system all ensure the monitoring to verify process outcome consistency.
production step is routinely monitored and operated within
Inclusion of EM in the CPV plan is unnecessary because an existing QC program is established for reporting and trending of EM established limits for many of the related parameters. The Partial Least Squares (PLS) multivariate model generated
results. during process characterization in the A-Mab case study
Turbidity at harvest (a KPA known to vary in response to [3, Section 3.10, Page 108] [25], includes other CPPs (e.g.
Table 7.2. Step 2 CPV recommendations bioreactor culture conditions) is not included in the CPV plan dissolved oxygen, pressure, gas addition rates) and KPAs (e.g.
because of the confidence that centrifugation and depth VCC, viability), noted in Table 7.3.
VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/ filtration can accommodate variability in the harvest material
IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH (low differential pressure across depth filters). However, if The CPV plan may optionally include selected KPPs and
there is a filter change, or the medium component change KPAs to provide additional measurements of robust process
VCC KPA – Include, to verify process Routine batch Discrete value, introduced between PPQ and commercial manufacturing consistency and to obtain sufficient data to resolve long-
(each passage end) consistency documentation for each univariate
indicates a shift in other monitored variables for this step or term control limits that account for normal process
passage.
process performance of the next step, establishing control variability. Two suggested discrete KPAs, peak VCC and
OPTIONAL ELEMENTS TO INCLUDE IN CPV limits for turbidity at the end of the production bioreactor culture viability at harvest, are optional in Table 7.3 for Step
Initial VCC/ split ratio KPP – Optional, to verify process Calculation from routine Discrete value, multivariate should be added to the CPV plan. 3. Other KPAs (glucose and lactate concentrations) are also
(each passage) consistency batch documentation for included as part of the PLS model described in the A-Mab
each passage, ratio of
passage ending cell density
The CPPs for medium osmolality and culture duration are case study.
over initial cell density of included in the CPV plan. For these CPPs, a large tolerance
next passage. for variation has been shown in development during In-process quality attributes for this step, namely bioburden,
Culture duration – Optional, to verify process Routine batch Discrete value, process characterization studies. Maximum pCO2, bioreactor Murine Minute Virus (MMV), mycoplasma, and Adventitious
KPP
(each passage) consistency documentation for each univariate temperature and bioreactor pH are other identified CPPs to Viral Agents (AVA) are controlled as routine in-process
passage. be included in the CPV plan. specifications linked to drug substance BR. Their binary
Culture viability KPA – Optional, to verify process Routine batch Discrete value, Multivariate pass/ fail nature does not permit meaningful SPC trend
(each passage end) consistency documentation for each At the time this protocol is initiated, the PLS model is monitoring, and does not provide prospective warning of
passage. classified as a KPA; it is a predictor of A-Mab oligosaccharide pending batch failures. These routine control measures are
structure CQAs and acidic variants. Model input parameters sufficient for maintaining the process in its validated state
of temperature and pH, and model input attributes of titer, and deviations detected will trigger investigations for out of
VCC, and viability are separately included in the initial control situations/events.
monitoring while the bioreactor model is qualified.
Regarding the productivity of the production culture
Remnant glucose concentration is not included in the CPV step, whether to include the Antibody-Dependent Cellular
plan because it is assumed to be a fixed value CPP which Cytotoxicity (ADCC) bioassay in the CPV plan or not, is an
triggers additions of glucose feed. However, as an attribute interesting and somewhat complicated question. ADCC is
of the culture, it is measured daily and when the glucose correlated with afucosylation in vitro. Thus measurement of
concentration drops below a particular level, a discrete volume potency by ADCC is an indicator for this quality attribute that
(assumed to be a fixed KPP) of a glucose solution is added as might impact Fc effector function. However, this bioassay
a bolus to ensure the glucose concentration remains ≥ 1.0 is not qualified to test crude production bioreactor material
g/L. A fixed volume of nutrient feed is added at a defined just prior to harvest due to broth interference. Fundamentally,
time under automation and routine batch document controls, that would not prevent reliable results that correlate with
therefore trending of the KPPs nutrient feed volume and the potency of the purified material. But, confirmation of

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functional activity is relevant to the finished dosage form bioassay qualified to enable collection of biological activity Table 7.3. Step 3 CPV recommendations
since it is the drug product that is provided to the patient. data related to ADCC functions, as a means to assess Fc-
So, monitoring of bioreactor harvest for potency is not oligosaccharide structure-function relationships. VARIABLE CLASS CQAS IMPACTED CPV RECOMMENDATION DETERMINATION TYPE OF DATA EXPECTED/
& JUSTIFICATION METHOD AND/OR ANALYTICAL APPROACH
recommended since ADCC activity has a drug product release SOURCE
specification for CPV trending and is a stability indicating CPV trend monitoring of afucosylated and galactosylated
assay included in routine stability testing protocols [derived glycans in the bioreactor for step 3 is recommended to Culture duration CPP Aggregates, Include, to establish Routine batch Discrete value,
from A-Mab case study section 6.4.2, Page 247]. build confidence in process consistency (see Table 7.12, glycosylated glycans, SPC capability and large documentation univariate
10.12). Note that sialylation, high mannose content (also HCP, DNA; can also tolerance for variation
impact turbidity at
The CS categorized the antifoam ingredient to be a critical afucosylated) and non-glycosylated heavy chain were also harvest, yield variation
raw material (CRM), probably because it is a process residual determined to be CQAs but recommended only as optional
Maximum CPP Glycosylated glycans, Include, to establish SPC Routine batch Discrete value,
CQA. However, there is no particular critical material elements to include in CPV monitoring (see Table 7.12,
(dissolved) pCO2 deamidated isoforms; capability and correlate documentation univariate
attribute (CMA) that requires enhanced monitoring. The 10.12). The frequency of lifecycle monitoring of glycans will also product yield with in-vitro cell age
addition of antifoam varies as needed up to a maximum 100 be reviewed and adjusted based on trends. Characterization (IVCA)
mg/L concentration (section 5). As a single antifoam lot is of the oligosaccharide profile will be conducted to confirm (Bioreactor) Glycosylated glycans, Include, to demonstrate Routine batch Continuous datastream,
CPP
used for multiple bioreactor batches, lot change points in comparability when needed to support process changes temperature deamidated isoforms appropriate range is documentation univariate
the batch genealogy will be traceable to correlate with any [derived from A-Mab case study section 6.4.5, Page 250 and established
process shifts in trends for this step, the clarification step, or section 6.6.1, Page 251-253]. (Bioreactor) pH Glycosylated glycans, Include, to demonstrate Routine batch Continuous datastream,
CPP
the Protein A chromatography step (steps 3, 4 and 5 in the deamidated isoforms that appropriate documentation univariate
process). Because only one lot of antifoam was introduced The mechanism and conditions conducive to formation of monitoring and
in the PPQ, three BDS batches during the initial CPV period, deamidated isoforms are widely known and well understood. automated adjustments
are established
which employ different antifoam lots in the upstream This knowledge, in conjunction with the level of risk
process, are tested to provide evidence of robust clearance associated with the quality attribute in the post-PPQ risk Afucosylated CQA – Include, to verify Will require non-routine Discrete value,
glycans process consistency test, record results in univariate
of the process residual. Due to the low turnover in antifoam assessment, negates the need for in-process CPV testing. Laboratory Information
lots, routine but periodic batches being tested for stability Process control includes testing with a routine CEX HPLC Management System
may also be selected for this extra testing in BDS, i.e. at ‘time method at lot release, of both drug substance and drug (LIMS)
zero’. This does not suggest that clearance of antifoam is a product, to confirm the identity of A-Mab, monitor charge Galactosylated – Include, to verify Will require non-routine Discrete value,
CQA
stability indicating attribute. heterogeneity and detect shifts in deamidated isoforms glycans process consistency test, record results in univariate
[derived from A-Mab case study section 6.6.4, Page 259]. LIMS
The oligosaccharide profile (a CQA) is solely influenced by the The method separates the main charged isoforms of A-Mab PLS model KPA Isoforms, variants, DNA, Include, to verify Routine batch Continuous datastream,
production bioreactor. Input material and procedural controls that are considered to be product-related substances as employing pH, monomer, aggregates, process consistency documentation multivariate
are in place to ensure the quality of raw materials and the defined in ICH Q6B. The resulting chromatographic profile is DO, temperature, HCP oligosaccharides
pressure, gas
cell line. Control of step 3 CPPs (temperature, pH, dissolved specific to A-Mab and unambiguously distinguishes it from
rates, weight, VCC,
carbon dioxide, culture duration, and medium osmolarity) other monoclonal antibodies. The spectrum of isoforms viability, titer,
within their limits ensures consistent glycosylation. No contained in the reference chromatogram for A-Mab glucose, lactate
process clearance or further glycan modification occurs in represents acidic and basic isoforms. The chromatogram is Product yield (titer – Include, to verify QC ELISA results in LIMS Discrete value,
KPA
downstream processing, and the oligosaccharide profile is inspected to ensure a consistent profile with the reference at harvest) process consistency univariate
not regarded as stability indicating. Routine testing is not standard and the absence of any new peaks. A quantitative
part of the drug substance lot release specification based definition of new peaks is included in the CEX test method.
on the development process design history, process risk Charged isoforms of A-Mab do not increase when stored
assesments, CS, and PPQ. The risk that exists is that no process at recommended conditions; therefore, the attribute is not
clearance or further modification is expected in downstream monitored on stability [derived from A-Mab case study
processing. An oligosaccharide profiling method utilizing section 6.4.2, Page 247].
Capillary Electrophoresis-Laser Induced Fluorescence (CE-
LIF) was developed and qualified for characterization of the The KPA of titer (yield) is included in CPV for trend monitoring
oligosaccharide profile. There is also an in vitro cell-based for process consistency.

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 VARIABLE CLASS CQAS IMPACTED CPV RECOMMENDATION DETERMINATION TYPE OF DATA EXPECTED/ 7.4
& JUSTIFICATION METHOD AND/OR ANALYTICAL APPROACH
SOURCE
STEP 4, CLARIFICATION (CENTRIFUGATION AND DEPTH FILTRATION)
OPTIONAL ELEMENTS TO INCLUDE IN CPV – CPV RECOMMENDATIONS
Antifoam lot CMA Residual Include, to track Routine batch Qualitative text/
antifoam C lot changes. Test document genealogy label, univariate The process risk assessment established that the clarification Evaluation of a change in the manufacturing method of the
clearance at BDS for step is unlikely to impact product quality. Monitoring culture medium used upstream (see Section 6, Scenario 1)
3 different lots for CPV is limited to process consistency for the purpose could include additional monitoring of downstream KPAs
of examining data to establish long-term control limits of inlet pressure to depth filters and duration of the broth
(Medium) CPP Glycosylated glycans, Include; large Routine batch Discrete value,
that account for normal process variability (per statistical clarification, which are noted in the Table 7.4 as optional
osmolality deamidated isoforms tolerance for variation documentation univariate
confidence criteria stated in section 12). Therefore, the KPA items for CPV. The small scale model evaluation of new
has been shown.
of yield is included in CPV for trend monitoring as a process lots of the medium material showed that product quality
Monitor by exception
performance indicator. One KPA, turbidity of filtrate, is also attributes of Host Cell Protein (HCP), DNA, and product
a
recommended to confirm process consistency following the structural characteristics are not impacted, so monitoring
Mannose content CQA – Optional, to verify Will require non- Discrete value, culture medium change (see section 6.2, scenario 1). of these KPAs is not included in the CPV recommendations.
process consistency routine test, record univariate The decisions not to include these KPAs in CPV could be re-
results in LIMS The PPQ demonstrated that BR procedures, SOPs, automated examined pending the results of the change management
Sialic acid CQA – Optional, to verify Will require non- Discrete value, process controls and alarming ensure the centrifuge and evaluation of the culture medium change.
content process consistency routine test, record univariate filtration step are routinely monitored and operate within
results in LIMS established limits. Temperature, centrifuge feed rate
Non-glycosylated – Optional, to verify Will require non- Discrete value, and rpm, and filter flow rate are not CPPs and are tightly
CQA
heavy chain process consistency routine test, record univariate controlled engineering or fixed design parameters that are
results in LIMS not subject to random variation and therefore do not merit
inclusion in CPV.
Time of glucose KPP – Optional, to verify Routine batch Discrete value,
feeds (hrs since process consistency documentation univariate Table 7.4. Step 4 CPV recommendations
inoculation)
VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/
Peak VCC KPA – Optional, to verify Routine batch Discrete value, IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH
process consistency documentation univariate
(Culture) viability – Optional, to verify Routine batch Discrete value, Turbidity KPA – Include, to confirm process Non-routine testing Discrete value, univariate
KPA
(of filtrate) consistency following needed
at harvest process consistency documentation multivariate medium change
a: The term “monitor by exception” means that reported data outside of established alert or action limits will be reported Step yield – Include, to verify process QC ELISA test results in Discrete value, univariate
KPP
as incident(s); for CPV, a review of reported incidents will examine the occurrence of any events outside of established (product in filtrate) consistency LIMS
limits and determine the collective impact of these events. OPTIONAL ELEMENTS TO INCLUDE IN CPV

Duration of broth KPP – Optional, to confirm Routine batch Discrete value, univariate
clarification process consistency documentation, elapsed
following medium change time from start of harvest
(opening of bioreactor
bottom valve) to end of
filtration (closing or filtrate
vessel inlet valve)
Inlet Pressure to filters KPP – Optional, to confirm Routine batch Continuous datastream or
process consistency documentation discrete value, univariate
following medium change

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 Table 7.5. Step 5 CPV recommendations

VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/
7.5 IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH

STEP 5, PROTEIN A CHROMATOGRAPHY – Protein load (ratio)

(in HCP model), each
CPP HCP, DNA,
process
Include, to establish SPC
capability
Routine batch
documentation, calculated
Discrete value, multivariate

CPV RECOMMENDATIONS sub-batch impurities using packed resin volume

The process risk assessment established that protein A
purification may impact product quality (aggregate; charge
variants; leached Protein A; clearance of HCP, DNA, and
methotrexate) and links to performance of chromatography
steps 7 and 8 (CEX and AEX). Platform and prior process
knowledge negate the need for specific process studies
except as noted below for HCP and leached Protein A.
CPV for step 5 (the first of the downstream DS process steps)
should focus on process consistency to obtain sufficient
data to establish long-term control limits that account
for normal process variability (see section 12 for statistical
confidence criteria). Variables recommended for inclusion
in the CPV plan are shown in the Table 7.5 below, including
CPPs identified for this step (protein load ratio and elution
buffer pH). Elution buffer pH is closely controlled by batch
procedure and buffer is not released for use if pH is out of
range. This variable is included in the CPV plan to monitor
the extent of buffer pH variability incorporated in the HCP
model prediction. Step duration, a KPP, is included in the
CPV recommendations to establish capability on processing
time for this step.
The key process attribute of yield is included in the
CPV recommendations for trend monitoring of process
consistency.
CPV need not include monitoring of flow rate through
the resin, nor the end collection point (column volume or
A280 absorbance) for the eluate because the PPQ verified
the expected control and minimal variation for these key
parameters. Operating temperature and other GPPs were
shown in characterization studies to not impact product Elution buffer pH (in CPP HCP, DNA, Include, to verify process Routine batch Discrete value, univariate
HCP model) process consistency documentation
quality or process consistency when controlled within easily impurities
achieved design ranges. The automated continuous process
Residual Protein A in CQA Protein A Include, to establish SPC Non-routine testing Discrete value, univariate
controls and alarm system, as well as BR sequencing and eluate pool capability needed, results recorded
SOPs, ensure the step is routinely monitored and operated in LIMIS
within its established limits.
Step duration KPP – Include, to verify that Routine batch Discrete value, univariate
process can capably control documentation, elapsed
A linkage model study was proposed in the A-Mab case
this CQA time from closing of
study to examine HCP levels at different points within the vessel inlet valve to eluate
process (after each chromatography step – steps 5, 7 and pooling is completed
8). This is included in the CPV plan and involves non-routine Step yield Include, to confirm process Routine batch Discrete value, multivariate
KPA
analysis to provide data on measured HCP levels at the final consistency documentation, calculation likely to exhibit normal
point in the process covered by the multivariate model (after using in-process A280 test distribution
AEX chromatography, step 8) against the predicted outcome. result
Storage of the Protein A resin (section 6, scenario 2) is
expected to potentially introduce a variable amount of 7.6
leached Protein A into the product stream. This will be
monitored via residual protein A (leached from the resin) STEP 6, LOW PH TREATMENT – CPV RECOMMENDATIONS
testing and trending of the results to establish process
capability for controlling this CQA. The process risk assessment established that the low pH susceptible to variation within their PARs. One additional
treatment step for viral inactivation impacts two product test, for aggregates, is also recommended for CPV to establish
Process control deviations for this step should evaluate the CQAs (aggregate and viral inactivation). There is no claim process capability for this CQA.
case-by-case potential impact on these attributes (and viral for removal of process related impurities (HCP, DNA,
clearance), as process streams continue further downstream methotrexate or leached Protein A) but some incidental CPV need not include inactivation temperature and agitation
for purification. For deviation investigations, it may be reduction in these impurities may be achieved in this mixing because PPQ verified the expected control and
appropriate to review the risk assessment justification for any step, which includes precipitation and downstream filter minimal variation for these key parameters. BR sequencing,
low risk CPPs. Note that the process has high Impurity Safety clearance. In general, CPV for this step should focus on automated process controls and the alarm system will
Factor (ISF) (for a definition, see A-Mab Case Study [3] Section obtaining sufficient data to resolve long-term control limits ensure the step is routinely monitored and operated within
4.10.3, Page 167) clearance (>5x104) for all process related related to viral inactivation, so CPPs for inactivation time its established limits for these parameters.
impurities for normal processing. and pH should be included in CPV. The viral safety risk
CQA (inactivation of particular AVA) for the A-Mab process The limit for maximum protein concentration in the Protein
has been validated in the small scale model during stage A pool is bound by the pH inactivation step requirements, but
1 process validation. Inactivation time and pH are readily trending of the protein concentration is not recommended
controlled within desired limits for the process as shown by as the information will provide little benefit in process
PPQ. However, inclusion of both these parameters in CPV understanding. However, a related optional inclusion for
is recommended, because they are manually controlled and CPV is to trend the amount of acid added, to ensure the

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A-Mab process does not drift or shift toward the edge of and variability around the expected 100% has been associated 7.7
the qualified conditions of the platform process without this with measurement uncertainty rather than process variability,
being recognised. therefore it does not merit CPV trending or monitoring. The STEP 7, CATION EXCHANGE CHROMATOGRAPHY (CEX) –
Step yield is not included as a CPV recommendation because
basis for yield for the next step (7, CEX) begins from the eluate
pool of the previous step (5, Protein A).
CPV RECOMMENDATIONS
yield is not expected to be impacted at this point in the process
The process risk assessment established that the CEX step key parameters. BR sequencing, automated process controls,
primarily impacts two product CQAs, aggregate and residual and the alarm system will ensure the step is routinely
Table 7.6. Step 6 CPV recommendations
HCP. Characterization studies showed that DNA and protein monitored and operated within its established limits for the
VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/ A clearance were not impacted by this step, and there is independent parameters. Development studies concluded a
IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH
no claim of viral clearance for this step. Trending of CPPs wide operating temperature range had no impact on product
identified as potentially impacting these CQAs are included quality or performance/ process consistency, so monitoring
pH (during CPP AVA, Include, to confirm process Routine batch Continuous datastream,
inactivation) aggregates consistency documentation, integrated univariate
as recommendations for CPV. of temperature beyond that routinely done for each batch is
average of online pH values not included in CPV recommendations.
during inactivation time CQAs for HCP (as supporting evidence for the linkage model
Post-inactivation – Include, to establish SPC Non-routine testing Discrete, multivariate prediction) and aggregate are included in CPV to establish CEX eluate volume (each sub-batch) is included in CPV to
CQA
aggregates capability needed, results recorded process capability, and the KPA of yield is included in CPV for determine a higher confidence range of the normal variation
in LIMS trend monitoring as a process performance indicator. due to the special cause event that occurred during PPQ (see
OPTIONAL ELEMENTS TO INCLUDE IN CPV section 6.2). Data obtained will be used to show process
Univariate monitoring is not required for flow rate through consistency with respect to this parameter.
(Inactivation) time CPP AVA Optional, to establish SPC Routine batch Discrete value, univariate
capability documentation, calculate the resin, elution buffer pH, load buffer pH, wash buffer pH,
from completion of re-equilibration buffer pH, eluate volume, nor the starting or The basis for yield for this step begins from the step 5 eluate
acid addition to start of end collection point (A280/A320) for the eluate because PPQ pool.
titration verified the expected control and minimal variation for these
Quantity of acid added KPP – Optional, to establish SPC Routine batch Discrete value, univariate
capability documentation, change in
supply vessel weight
Table 7.7. Step 7 CPV recommendations

VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/
IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH

Protein load (ratio) (in CPP Aggre- Include, to establish SPC Routine batch documen- Discrete value, multivariate
HCP model) gates, HCP capability tation, calculation using
packed resin volume
Wash conductivity (in CPP HCP Include, to confirm process Routine batch documenta- Discrete value, univariate
HCP model) consistency tion
Elution pH CPP HCP, DNA, Include, to confirm process Routine batch documenta- Continuous datastream,
Protein A, consistency tion univariate
aggregates
Aggregates in CEX CQA – Include, to verify process Will require non-routine Discrete value, multivariate
eluate pool performance in-process test, results
recorded in LIMS

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 VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/ Table 7.8. Step 8 CPV recommendations
IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH
VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/
IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH
HCP content in CEX CQA – Include, to verify process Will require non-routine Discrete value, univariate
eluate pool performance in-process test, record
Protein load (ratio) CPP HCP, viral Include, to establish SPC Routine batch Discrete value, univariate
results in LIMS
clearance capability documentation, calculation
CEX Eluate volume KPA – Include, to confirm process Routine batch Discrete value, univariate using packed resin volume
(each sub-batch) consistency documentation
Load conductivity CPP Viral Include, to confirm process Routine sample and test Discrete value, univariate
Step yield KPA – Include, to confirm SPC Routine batch document Discrete value, multivariate clearance consistency for buffer use
capability calculation using field
Load pH (in HCP CPP HCP, viral Include, to confirm process Routine batch Discrete value, univariate
A280 test result
model) clearance consistency documentation, sample
OPTIONAL ELEMENTS TO INCLUDE IN CPV test
Step duration KPP – Optional, to confirm SPC Routine batch Discrete value, Equilibrium/ Wash 1 CPP HCP, viral Include, to verify process Routine sample and test Discrete value, multivariate
capability documentation; elapsed univariate buffer conductivity (in clearance performance for buffer use
time from end of step 6 HCP model)
(vessel inlet valve closes) Linkage model output – Include as outcome of Calculated from six variable Discrete value, multivariate
KPA
for HCP content in HCP linkage model, to terms logged in batch
AEX eluate (predicted) demonstrate understanding documents for step 5,7,8
of HCP clearance through
7.8 multiple processing steps

STEP 8, ANION EXCHANGE CHROMATOGRAPHY (AEX) – HCP content in AEX

eluate (measured)
CQA – Verify model of HCP
clearance through multiple
Non-routine test, results
recorded in LIMS
Discrete value, univariate

CPV RECOMMENDATIONS Residual Protein A in –

processing steps
Include, to confirm process Will require non-routine Discrete value, univariate
CQA
eluate consistency in-process test, record
The process risk assessment established that the AEX step Monitoring of step duration (a KPP) is suggested as
results in LIMS
impacts several CQAs (viral clearance, aggregate, endotoxin, an optional inclusion for measuring process capability.
and clearance of protein A, charge variants, HCP, DNA, Inclusion of other process parameters including flow rate Step yield KPA – Include, to confirm SPC Routine batch document Discrete value, multivariate
capability calculation using field
and methotrexate). Trending of three CPPs identified (a CPP) and KPPs such as starting or end collection UV for A280 test result
as potentially impacting these CQAs (protein load ratio, the eluate, or pH of the prepared equilibration/wash 1 buffer
OPTIONAL ELEMENTS TO INCLUDE IN CPV
equilibration buffer conductivity and load pH) are included are not suggested because PPQ verified the expected control
as recommendations for CPV. and minimal variation for these parameters. BR sequencing, Step duration KPP – Optional, to confirm SPC Routine batch Discrete value, univariate
automated process controls, and the alarm system will capability documentation; elapsed
time from end of step 7
Monitoring of other CQAs impacted by this step is not ensure the step is routinely monitored and operated within (vessel inlet valve closes)
recommended because trending for HCP and Protein A are its established limits for these independent parameters. until product elution
sufficient to represent the performance and establish the Development studies concluded that a wide protein completed in step 8
capability of this step. Since the step 5, 7, 8 linkage model concentration range had no impact on product quality or
(see Section 12) is for predicting an impurity CQA (residual performance/process consistency, so trending of protein
HCP), the output of the model is classified as a KPA, and is concentration is also not included in CPV recommendations.
also included for monitoring against CPV control limits (not
BR acceptance criteria). Monitoring of step yield will serve as an indicator of any drift
in process control for this step.

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7.9 7.10
STEP 9, SMALL VIRUS RETENTIVE FILTRATION (SVRF) – STEP 10, ULTRAFILTRATION AND DIAFILTRATION (UF/DF) –
CPV RECOMMENDATIONS CPV RECOMMENDATIONS
SVRF is a physical size separation step that is critical for Verification of the filter integrity testing was included in The A-Mab case study does not provide sufficient detail to concentration and dia-volumes (affects osmolality), the
viral clearance. Filter function is confirmed after each batch PPQ and will be included upon completion of the filtration trace CPV rationale back to a CS, risk assessment, or process potential formation of aggregate (from lengthy processing
by standardized integrity testing. Introduction of leachate of every process batch. Re-filtration has also been validated development for this step. Therefore, six well known process time and/or incorrect pH), and because process validation
from the filter is minimized by a routine pre-use rinse of the and details are registered in regulatory licenses. Detectable parameters typical for the operations of a UF/DF step are has not yet provided sufficient data to demonstrate process
filter with a validated quantity of AEX elution buffer. impact of re-filtration is a decrease in the measured protein considered for CPV: capability for these parameters.
concentration due to dilution by a hold-up recovery flush
Operating pressure is a WC-CPP recommended for after filtration to optimize step yield. Incidents of failed • Trans-Membrane Pressure (TMP); It is assumed that a risk assessment established that the
including in the CPV plan. Some variation in pressure has filter integrity and/ or when re-filtration is performed are • Temperature of the product containing stream; UF/DF step has potential to affect various product quality
been observed; trending of pressure data will increase tracked with the change control system as incidents and are • Permeate and recirculation flow rates; attributes. Variation in protein concentration prior to
predictability and confidence in knowledge of the natural trended as part of Annual Product Review, so will not be • Number of dia-volumes to complete the buffer BDS freeze and fill (step 11, post-filtration) may affect
variation and what, if any, impact this variation may have included in CPV. exchange; downstream drug product manufacturing controls/
on process consistency. Correlation of operating pressure • Product concentration (prior to and after buffer capability, so trending of this CQA is included in CPV
with filtration volume (the other CPP to be monitored) and Step yield is not included as a CPV recommendation because exchange); recommendations. These data will also provide evidence for
protein concentration will also ensure consistent viral Log yield is not expected to be impacted by this step. Yield after • Step processing time. any correlation with other variables (e.g. dia-volumes needed
Reduction Value (LRV) and serve as a basis for future process step 10 will include step 9. for buffer exchange). Optionally, CPV may include selected
improvements/change controls. Small-scale studies have Platform knowledge was leveraged to define an initial product CQAs, chosen because of knowledge that they may
shown that the likely variation in these parameters does not Rinse or processing flow rate through the filter and the membrane life limit controlled via batch documentation reveal the impact of variability in the process or provide
represent a BR risk for product safety or quality. Including flush volume used are not recommended for inclusion in and equipment logbooks. A specific membrane lifetime useful information about process capability. The product
filtration load volume in CPV provides an alternate measure CPV, because PPQ demonstrated tight control and minimal monitoring protocol is expected to be in place alongside the solution identity, composition, and aggregation could be
of process consistency, given its impact on processing time variation of these KPPs. Although these variables are CPV plan, to verify filter performance. altered by either post-diafiltration pH or osmolality (or by
for this step. manually controlled, the BR instructions and sequence will a trace contaminant in compendial grade raw material), so
ensure the step is routinely monitored and operated within Flow rates are response variables that automatically adjust inclusion of these CQAs should be considered for CPV. The
its established limits. to maintain a fixed TMP set point (pressure controlled A-Mab case study CS established that impurity clearance
operation). Because flow rate profiles tend to vary over capability for residual methotrexate is very high and does
Table 7.9. Step 9 CPV recommendations the re-use lifetime of the membranes, an optional choice not require further verification. The genealogy link between
for CPV includes monitoring of permeate and recirculation the culture media used in the upstream process batches
VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/
IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH flow rates via a trajectory profile of the continuous dynamic (impurity clearance of antifoam and methotrexate) and the
data. Reference standard profiles (3SD tunnels, i.e. control UF/DF membrane lot will be logged in the enterprise resource
Operating (inlet) CPP Viral Include, to confirm process From online data Continuous datastream, charts with + 3 standard deviation acceptability limits) will planning system for use in investigations.
pressure clearance consistency acquisition, plot results univariate be shown for comparison (sourced from the initial use cycles
with range of acceptable
for the membrane and from the PPQ batches). Protein concentration prior to diafiltration is suggested as
standard profiles. Correlate
these data with filtration an option for inclusion in CPV, to provide data linking this
volume and protein It is assumed that PPQ demonstrated that BR procedures, in-process CQA measure to the final protein concentration
concentration. automated process controls, and alarming ensure the UF/DF at completion of this step. Another suggested option is to
Filtration (load) Viral Include, to confirm process Routine batch Discrete value, univariate step is routinely monitored and operated within established trend aggregates in the final retentate with the intent of
CPP
volume clearance consistency documentation, vessel limits characterized in small scale development DOE studies. providing additional data to trend this step for ability to
weight change from pre- Therefore temperature and TMP are dismissed as non-CPPs control formation of this process-related impurity.
rinse tare to filled weight and are not recommended for inclusion in CPV.
Diafiltration and final formulation buffer ingredients are
The number of dia-volumes needed to complete the buffer excipients of the drug product and therefore are critical
exchange, pH of the AEX eluate solution to be processed in raw materials. Supplier quality management includes
this step, and UF/DF processing time are additional CPPs to specifications for material purity, content of particular
include in CPV, because of their potential impact on product elemental impurities, and endotoxin from inspection of

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Certificate of Assay (CoA) summaries and/or in-house The key process attribute of yield is included in CPV for trend
verification testing. Reserve samples and CoA summaries for monitoring as a process performance indicator.
7.11
each excipient lot are preserved until drug product expiration
to enable investigations as needed. Although not specifically Normalized Water Permeability (NWP) and average filtrate
STEP 11, FINAL FILTRATION AND FREEZING OF BDS –
identified here, an un-named Critical Material Attribute flux are monitored and verified by a membrane lifetime CPV RECOMMENDATIONS
(CMA) for ‘excipient 1’ may require characterization of the protocol and new membrane installation SOP. Sampling for
Final filtration performed while filling sterile containers Although it is not a CPP, maximum inlet pressure (filter
variability of ‘attribute A’ during CPV as a risk mitigation lifetime monitoring, verification, and potentially extension
provides assurance of microbial control of the drug pressure) is known to exhibit product specific batch variation
action for the CS, so this has been included as an option of the number of reuses is managed under this separate
substance intermediate, but is otherwise unlikely to impact from platform process knowledge and so is suggested as
for CPV. protocol and is therefore not considered here for CPV.
product quality. No provisions are assumed for a validated an optional inclusion in CPV. Filtration volume is another
re-filtration option. Filter function is confirmed after each KPP that would be a reasonable optional choice for CPV,
batch by standardized filter integrity testing. Introduction providing a different measure for assessing processing
of filter leachates are minimized by process design and capability. Correlation of filter pressure with filtration
Table 7.10. Step 10 CPV Recommendations leachable studies, which include a pre-use rinse of the filter volume, protein concentration, and filtration time are other
with a qualified fixed amount of final formulation buffer. optional considerations that could be included in the CPV
VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/ plan, to characterize normal performance and variation for
IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH
The KPA of yield was chosen for monitoring this step in the A-Mab process for future predictability.
CPV, because trend monitoring of yield will provide a good
UF/DF processing time CPP Aggregates Include, to verify process Routine batch Discrete, univariate
capability documentation, elapsed process performance indicator.
time from UF start until
defined UF end
Number of dia- CPP Product Include, to establish From online data Discrete, univariate
volumes concentra- process consistency acquisition, include in
tion and batch documentation
several
others
UF/DF retentate final CPP Aggregates Include, to establish Routine batch Discrete, univariate
pH process consistency documentation
Protein concentration CPP Protein Include, to establish Routine batch document Discrete, univariate
prior to BDS fill step conc. of process consistency recording of field A280 test
BDS results
Yield (final retentate) KPA – Include, to confirm SPC Routine batch document Discrete value, multivariate
capability calculation using field
A280 test result
OPTIONAL ELEMENTS TO INCLUDE IN CPV
Excipient ”1” Attribute CMA – Optional, to examine Released by compendia Discrete, univariate
“A” variability of materials used testing or COA, results
recorded in LIMS
SEC aggregates in final CQA – Optional, to confirm Will require non-routine Discrete value, multivariate
retentate consistency of mixing and in-process test, record
foam control results in LIMS
Protein concentration KPP – Optional, to establish Routine batch document Discrete, univariate
prior to dia-filtration process consistency recording of field A280 test
results
Recirculation flow rate KPP – Optional, to establish From online data Continuous datastream,
process consistency acquisition, include in univariate
batch documentation
Permeate flow rate KPA Optional, to establish From online data Continuous datastream,
process consistency acquisition, include in univariate
batch documentation

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The BDS freezing rate profile and container seal integrity has ensure the step is routinely monitored and operated within
been validated at commercial scale and the freezing time and its established limits. The time the intermediate is stored
7.12
conditions are well controlled and documented to support
any investigations. The freezing equipment is included
frozen prior to shipment for drug product manufacturing,
could be considered as a means of identifying any potential
BULK DRUG SUBSTANCE LOT DATA – CPV RECOMMENDATIONS
in the periodic validation maintenance and instrument correlation with data from the stability program, but this is
preventative maintenance programs. CPV monitoring is not not included in the CPV recommendations here.
The QC group ensures each drug substance batch meets variants are required for CPV monitoring. The routine drug
proposed for several related operating variables because PPQ
specifications for lot release to drug product manufacturing. substance specification confirmation of A-Mab identity
demonstrated tight control and minimal variation of these EM is a supporting quality system subject to periodic
Some specifications, such as the identity attribute of includes a CEX HPLC method which separates isoforms
variables, including: bulk mixing after UF/DF and during the monitoring, so it is not included in CPV recommendations,
consistency with reference standard and inspection for new (product-related substances as defined by ICH Q6B) and
fill, the fixed flow rate through the filter, the flush volume despite a related incident report for this step (see Section 6,
peaks, are not amendable to trend analysis for CPV. The both a consistent profile with the reference standard and
used, verification of the filter integrity testing and product scenario 5).
QC microbiology laboratory monitors all drug substance lot absence of new peaks are part of the acceptance criteria, so
intermediate freezing temperature. BR sequence and
data for endotoxin and bioburden against alert and action this would not be included in the plan.
instructions, automation monitoring and alarm systems will
limits to provide appropriate monitoring of the process and
Table 7.11. Step 10 CPV Recommendations
management of microbial control deviations. It is recommended for CPV, that the routine lot release
Size Exclusion Chromatography (SEC) results for percent
In the A-Mab case study, routine BR specifications proposed monomer and aggregates be trended and long-term control
VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/
IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH for the drug substance were intentionally minimized to (alert) limits defined within their release and stability
show a potential application of QbD development for specifications. The data for these parameters will not form
Bulk Fill step yield KPA – Include, to establish Routine batch document Discrete value, multivariate process validation Stage 1. Endotoxin testing, a BDS and a normal distribution, so control will involve QC review of
process consistency determination using field drug product release requirement is reviewed as per the the results against action and alert limits. Note that samples
A280 test result QC laboratory SOP, with SPC based alert limits which are for SEC testing are collected from the product intermediate
OPTIONAL ELEMENTS TO INCLUDE IN CPV assessed for suitability during each annual product review. prior to bulk freezing and the effect of freezing, storage, and
Filtration volume – Optional, to verify process From online data Discrete value, univariate
For the CPV plan, additional BDS CQAs were selected shipping conditions on aggregation should be considered for
KPP
capability acquisition, include in for continued verification and enhanced monitoring, to inclusion in CPV as inputs to the DP process.
batch documentation demonstrate consistency over a longer period during which
Maximum (inlet) – Optional, to establish Routine batch Discrete value, univariate more process variation may be observed. Content of various Additional CQAs are listed here as optional for inclusion
KPP
pressure process consistency documentation, max. inlet oligosaccharide structures were selected as high risk CQA in the CPV plan. Those CQAs that should perhaps be
pressure from online data examples from the A-Mab case study (refer to section 7.3 included in trending more often than annually for the
acquisition during fill and 10.3). Control limits are set inside the claimed acceptable Annual Product Review, as a result of relatively frequent
Filtration time KPP – Optional, to define normal Routine batch Discrete value, univariate range (see section 5) based on statistical analysis of data to manufacture, should be included in CPV. Content of three
documentation, range provide early warning during trend monitoring. oligosaccharide structures (sialic acid, mannose and non-
elapsed time glycosylated heavy chain) and two process impurities (DNA
Some additional process and product related impurity and methotrexate) were selected as options for CQAs to be
parameters are included in the CPV plan for this process added to CPV trending. As noted earlier, trending of results
step. For example, monitoring of antifoam C rather than for two other oligosaccharide structures will be done at step
methotrexate clearance was chosen. Antifoam additions 3. Methotrexate is a raw material used in steps 1 and 2
vary batch-to-batch to control foam and clearance is and there are no specific controls for its removal but since
combined over steps 4 and 5. In contrast, methotrexate is a there is a high safety clearance limit for this residual process
fixed addition prior to the N-1 seed bioreactor, resulting in impurity, testing for it in the BDS is optional.
significant dilution as the process scales up to 15,000L and a
high log reduction factor was demonstrated for the Protein Shipping of the drug substance has been validated.
A step 5 alone. HCP is not included for CPV at BDS because Monitoring of in-shipment time and maximum temperature
it is monitored for CPV at step 8 (AEX), as both a special during shipment is routinely verified to be within qualified
sample test with a control limit well inside the 0 to 100 ng/ limits. Trending of shipping conditions should be considered
mg acceptable range (based on the similar X-mAb process) for monitoring of the shipping process, though these
and via the multivariate model for linked chromatography parameters are considered out of scope for Stage 3 CPV, so
parameters [25]. No particular deamidated isoforms (which they are not included in the plan.
incidentally, were not designated as CQAs) or other charge

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 SECTION 8.0

8.0 FREQUENCY AND SCOPE OF

Table 7.12. Step 10 CPV Recommendations

VARIABLE CLASS CQAS CPV RECOMMENDATION & DETERMINATION METHOD TYPE OF DATA EXPECTED/
IMPACTED JUSTIFICATION AND/OR SOURCE ANALYTICAL APPROACH

Monomer (by SEC) CQA – Include, to establish SPC LIMS results from routine
testing of BDS
Discrete value, univariate
CPV ANALYSIS
Aggregates (by SEC) CQA – Include, to establish SPC LIMS results from routine Discrete value, multivariate
testing of BDS
CPV analysis commences with commercial production, following successful completion of the PPQ
Galactose content CQA – Include, to establish SPC LIMS results from routine Discrete value batches. The start of data collection and analysis begins with the first representative commercial
testing of BDS
batches produced at the commercial scale facility. Due to potential scale and facility differences,
Afucosylation CQA – Include, to establish SPC LIMS results from routine Discrete value as well as modifications in the process control or adjustments to test methods prior to PPQ, CPV
testing of BDS
monitoring will not include data from clinical batches, though experience gained in these project
OPTIONAL ELEMENTS TO INCLUDE IN CPV phases are likely to help in assigning initial control limits. As a result, the amount of directly
DNA CQA Include, to establish SPC LIMS results from routine Discrete value relevant data available to set appropriate monitoring limits will be limited at this point. This poses
testing of BDS a problem, at least until significant quantities of data have been gathered.
Methotrexate and/or CQA Include, to establish SPC LIMS results from routine Discrete value
antifoam C testing of BDS
8.1
Sialic acid content CQA Include, to establish SPC LIMS results from routine Discrete value
testing of BDS
SCOPE OF CPV ANALYSIS
Mannose content CQA Include, to establish SPC LIMS results from routine Discrete value
testing of BDS To address the problem of limited data when commercial fit approximately the description of a Normal distribution.
production starts, it is recommended that CPV analysis is But, the actual sample size needed to establish variation with
Non-glycosylated CQA Include, to establish SPC LIMS results from routine Discrete value performed in two phases, the initial CPV phase and the long- a good level of confidence could involve a larger number of
heavy chain testing of BDS
term CPV phase. batches. It is recommended that a statistician is consulted
in the context of a particular data set.
Phase 1: Initial CPV Phase
The initial CPV phase is considered pre-SPC and provides the At the conclusion of the initial CPV phase, alert limits for
ability to analyze process performance based on a limited the monitored parameters should be established where
data set to gain understanding of the normal process applicable, if they do not already exist, or to justify the alert
variability in the commercial facility. This phase should limits that have been set. Additionally, the risk assessment
include enough batches to provide data to reflect the performed following completion of the PPQ batches should
range of potential variability and allow statistical process be reviewed to determine whether the additional process
ranges to be established. During this phase, charts are run experience has changed the risk score for the monitored
using the specifications based on PPQ, clinical and process parameters. Trends in process related non-conformances
characterization information. Data collected will be used should also be included in the review of the risk assessment,
to identify possible trends and to demonstrate that the and this should involve considering whether parameters not
process remains in a state of control. For A-Mab, the initial originally included in the plan for the initial CPV phase ought
CPV phase will continue until at least 30 batches have been to be added. Should there be an increase or decrease in risk
produced (this is assuming one upstream cell culture batch for the monitored parameters, or a noted non-conformance
feeds one downstream purification batch). It is worth noting trend for a parameter which was not previously monitored
that, though 30 batches are suggested as the minimum for CPV analysis, the plan may be revised to reflect the
number to form a representative data set, this should not be updated process understanding and risk analysis prior to
regarded as a ‘magic number’. Many introductory statistical initiation of the long-term CPV phase.
texts cite 30 as a reasonable start for independent data that

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Phase 2: Long-term CPV Phase
The long-term CPV phase is the statistical process control
phase. This phase has the following objectives:
• Ongoing verification of the process over the lifetime
of the product to demonstrate the process remains in
control;
• Identify trends which may be within the normal process
variability, but indicate a potential to trend outside the
alert limits;
8.2
FREQUENCY OF ANALYSIS
A documented analysis and conclusion as to whether the
process remains in a state of control (a CPV Report) may be
performed based on the production schedule. For example,
the CPV plan might include the following conditions for a
particular product like A-Mab:
• Campaign (< 10 batches) – Minimally at the conclusion
of the campaign;
• Campaign (> 10 batches) – Minimally every 10
batches, and at the conclusion of the campaign, or at a
predetermined time interval (e.g. quarterly);
• Continuous – Minimally every 10 batches, or at a
predetermined time interval;
Page 50 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
SECTION 9.0
• Continue to build understanding of the sources of
variability in the process and their impact.
9.0 ESTABLISHING
Section 10 provides detail proposing how monitored items
fit into the plans for short-term and long-term CPV.
CONTROL LIMITS
Note: Control limits (for parameters and attributes selected for the CPV Plan) need to be established initially. However, they are
likely to be re-established at some point and this may require change control (see Section 13). This section focuses on the principles
involved in establishing initial and long-term control limits, in preparation for the example of a CPV execution plan (Section 10).
More detailed, mathematical considerations are covered in Section 12.
To initially establish control limits a documented business consistency. Initial control limits in a CPV plan should not
process should be in place to address collecting, analysing, be interpreted as acceptance limits (i.e. a specification for
reporting and storing of data for the process at the the product).
manufacturing scale. Additionally, data generated during
development, scale up, as well as small scale data, can be used Through the initial control limits evaluation, the strategy for
to set control limits. By evaluating process performance, the process control should be identified and applicable limits
initial control limits would help provide an early indication of established based on process and measurement system
a lack of control in the process for certain process parameters capability. The Process Capability Index (Cpk) and Process
or quality attributes, by establishing the anticipated range Performance Index (Ppk) provide useful indicators of the
of expected variation. During the evaluation process, such level of control likely to be achievable for the process.
• A frequency preference of every 10 batches has been
indications may need timely intervention to drive process
selected to enable trend identification via typical tests
for special causes of variation in control charts. Note
Figure 9-1. A Mab case study example indicating different limits during monitoring of certain process parameter
that analysis will be performed as described in section
9 per the requirements of the phase of CPV analysis.
Frequency of documented analysis and conclusion
may be increased when greater than desired process
variability is noted or if conclusions are needed to
support product disposition.
It is important to note that these statements are given as an
example for a product like A-Mab, being manufactured at a
frequency of the order of two to ten batches a month. Even
so, formal CPV Reports are only likely to be created up to
four times a year. For products where the frequency of batch
manufacture is low e.g. once a year, it wouldn’t make sense
to have more than one CPV Report a year.
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 51

The means of establishing SPC limits for an initial period
and for the long-term, is described in detail in Section
12.4. Additionally, an SPC chart showing different limits:
upper and lower control limits (UCL, LCL), being the most
commonly used and arguably important for many data
sets, is presented in the Figure 9-1. If insufficient data are
available, either with a new process or after a major process/
assay change, initial, temporary limits may be proposed,
based on available development, initial small scale data
and process knowledge. If so, small scale models should be
appropriately developed and qualified in order to guarantee
the scale process is representative and predictable.
Statistical and scientific rationale should pre-determine
what data set is required. Once sufficient at-scale data are
available long-term SPC limits can be established.
Understanding which elements (e.g. raw materials, operators,
facility etc.) contribute to common-cause variation may
depend on the relevance and knowledge of the specific
process, and will help to set relevant and appropriate
SPC limits. This requires the inclusion of sufficient data
(initially determined or statistically relevant) to capture
long-term common-cause variation. Factors that may
lead to variation include for example: pack-to-pack
variation in chromatography columns, measurement system
recalibrations, raw material lot-to-lot variability, etc.
The calculation of control limits depends on an assumption
that data is normally distributed and each datum point is
independent. This may not always be the case, and data
transformation can be helpful in making data meet the
Page 52 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
assumptions of normality. Process knowledge may help
in transforming data to a more SPC-amenable form. For
example when a known and codified relationship exists
between process parameters and QAs, normalizing the data
(taking into account the available process knowledge) can
lead to a more relevant and reliable value for trending.
Data distribution should be considered when selecting
analysis tools. The method of reporting each data set should
be defined and approved in applicable GMP documentation.
All excursions outside approved documentation should
be further investigated, justified and documented in
appropriate GMP documentation.
When more data are available, calculated SPC limits can be
identified. The SPC limits should be periodically reviewed to
capture process variability and be brought into line with any
new regulatory or quality guidance or additional CPV Plan
requirements. Established SPC limits should be reviewed
in light of process changes to confirm their continuing
validity and may be adjusted in response to generation of
additional data. The process monitoring procedure, as well as
process capability review, should be established in applicable
documentation (e.g. the CPV Plan). With a given frequency
of analysis, further statistical examination is required to
determine if the results suggest a potential impact on the
product. This is described further in Section 10. Multiple
data sources and applicable analysis should be organized
and integrated in appropriate process data analysis tools.
Subsequent statistical tools should be appropriate for the
data to be analyzed (see Section 12).
SECTION 10.0
10.0 EXAMPLE CPV EXECUTION
PLAN FOR DRUG SUBSTANCE
After completion of the PPQ, continued process verification should demonstrate that the process is
in control. In the words of the FDA guidance from 2011, it should offer: ‘assurance that the process
is reasonably protected against sources of variability that could affect production output, cause
supply problems, and negatively affect public health’ [5]. A monitoring and trending program for
the A-Mab drug substance process parameters and attributes is outlined in this section, but the
reader should view the discussion and content of the tables as recommendations and ensure that
the parameters and values they use are appropriate for their product and process. It is applicable
for both initial and long-term monitoring of the drug substance manufacturing process. Selection
of variables for monitoring is based on information and rationale in Sections 5 and 7.
Note: This plan sub-section is neither a minimalistic Continued assurance of consistent process performance
nor comprehensive listing of variables expected for CPV and identification of potential out of trend results is
monitoring. Rather we attempt to maintain a reasonable achieved by applying SPC rules and capability analysis (Ppk)
consistency with the A-Mab case study to provide an example as discussed in Section 12. CPV datasets enable process
of likely CPV variables associated with a product launch capability predictions with higher confidence, deepen
(where in this case, understanding of variability is not evident process understanding, and improve process robustness by
immediately after completing a platform-based Process increasing the likelihood of detecting sources of process
Validation (PV) Stage 2 PPQ with only two commercial scale variability before they cause batch failures. The CS is
batches of the particular A-Mab molecule). This is meant to updated based upon reviews of related risk assessments, as
demonstrate reliable process control and ability to detect a part of assessing accumulated CPV data in summary CPV
process drift. Commercial scale process data for legacy Reports. CPV should be integrated into the organization’s
processes would likely be available and may justify a smaller development process and quality system. A CPV Master Plan
set of CPV monitored variables. It is emphasized that this is may be used across a corporation, to guide development of
an untested example package for consideration, not general product specific CPV procedures including the incorporation
guidance or proven best practice approach. of outputs from Stage 1 and Stage 2 (e.g., CQA, CPP). CPV
output (from the executed plan) will be documented and
summarized at a frequency defined by the plan. Figure
10.1 is a schematic showing the continuity of review in the
product lifecycle.
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 53
Figure 10.1: Continued review as part of the product lifecycle. The A-Mab case study (and assumed post-PPQ CS) contains
information on the linkage between product quality
attributes and CPPs across the eleven process steps. These
relationships and the relationships between KPPs and KPAs
are specific to each step. Therefore, this section is divided into
Process Understanding
1
tables for each (Steps 1 through 11, plus BDS) in order to list
CPP/CQA’s process parameters and attributes to be monitored to verify
Risk Assessment Review process control over the entire lifetime of manufacturing
Process Knowledge Report the drug substance. Non-routine sampling and specific data
2
gathering will augment routine sampling and data recording
to generate the data for trending and monitoring under this
CPV plan.
For the tables presented in this section, CPV process variables
Continuous and their classification are listed in Columns A and B,
Continuous Quality as recommended earlier in Section 7. Column C includes
information on any data treatment required before graphing
Monitoring
Process
Improvement Product and Feedback
to monitor trends. ‘Unadjusted’ raw data are measurement
results (source data) that are directly charted. ‘Converted’
Quality Process Control data indicate that monitoring the process variable involves
Change treatment of measured results and either combining with
Management Strategy
Batch Record Data other process data (e.g. yield is a ratio of combined raw data)
Documentation or standardizing to match the intent of control limits (e.g.
Specifications
weight measurements converted to volume or converting
totalized flow through volume to column volumes). Raw
(or converted) data that is mathematically ‘transformed’ is
4
a third type of data treatment that may be required before
charting for trend monitoring.
Process Analysis
Column D specifies the recommended SPC tool for monitoring
3
Initial Process Performance
performance trends against control limits. The tool listed
Evaluation Acceptance & Release
is selected based on subject matter expert experience with
Ongoing Process Monitoring
the process development history. The chosen tool provides a
CpK Statistics Database
means to visually review the data and may be revised when
Annual Product Review
the nature of the data is better understood. The options
included in the plan include: ‘individual run chart’ for
data without initial control limits; ‘individual measurement
chart‘ (a control chart) for data that can be plotted with an
expected fixed mean and proposed control limits; ‘EWMA
chart’ (Exponentially Weighted Moving Average control
chart) (see Section 12 for application); ‘3SD tunnel’ (a
control chart with +3 standard deviation control limits) for
data that has a dynamically changing mean during the batch
processing time (such as a VCC profile, UV chromatogram,
or UF/DF flow rate); or ‘exception flag’ which uses routine
process monitoring for process parameters and reporting of
any out of range result (exception). Any custom correlations
Page 54 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 55
that are developed during CPV would also be shown in this
column (e.g. VCC versus dCO2, or step processing time versus
step yield).
Column E identifies plan monitoring requirements for an
initial short-term CPV period of manufacturing which
follows completion of PPQ in order to obtain sufficient
data to set long-term control limits (unless limits already
exist with sufficient confidence and understanding of the
expected long-term normal variation). This period is based
on a minimum number of independent batch experiences,
e.g. 30 as mentioned in Section 8.1 (with a reminder to
consider that raw material lot impact experience may lag
process lot experience), or achieving a target Ppk for the
variable’s range of control. Proposed initial control limits
to use when starting CPV baseline monitoring are given in
column F and are based on assumed PPQ criteria for A-Mab,
or a fictitious control range proposed after completing the
process validation Stage 2 effort. See Section 9 for more
information on establishing initial control limits.
Note: Due to various strategies for combining batches in
manufacturing, 30 completed batches may not necessarily
be sourced from 30 independent vial thaws; or use 30
uniquely prepared lots of the involved solutions; or employ
30 different raw material lots (which could be sub-lots
of fewer supplier bulk lots); or may not produce 30 drug
substance or drug product batches. Awareness and tracking
of different lot counts for different variables is important
information during CPV.
Column G is dedicated to the CPV plan after the initial
baseline period ends and the frequency of sampling and/
or trending is subject to long-term monitoring during
commercial manufacturing. At this future point in the CPV
lifetime, it is assumed that sizeable specific commercial
manufacturing experience and knowledge of the A-Mab
process exists and sources of variation are understood well
enough to support a reduced frequency of testing or review
of data trends with lowered risk for undetected process drift.
In some cases it may be possible to gain enough confidence
in the behavior of certain parameters and their relationship
to the process, that they may be removed from the CPV Plan
and only reconsidered for enhanced monitoring to evaluate
future process changes. In column H, ‘Initial limits’ is an
abbreviated placeholder term for documenting the dates
that particular life-time control limits apply which would
be documented as ‘Range1’. This information would be These assumed known ‘for-cause’ events are shown in
populated after the initial baseline monitoring is complete column I and new SME knowledge can be added as it is
10.1
and short-term control limits are superseded by long-term
limits. Long-term limits and ‘Range2’ are included in the
gained. These changes (e.g. critical raw material lot changes
or process improvements) may have an impact that extends
STEP 1, SEED CULTURE EXPANSION IN DISPOSABLE VESSELS
early tables to demonstrate the historical nature of CPV beyond the change implementation and may make previous – CPV VARIABLES
lifecycle management. Control limits may change at a given data and trend characteristics obsolete and invalidate
time for a particular justified reason (such as appearance of previous short-term or long-term control limits.
very long-term variation or change factors), and past data When available, collected monitoring data should be provided The CPV plan for process variables in this step are shown in this example. In this example, it was assumed the split ratio
profiles should not necessarily be assessed (or displayed) with the resolution recorded in its raw data form, rather than the following table and align with the rationale in Section for this step did not have PPQ acceptance criteria (VCC, %
against more recent control limits. However, the ability to reflecting any rounding to the significant figures included 7. The qualification of new cell banks is beyond the scope viability, and duration ranges employed in PPQ) nor was
review historical data ranges along with changes in more in the control limits. This enables more accurate statistical of this CPV plan and subject to change control management there sufficient process data from the A-Mab working cell
recent predecessor control limits can enhance process analysis and determination of capability. by registered regulatory agreements. Monitoring and bank to adopt initial CPV control limits.
understanding over the product lifespan, especially if these verification of the commercial scale impact of a change
changes are associated with a set of diagnosed root causes. Note: Situations that would result in duplicating in a medium component presented earlier are included in
information across a table are occasionally presented with
Collection of data may at some point provide sufficient alternative proposals to offer the reader different options Table 10.1. Step 1 CPV variables
demonstration of control of a variable that it may be to consider for CPV. Various charting options are presented
removed from the long-term monitoring plan, or that the as examples and different life-time plans shown for the
A B C D E F G H I
frequency with which a particular variable is monitored variables. Rationale would be subject to SME justification
can be reduced to an occasional (audit) basis. Examples of for each individual variable, and as not shown below, may VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE
TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING
variables that might be removed from long-term monitoring actually result in the same monitoring tool and life-time PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE-
include CPPs that have been identified as being well- monitoring plan. ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED)
controlled (WC-CPP). Initial (short-term) monitoring data (SHORT- BASED) TERM)
TERM)
may verify that the expected control is routinely achieved, Note: Since the contents of column H are subject to more
and that there are select CQAs for which monitoring data frequent updates than the other plan elements, the reader Viable Cell Conc., KPA Unadjusted Individual Every batch 0.7 to 2.8 Every batch LT range1 Cell bank
shows little variability. Responding to signals in the data could consider migrating or referencing the column H each passage end (raw data) chart with until long- x 106 (vc/ TBD or growth
in this way allows adjustment of the long-term monitoring lifetime control limits for each variable (as they become long-term term limits set mL) (from medium
3-sigma limits date X changes
plan to tailor it for monitoring those elements of the process available) in a separate document for efficient review and
to Y) LT
most likely to exhibit variability and hence need the greatest approval of revised ranges to maintain both the historical range2
attention. control ranges with current control ranges. (from
date Y
Besides time-based risks to maintaining the validated state to Z)
of process control, the other type of risk that requires OPTIONAL ELEMENTS
verification and monitoring involves change-based risks. Initial VCC split ratio, Converted Individual Run Every batch Char- Once annu- LT Cell bank
KPP
each passage (ratio) chart until long- acterize ally Period1 or growth
term limits set (No PPQ Range1 medium
limits) TBD LT changes
Period2
Range2
Culture duration, KPP Raw data Individual Every batch 3 to 4 While PpK LT range Cell bank
each passage chart with until long- (days) < 1.0, Oth- TBD or growth
long-term term limits set erwise not (dates: medium
3-sigma limits required TBD) changes
Culture viability, KPA Converted EWMA chart Every batch 88 to 98 not required LT range Cell bank
each passage end (ratio) until long- (%) TBD or growth
term limits set (from medium
date X changes
to Y)

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10.2 10.3
STEP 2, SEED CULTURE EXPANSION IN BIOREACTORS – STEP 3, PRODUCTION CULTURE BIOREACTOR –
CPV VARIABLES CPV VARIABLES
The CPV plan for process variables in this step is shown in included in this example. It was assumed the cell culture To be consistent with the status of the A-mab case study A fixed volume of nutrient feed is added at a defined time
the following table and follows the rationale in Section 7. split ratio for this step had sufficient data for the expected when this plan is initiated, the option of creating a time- under automation and routine batch document controls,
Monitoring and verification of the commercial scale impact bioreactor expansion performance to adopt initial control dependent multivariate PLS (partial least squares) bioreactor therefore trending the amount and timing of the nutrient
of a change in a medium component presented earlier is limits. model is a CPV objective, based on previous successful feed addition does not provide value because they are
experiences [25]. The A-mab case study [3, Section 3.10, not subject to random variation. Production cultures are
Table 10.2. Step 2 CPV variables Page 107-109] describes a principle components bioreactor harvested within an acceptable duration based on viability
model as a predictor of acceptable oligosaccharide structure and titer considerations.
A B C D E F G H I
and acidic variant CQAs. The parameter inputs to the model
include temperature and pH, and attribute inputs to the Temperature and pH are continuously feedback controlled to
VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE model include titer, VCC, and viability. All these variables are set points, during the 16 to 18 day culture but measured values
TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING
PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE- included individually for CPV monitoring while the bioreactor are dynamic over that time period. Therefore, 3SD tunnels (the
ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED) model is qualified. The output of the model for each batch range defined by the mean + 3 standard deviations) for the
(SHORT- BASED) TERM)
TERM)
is classified as a KPA. The potential added value in using the parameter profiles will be developed during the initial CPV
model is in ensuring internal correlations among different period, to generate an expected ’conduit’ for results when
Viable Cell Conc., KPA Unadjusted Individual Every batch 3.9 to 6.0 Every batch LT range Cell bank variables are considered. In the future, the values generated tracking consistent control of the CPP.
each passage end (raw data) chart with until long- x 106 TBD or growth from this model may provide a multivariate output for trend
long-term term limits set (vc/mL) (from medium
monitoring that is predictive of process performance, with
3-sigma limits date X changes
to Y) its own alert and action limits.
Optional elements
Initial VCC split ratio, Converted Individual Run Every batch 3.0 to 4.1 Once LT range Cell bank
KPP Table 10.3. Step 3 CPV variables
each passage (ratio) chart until long- annually TBD or growth
term limits set (from medium
date X changes A B C D E F G H I
to Y)
VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE
Culture duration, Unadjusted Individual Every batch 3 to 5 While PpK LT range Cell bank TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING
KPP
each passage (x.x chart with until long- (days) < 1.0, TBD or growth PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE-
ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED)
resolution) long-term term limits set Otherwise (from medium
(SHORT- BASED) TERM)
3-sigma limits not required date X changes TERM)
to Y)
Culture viability, Converted Individual Every batch 90 to 99 not required LT range Cell bank Culture duration CPP Unadjusted Individual Every batch 16 to 18 Every Batch LT range Change in cell
KPA
each passage end (ratio) chart with until long- (%) TBD or growth (x.x chart with until long- (days) TBD bank, culture
long-term term limits set (from medium resolution) long-term term limits set (dates: medium,
3-sigma limits date X changes 3-sigma limits TBD) or process
to Y) setpoint
Maximum pCO2 CPP Unadjusted Individual Every batch 45 to 140 Every Batch LT range Change in cell
(raw data) chart with until long- (mmHg) TBD bank, culture
long-term term limits set, (dates: medium,
3-sigma limits also correlate TBD) or process
w/ IVCA setpoint

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 A B C D E F G H I A B C D E F G H I

VARIABLE CLASS DATA TREAT- MONITORING INITIAL BASE- INITIAL PERIODIC LIFETIME FOR CAUSE VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE
MENT PRIOR TOOL LINE BASELINE MONITORING CONTROL MONITORING TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING
TO ANALYSIS MONITORING CONTROL (TIME/ LIMITS (CHANGE- PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE-
(SHORT-TERM) LIMITS CYCLE- (LONG- BASED) ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED)
(SHORT- BASED) TERM) (SHORT- BASED) TERM)
TERM) TERM)

Culture duration CPP Unadjusted Individual Every batch 16 to 18 Every Batch LT range Change in cell OPTIONAL ELEMENTS
(x.x chart with until long- (days) TBD bank, culture
resolution) long-term term limits set (dates: medium, Antifoam lot CMA Unadjusted Exception Test BDS < LOD Not required < LOD Change in
3-sigma limits TBD) or process (raw data) Flag (new lot) clearance material
setpoint for 3 different ID or supplier
lots
Bioreactor pH CPP Unadjusted 3SD tunnel Every batch 6.75 to Not See PLS Change in cell
(raw data) until long- 6.95 (-log required, model, bank, culture Medium CPP Unadjusted Individual Track OOR 365 to Track OOR 375 to Change in
term limits set [H+]) included in LT range medium, osmolality (raw data) chart with Exception flags 435 Exception 425 medium prep
for reference PLS model TBD or process long-term (mOsm) flags mOsm
(dates: setpoint 3-sigma limits (dates:
TBD) current)
Afucosylated glycans Unadjusted Individual Required 5 to 10 Once LT range Change in cell Mannose CQA Unadjusted Individual Required 5 to 8 Not required LT range Changes in
CQA
(raw results) chart with for model (%) annually 5 to 10 bank, culture content (raw data) chart with for model (%) at this time TBD cell bank
long-term qualification (time 0 Initial to medium, long-term qualification (dates: or step 3
3-sigma limits only of annual current or process 3-sigma limits only TBD) setpoints
stability date setpoint
batch) Sialic acid Unadjusted Individual Required NMT 1.6 Not required LT range Changes in
CQA
Galactosylated Unadjusted Individual Required 15 to 35 Once LT range Change in cell content (raw data) chart with for model (%) at this time TBD cell bank
CQA
glycans (raw results) chart with for model (%) annually 15 to 35 bank, culture long-term qualification (dates: or step 3
long-term qualification (time 0 Initial to medium, 3-sigma limits only TBD) setpoints
3-sigma limits only of annual current or process
stability date setpoint Non-glycosylated Unadjusted Individual Required 0 to 2.4 Not required LT range Changes in
CQA
batch) heavy chain (raw data) chart with for model (%) at this time TBD cell bank
PLS model employ- Converted & Custom Every batch Trajectory Every Batch LT range Change in cell long-term qualification (dates: or step 3
KPA
ing pH, DO, tem- Transformed PLS model until versus TBD bank, 3-sigma limits only TBD) setpoints
perature, pressure, PCA t1 model is > time (dates: culture
gas rates, weight, 95% ± 3 StDev TBD medium, or Time of glucose Unadjusted Individual Every batch Feed 1: a Not required LT range Change in cell
KPP
VCC, viability, titer, predictive process feeds (raw data) chart with until to b hrs at this time TBD bank,
glucose, lactate setpoint (hrs since inocula- long-term long-term Feed 2: c (dates: culture
tion 3-sigma limits limits set to d hrs TBD) medium, or
Product yield (titer) Unadjusted Individual Every batch 4.0 to 5.5 Not See PLS Change in cell Feed 3: e process
KPA
at Harvest (raw data) chart with until (g/L) required, model, bank, to f hrs setpoint
long-term long-term included in LT range culture Peak VCC Unadjusted Individual Every batch 20 to 30 Not See PLS Change in cell
KPA
3-sigma limits limits set PLS model TBD medium, or (Viable Cell Conc.) (raw data) chart with until x 106 required, model, bank,
and PpK >1.0 (dates: process long-term PLS qualified (vc/mL) included in LT range culture
TBD) setpoint 3-sigma limits PLS model TBD medium, or
(dates: process
TBD) setpoint
Culture viability KPA Converted Individual Every batch 40 to 61 Not See PLS Change in cell
at Harvest (ratio) chart with until (%) required, model, bank,
long-term PLS qualified included in LT range culture
3-sigma limits PLS model TBD medium, or
(dates: process
TBD setpoint

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10.4 10.5
STEP 4, CENTRIFUGATION AND DEPTH FILTRATION – STEP 5, PROTEIN A CHROMATOGRAPHY – CPV VARIABLES
CPV VARIABLES Initial control limits for load ratio and elution buffer pH are resin to clear protein A (spiking study) and, characterization
assumed, based on a simulated normal range within the of potential Protein A leachate from both high and low use
For Step 4, Critical Raw Materials (CRM) that impact the step attenuate upstream process variability prior to purification. DOE PAR provided in the A-Mab case study. Likewise, the cycle counts with respect to resin storage time. Note that
include the working cell bank, upstream growth medium If turbidity or the duration of depth filtration shifts upward, short-term residual protein A control limits are based on elution buffer pH data is included while the limits for the
components, and depth filters. Changes to these items monitoring the inlet pressure parameter or the attribute of the outcome of a fictional study done after PPQ at small HCP model are generated.
would require a period of enhanced monitoring of filtrate differential pressure across the filters may need to be added scale, which examined the capacity for high cycle count AEX
turbidity and step yield, to demonstrate that the process can to CPV.
Table 10.5. Step 5 CPV variables
Table 10.4. Step 4 CPV variables
A B C D E F G H I
A B C D E F G H I
VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE
VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING
TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE-
PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE- ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED)
ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED) (SHORT- BASED) TERM)
(SHORT- BASED) TERM) TERM)
TERM)
Protein Load Ratio CPP Converted Individual Every batch 15 to 40 Every Batch LT range Resin, or
Turbidity KPA Unadjusted Individual Every batch <2 Not required LT range CRM or pro- (in HCP model) (ratio) chart with until (g A- TBD process
of filtrate (raw data) chart with until (NTU) TBD cess change Each sub-batch long-term long-term mAb/L (dates: change to
long-term long-term (dates: to this or 3-sigma limits limits set resin) TBD) this or previ-
3-sigma limits limits set TBD) previous step ous step

Step yield KPA Converted Individual Every batch Charac- Every batch LT range CRM or pro-
Filtrate (ratio) Run chart until terize TBD cess change Elution buffer Unadjusted Individual Every batch 3.4 to 3.8 Track OOR LT range Buffer formu-
CPP
long-term (No PPQ (dates: to this or pH (in HCP model) (x.xx resolu- chart with until (-log Exception 3.4 to lation
limits set limits) TBD) previous step tion) long-term HCP model [H+]) flags 3.8 scale-up
3-sigma limits limits set (dates:
OPTIONAL ELEMENTS initial to
current)
Duration of Broth KPP Converted Individual Every batch Charac- Once annu- LT range Upstream
Clarification (end minus Run chart until terize ally TBD scale-up,
start time) long-term (No PPQ (dates: Centrifuge Residual Protein A CQA Unadjusted w/ upper limit, Every batch ≤ 1234 Per resin/ LT range First two
limits set limits) TBD) feed or flow in eluate pool (raw data) & correlation until (ng/mg column TBD cycles after
rate setpoint vs. storage age long-term A-mAb) lifetime (dates: extended
changes limits set protocol TBD) storage
Inlet pressure, Unadjusted Individual Not required None Not required ±3 Upstream (≥ 3 months)
KPP
depth filters (raw data) chart with StDev of scale-up,
long-term most filter changes,
3-sigma limits recent 30 Centrifuge Step duration Converted Individual Every batch Charac- Once annu- LT range Scale in-
KPP
batches feed, or filter (elapsed) Run chart until terize ally TBD creases
(pre- flow rate long-term (No PPQ (dates:
change) setpoint limits set limits) TBD
changes,
shifts in Step yield KPA Converted Individual Every batch 68 to 88 Every Batch LT range Reset range
turbidity or (ratio) chart with until (%) TBD for process
filtration long-term long-term (dates: change to
time. 3-sigma limits limits set TBD) this or previ-
ous step

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10.6
STEP 6, LOW PH TREATMENT – CPV VARIABLES
The viral safety risk CQA (inactivation of particular AVA) for
the A-Mab process has been validated in the small scale
model during Stage 1 process validation. Initial control
limits for inactivation time and pH are assumed, based
on a fictitious normal range within the DOE PAR provided
in the A-Mab case study. 3SD tunnel monitoring of pH
during inactivation ensures the parameter remains in range
throughout the inactivation time and it is not monitored as
a single point measurement. Aggregate results are assumed
to include a sum of all quantifiable non-monomer SEC peaks
(dimer, trimer, etc). Yield is not expected to be impacted by
this step and variability around 100% has been associated
with measurement uncertainty, therefore it does not merit
CPV trending or monitoring. The basis of yield for the next
step (7, CEX) begins from the eluate pool of the previous step
(5, Protein A).
10.7
STEP 7, CATION EXCHANGE CHROMATOGRAPHY – CPV VARIABLES
Initial control limits provided in the table below are assumed, A-Mab CPV a typical range will be determined for historical
based on a fictitious normal range within the DOE PAR reference. Aggregate results are assumed to include all
provided in the A-Mab case study. Step duration has a batch quantifiable non-monomer SEC peaks (dimer, trimer, etc).
document control limit based on platform experience, but for
Table 10.7. Step 7 CPV variables
A B C D E F G H I

VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE
Table 10.6. Step 6 CPV variables TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING
PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE-
ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED)
A B C D E F G H I (SHORT- BASED) TERM)
TERM)
VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE
TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING
PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE-
Protein Load Ratio CPP Converted Individual Every batch 15 to 25 Every Batch LT range Process
ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED) (in HCP model) (ratio) chart with until (g TBD change
(SHORT- BASED) TERM) long-term long-term A-mAb/L (dates: to this or
TERM) 3-sigma limits limits set resin) TBD) previous step

pH during Unadjusted 3SD tunnel Every batch 3.4 to 3.8 Every Batch LT range Scale in- Wash Conductivity CPP Unadjusted Individual Every batch 4 to 6 Track OOR LT range Buffer
CPP (in HCP model) (x.x chart with until (mS/cm) Exception TBD formulation
inactivation (raw data) until (-log TBD creases
long-term [H+]) (dates: resolution) long-term long-term flags (dates: scale-up
tunnel set TBD) 3-sigma limits limits set TBD)
Elution pH CPP Unadjusted 3SD tunnel Every batch 5.9 to 6.1 Every Batch LT range Process
Post inactivation Converted Individual Every batch ≤ 3.0 Once annu- LT range Process (x.xx until (-log TBD change to
CQA resolution) long-term [H+]) (dates: this or
aggregates (additive) chart with until long- (%) ally TBD change
long-term term limits (dates: to this or tunnel set TBD) previous step
3-sigma limits end and PpK TBD previous step Aggregates CQA Converted Individual Every batch ≤ 1.0 Per resin/ LT range Process
>1.3 in CEX eluate pool (additive) chart with until long term (%) column TBD change to
OPTIONAL ELEMENTS long-term limits set lifetime (dates: this or
3-sigma limits and PpK >1.3 protocol TBD) previous step
Inactivation CPP Converted Individual Every batch 80 to 120 Track OOR LT range No known
HCP content CQA Unadjusted Individual Every batch ≤ 130 Per resin/ LT range Process
time (elapsed) chart with until a (minutes) Exception TBD risk events
in CEX eluate pool (raw data) chart with until a (ppm) column TBD change to
long-term long-term flags (dates:
long-term long-term lifetime (dates: this or
3-sigma limits sigma set TBD)
3-sigma limits sigma set protocol TBD) previous step
CEX eluate volume KPA Unadjusted Individual Every batch 3.7 to 4.7 Not LT range Column pack
Quantity of KPP Unadjusted Individual Every batch Charac- Not Re- LT range Scale in-
(each sub-batch) (raw data) chart with until (CV) Required TBD or repack
acid added (raw data) chart with until a terize quired TBD creases
long-term long-term (dates:
long-term long-term (No PPQ (dates:
3-sigma limits limits set TBD)
3-sigma limits sigma set limits) TBD)
Step yield KPA Converted Individual Every batch 83 to 97 Every Batch LT range Process
(ratio) chart with until a (%) TBD change to
long-term long-term (dates: step
3-sigma limits sigma set TBD)

OPTIONAL ELEMENTS

Step duration KPP Converted Individual Every batch Charac- Not Re- LT range Process
(elapsed Run chart until terize quired TBD change to
long-term (No PPQ (dates: step
limits set limits) TBD)

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10.8 A B C D E F G H I

VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE
STEP 8, ANION EXCHANGE CHROMATOGRAPHY – CPV VARIABLES TREATMENT
PRIOR TO
TOOL BASELINE
MONITORING
BASELINE
CONTROL
MONITORING
(TIME/
CONTROL
LIMITS
MONITORING
(CHANGE-
ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED)
Initial control limits provided in the table below are assumed, clearance linkage model for the three chromatography steps (SHORT- BASED) TERM)
based on a fictitious normal range within a DOE PAR (Protein A, CEX, and AEX) is included here for monitoring the TERM)
provided in the A-Mab case study. The CEX eluate is adjusted trend in the algorithm output, using the 6 parameters (two
to a target pH and conductivity (CPPs) before loading for from each step) for a given batch. HCP content CQA Unadjusted Individual Every batch ≤ 15 Per resin LT range Process
in AEX eluate (raw data) chart with until a (ng/mg) column TBD change to any
flow-through mode chromatography. The fictitious HCP (measured) long-term long-term Lifetime (dates: chromatogra-
3-sigma limits sigma set protocol TBD) phy step

Table 10.8. Step 8 CPV variables Residual Protein A CQA Unadjusted Individual Not Required ≤ 10 Per resin LT range Align moni-
in eluate (raw data) chart with (ng/mg column TBD toring with
long-term A-mAb) Lifetime (dates: ProA process
A B C D E F G H I 3-sigma limits program TBD changes
VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE Step yield CQA Converted Individual Every batch ≥ 87 Trend every LT range Reset range
TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING (ratio) chart with until a (%) batch vs. TBD for Process
PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE- long-term long-term long-term (dates: change to
ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED)
3-sigma limits sigma set limits TBD) step
(SHORT- BASED) TERM)
TERM) Unadjusted Individual Every batch Feed 1: a Not required LT range Change in cell
KPA
(raw data) chart with until to b hrs at this time TBD bank, culture
Protein CPP Converted Individual Every batch 100 to Every Batch LT range Process long-term long-term Feed 2: c (dates: medium,
Load Ratio (ratio) chart with until 200 TBD change 3-sigma limits limits set to d hrs TBD) or process
long-term long-term (g (dates: to this or Feed 3: e setpoint
3-sigma limits limits set A-mAb/L TBD) previous step to f hrs
resin)
OPTIONAL ELEMENTS
Load Conductivity CPP Unadjusted Individual Every batch 4.0 to 7.0 Every Batch LT range Process
(raw data) chart with until (mS/cm) TBD change KPP Converted Individual Every batch Charac- Not LT range Reset range
long-term long-term (dates: to this or (elapsed) Run chart until terize Required TBD for
3-sigma limits limits set TBD) previous step long-term (No PPQ (dates: Process
limits set limits) TBD) change to
step
Load pH CPP Unadjusted Individual Every batch 7.4 to 7.7 Track OOR LT range Process
(in HCP model) (x.xx chart with until (-log Exception TBD change to
resolution) long-term long-term [H+]) flags (dates: previous step
3-sigma limits limits set TBD

Equilibration/ Wash CPP Unadjusted Individual Every batch 2.0 to 3.2 Track OOR LT range Buffer formu-
1 Buffer Conductiv- (raw data) chart with until (mS/cm) Exception TBD lation
ity (in HCP model) long-term long-term flags (dates: scale-up
3-sigma limits limits set TBD)

Linkage model KPA Transformed Individual Every batch 99.5% Every Batch LT range Re-qualify
output for HCP A-mAb case chart with until AEX predic- TBD model for
(predicted) study long-term eluate HCP tion (dates: process
model equa- 3-sigma limits is predictive interval TBD) changes in
tion 6 with 95% for mean ProA, CEX, or
(Pg 158) confidence of HCP AEX steps
output

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 Table 10.10. Step 10 CPV variables
10.9
STEP 9, SMALL VIRUS RETENTIVE FILTRATION – CPV VARIABLES A B C D E F G H I

VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE
TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING
3SD tunnel monitoring of the operating inlet pressure range within a DOE PAR, provided in the A-Mab case study. PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE-
ensures the parameter (and filtration flow rate) remains Platform knowledge of SVRF operations indicates this step ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED)
(SHORT- BASED) TERM)
consistent throughout the filtration; it is not monitored as does not impact yield, therefore consideration is limited to
TERM)
a single point measurement. Initial control limits provided any future qualification of re-filtration.
in the table below are assumed based on a fictitious normal UF/DF CPP Converted Individual Every batch ≤7 Trend every LT range Scale or
processing time (elapsed) Run chart until (hours) batch TBD process
Table 10.9. Step 9 CPV variables long-term vs. long- (dates: change to
limits set term limits TBD) step

A B C D E F G H I Number of CPP Converted Individual Every batch 9.5 t 10.4 Not LT range Buffer
dia-volumes (ratio) Run chart until (DV) Required TBD formulation
VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE long-term (dates: or protein
TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING limits set TBD) conc. changes
PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE-
ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED) UF/DF retentate Unadjusted Individual Every batch 5.2 to 5.4 Once LT range Step 10 or
CPP
(SHORT- BASED) TERM) final pH (raw data) chart with until (-log annually TBD 11 process or
TERM)
long-term long-term [H+]) (dates: raw material
3-sigma limits limits set TBD) changes
Operating CPP Unadjusted 3SD tunnel Every batch Tunnel Trend every LT range Process
Inlet pressure (raw data) until derived batch TBD change Protein Conc. A280 CPP Unadjusted Individual Every batch 65 to 85 Trend every LT range Process
long-term from vs. long- (dates: to this or Prior to BDS fill step (raw data) chart with until (mg/mL) batch TBD change
limits set PPQ and term limits TBD) previous step long-term long-term vs. long- (dates: to this step
platform 3-sigma limits limits set term limits TBD)
batches
Product yield, KPA Converted Individual Every batch Per mem- Trend every LT range When
at same
Final Retentate (ratio) chart with until a brane batch TBD extending
scale
long-term long-term lifetime vs. long- (dates: re-use cycles
Filtration load CPP Unadjusted Individual Every batch 640 to Not Re- LT range No known 3-sigma limits sigma set program term limits TBD)
volume (raw data) chart with until a 1040 quired TBD risk events
long-term long-term (L) (dates: OPTIONAL ELEMENTS
3-sigma limits sigma set TBD) Excipient1 Unadjusted Individual Each new lot Charac- Not LT range Qualify new
CMA
AttributeA (raw data) Run chart until terize Required TBD suppliers,
30 lots tested (No PPQ (dates: RM or CoA
10.10 limits) TBD changes

SEC aggregates in Unadjusted Individual Every batch ≤ 1.4 Not LT range Process
STEP 10, ULTRAFILTRATION AND DIAFILTRATION – CPV VARIABLES final retentate
CQA
(raw data) chart with until (%) Required TBD change to
long-term long-term (dates: this step,
To address the risk that future incoming buffer component this process step. The A-Mab case study includes IPC tests 3-sigma limits limits set TBD) extensions of
lots test within specification, but outside a typical experience for pH and osmolality in drug product manufacturing, but membrane
lifetime
to cause an undesired or unpredicted variation not controlled does not include BDS specifications for these attributes.
by the process, we propose monitoring a trend of the CoA It will be assumed, based on the case study information, Protein Conc. A280 KPP Unadjusted Individual Every batch 40 to 60 Not LT range No known
Prior to diafiltration (raw data chart with until (mg/mL) Required TBD risk events
reported attribute for at least 30 batches from each approved that the process stream after UF/DF (rather than after Step
long-term long-term (dates:
supplier (manufacturer/ packager/ distributor/ vendor) as an 11) is subject to probe monitoring for pH (PAT), to show 3-sigma limits limits set TBD)
optional item (see ‘Excipient 1’ in Table 10.10). If the actual performance prior to final filtration, as an input to the
Recirculation KPP Unadjusted 3SD tunnel Every batch Profile Not LT range When
range for this material attribute does not exhibit a Ppk > 1.3 drug product CPV effort (which occurs after BDS storage,
flow rate (raw data) until within Required TBD extending
against its ICH Q3D limit, further monitoring and control shipping, and thawing). long-term tunnel (dates: re-use cycles
actions may be necessary. limits set limits TBD)
TMP is a design parameter with a fixed setpoint even as
Permeate KPA Unadjusted 3SD tunnel Every batch Profile Verify LT range When
The initial control limits provided, are based on fictitious membrane use cycles increase. The permeate flow output
flow rate (raw data) until within when new TBD extending
normal ranges to serve as early warning triggers. Buffer pH, attribute varies and the input retentate flow parameter long-term tunnel membranes (dates: re-use cycles
osmolality, and conductivity are controlled (and adjusted responds to achieve and maintain the TMP setpoint. limits set limits installed TBD)
as necessary), before the solutions are released for use in

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10.11 10.12

STEP 11, FINAL FILTRATION/BULK FILL AND FREEZING OF BDS – CPV MONITORING OF BULK DRUG SUBSTANCE LOT DATA
CPV VARIABLES As with the process steps, BR depends on a rational assessment of lot data. This is shown in the next table.
The initial control limits provided in the next table are consistency limits, or in the case of yield, an assumed limit
assumed, based on a fictitious normal range and PPQ from fictitious platform knowledge. Table 10.12. CPV variables for BDS lot release data

Table 10.11. Step 11 CPV variables A B C D E F G H I

VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE
TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING
A B C D E F G H I
PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE-
VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED)
TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING (SHORT- BASED) TERM)
PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE- TERM)
ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED)
(SHORT- BASED) TERM) Monomer CQA Peak Individual Every batch NLT 98 Trend every LT range Per BDS
TERM) by SEC integration chart with until a (%) batch TBD stability
(raw data long-term long-term vs. long- (dates: monitoring
Bulk Fill KPA Converted Individual Every batch ≥ 98 Once LT range No known 3-sigma limits sigma set term limits TBD protocol
Step yield (ratio) chart with until a (%) annually TBD risk events
long-term long-term (dates:
3-sigma limits sigma set TBD) Aggregates CQA Converted Individual Every batch NMT 2 Trend every LT range Per BDS
by SEC (additive) chart with until a (%) batch TBD stability
long-term long-term vs. long- (dates: monitoring
OPTIONAL ELEMENTS 3-sigma limits sigma set term limits TBD) protocol
Filtration KPP Unadjusted Individual Every batch 200 to Trend every LT range Reset range
volume (raw data) Run chart until a 300 batch TBD for scale or Galactosylated CQA Unadjusted Individual Every batch 15 to 35 Not LT range Confirm
long-term (L) vs. long- (dates: process Glycans (raw data) chart with until (%) required, TBD comparability
sigma set term limits TBD) change to long-term long-term Not (dates: for
this 3-sigma limits limits set stability TBD changes in
or previous and PpK >1.0 indicating cell bank or
step step 3
setpoints
Maximum KPP Unadjusted Individual Every batch ≤2 Not LT range No known
Inlet pressure (raw data) chart with until a (psig) Required TBD risk events
long-term long-term (dates: Afucosylated CQA Unadjusted Individual Every batch 5 to 10 Not LT range Confirm
3-sigma limits sigma set TBD) Glycans (raw data) chart with until (%) required, TBD comparability
long-term long-term Not (dates: for
Filtration KPP Converted Individual Every batch ≤3 Trend every LT range Scale or 3-sigma limits limits set stability TBD) changes in
time (elapsed) Run chart until (hours) batch TBD process and PpK >1.0 indicating cell bank or
long-term vs. long- (dates: change to step 3
limits set term limits TBD) step setpoints

Page 70 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 71
 SECTION 11.0

11.0 CPV SAMPLING PLAN

A B C D E F G H I

VARIABLE CLASS DATA MONITORING INITIAL INITIAL PERIODIC LIFETIME FOR CAUSE
TREATMENT TOOL BASELINE BASELINE MONITORING CONTROL MONITORING
PRIOR TO MONITORING CONTROL (TIME/ LIMITS (CHANGE-
ANALYSIS (SHORT-TERM) LIMITS CYCLE- (LONG- BASED)
(SHORT- BASED) TERM)
TERM)
A sampling plan makes it clear which samples need to be taken to meet the data acquisition
OPTIONAL ELEMENTS requirements of CPV. This section shows how this might be done giving examples and using
DNA Unadjusted Individual Every batch None Per column LT range Per column
templates. A sampling plan matrix is presented in Table 11.0.1. Please note, this table is not
CQA
(raw data) Run chart for 30 BDS detected resin TBD resin Lifetime intended to be complete, or entirely consistent with information contained previously. It is an
batches Lifetime (dates: protocols example of a visual tool that can usefully summarize an otherwise complex plan, making it easier
protocols TBD)
to develop and communicate.
Methotrexate and/or CQA Unadjusted Individual Every batch None Per column LT range One BDS
Antifoam C (raw data) Run chart for detected resin TBD batch for
30 BDS Lifetime (dates: 3 raw
batches protocols TBD) material lots Considerations for non-routine sampling and testing • Sample container and container size (e.g. polypropylene
include: tubes);
Sialic acid CQA Unadjusted Individual Not required NMT 1.6 Not LT range Confirm
Content (raw data) chart with at this time (%) required, TBD comparability • Sample plan for routine monitoring, baseline • Sample volume, number of aliquots, and retains;
long-term Not (dates: for monitoring, time-based periodic monitoring, or special • Sample labelling (may be driven by site SOP);
3-sigma limits stability TBD cell bank event / change based monitoring; • Sample storage temperature and transport conditions;
indicating or process • Sample frequency (e.g. every day during a reactor run, • Tests to be performed (including any additional
changes
every batch, or every 5 batches, etc); sampling due to assay needs (e.g. a blank solution as
Mannose CQA Unadjusted Individual Not required 5 to 8 Not LT range Confirm • Specific sampling location within the process. Provide reference for the test);
Content (raw data) chart with at this time (%) required, TBD comparability specific and clear instructions for collection of the required • Testing acceptance criteria.
long-term Not (dates: for
3-sigma limits stability TBD) cell bank
sample, e.g. BRc, BRc step number, sampling device such
indicating or process as manual sample valve or automated sample valve. It is
changes critical to ensure that samples collected at the selected
Non-glycosylated Unadjusted Individual Not required 0 to 2.4 Not LT range Confirm
sampling points are representative of the drug substance
CQA
heavy chain (raw data) chart with at this time (%) required, TBD comparability or process intermediates;
long-term Not (dates: for
3-sigma limits stability TBD changes in
indicating cell bank or
step 3
setpoints

Page 72 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 73
 Table 11.0.1. Sampling Plan Matrix
SAMPLING PLAN FOR PROCESS ATTRIBUTES

ON-FLOOR QC PRODUCT QUALITY TESTING

TESTS MICRO

RETAIN
A280 CONC
PH
CONDUCTIVITY
BIOBURDEN
ENDOTOXON
RP-HPLC
CIEF
CGE
SEC
HCP
PRODUCT CONC.
BIOASSAY
DNA
AFFINITY LIGAND
METHOTREXATE
ANTIFOAM
TRUNCATED IMPURITY
PRODUCT VARIANT

Vol req'd for assay

Storage temp <-40 °C
Testing offsite
Testing onsite
Method SOP
Stage 1: Cell Expansion
After last open manipulation
prior to transfer to production
stage
Stage 2: Product Expression
EOR prior to harvest
Stage 3: Clarification
Centrate

Page 74 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
Clarified filtered broth •
Step 4: Affinity chromatography
Load post hold period
Load flow-through
Elution pool • • • ο ο ο ο ο ο
Strip flow thru

ON-FLOOR QC PRODUCT QUALITY TESTING

TESTS MICRO
RETAIN
A280 CONC
PH
CONDUCTIVITY
BIOBURDEN
ENDOTOXON
RP-HPLC
CIEF
CGE
SEC
HCP
PRODUCT CONC.
BIOASSAY
DNA
AFFINITY LIGAND
METHOTREXATE
ANTIFOAM
TRUNCATED IMPURITY
PRODUCT VARIANT

Step 5: CEX chromatography

Load post hold period
Load flow-through
Elution pool • • • ο ο
Strip flow thru
Step 6: IEX chromatography
Load post hold period
Load flow-through
Elution pool • • • ο ο ο
Strip flow thru
Step 7: Viral Filtration
None
Step 9: UFDF
Load pool post hold period
Permeate during concentration
Retentate pool post diafiltration • • ο
Step 10: BDS filtration
and Freezing
Post hold period,
prior to filter
BDS sample prior to freeze • • • • • • •

Symbols are used to indicate which sampling is relevant to each A-Mab process step so the intention of sampling is clear:• (Routine test), ο (CPV test), ∆ (Retain),  (Stability),
 (Reuse Lifetime Performance),  (Cleaning Verification)
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 75
11.1 Sample
Sample Location Bioreactor
Collection
TEMPLATE FOR SPECIFIC PROCESS STEPS Manual Sample Automated Automated
Sampling Device In-Line Sensor
Valve Sample Valve Sampling Device
Container
For each sampling activity, it can be helpful to have a breakout template which shows what Materials Of No Sample - On-
Pp Tube, Sterile
needs to occur (thus a symbol on Table 11.0.1 may become a template table in itself. Examples Construction Line Instrument
(Moc)
of templates for sample collection and testing are presented (Table 11.1.1 and 11.1.2). The rows
represent the considerations for sampling and testing and suggested alternatives. The yellow Container Size 10 Ml N/A
highlighted cells in Table 11.1.1 are the choices for the peak viable cell concentration tested at
Step 3 in the process (Production Culture Bioreactor. In Table 11.1.2, the yellow highlighted cells Sample Volume 5 Ml
relate to aggregates tested at process Step 7, CEX. It is worth noting that, though justification
for the choices made is not given fully in this example, justification would be expected as part Sample
No 2
Replicates
of the CPV plan.
Sample Retain No Yes
Note: Whilst a sampling template may be regarded as good activity to elements of process monitoring not included in
practice, it is not mandatory. Readers may feel it is worth CPV on a risk managed basis. Prepared For
Sample Handling No Aliquoted
creating such plans for CPV as a priority and extending the Shipping

Table 11.1.1. Template for Sampling and Testing (CPP). Completed example is for Step 3, Production Culture Bioreactor Sample Labeling Driven By Sop N/A

OPTIONS Sample Storage Temperature Ambient 2-8 C -20 C -70 C N/A

Step 3:
Production Location Manufacturing Qc Lab Development Lab Sample Control N/A
Process Step
Culture
Bioreactor Sample
Transport Yes (Per Sop) No
Peak Viable Cell Transportation
Variable
Conc.
Development In-Situ (On-Line
Assay Testing Who Manufacturing Qc Dept External Lab
Classification Dept Sensor)
(Product Quality
Attribute CQA CPP KPP KPA Reference/Blank Reference Blank Solution Control No
Or Process
Parameter)
Capacitance
Assay Method
Probe, Per Sop
Time-Based Special Event Or
Routine Baseline
Sample Plan Periodic Change Based
Monitoring Monitoring
Monitoring Monitoring
Multiple Times
Sample In A Batch (E.G.,
Once Per Batch Every X Batches
Frequency Every Day For
Bioreactor)

Page 76 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 77
Table 11.1.2. Template for Sampling and Testing (CQA). Completed example is for Step 7, Cation Exchange Chromatography OPTIONS
(CEX)
Sample Sample
Collection
No 2
OPTIONS Replicates

Step 7: Cation Sample Retain No Yes

Process Step
Exchange Chrom.
Sample Prepared For
No Aliquotted
Variable Aggregation Handling Shipping
Sample
Classification Driven By Sop
(Product Quality Labeling
Attribute CQA CPP KPP KPA
Or Process Sample Storage Temperature Ambient 2-8 C -20 C -70 C N/A
Parameter)
Development
Assay Method SEC
Location Manufacturing Qc Lab Sample Control N/A
Lab

Time-Based Special Event Or Sample

Routine Baseline Transport Yes (Per Sop) No
Sample Plan Periodic Change Based Transportation
Monitoring Monitoring
Monitoring Monitoring
Development In-situ (on-line
Multiple Times Assay Testing Who Manufacturing Qc Dept External Lab
Dept sensor)
Sample In A Batch (E.G.,
Once Per Batch Every X Batches Reference/
Frequency Every Day For
Reference Blank Solution Control No
Bioreactor) Blank
After Eluate
Sample Is Well Mixed
Sample Location
Collection At The Eluate
Collection Tank
Manual Sample Automated Automated
Sampling Device In-Line Sensor
Valve Sample Valve Sampling Device

No Sample - On-
Container Moc Pp Tube, Sterile
Line Instrument

Container Size 10 ml

Sample Volume 5 ml

Page 78 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 79
 SECTION 12.0
12.0 HOW DATA WILL BE
ANALYZED
Fundamentally, the aim of setting values for capability criteria and analyzing data against those
criteria is to establish a plan that provides sound rationale for decision making. This section provides
a basic introduction to the statistical tools likely to be used in support of analytical elements of a
CPV plan.
Statistics is a mature though complex mathematical discipline
and it is recommended that specialists are consulted when
applying the approaches described in this section. A number
of references are provided, but given the maturity of the
subject, the authors recognize this list is far from exhaustive.
The focus here is on recent regulatory guidance and what
might be regarded as a few useful, standard texts.
Note: In this paper we are describing some ways in which
data can be analysed, but these are not intended to be
exclusive of any others. Other analytical methods may be
better suited to particular data sets.
12.1
IDENTIFYING SOFTWARE
Software supporting CPV should make it as easy as possible
for CPV reports to be consistent with the APR, in order to
avoid redundant effort by the technical and quality staff.
The charts of quantitative results included in CPV should
meet all requirements of the APR, such that the CPV charts
may be copied and pasted directly into the APR or included
as attachments. The APR would provide context and tie
together the information brought forward from the CPV
Reports.
Page 80 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
CPV Reports focus on quantitative attributes and parameters
which can be monitored using statistical process control
charts, to identify shifts, trends, and unusual results. Typical
practice is that the attributes and parameters in a CPV
Report include all the quantitative attributes and parameters
which are included in the APR. CPV Reports can also include
additional attributes or parameters, which are useful for
building process understanding and identifying sources of
variation. Whilst the scope of quantitative attributes included
in CPV is equal to, or broader than, the scope included in APR,
the APR includes additional sections not required for CPV.
The APR will provide comprehensive assessments of product
performance that are only made once a year.
The CPV analysis may be performed using well established
software such as MINITAB, JMP, Discoverant or Statistica.
The software vendor should provide documentation of their
quality and validation procedures if data is used to support
GMP functions [18-20].
‘Homegrown’ analysis routines should be similarly validated
if used to support GMP functions. If specific calculations
outside the base software packages are used to support GMP
functions, they should be validated also.
12.2
DESCRIPTION OF TOOLS TO TREND AND EVALUATE DATA
Tools to trend and assist in the evaluation of CPV data include
types of charts and mathematical treatments. The rationale
and approaches to evaluation should be documented in
a standardized way. The three key documents are a Risk
Assessment justification, CPV Plan and CPV Report. Process
Risk Assessments that support CPV plan development and
implementation have the important purpose of justifying the
scope and frequency with which CPV reports are required.
They are performed at the start of CPV plan preparation. For
new processes they should draw on the outcomes of PPQ
and it is recommended they also take into account a Process
Failure Mode Effects Analysis (FMEA), which may have been
conducted during Stage 1 process design and updated after
the Stage 2 PPQ experience.
For legacy products, risk assessments should include the
following sets of data: process capability, analysis of
campaign trends, historical causes of discards, customer
complaints and failure investigations.
A CPV Plan should be written with the purpose of specifying
what must be monitored to provide for CPV and how data
should be interpreted. Interpretation should involve: how
data will be collected, transformed, and evaluated. It is
strongly recommended that data driven rules by which
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 81
decisions will be made, and the expected outcomes, are
recorded in the Plan. A CPV plan should be created and
issued following the risk assessment and before the start
of Stage 3. As stated previously, the definition of an initial
phase and long-term phase of CPV Plan development may be
helpful. This approach is designed to ensure that variation in
process performance is understood before long-term control
limits are established in the control strategy.
Regular assessments of process performance should be
documented in CPV Reports. The frequency with which
these are created will depend on the assessment of risk as
described previously. CPV Reports should detail any control
alerts, as defined by the CPV Plan, whether these have
led to a formal Quality investigation or not. Justification
supporting the response made to these alerts should be
given, including any outcomes for the control strategy.
Typically, CPV Reports will contain calculations of process
capability, statistical process control (SPC) charts, any other
chosen charts, control limits and alerts arising from the data.
In combination, these tools help make any changes in the
performance of the process obvious, revealing any non-
random patterns. The following sections expand on these
tools.

12.3
PROCESS CAPABILITY INDEX
Process capability assessment evaluates the risk that an
attribute will fail to meet specifications; in other words, it
quantifies the likelihood that an attribute will routinely meet
specifications.
Any assessment of process capability requires the assumption
that the same sources of variation that affected previous
results will continue to affect future results, and the expected
range of variability does not change.
There are many indices that measure process capability, but
two are especially popular: Ppk and Cpk . Both indices compare
the width of the specification range to the width of the typical
variation range. The key difference is that Cpk uses a short-
term estimate of variation, whereas Ppk uses a long-term
estimate of variation [13, Chapter 7]. These indices take into
account the centering of the process within the specification
range, and higher values of either index indicates higher
process capability (or lower risk of missing specifications).
The short-term estimate of sigma is a best-case value that
represents the minimum variation that could be achieved if
all longer-term sources of variation were eliminated from
the process. The long-term estimate of sigma includes both
the short-term and the longer-term sources of variation. For
many manufacturing processes, these longer-term sources
of variation are an expected part of the total, routine process
variation.
Cpk provides a more optimistic estimate of the potential
process capability if all longer-term sources of variation are
removed; Ppk provides a more realistic estimate of the process
capability that has been achieved in routine production. For
this reason, Ppk is preferred here over Cpk as an indicator
of expected process capability; although either measure
could be used, depending on process circumstances. Table
12.3 contains guidelines rating the level of control over the
process based on Ppk values. In this paper, we recommend
Page 82 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
Table 12.3. Rating of PpK Index.
Note: Ppk values are recognized indicators of process
PPK INDEX RATING
an initial period in which control limits are estimated from capability. Although quantitative ranges have been
Stage 1 and Stage 2 and experience with similar processes. selected and matched with the potential for improvement
>1.33 Limited Opportunity:
Given the nature of Ppk, it becomes most useful as actual opportunities, these ranges should not replace reasonable
Attribute meets specifications with a very
manufacturing experience develops and robust control high level of consistency. It may be more investigation efforts to determine the factors influencing
limits are established for the long term. valuable to look for opportunities in other the Ppk value obtained. The levels presented in Table 12.3
areas of the process or other processes. reflect one example of a commonly accepted set of ranges
In cases where longer-term variation exceeds short-term for a monoclonal antibody manufacturing process.
variation, and the longer-term shifts cannot be tolerated,
Cpk can be used. However, Cpk should not be calculated 1 - 1.33 Some Opportunity: Other approaches to both assessing process capability
Attribute is routinely meeting
until the SPC charts provide evidence that the process is in as well as matching this assessment to the potential
specifications but there are indications that
a state of statistical control, such that no signals of non- it might not always do so consistently. improvement opportunity may be more suitable for specific
random variation are present. This means there should be processes.
no evidence of shifts, trends, or results outside of control
limits. This is a prerequisite to calculate a meaningful Cpk. 0.68 – 1.00 Considerable Opportunity:
Attribute typically meets specifications, but
Ppk can be calculated even when some non-random signals
does not do so to the extent that might be
are present, as long as those signals are considered to be part expected.
of the routine, expected, longer-term variation inherent to
a process.
≤ 0.67 Significant Opportunity:
The index also assumes the data follow a normal distribution. Attribute/process cannot be expected to
Transformations are sometimes needed to enable non- routinely meet specifications.
normal data to be analyzed in a rigorous statistical manner.
A common source of non-normal data is where negative
values cannot arise, and the most frequent values are close
to zero. Such data sets may be termed ‘log-normal’ and
taking the logarithm of the data can transform it into a
normal distribution. There is more discussion on this topic
in Section 12.4 that follows, but in the context of this paper,
we refer the reader to Reference 13, recognize there are
many other texts on this topic and recommend consulting
a trained statistician.
When reporting process capability, a control chart of the
same data should always be constructed to provide a visual
check that the index is reasonable.
For discussion of frequency and scope of CPV analysis see
Section 8.
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 83

12.4
CONTROL CHARTS
Control charts consist of a few simple elements:
• Results plotted in time order;
• A centerline, usually at the average of the results;
• Statistical control limits.
There are many varieties of control charts. The type of
chart should be selected based on the type of data to be
plotted [13, Chapter 11]. Most attributes plotted for CPV are
individual continuous measurements.
One important consideration for control charts is the choice
of time order. Results may be plotted in date of manufacturing
order (upstream or downstream) or in date of test order. Any
of these orders can be informative, since each order highlights
sources of variation that occur in the related process steps.
When processes are carried out in strict first-in, first-out
sequence from upstream to downstream to assay, the time
order will be the same and the choice of time variable has no
impact on the charts. For CPV, generally one time order will be
selected and used; other time orders may be plotted as needed
for investigations and process understanding.
Another important consideration is the method for
calculating control limits. Control limits should always be
set at plus and minus three sigma (standard deviations),
but sigma may be estimated using either a short-term
formula or a long-term formula, the same as for Cpk and
Ppk. For most charts, the long-term estimate of sigma is
recommended; this corresponds to the use of Ppk rather
than Cpk. Control limits based on the long-term estimate of
sigma will encompass the longer-term sources of variation
that are an expected part of total routine process variation;
short-term estimates will generally be narrower, and may
produce false statistical signals when longer-term variation
impacts process results.
Standard Shewhart control charts are simple to set up, easy
to understand and explain, and good at detecting large shifts
quickly. However, the Shewhart charts are not as good at
detecting small shifts (relative to variation), and do not build
any memory of previous observations. For quick detection
of small shifts, EWMA and Cumulative Sum (CUSUM)
control charts are recommended. These are easy to set up
Page 84 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
using software, and have the advantage of using previous
observations to filter noise and detect small shifts more
quickly. However, they are slower than Shewhart charts to
detect large shifts, and are more difficult to explain to shop
floor personnel and business leaders.
Statistical control charts are based on some assumptions
about the process results. When these assumptions are not
met, the probability of false signals can rise dramatically.
The most important assumptions are that the results are
independent over time and that the underlying results are
approximately normally distributed.
In real manufacturing processes, results are rarely
independent over time. Instead, there is some correlation
across sequential results (autocorrelation). This can be a
natural result of operating conditions, such as raw material
lots that are used for several upstream lots in sequence.
The presence of autocorrelation can produce many small
shifts and trends within the control limits; the science and
technology process support and statistical personnel should
document in the CPV Plan whether these types of shifts and
trends will be addressed as signals of unusual variation, or
treated as expected routine variation.
The assumption of normally distributed data is also
important, and should be checked using a histogram, box
plot, and normal quartile plot. Statistical tests for normality
are not generally recommended, since they will be triggered
by other issues in the data, such as occasional outliers, or
the very shifts and trends that the control chart is intended
to identify.
One common violation of the normality assumption is
proportional variance. Proportional variance is variability
that is proportional to the level of results. For example,
measurements of concentration often have higher variability
at higher concentrations, and lower variability at lower
concentrations. When variation is expressed as a percentage
or Relative Standard Deviation, RSD) instead of a simple
standard deviation, this is an indication that the variance may
be proportional, and should be checked.
Most common SPC tools were designed for results with
constant variance, not proportional variance. When
proportional variance is present, a simple solution is to
transform results from the original scale to a log scale.
Proportional variance on the original scale is stabilized to
constant variance by transforming to the log scale. The choice
of natural or base 10 log scale does not matter, but one or
the other should be used consistently. It is worth noting
that significant data are required to make transformation
a justifiable approach. If there is any doubt about there
being sufficient data, transformation is better avoided and
a statistician should be consulted.
The control charts below illustrate the importance of finding
the appropriate scale for results before identifying special
causes of variation or estimating capability. In the chart on
the left, log-normally distributed data are treated assuming
they are actually normally distributed. The results are not
symmetrically distributed within the control limits, and
there are several results outside the upper control limit.
Figure 12.4.1. Control charts, showing the effect of different scales
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 85
These signals would require a response from the process
owners in CPV. In the chart on the right, the same results are
transformed to the log scale. The log transformation expands
the scale at the lower end of the range, and compresses the
scale at the upper end of the range. Now the results are more
symmetric within the limits, and no results exceed either
upper or lower control limits. Capability indices are best
calculated on the transformed data, using specifications,
mean, and sigma in the transformed scale.
In many situations, the average of a data set is expected
to remain fairly constant over time. However, there are
circumstances when the mean is expected to change over
time, based on process knowledge and experience. When
this is the case, additional tools may be used to monitor for
departures from the expected behavior. These include “tool
wear charts” and other similar charts based on monitoring
the residual result (actual – predicted by a model). These
tools will not be expanded upon further in this document.
To summarize the recommendations for trending and
evaluating data:
• Start simply – always plot the data;
• Use long-term estimates of sigma for most situations,
both to set the control limits, and to evaluate process
capability (Ppk);
• For some special cases when standard control charts
are not providing satisfactory assessments, consult
a statistician and other process experts. These special
cases include:
– Results with low resolution (few distinct values are
possible within the specification range);
– The original scale does not provide normally
distributed data, and a scale transformation may
be needed;
– EWMA charts or CUSUM charts may be preferred
when it is important to detect relatively small
shifts in data with high variation [14, Chapter 9];
– Statistical methods may not produce meaningful
estimates, for example when a very small number
of results are available, so technically justified
limits must be used either initially or permanently.
An algorithm can be used to support the selection of control
charts (Figure 12.4.2).
 Figure 12.4.2. Guide to selecting control charts
12.6

Obtain data   RESPONSES TO SHIFTS AND TRENDS

for an  
attribute  
CPV is only one part of an overall CS. It is envisaged to CPV Plan and in most cases, a formal quality investigation/
function at a supervisory level and is not typically tied directly deviation will not be required, as an OOS situation will not
yes   yes   no   to lot release. There are other basal level control elements normally have occurred alongside a CPV trend.
At least   Many   no   Detecting   such as alarms and alerts, in-process testing and release
30   related   At least   small  
results  
analytics that are designed to be more immediate controls of A typical path for root cause analysis in response to a signal
results     5 distinct   shifts in  
available   available   values  ?  
product quality. Any result that is Out Of Specification (OOS) includes:
noisy  
?   ?   data  ?   should be investigated under existing Quality procedures for • Establish that the results are valid;
handling deviations. • Check for any indications of inconsistency, e.g. within
a laboratory, during the timeframe the result was
no   yes   no   yes   CPV is intended to serve as an ‘early warning system’ where obtained;
process drift can be detected before it can cause an OOS • Evaluate any other attributes that typically correlate
Plot on a run   Plot on a run  
CUSUM or failure that could otherwise have product quality impact. with the result, to determine if all attributes trended
chart (no   MVDA   chart (no  
EWM Thus, responses to shifts and trends discovered during CPV together as expected, or if the particular result was
limits)   limits)  
typically include those that remain within specifications. exceptional;
Investigations or other activities may be triggered to • Walk the process upstream from the sample point,
identify the root cause of the process and/or quality shift or and collect process performance data to understand
Shewhar  t  
chart   perturbation; however, closure of the investigation triggered any unusual patterns in process operations during the
in this way, is not typically tied to lot release; unless an ‘out- timeframe the result was obtained.
1    
of-specification’ (OOS) situation has also occurred.
The explanation of within-specification shifts and trends
Shifts and trends that remain within specifications should should be documented in the routine CPV Report. If the
be evaluated by trained personnel who are most familiar reason for a shift or trend cannot be identified during CPV, it
12.5 with the process and assay; typically floor support engineers may be escalated to the status of an official quality deviation,
and laboratory scientists. The response to the shift or trend for further investigation. It may be advantageous to define
MULTIVARIATE DATA ANALYSIS may be determined by the local engineering or technology a ‘tiered’, risk-based approach linked to anticipated actions
function, with consultation from the quality, operations, and when a shift or trend is observed. This approach could be
Multivariate Data Analysis (MVDA) [25] combines multiple to process data in real-time, while there is still an opportunity
statistical functions. These investigations form part of the developed over time.
parameters to provide greater power for detecting changes to adjust and improve batch results. MVDA is often used to
in results, and to develop deeper understanding of the evaluate and improve within-batch performance, while CPV
sources of variation in a process. MVDA requires access to is most commonly focused inter-batch monitoring. CPV
larger bodies of data than univariate approaches. When using univariate approaches represents the most common
MVDA is feasible, it should be considered as a powerful approach within the industry at the moment; MVDA
extension of CPV; it is most effective when it can be applied represents where the industry is heading in the future.

Page 86 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 87
12.7
ESTABLISHING INITIAL LIMITS
Note: Establishing initial control limits and the choice of
analysis tools is also discussed in Sections 9 and 10. This
section provides further thoughts on their application to
CPV, given the importance of establishing them as part of
a CPV Plan.
In general, statistical control limits should be set at the
centerline plus and minus 3 sigma (standard deviation).
Sigma may be estimated from short-term variation [13,
Chapter 11] or long-term variation, using the formula for
standard deviation.
Long-term variation is preferred for two reasons. The most
important is that long-term sigma includes all the sources of
variation that are expected to be inherent to the process. This
provides more realistic control limits, which will be better
able to distinguish between expected and unusual instances
12.8
ESTABLISHING LONG-TERM LIMITS
Once sufficient process history is established, long-term
control limits should be established against which the
performance of the process can be assessed. Long-term
control limits are sometimes said to be ‘fixed’ meaning
they should not be changed without a sound, recorded
justification. Fixed limits should be based on a minimum
of 30 batches, and should reflect all expected sources of
variation. If there are potential sources of significant longer
term variation, such as a change of raw material lot, it is
important to gather data over a sufficient time period to
account for that variation.
Page 88 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
12.9
FINDING SIGNALS OF SPECIAL CAUSE VARIATION
Additional rules may be applied to a control chart to Low resolution results occur frequently in regulated
of variation in results. The second reason is that during initial
increase the sensitivity of detecting shifts and trends that processes, often because results have been rounded before
production, when fewer than 30 results are available for
may remain within the control limits. The Western Electric they are charted. Whenever possible, use the unrounded
calculating sigma, the long-term estimate stabilizes more
[15] and Nelson [16] rules are implemented in commercially result for SPC charting and estimation of sigma. It is
quickly than the short-term estimate. For independent,
available SPC software. Note that these tests were designed recommended that the validation procedure and history
normally distributed results, the long-term and short-term
on the assumptions of independent successive results (no of measuring systems is checked for repeatability and
formulas for sigma will provide very similar values.
autocorrelation) and a normal distribution. The possibility reproducibility. Such data helps decide whether rounding
of false alarms may rise dramatically when either of these is appropriate and to what extent. If in doubt, a statistician
During initial production or after a process change, when
assumptions is violated. Low-resolution data in particular should be consulted. When low resolution data is to be
fewer than 30 results are available to estimate sigma, it
will generate many false alarms, and the rules should not evaluated, the recommended approach is to plot the data
is recommended that limits are set, based on technical
be applied for data not meeting these assumptions. Also, on a run chart in time order, but avoid setting statistical
knowledge of the process. If statistical approaches must be
the number of rules applied should be limited, at least in control limits. Limits may be set using technical judgment
used to set initial limits, use the long-term sigma formula.
the initial phase of CPV, since the probability of false alarms and process experience [17, 18].
Set temporary limits to be updated once 30 or more results
increases with each additional test applied.
are available. If longer-term sources of variation occur over
extended timeframes, more than 30 results may be needed
to capture typical long-term variation within sigma and the
control limit values.
Initial OOS results which are determined to be invalid may
be excluded when setting limits. Examples of invalid results
may include laboratory errors. Such data points should be
excluded from sigma calculations and charts. However, if the
root cause is unknown or representative of the process or
testing method, the data points should be retained in the
sigma calculation and chart.
When a process change or improvement shifts the mean or
changes the variability, control limits should be re-set based
on a minimum of 30 results following the change.
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 89
SECTION 13.0
13.0 CHANGE MANAGEMENT
Good change management is critical to getting the greatest possible benefits from a CPV system.
Some important general principles of change management are presented here, along with some more
specific scenarios related to CPV observations.
Change management is complementary to effective CPV.
Product and process-related changes may impact the CPV
plan (including any CPV limits document that might exist
separately from the plan), and the RA and CS documents that
form the basis for the CPV plan. Changes to these controlled
documents should proceed per the company’s normal change
control procedures, which should include the description,
rationale and justification for all significant changes. Changes
that do not impact monitored parameters, sampling points or
control limits do not require revision of the CPV plan; however
the change control should consider whether evaluation of
normal process variability for a particular parameter should
start again at the initial CPV phase for analysis. After noting in
the change control documentation, this may be noted in the
next CPV analysis / report.
Process changes or experience with special or common
cause variation may require investigations and a revision
of the CPV execution plan during the lifetime of a process.
Adjustments to the frequency of periodic monitoring, or
a return to collecting baseline data before setting (or re-
setting) future long-term control limits may be necessary to
Page 90 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
manage control of changes to reduce variability or achieve an
improved outcome. A deviation which leads to a corrective
or preventative action to begin monitoring a new variable
trend not previously monitored, or to re-activate monitoring
a trend discontinued for CPV may also need to be added to
the plan.
Changes to the control strategy need to consider the
potential impact to the current status of the CPV plan.
Facility, process, equipment, field measurements, or
analytical laboratory method changes (examples of normal
change controls) require a review of the CS, any related risk
assessments, and the current monitoring plan for the steps
being changed as well as the downstream steps that have
linked parameters or attributes. If a process variable is re-
classified in the CS based on new process understanding,
changes to the CPV monitoring plan may also be needed and
any impact to registered details of regulatory licenses need
to be addressed. Below, a decision flow outlines a process for
managing changes needed due to ongoing CPV monitoring
(Figure 10.13).
Figure 13. Decision Flow for changes to CPV Execution Plan for Drug Substance Lifetime. OOT stands for Out-of-Trend, NOR
is Normal Operating Range and PAR is Proven Acceptable Range.
C onfirm O O T , inve s tiga te to
U ne xpe cte d incide nt re porte d/ de te rmine if a s pe cia l ca us e a nd
impe nding cha nge notifica tion
communica te d, C P V da ta O O T
e xcluding da ta from futre na tura l
va ria tion s igma ca lcula tion
R e vie w C ontrol S tra te gie s & R is k
A s s e s s me nts for a ctua l or
pote ntia lly impa cte d control
N o, but it is not in C P V
pa ra me te rs a nd pe rforma nce Is it comple te ly ne w? N ot
indica tors ...a nd if cla s s ifica tion a ddre s s e d in e xis ting ris k
monitoring, jus tify a dding
or not a dding to progra m
ra tiona le is s till jus tifie d or if a s s e s s me nts or control
de cis ions ne e d to be a djus te d s tra te gie s ye t
in inve s tiga tion or cha nge
impa ct a s s e s s me nt
D oe s Incide nt/ C ha nge indica te
N o, C urre nt s ta tus ca n
s e tpoints or ra nge s for a ny
fixe d or re s pons e va ria ble s
continue (routine control or
C P V e nha nce d monitoring
ne e d a dditiona l monitoring,
ve rifica tion, re qua lifica tion,
a s curre ntly in-pla ce )
re s e tting, re de finition
(S e tpoints , a le rt/ a ction limits ,
Y e s . C omple te ne w or
s upple me nt e xis ting ris k
or N O R / P A R controls )
a s s e s s me nt, re vis e control
s tra te gy
G e ne ra te informa tion S us pe nd a ny e xis ting C P V comme rcia l da ta
Y e s , de te rmine
s a mple te s t/
ne e de d to e s ta blis h initia l
proce s s unde rs ta nding/
crite ria / limits , a nd re pla ce
with lowe r confide nce
colle ction/ a s s e s s me nt
to e s ta blis h long te rm
da ta ca pture
re quire me nts
product knowle dge
(R &D , S S M, s upplie r da ta ,
control ra nge s via Q MS
me cha nis m of protocol
confide nce in ne w
unde rs ta nding, a nd
his torica l da ta a na lys is ) cha nge ma na ge me nt a s s ura nce of control
Assessments of CPV trends and CPV plan deviations are to In this A-Mab example, for cases where a change would
be documented in CPV reports. This should indicate actions cancel out capability indices or remove confidence in
taken and capture rationale to justify any recommended CPV continued use of existing control limits, a plan deviation
plan revisions. These reports are then used as inputs into a would be used to document suspending or making these
periodic APR / Product Quality Review package. Assessments control limits obsolete. The process performance trend
may be as simple as chart status, or include an evaluation can then be monitored against a new provisional control
into whether a capability index value demonstrates it is range (justified via the deviation and based on PARs, recent
possible to reduce or stop monitoring a particular parameter history, equipment capability, or qualified small scale model
or attribute. If sufficient data has been obtained to calculate studies). Data collected prior to the change may be used for
and implement long-term limits with high confidence, comparison to assess the impact of the change.
this should be documented in the CPV Report, before the
CPV Plan is changed. An assessment may conclude that The following table presents several cases where CPV-related
monitoring will continue to a new planned milestone changes may occur, the impacted documents and required
without change setting new limits. If the capability index actions. The change management process is very similar to
is low, the monitoring plan may need to be changed (e.g. the initial setup of the CPV plan, as presented in preceding
to obtain data more frequently, or a Corrective Action and sections of this paper. An assessment of the RA document
Preventive Action (CAPA), might be considered to improve and its impact on the CS document is always required, even
control. In any case the decision should be documented in a if not explicitly stated in table 13-1 below.
CPV Report with its rationale.
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 91

Table 13-1. Change Management Examples
REASON FOR CHANGE
CHANGES WITHIN CPV PLAN
Transition from initial control limits to long-term
limitsEnough data available (e.g. n = 30) to establish
statistically based control limits
OOT results (e.g. control limit or run rule violations)
due to newly experienced, but normal, variability (e.g.
due to a new raw material lot)
Shift in mean or a change in variability (e.g. due to a
process improvement)
Add / Remove control elements based on process
knowledge gained through CPV, e.g. after periodic
monitoring. This data could point to ways to improve
the product or optimize the process. Elements may be
deleted (or have reduced sampling frequency) if their
process capability index is high and variability is well
controlled. Elements may be added if a new source of
process variability is discovered.
CHANGES EXTERNAL TO CPV PLAN
• Add or Remove control elements based on new
process knowledge, e.g. from lab scale studies,
CAPA’s, complaints, etc.
• Process changes (e.g. new raw material)
• Change or add manufacturing site
• New equipment (excluding like-for-like changes)
New or changed analytical capabilities
Page 92 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
SECTION 14.0
IMPACTED
DOCUMENT(S)
ACTIONS 14.0 DATA VERIFICATION
This section describes in general the types of data sources in a CPV reporting system. It goes on
Document (e.g. in a CPV limits document) how statistically
CPV Plan / Limits
based control limits (CL) were determined. Start routine
to make recommendations as to how data in these systems should be verified and hence how the
Document systems should be validated.
monitoring with CL’s and run rules
Justify removal of current CPV limits (if applicable), and
continue to collect data until sufficient to recalculate new
CPV Limits
control limits. During the extended data collection period, Three major sources of data are used for CPV: 2. Single data entry and independent verification: The
Document
continue to monitor for trends (e.g. average ± 3 SD), but
without run rules.
data are entered from the original data source by
1. Process data e.g. viable cell concentration in the one operator and independently verified by a second
Justify removal of current CPV limits, and reset counter for
bioreactor [26], offline pH / conductivity measurements operator using the source documents. This process
CPV Limits the number of runs required to set new control limits for
Document the impacted attribute / parameter. Continue to monitor or process volumes which are recorded in either paper is used in many companies, but cannot completely
for trends (e.g. average ± 3 SD). or electronic BRcs. eliminate errors because the data verifier may not
always catch all data entry errors.
2. Analytical data generated in QC laboratories which are
RA / CS Update to reflect the new knowledge typically recorded in a LIMS or Data Historian. 3. SMART Data entry / Error proofing: for a parameter
or attribute being transcribed, the data archival system
3. Data recorded by inline instruments e.g. pH of can limit the allowable values that can be entered, thus
bioreactor, or buffer flow rates for chromatography any errors can be readily pointed out and corrections
operations. These data are archived and managed by can be made, for example:
Update. New elements may be monitored (e.g. using
CPV Plan / Limits
average ± 3 SD) until statistically based control limits can
the data historian component of the plant control
Document system. Examples of data archival systems include • Offline pH measurements can be restricted to
be established (n ≥ 30).
Plant Information (PI_System) by OSISoft and InfoPlus values from 0.0 to 14.0;
21 by Aspentech. • Viable cell concentration data can be restricted to
the expected range of values [26].
Perform PPQ run(s) if deemed necessary (consult with QA Data recorded on paper-based systems require transcribing
PPQ
and Regulatory Affairs). into a secure electronic archiving system (e.g. a database) Alternatively, the data archival system can generate a report
so that it can be retrieved in the future for data analysis, of observed minimum and maximum values for a process
RA/ CS See “Add/Remove control elements” above
control charting and CPV. The manual data entry process is parameter or attribute. Any discrepant result outside of the
CPV Plan / Limits
See “Add/Remove control elements” above prone to human error. Several options are available to ensure normally observed range can be readily detected.
Document
data integrity during the data transcription process. These
RA/ CS Only if impacted
are described below. While a SMART Data entry system can detect some errors,
it is also not foolproof. Suppose the observed values for
1. Blinded data entry: Data are independently entered into chromatography step yield vary from 50.2 to 80.4 %. For a
the data archival system by two different operators. The particular batch, if the yield recorded in the source BRc is
data archival system prompts the operators if there is a 62.6%; this could be wrongly entered as 66.2% which would
discrepancy noted between the two separate entries for still fall within the expected observed values and may remain
a process parameter or attribute so corrections can be undetected.
made. However there is a remote possibility that both
data entry operators can make the same mistake.
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 93

In summary, there are hidden sources of error in transcribing
data from paper to electronic data archival systems. It is
important to recognize that verification is critical for some
parameters (e.g. CPPs) but may not be necessary for other
process parameters. Therefore verification depends on
purpose and criticality of the parameter being measured. The
intention should to reduce data entry errors to zero. This may
require continuous improvement and it is important to know
the extent to which any error impacts the process parameter.
Transcribing data from electronic sources e.g. electronic
BRcs or plant information into data archival systems, is not
likely to introduce errors provided the data transfer system is
designed robustly and the ability to transfer data is validated.
For either paper or electronic sources, the ability to retrieve
data from the data archival system should undergo an initial
validation. Similarly if the data from the data archival system
is used routinely for generating control charts or data tables
for process monitoring and CPV, the procedure for generating
control charts or data tables should be validated or as
recommended in section 12 of this document, established
software should be used. A number of software suppliers
will provide a quality statements regarding the validation of
their statistical software [e.g. 19, 20, 21].
Page 94 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
SECTION 15.0
Whether the source data are from paper systems or electronic
systems, a record should be kept (and continually updated)
of the BRc step number or the Tag ID for electronic sources.
15.0 DISCRETIONARY ELEMENTS
It is recommended (although not an absolute requirement)
for the data archival system to have the ability to record
data entry operator ID / time stamp, any corrections made;
OF A CPV PROGRAM
i.e. an audit trail of all entries and changes.
The Table below shows some elements that may be included within a CPV program based upon the
Finally it would be good practice for any process parameter
or quality attribute observed to be out of controllable range needs and decisions of the individual operating company. The following elements are not considered
(trend) or for observed shifts and trends to be independently mandatory for inclusion in CPV, but may provide the operating company with information valuable
verified by re-examining the source data. to the manufacturing of drug substances.
Thus in conclusion, it is recommended that robust systems
Figure 15.1. Discretionary Elements of CPV
and procedures are designed and developed in order to
archive data and validate the accuracy of data retrieval
ELEMENT DESCRIPTION
in order to minimize errors during CPV. It is of course, the
responsibility of each individual organization to apply the
recommendations in this section as they see fit. Operational or Performance Elements Process performance attributes (i.e., bioreactor titer, column elution volumes) or input
parameters linked to process performance attributes.
Multivariate Data Analysis MVDA, particularly Partial least squares (PLS) regression or Principal component analysis
(PCA) may be useful to identify latent variables within the CPV data set and increase an
understanding of the design space of the drug substance manufacturing process.
Column/Resin/UF Membrane Cleaning and The full scale verification of column and/or ultra-filtration membrane cleaning and
Performance Lifetime Verification performance, out to established lifetime limits, may be included within the scope of the
operating company’s CPV program.
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 95
SECTION 16.0
16.0 TECHNICAL REFERENCES
1. Technical Report No. 60. Process Validation: A Lifecycle
Approach. PDA, Inc. 2013
2. ISPE PQLI Guidance Series Part 4
3. A-Mab: A case study in Bioprocess Development. CMC
Biotech Working Group. 2009
4. FDA Code of Federal Regulations 21 Part 211, Jan. 2013
5. Process Validation: General Principles and Practices,
guidance for industry, FDA (CDER, CBER, and CVM), January
2011
6. A-Mab study; Pharmaceutical Quality by Design: Product
and Process Development, Understanding, and Control;
By Lawrence X. Yu, Ph. D.; Director for Science; Office of
Generic Drugs; Food and Drug Administration
7. ICH Q8 Pharmaceutical Development: http://www.ich.
org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/
Quality/Q8_R1/Step4/Q8_R2_Guideline.pdf
8. ICH Q9 Quality Risk Management: http://www.ema.
europa.eu/docs/en_GB/document_library/Scientific_
guideline/2009/09/WC500002873.pdf
9. ICH Q10 Pharmaceutical Quality System: http://www.
ema.europa.eu/docs/en_GB/document_library/Scientific_
guideline/2009/09/WC500002871.pdf
10. Technical Report No. 15. Validation of Tangential Flow
Filtration in Biopharmaceutical applications. PDA, Inc. 2009
11. Technical Report No. 14. Validation of column-based
chromatography processes for purification of proteins.
PDA, Inc. 2008
12. Biopharmaceutical Manufacturing Facilities- Volume 6. ISPE
Baseline Pharmaceutical Engineering Guide. June 2004
13. Pena-Rodriguez, ME. Statistical Process Control for the
FDA-Regulated Industry, 2013. ASQ Press: Milwaukee, WI
14. Montgomery DC. Introduction to Statistical Quality
Control, 2013. 7th edition, Wiley: Hoboken, NJ
15. 15 Western Electric. Statistical Quality Control Handbook
1956, Western Electric Corporation, Indianapolis, IN
Page 96 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
SECTION 17.0
17.0 GLOSSARY
TERM EXPLANATION SOURCE (S)
16. Nelson, LS. The Shewhart Control Chart – Tests for Special
Causes, Journal of Quality Technology 1984; 16: 237-239 Acceptance criteria Numerical limits, ranges, or other suitable measures for acceptance which the drug Q6b
17. Woodall, WH. Controversies and Contradictions in substance or drug product or materials at other stages of their manufacture should
meet to conform to the specification for analytical procedures.
Statistical Process Control, Journal of Quality Technology
2000; 32: 341-350 Action limits An action limit is an internal (in-house) value used to assess the consistency of the Q6b
process at less critical steps. These limits are the responsibility of the manufacturer.
18. Limpert, E, Stahel, WA, Abbt, M, Log-normal Distributions
across the Sciences: Keys and Clues. BioScience 2001; Vol. Batch Records (BRc) A record of specific identifiers for the batch of material being produced, that includes [4]
all activities required to prepare for production, produce the material and close
51 No. 5
down the process. It provides traceability of who did what, when, and the outcomes
19. www.jmp.com/software/qualitystatement.shtml of those actions, including any observations on or deviations from the process or
20. www.minitab.com/en-US/support/documentation/ anticipated results.
software-validation.aspx?langType=1033 Batch Release (BR) The process by which the product is tested and results reviewed to ensure product Q8(R2)
quality under cGMP regulations and guidelines.
21. www.statsoft.com/services/validation-services/
22. ICH Q11 Development and Manufacture of drug substances BPOG BioPhorum Operations Group, a collaboration of biopharmaceutical companies,
(Chemical Entities and Biotechnological/Biological Entities) seeking to accelerate the rate at which the industry achieves a lean state.
23. http://www.ema.europa.eu/docs/en_GB/document_library/ Bulk Drug Substance According to 21CFR207.3(a)(4) this means any substance that is represented for use in 21CFR207.3(a)[4]
Other/2013/08/WC500148215.pdf (BDS) a drug and that, when used in the manufacturing, processing, or packaging of a drug,
becomes an active ingredient or a finished dosage form of the drug, but the term does
24. ISPE Discussion Paper: Applying Continued Process not include intermediates used in the synthesis of such substances.
Verification Expectations to New and Existing Capability of a Process Ability of a process to realise a product that will fulfil the requirements of that Q10
Products”, D. Bika, P. Butterell, J. Walsh, K. Epp and (Ppk) product. The concept of process capability can also be defined in statistical terms
J. Barrick, 2012. https://www.google.com/url?sa=t& via the process performance index Ppk or the process capability index Cpk (ISO
rct=j&q=&esrc=s&frm=1&source=web&cd=1&cad 9000:2005).
=rja&ved=0CCkQFjAA&url=https%3A%2F%2Fwww. CMC BWG Chemistry, manufacturing and control, biotech working group of the International
ispe.org%2Fdiscussion-papers%2Fstage-3-process- Society for Pharmaceutical Engineers (ISPE).
validation.pdf&ei=FIEXU8z1Gurx0wGftoGIBg&usg=AFQ Continued Process A formal process that enables the detection of variation in the manufacturing process [5]
jCNFvOl1WjtGX-vPHZjFsPq8n44cI3Q&sig2=QzSLW0X3- Verification that might have an impact on the product. It provides opportunities to proactively
control variation and assure that, during routine production the process remains in a
cQvbUnwYDGYDA&bvm=bv.62286460,d.dmQ
state of control.
25. Guidance for Industry Analytical Procedures and
Methods Validation for Drugs and Biologics, Draft, Control Strategy A planned set of controls, derived from current product and process understanding Q10
that assures process performance and product quality. The controls can include
February 2014 http://www.fda.gov/downloads/Drugs/ parameters and attributes related to drug substance and drug product materials and
GuidanceComplianceRegulatoryInformation/Guidances/ components, facility and equipment operating conditions, in-process controls, finished
UCM386366.pdf product specifications, and the associated methods and frequency of monitoring and
control.
26. European Pharmacopoeia, 2.7.29. Nucleated cell count and
viability, p233 Critical Describes a process step, process condition, test requirement, or other relevant Q7
parameter or item that must be controlled within predetermined criteria to ensure
that the API meets its specification.
Critical Material Attribute A material attribute, whose variability has an impact on a critical quality attribute Q8(R2)
(CMA) and therefore should be monitored or controlled to ensure the process produces the
desired quality.
Critical Process Parameter A process parameter whose variability has an impact on a critical quality attribute Q8(R2)
(CPP) and therefore should be monitored or controlled to ensure the process produces the
desired quality.
BPOG Continued Process Verification: An Industry Position Paper With Example Plan – Page 97
 Critical Quality Attribute A physical, chemical, biological or microbiological property or characteristic that Q8(R2) Key Process Attribute An important attribute or output measure of the process used in this paper to A-MaB Case Study
(CQA) should be within an appropriate limit, range, or distribution to ensure the desired (KPA) maintain consistency with the language used in the A-MaB case study. N.B. It is [3]
product quality. important not to confuse a KPA, which is a measure of process consistency with
measures of quality such as CQAs.
Design Space The multidimensional combination and interaction of input variables (eg, material Q8(R2)
attributes) and process parameters that have been demonstrated to provide assurance N.B. at the time of writing, the European Medicines Agency (EMA) draft guidance on
of quality. Working within the design space is not considered as a change. Movement Process Validation is out for consultation, referring to KPAs as 'performance indicators'.
out of the design space is considered to be a change and would normally initiate a Key Process Parameter An adjustable parameter (variable) of the process that, when maintained within CMC BWG
regulatory post approval change process. Design space is proposed by the applicant (KPP) a narrow range, ensures optimum process performance. A key process parameter
and is subject to regulatory assessment and approval. does not meaningfully affect critical product quality attributes. Ranges for KPPs are
Detect-ability The ability to discover or determine the existence, presence, or fact of a hazard. Q9 established during process development, and changes to operating ranges will be
Detect-ability is a component of a Failure Modes Effects Analysis (FMEA). managed within the quality system. N.B. this category of parameter is not recognised
by the FDA or the EMA for use in formal submissions and reports, though they do not
Drug product (Dosage A pharmaceutical product type that contains a drug substance, generally in Q6b oppose its use internally. The agencies see all parameters that may have an impact on
form; Finished product) association with excipients. Drug substance (Bulk material): The drug substance is CQAs as Critical and hence CPPs [23].
the material which is subsequently formulated with excipients to produce the drug
product. It can be composed of the desired product, product-related substances, and Knowledge Management Systematic approach to acquiring, analyzing, storing, and disseminating information Q10
product- and process-related impurities. It may also contain excipients and other related to products, manufacturing processes and components.
components, such as buffers.
Multivariate Analysis MDVA, particularly Partial least squares (PLS) regression or Principal component analysis [25]
Failure Modes Effects One of the first systematic techniques for failure analysis. It was developed Q8, IEC 60812 (PCA) may be useful to identify latent variables within the CPV data set and increase an
Analysis (FMEA) by reliability engineers in the 1950s to study problems that might arise from Analysis techniques understanding of the design space of the drug substance manufacturing process.
malfunctions of military systems. A FMEA is often the first step of a system reliability for system
study. It involves reviewing as many components, assemblies, and subsystems as reliability— Normal Operating Range A defined range, within the Proven Acceptable Range, specified in the manufacturing PQRI
possible to identify failure modes, and their causes and effects. For each component, Procedure for (NOR) instructions as the target and range at which a process parameter is controlled, while
the failure modes and their resulting effects on the rest of the system are recorded in failure mode and producing unit operation material or final product meeting release criteria and Critical
a specific FMEA worksheet. There are numerous variations of such worksheets. effects analysis Quality Attributes.
(FMEA). Performance Indicators Measurable values used to quantify quality objectives to reflect the performance of an Q10
General process An adjustable parameter (variable) of the process that does not have a critical effect CMC-BWG organisation, process or system, also known as ―performance metrics in some regions.
parameter (GPP) on product quality or process performance. Ranges for GPPs are established during
process development, and changes to operating ranges will be managed within the Pharmaceutical Quality Management system to direct and control a pharmaceutical company with regard to ICH Q10
quality system. System (PQS) quality.
Impurity Any component present in the drug substance or drug product that is not the Q6b Plan A detailed description of how something is going to be done. Oxford English
desired product, a product-related substance, or an excipient (including added buffer Dictionary online
components). It may be either process- or product-related.
In-process quality Parameters used in the A-Mab Case Study model of a control strategy, to provide a [3] Potency Potency is the measure of the biological activity using a suitably quantitative Q6b
attributes (IPQA) link between KPPs and KPAs biological assay (also called potency assay or bioassay), based on the attribute of the
product which is linked to the relevant biological properties.
In-Process Control also Checks performed during production in order to monitor and if necessary to Q7
Prior product knowledge The accumulated laboratory, nonclinical, and clinical experience for a specific product CMC BWG
called Process Control adjust the process and/or to ensure that the intermediate or API conforms to its
quality attribute. This knowledge may also include relevant data from other similar
specifications.
molecules or from the scientific literature.
In-process test In-process inspection and testing should be performed by monitoring the process or WHO Portal
Procedure A written, established way of doing something in the operating environment. Oxford English
by actual sample analysis at defined locations and times. The results should conform http://apps.who.
Dictionary online
to established process parameters or acceptable tolerances. Work instructions should int/medicinedocs
delineate the procedure to follow and how to use the inspection and test data to /en/d/Jh1792e/ Process Analytical A system for designing, analyzing, and controlling manufacturing through timely Q8(R2)
control the process. 20.7.3.3.html Technology (PAT) measurements (ie, during processing) of critical quality and performance attributes of raw
and in-process materials and processes with the goal of ensuring final product quality.
In-process tests Tests which may be performed during the manufacture of either the drug substance Q6a
or drug product, rather than as part of the formal battery of tests which are Process Control See In-Process Control. Q7
conducted prior to release.
Process Robustness Ability of a process to tolerate variability of materials and changes of the process and Q8(R2)
Intermediate For biotechnological/ biological products, a material produced during a manufacturing Q5c equipment without negative impact on quality.
process that is not the drug substance or the drug product but for which manufacture
is critical to the successful production of the drug substance or the drug product. Process-related impurities Impurities that are derived from the manufacturing process. They may be derived Q6b
Generally, an intermediate will be quantifiable and specifications will be established to from cell substrates, culture (eg, inducers, antibiotics, or media components), or from
determine the successful completion of the manufacturing step before continuation downstream processing (eg, processing reagents or column leachables).
of the manufacturing process. This includes material that may undergo further
molecular modification or be held for an extended period before further processing. Process-related impurities These are impurities that develop from, or are introduced by, the biological or chemical Q3B(R2),
processes by which the product is made.

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 Product lifecycle All phases in the life of a product from the initial development through marketing Q8(R2) Risk evaluation The comparison of the estimated risk to given risk criteria using a quantitative or Q9
until the product's discontinuation. qualitative scale to determine the significance of the risk.

All phases in the life of the product from the initial development through marketing Q9 Severity A measure of the possible consequences of a hazard, which is a component of a Q9
until the product‘s discontinuation. Failure Modes Effects Analysis (FMEA).
Product-related impurities Product-related impurities are molecular variants of the desired product arising from Q6b Specification A specification is a list of tests, references to analytical procedures, and appropriate Q6b
processing or during storage (eg, certain degradation products) which do not have acceptance criteria with numerical limits, ranges, or other criteria for the tests
properties comparable to those of the desired product with respect to activity, efficacy, described, which establishes the set of criteria to which a drug substance or drug
and safety. product or materials at other stages of their manufacture should conform to be
Product-related Product-related substances are molecular variants of the desired product which are Q6b considered acceptable for its intended use.
substances active and have no deleterious effect on the safety and efficacy of the drug product. Specification - Release The combination of physical, chemical, biological and microbiological tests and Q1a(R2)
These variants possess properties comparable to the desired product and are not acceptance criteria that determine the suitability of a drug product at the time of its
considered impurities. release.
Protocol Method for carrying out an experiment and/or creating an official record of scientific Oxford English Statistical Process Control Statistical process control (SPC) is a method of quality control which uses statistical Q8 (R2), [13],
or experimental observations. Written GMP Protocols define prospectively the Dictionary online (SPC) methods. SPC is applied in order to monitor and control a process. Monitoring and
conditions which will be tested, sample testing plan, and acceptance criteria for controlling the process ensures that it operates at its full potential. At its full potential,
results. the process can make as much conforming product as possible with a minimum (if not
Proven Acceptable Range A characterized range of a process parameter for which operation within this range, Q8(R2) an elimination) of waste (rework or Scrap). SPC can be applied to any process where
while keeping other parameters constant, will result in producing a material meeting the "conforming product" (product meeting specifications) output can be measured.
relevant quality criteria. Key tools used in SPC include control charts; a focus on continuous improvement;
and the design of experiments. An example of a process where SPC is applied is
manufacturing lines.
Quality The degree to which a set of inherent properties of a product, system or process fulfils Q9
requirements. Testing plan A determination as to whether routine monitoring, characterization testing, in CMC-BWG
process monitoring, stability testing, or no testing is conducted as a part of the overall
Quality Attribute (QA) A molecular or product characteristic that is selected for its ability to help indicate Q5e control strategy. Extended testing plans may be put in place to demonstrate that
the quality of the product. Collectively, the quality attributes define the adventitious valuable resources can be used more than once. It may also be necessary to establish
agent safety, purity, potency, identity, and stability of the product. Specifications additional tests to understand sources of variation and to demonstrate that changes
measure a selected subset of the quality attributes. to the process have addressed sources of variation that are considered to present
Quality by Design A systematic approach to development that begins with predefined objectives and Q8(R2) appreciable risk to product quality.
emphasizes product and process understanding and process control, based on sound TPP See Quality Target Product Profile. Q8 (R2)
science and quality risk management.
Quality Control (QC) Checking or testing, that specifications are met. Q7 Viable Cell Concentration A measure of the number of viable cells per unit volume. [25]
(VCC)
Quality Target Product A prospective summary of the quality characteristics of a drug product that ideally Q8 (R2)
Well Controlled Critical A process parameter which is controlled by process design and standardized CMC-BWG
Profile (QTPP) will be achieved to ensure the desired quality, taking into account safety and efficacy
Process Parameter (WC- procedures or automated control systems that ensure it remains within the design
of the drug product.
CPP) space of the process. It is only likely to vary beyond the design space if there is a
Quality risk management A systematic process for the assessment, control, communication, and review of risks Q9 failure in the control system and failure modes for this situation are likely to be
to the quality of the drug product across the product lifecycle. mitigated.
Raw material Raw material is a collective name for substances or components used in the Q6b
manufacture of the drug substance or drug product.
Reference standards/ In addition to the existing international/national standards, it is usually necessary to Q6b
materials create in-house reference materials.

In-house primary reference material: a primary reference material is an appropriately

characterized material prepared by the manufacturer from a representative lot(s) for
the purpose of biological assay and physicochemical testing of subsequent lots, and
against which in-house working reference material is calibrated.
Risk The combination of the probability of occurrence of harm and the severity of that Q9
harm (ISO/IEC Guide 51).

Risk analysis The estimation of the risk associated with the identified hazards. Q9

Risk assessment A systematic process of organizing information to support a risk decision to be made Q9
within a risk management process. It consists of the identification of hazards and the
analysis and evaluation of risks associated with exposure to those hazards.

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