CONTINUED PROCESS
VERIFICATION: AN INDUSTRY
POSITION PAPER WITH
Page 2 – BPOG CONTINUED PROCESS VERIFICATION: AN INDUSTRY POSITION PAPER WITH EXAMPLE PLAN
The following people were lead contributors to the content of this document, writing sections,
editing and liaising with colleagues to ensure that the messages it contains are representative
of current thinking across the biopharmaceutical industry. This document is a consensus view
of a model CPV Plan, but it does not represent fully, the internal policies of the contributing
companies.
Cynthia Ball (AstraZeneca), Joerg Gampfer (Baxter), John Grunkemeier (Bayer), Madeline Roche (Gallus), Lada Laenan (Genzyme), Dan Baker (GSK), Rajesh Beri (Lonza), Julia O’Neill (Merck), Abe Germansderfer (Novartis), Jeff Fleming (Pfizer), Jenny McNay (Regeneron).
Additionally, excellent editorial support and constructive criticism was provided by:
Ranjit Deschmukh (AstraZeneca), Mark Smith (Genentech/Roche), Beth Junker (Merck), Christelle Pradines (Novartis) Eric Hamann (Pfizer), Paul McCormac (Pfizer), Rajesh Ahuja (Regeneron), Bert Frohlich (Shire).
The work was facilitated by Darren Whitman and Robin Payne of the BioPhorum Operations Group (BPOG).
Though this paper is issued under copyright, © 2014, BPOG - Biophorum Operations Group, it is intended to be readily accessed across the industry, free of charge and can be accessed from the BioPhorum website at the following address: www.biophorum.com/Page/123/BPOG-CPV-Case-Study.htm
When citing this paper, please use the following form:
BPOG, 2014, Continued Process Verification: An Industry Position Paper with Example Plan, © 2014, BPOG - Biophorum Operations Group
CPV PAPER LEADING
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,
manufacturers in the biopharmaceutical sector all wish to respond to this guidance appropriately.
A group of 20+ companies felt it would be valuable to work on this topic together, using the
facilitation services of the BioPhorum Operations Group (BPOG) (www.biophorum.com). This
paper is one of the results of the collaborative effort. It is written as a consensus view of an
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.
The authors believe this is one of the first comprehensive papers on this topic.
EXECUTIVE SUMMARY
SUMMARY
The paper seeks to provide practical developments on the themes: what is CPV, why is it important, and how might it be implemented. It offers some specific recommendations on the content of a CPV Plan, along with associated rationale. These recommendations are based on a typical cell culture production process for making a fictitious monoclonal antibody product, described in the ‘A-Mab Case Study’ [3]. Consequently, not all of the details contained in this paper are going to apply directly to actual products or processes. The authors recognize that the A-Mab Case Study represents only one industry archetype, and that there are a number of others that are important. However, the concepts and principles upon which the content of this paper was derived should help with CPV implementation for a real product. Some of the complications of implementation are addressed, with recommended approaches, but the issue of information technology (IT) systems is not dealt with directly here. The case for IT systems, their design and introduction, is the subject of other collaborative efforts facilitated by BPOG and some of the results of that work may be published in the future.
CPV is fundamentally a formal means by which a commercial manufacturing process is monitored to ensure product quality.
It encompasses a written plan for monitoring a licensed biopharmaceutical manufacturing process, as well as regular reporting and actions based on the results of monitoring the process. CPV reporting provides a basis from which to improve process understanding, risk assessment, the control strategy (CS) [9], and ultimately the process itself. In general, the nature and extent of CPV is aligned with the outcomes of process qualification. Whilst a CPV Plan is likely to include data related to Batch Release (BR), and so may be useful in supporting BR decisions, CPV operates independently from the BR process and is not expected to have any impact on batches that have been previously released.
Adopting or building on an existing system of monitoring manufacturing process performance means more data will be collected over the lifetime of the product. CPV execution may involve examination of existing process control measurements and improved methods for data tracking and analysis. Enhanced monitoring of process performance provides the opportunity to identify and control sources of variation and hence improve process robustness, offering the major benefit of reliable supply to the market.
Page 4 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan 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
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: [email protected].
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
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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
10.4 STEP 4, CENTRIFUGATION AND DEPTH FILTRATION – CPV VARIABLES ...62
10.5 STEP 5, PROTEIN A CHROMATOGRAPHY – CPV VARIABLES ...63
10.6 STEP 6, LOW PH TREATMENT – CPV VARIABLES ...64
10.7 STEP 7, CATION EXCHANGE CHROMATOGRAPHY – CPV VARIABLES ...65
10.8 STEP 8, ANION EXCHANGE CHROMATOGRAPHY – CPV VARIABLES ...66
10.9 STEP 9, SMALL VIRUS RETENTIVE FILTRATION – CPV VARIABLES ...68
10.10 STEP 10, ULTRAFILTRATION AND DIAFILTRATION – CPV VARIABLES ...68
10.11 STEP 11, FINAL FILTRATION/BULK FILL AND FREEZING OF BDS – CPV VARIABLES ... 70
10.12 CPV MONITORING OF BULK DRUG SUBSTANCE LOT DATA ... 71
11.0 CPV SAMPLING PLAN ...73
11.1 TEMPLATE FOR SPECIFIC PROCESS STEPS ...76
12.1 IDENTIFYING SOFTWARE ...80
12.2 DESCRIPTION OF TOOLS TO TREND AND EVALUATE DATA ... 81
12.3 PROCESS CAPABILITY INDEX ...82
12.4 CONTROL CHARTS ...84
12.5 MULTIVARIATE DATA ANALYSIS ...86
12.6 RESPONSES TO SHIFTS AND TRENDS ...87
12.7 ESTABLISHING INITIAL LIMITS ...88
12.8 ESTABLISHING LONG-TERM LIMITS ...88
12.9 FINDING SIGNALS OF SPECIAL CAUSE VARIATION ...89
13.0 CHANGE MANAGEMENT ...90
14.0 DATA VERIFICATION ...93
15.0 DISCRETIONARY ELEMENTS OF A CPV PROGRAM ...95
16.0 TECHNICAL REFERENCES ...96
This document is written with the aim of providing a technical, non-binding, industry consensus
response to regulatory guidance. It is not in itself guidance. The objective of this paper is to provide:
(1) an example of key portions of a Continued Process Verification (CPV) plan for a biologics
process; (2) relevant industry thinking on CPV plan development and implementation.
This document is different from others on this subject [1, 2] because it is specific to a biologics
manufacturing process and provides a comprehensive case-study lifecycle view that leverages
antibody manufacturing process development, as described in the A-Mab Quality-by-Design
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
process is just one archetype in the industry, though it is a useful one upon which to demonstrate
principles, as it is known to many.
1.0 PURPOSE
The example of a CPV plan shown in this paper describes how to meet expectations [5] for routine monitoring of critical process parameters (CPPs), critical quality attributes (CQAs), key process attributes (KPAs) and key process parameters (KPPs) to demonstrate the state of control over the manufacturing process. N.B. at the time of writing, the European Medicines Agency (EMA) draft guidance on Process Validation is out for consultation, referring to KPAs as 'performance indicators'. The thought processes and examples presented in this document are backed by biotech industry experience with, subject matter expertise
in process monitoring for monoclonal antibody and similar manufacturing processes.
Furthermore, this document describes the thought processes that determine the content for a CPV plan. The plan serves as the procedure governing document for the implementation and maintenance of CPV for a licensed manufacturing process. Various parts of the plan are described in the following sections of the document, as noted in Table 1.1 overleaf:
SECTION 1.0
GENERAL TOPIC SECTION SECTION NUMBER/ TITLE
DESCRIPTION
Manufacturing Process 5 Summary of the A-Mab manufacturing process and the A-Mab product description.
6 Selection of the process monitoring sampling plan backed by the process validation Phase I and II data and the updated risk assessment.
7 The rationale for classification of quality-linked process parameters summarized in 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 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 SECTION NUMBER/ TITLE
DESCRIPTION
Verification process 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.
12 Aspects of data analysis and evaluation of results are discussed in this section. The emphasis is on the possible outcomes of routine monitoring.
13 Change management and the impact of CPV on this process. 14 The specific need for data verification.
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.
2.0 SCOPE
The application of the principles discussed in this document for new products relies on product and process development and characterization studies (Stage 1) to define the scope of the CPV program. This document is based on the CS presented in the A-Mab bioprocess development case study and is primarily focused on the commercialization of a new product. However, the proposed approach for CPV 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.
The BPOG is initiating collaborative work, specifically focused on CPV for established, licensed (or legacy) products and the resulting recommendations may be published in the future. An ISPE group produced an article covering this broadened scope in 2012 [24]; here we believe we address a reduced scope in greater detail, providing deeper development of a model CPV Plan.
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SECTION 3.0
3.0 ROLES AND
RESPONSIBILITIES
The roles and responsibilities suggested here as examples, are based upon a typical organizational
structure of a biopharmaceutical manufacturing company (Table 3.1.).
Table 3.1. Roles and Responsibilities for a CPV Program:
FUNCTIONAL AREA RESPONSIBILITY
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.
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.
• Provide documented scientific justification for parameters, limits, ranges and elements of the CS, based upon development studies or other prior knowledge.
• Provide technical input to develop response actions, including input in prioritization of continuous improvement activities.
• Consider application of CPV outcomes to new processes in development.
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. Several primary functional areas have important responsibilities
required to successfully execute the CPV program. These areas are: Development, Validation, Operations, Quality Control, Quality Engineering and Quality Assurance. Operations, a function which may also be known as Technical Operations, is assumed to contain Manufacturing as well as Manufacturing Science and Technology personnel. Mathematical sciences or non-clinical statistics support is of paramount importance in achieving sound data interpretation. Each functional area has responsibility for specific activities, as shown in Table 3.1.
Outputs of the CPV program can be used by the Regulatory Affairs and Quality organizations for annual agency updates, such as the Annual Product Review (APR) and Product Quality Review (PQR). Terminology for each function may vary by organization.
Note: The responsibilities for continued process monitoring should be clearly defined within the organization and recorded in the CPV Plan. Responsibilities can be tailored to a specific organizational structure, given its maturity and size.
FUNCTIONAL AREA RESPONSIBILITY
Operations / Manufacturing Science and Technology (N.B. It is not unusual for a Manufacturing Science and Technology function to be independent of Operations and Quality organisations. An alternative arrangement may be reporting into Process Sciences.)
• Own the manufacturing process and take responsibility to ensure that it is maintained in a state of control throughout the product lifecycle in manufacturing.
• Ensure that all required production and process data are collected as part of executing the CPV plan for the product.
• Performs continued process monitoring activities, including collecting, entering, verifying, reviewing and analyzing process data.
• Generate control charts and document CPV analysis for process data.
• Regularly participate in cross-functional teams in order to review production and QC data as part of the CPV program.
• Maintain the process commercial master batch production and control records up to date, capturing continuous improvements resulting from CPV in documentation as necessary. Quality Control • Perform quality control testing and document results that are used in CPV evaluations.
• Perform continued process monitoring activities, including collecting, entering, verifying, reviewing and analyzing QC data.
• Generate control charts and document CPV analysis for QC data.
• Participate in cross-functional teams to review production and QC data as part of the CPV program.
Quality Engineering / Mathematical Sciences / Non-Clinical Statistics
• Provide internal advice on statistical analyses needed to successfully complete CPV activities. • Act as a Subject Matter Expert (SME) and train personnel in other groups on statistical data
analysis techniques used in CPV.
• 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.
• 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.
Quality Assurance • Review and approve CPV plans and reports.
• Review and approve the list of attributes and parameters to be monitored, and control chart limits.
• Participate in cross-functional data review to review production and QC data as part of the CPV program.
• Review CPV reports and establish where signals require formal non-conformance investigations.
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SECTION 4.0
4.0 CPV PLAN
REFERENCES
The following references are expected to be created in the quality management system and are
important when constructing a CPV plan, providing background and critical internal interpretation
of regulatory guidance. They should be referenced accurately in a CPV Plan document. Note,
a CPV Plan is expected to be product and process specific. It may be advantageous to develop
corporate policies and this forms the basis for some of the list of references that follows.
• Quality Policy, Manual or Master Plan on CPV
• Company Standard/Guideline for CPV (requirements for CPV, for e.g. timing, relationship to APRs, etc)
• SOP on CPV (Definitions, Abbreviations, responses to deviations, report generation, etc)
• SOP on Statistical Methods for trending, statistical analysis and identifying special cause variations
• Template for CPV Plan
• Template for CPV Charts & Graphs • Template for CPV Report
• Manufacturing process description
• Control Strategy for the process (version number) • Process risk assessment (version number)
• Applicable Risk assessment(s) (version number) providing basis for rationale of CPV monitoring selection • Previous annual product report(s) if available, otherwise
consider evidence for a similar product*.
Technical references relevant to the detailed sections of this paper are provided in section 16. References 1 to 9 are recommended as initial texts when creating or updating a CPV plan.
* 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.
5.0 PRODUCT AND
PROCESS DESCRIPTION
In preparing this CPV example plan, it is assumed that Stage 2, was completed successfully for the A-Mab process. The plan described applies to Stage 3 of the process validation lifecycle.
Note: Whilst a QbD approach could be said to provide advantages in terms of process understanding, it is not an approach that has to be applied. However, it is necessary to have a CPV Plan for each product, even if a QbD approach has not been applied.
The A-Mab case study describes a model Quality by Design (QbD) approach for development of
a monoclonal antibody (A-Mab) [3, 6]. Considering the FDA process validation guideline [5],
the case study includes work covered during Stage 1 (Process Design) but does not include
information on Stage 2, Process Performance Qualification (PPQ) [5].
Page 14 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan PPQ CPV CPV TTP QTTP CQA CCP EQ Proven Acceptable Ranges (Design Space) Covered in A-Map Study
Short-term
Plan Long-termPlan
Development of Control Strategy
PV Stage 2 PV Stage 3
PV Stage 1
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.
5.1
BRIEF DESCRIPTION OF THE GENERAL APPROACH USED IN THE
A-MAB CASE STUDY
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);
• 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].
5.2
PARAMETERS TO BE INCLUDED IN CPV
All types of parameters should be considered for inclusionin 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.
(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.
Page 16 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
Thaw Working Cell Bank
Seed Culture Expansion in disposable shake flasks
and/or bags
Seed Culture Expansion in fixed stirred tank reactors
N-1 Seed Culture Bioreactor 3000L WV
Production Bioreactor 15,000 L WV
Harvest Centrifugation & Depth Filtration
Clarified bulk Step 4 Step 3 Step 2 Step 1 Nutrient feed Glucose feeds Seed maintenance Seed maintenance
Seed cultures are expanded through multiple passages by increasing the volume and/or number of disposable culture vessels. Seed cultures may be maintained for additional culture passages or used to generate additional inoculums trains.
Additional seed expansion in fixed stirred tank bioreactors. Cultures obtained from Step 1 are expanded to increase the volume of culture to meet the target initial cell density for the production bioreactor.
Production bioreactor is inoculated with the seed culture prepared in Step 2 to achieve an initial Viable Cell Concentration (VCC) and is cultivated at controlled conditions for temperature, pH and dissolved oxygen (DO). A bolus addition of nutrient feed (NF-1) and multiple discrete glucose feeds are used to maintain the glucose concentration at > 1.0 g/L. Antifoam solution is used for foam control of the agitated mixture. VCC, culture viability and residual glucose concentration are monitored periodically. The fermentation reaction produces a mixture containing the A-Mab drug substance. Cultures are clarified by a primary continuous 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 provide a clarified bulk solution of A-Mab.
5.3
UPSTREAM PROCESS OVERVIEW
The upstream commercial manufacturing process for A-Mab comprises 4 steps and is summarized below and in Figure 5.4. The A-Mab cell culture process uses a proprietary, chemically defined, basal medium formulation. The medium is essentially protein free with recombinant human insulin (1 mg/mL) being the only protein component added. The growth medium also contains 1 g/L pluronic and 50 nM methotrexate, which are added up to the N-2 seed bioreactor. The N-1 and production bioreactor steps do not contain methotrexate.
Step 5
Protein A Affinity Chromatography
Step 6 Low pH Incubation
Step 7
Cation Exchange Chromatography
Step 8
Anion Exchange Chromatography
Step 9 Small Virus Retentive Filtration
Step 11 Final Filtration, Fill and Freeze
Clarified Purpose
Purpose of step
• Capture monoclonal antibody from clarified harvest liquid
• Removal of process-related impurities (HCP, DNA and small molecules)
Step 10 Formulation: Ultrafiltration and Diafiltration A
A-Mab drug substance
• Inactivate enveloped viruses that are potentially present in therapeutic protein products derived from mammalian cell culture
• Reduce aggregate to acceptable levels for drug substance
• Reduce HCP to acceptable levels for subsequent processing by AEX chromatography
• Remove HCP, DNA, Protein A and endotoxins to levels that meet drug substance acceptance criteria • Virus removal
• Removal of small parvoviruses such as minute virus of mice (MVM) and larger viruses such as murine leukemia virus (MuLV), potentially present in product derived from mammalian cell culture • Formulation and concentration of mAb to drug substance specifications (e.g. 75 g A-Mab/L)
• Sterilize filtration and dispensing for drug substance storage
5.4
DOWNSTREAM PROCESS OVERVIEW
The downstream manufacturing process for A-Mab comprises 7 steps which are summarized in Figure 5.5.
The downstream process captures A-Mab from the clarified bulk and purifies the antibody by a combination of chromatography unit operations [11]. Also included in the process are two orthogonal steps dedicated to virus inactivation and removal. The antibody is formulated through an Ultra-Filtration/Dia-Filtration (UF/DF) step to a composition and concentration suitable for drug product manufacturing. The formulated product is 0.2 μm filtered, filled into the appropriate storage containers and stored frozen. Figure 5.5. Downstream process flow diagram. [Adapted from A-Mab case study, Pages 113 (Figure 4.1) and 114 (Table 4.1)]
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5.5
IDENTIFICATION OF CQAS AND ACCEPTANCE RANGES
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 in the label. Attributes in the red box are determined during Drug Substance (DS) manufacturing. Therefore, these attributes guide determination of DS CQAs [22] relevant for establishing a CPV strategy.
Table 5.6.1. QTPP for A-Mab (reference 3, Page 180). DS relevant product attributes are marked with a red box.
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 impact on patient safety.
PRODUCT ATTRIBUTE TARGET
Dosage Form Liquid, single use
Protein content per vial 500mg
Dose 10mg/kg
Concentration 25mg/mL
Mode of administration IV, diluted with isotonic saline or dextrose
Viscosity Acceptable for manufacturing, storage and delivery without the use of special devices (for example, less than 10 cP at room temperature
Container 20R type 1 borosilicate glass vials, fluro-resin laminated stopper
Shelf life ≥ 2 years at 2–8°C
Compatibility with manufacturing
process Minimum 14 days at 25°C and subsequent 2 years at 2–8°C, soluble at higher concentration during UF/DF
Biocompatibility Acceptable toleration on infusion
Degradants and impurites Below safety threshold, or qualified
Pharmacopeial compliance Meets pharmacopoeial requirements for parental dosage forms, colorless to slightly yellow, practically free of visible particles and meets USP criteria for
sub-visiable particles
Aggregate 0–5%
Fucose conent 2–13%
Galactosylation (%G1+%G2) 10–40%
“PRODUCT QUALITY ATTRIBUTES” RAW MATERIAL CONTROLS STEPS 1 & 2: SEED CULTURE EXPANSION STEP3: PRODUCTION BIOREACTOR STEP 4: CENTRIFUGATION AND CLARIFICATION STEP 5: PROTEIN A CHROMATOGRAPHY STEP 6: LOW PH TREATMENT STEP 7: CEX CHROMATOGRAPHY STEP 8: AEX CHROMATOGRAPHY STEP 9: NANO-FILTRATION (SVRF) STEP 10: ULTRA-FILTRATION (UF/DF) STEP 11: FINAL FILTRATION AND FREEZING BDS OR DP TESTING FOR THIS CQA?
IDENTITY Form Form BDS, DP PRO TEIN CONCENTRA TION Form Alter Alter Alter Alter Alter DP IPC ADCC ACTIVITY Form DP SEC MONOMER Form BDS, DP SEC AGGREGA TES Form Remove Form Remove Remove Form Form Form BDS, DP COLOR Intr oduce Alter Alter DP
CLARITY & SUB-VISIBLE PARTICLES
Intr oduce Alter Remove Remove DP DEAMIDA TED ISOFORMS Form Remove Remove Remove BDS, DP O THER ACIDIC V ARIANTS Form Remove Remove Remove BDS, DP CHARGE V ARIANTS Form Remove Remove Remove BDS, DP “OLIGOSACCHARIDES: AFUCOSYLA TED GL YCANS GALACT OSYLA TED GL YCANS” Form “GL YCOSYLA TION RELA TED:
SIALIC ACID CONTENT
, MANNOSE CONTENT , NON-GL YCOSYLA TED HEA VY CHAIN” Form OSMOLALITY Alter DP IPC PH Alter Alter Alter Alter Alter Alter DP IPC METHO TREXA TE Intr oduce Intr oduce Remove Remove Remove non-r outine ANTIFOAM C Intr oduce Intr oduce Remove Remove non-r outine PRO TEIN A LIGAND Intr oduce Intr oduce Remove Remove Remove
HOST CELL PRO
TEIN (HCP) Form Form Remove Remove Remove Remove non-r outine DNA Form Form Remove Remove BIOBURDEN Intr oduce Intr oduce Intr oduce Intr oduce Intr oduce Intr oduce Intr oduce Intr oduce Intr oduce Remove DP ENDO TOXIN Intr oduce Intr oduce Intr oduce Intr oduce Intr oduce Intr oduce Intr oduce Intr oduce BDS, DP
“ADVENTITIOUS VIRAL AGENTS (A
VA)” Intr oduce Intr oduce Intr oduce Inactivation Remove Remove step 3 IPC, BDS r elease impacted by CPP= impacted by WC-CPP= impacted by KPP=
no key impact claimed=
entry test or pr
ep contr
ol=
The product quality attributes and the points where they are impacted in the A-Mab drug substance process are summarized in the Table 5.6.2 below.
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.
Page 20 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
5.6
PROCESS PARAMETER CHARACTERIZATION
In reviewing the A-Mab process information while preparing the CPV plan, members of the BPOG team questioned the completeness of the CPPs, KPPs and Key Process Attributes (KPAs) identified in the case study. Specifically, it was felt two steps of the downstream process (step 10 UF/DF, and step 11 final filtration and freezing of the Bulk Drug Substance, BDS) were not addressed in sufficient detail in the case study for the purpose of developing a CPV Plan, so typical characterization outcomes 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 processes. The following table summarizes all CPPs, in-process quality attributes (IPQAs), KPPs and KPAs identified for the process in preparation for CPV.
Table 5.7. Critical and key process parameters and key process attributes identified during process characterization. Lists were amended during planning for CPV (bold entries)
PROCESS STEP CRITICAL PROCESS
PARAMETERS IN-PROCESS CONTROLS KEY PROCESS PARAMETERS KEY PROCESS ATTRIBUTES
Step 1: Seed Culture
Expansion in disposable shake flasks and/ or bags
None None Temperature,
Culture duration, Initial VCC/ split ratio
VCC (viable cell conc), Culture viability
Step 2: Seed Culture
Expansion in fixed stirred tank reactors
None None Temperature,
pH, Dissolved oxygen, Culture duration, Initial VCC/ split ratio
VCC,
Culture viability
Step 3: Production
Bioreactor 15,000L WV Temperature,pH,
Max partial pressure of CO2 (pCO2), Culture duration, Medium Osmolality Bioburden, Mycoplasma, MMV and AVA
(murine minute virus and adventitious viral agents)
Antifoam conc., Time of nutrient feed, Volume of nutrient feed, Time of glucose feed, Volume of glucose feed, Dissolved oxygen
Product yield (titer), Viability at harvest, Turbidity at harvest, Peak VCC, Remnant glucose concentration
Step 4: Harvest
Centrifugation & Depth Filtration
None None Flow rate, Pressure,
PROCESS STEP CRITICAL PROCESS
PARAMETERS IN-PROCESS CONTROLS KEY PROCESS PARAMETERS KEY PROCESS ATTRIBUTES
Step 5: Protein
A Affinity Chromatography
Protein load ratio,
Elution buffer pH Bioburden, Endotoxin End collection,Step duration Step yield
Step 6: Low pH
Incubation pH,Time, Temperature
Bioburden,
Endotoxin Quantity of acid added
Step 7: Cation
Exchange Chromatography
Protein load ratio, Wash conductivity, Elution pH, Elution stop collect
Bioburden,
Endotoxin Step duration Step yield,Eluate volume
Step 8: Anion Exchange
Chromatography Equilibration/ Wash1 buffer conductivity, Protein load ratio, Load conductivity, Load pH, Flow rate
Bioburden,
Endotoxin Step duration Step yield
Step 9: Small Virus
Retentive Filtration Operating pressure,Filtration volume Bioburden, Endotoxin None Step yield
Step 10: Formulation: Ultrafiltration and Diafiltraion Number of dia-volumes, pH,
Step processing time, Protein conc. prior to fill
Bioburden,
Endotoxin Protein conc. prior to Diafiltration, Recirculation flow rate
Step yield,
Permeate flow rate
Step 11: Final
Filtration, Fill and Freeze None Bioburden, Endotoxin Filtration volume,Filtration time, Maximum (inlet) pressure
Page 22 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
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 impactproduct 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.
6.1
RATIONALE AND BACKGROUND
In general, the points in the process to be monitored during CPV should be comparable to, but not necessarily include all of those selected during the initial validation. If limited data results are available at the time of PPQ completion, prior to execution of the CPV plan, a short term sampling plan may be established to continue sampling based on the PPQ protocol until sufficient data results are gathered in preparation for CPV. Additional considerations that influence the determination of which points in the process are monitored during a CPV exercise are summarized below. (1) The final classification of attributes should be revisited. (2) The process risk assessment, which is typically performed prior to the initial PPQ, should be revisited and updated to develop the CPV plan. The revised risk assessment should reflect learning obtained during PPQ, any additional laboratory process characterization information, and key findings from historical manufacturing experience. In revisiting the process risk assessment prior to commercial manufacture, late stage clinical manufacturing knowledge is particularly important. Levels of risk, and indeed the range of risks, that apply in the manufacturing environment might
be quite different to those anticipated from the early stage development environment.
(3) The control strategy should be updated as necessary and hence the CPV Plan.
The selection of points in the manufacturing process that are to be monitored for CPV purposes may be either a subset of those selected during PPQ or include additional monitoring points beyond those included in the initial PPQ to reflect new learning obtained since the initial validation was conducted. This includes but is not limited to:
• New CS elements
• Process elements that have proved challenging but may not have been covered during the initial process validation
• Changed or additional analytical capabilities, including the availability of online data collection systems and improvements in assay or instrument capabilities • If a parameter has been shown to have good control and
consistency, it may not be necessary to continue monitoring this parameter in subsequent CPV evaluations.
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.
6.0 DEVELOPING A MONITORING
STRATEGY
Page 24 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan (4) CPPs, WC-CPPs, KPPs and GPPs should be clearly specified.
These parameters and established release specifications, additional product characterization testing, and KPAs should be appropriately considered during CPV. Any changes since the initial validation should be explained and justified. (5) All changes implemented should be assessed in the context of potential impact on process validation. Process changes which may have occurred after the PPQ, such as vendor initiated change in a raw material, should be handled a change control process including but not limited to data trending and risk assessments, to determine if the change has any impact on process performance and/ or product quality. These changes may potentially require additional testing beyond that performed as part of PPQ to ensure full characterization. Such testing may be incorporated as part of CPV or may be handled separately as part of the company’s change control process, depending on the nature of the change and the potential for product impact.
(6) Appropriate regulatory reporting of CPV outcomes, such as inclusion in the Annual Product Review (APR), must be made for any conclusions related to process assessment conducted during CPV. The CPV reports should be consistent with regulatory reporting standards, so that CPV charts may be copied and pasted directly into the regulatory submissions or included as an attachment. The regulatory submissions then provide context and unify the information presented in the attached CPV reports.
(7) Other elements of Good Manufacturing Practice (GMP) applicable to biopharmaceutical production operations are assumed to be handled by appropriate quality systems and are therefore outside the scope of this document, and will not be discussed further in the context of process validation. In particular, acceptable microbial control is a critical element for any biopharmaceutical process and is typically demonstrated via initial validation efforts and then monitored as part of routine operations.
Scenario 1: Supplier change notification -
culture medium change.
A supplier converted to a new process to manufacture a cell culture medium ingredient that may alter its performance in the A-Mab process without impacting the material procurement specifications. No intentional changes to composition, test requirements or certificate of analysis were made. The following justification for the change was provided:
(1) Improved control of temperature during blending reduces potential for degradation of the heat labile components; (2) Equipment cleaning will use robust validated cycles to reduce ingredient carryover risks;
(3) Equipment is located in an Animal Origin Free area to reduce cross contamination risks.
The following strategy was employed to introduce the revised cell culture medium:
6.2
HYPOTHETICAL SCENARIOS AND PLANNED PROCESS CHANGES
Five hypothetical scenarios and planned changes are provided below to illustrate how the CPV
monitoring plan might be affected by events encountered during commercialization of a product
such as A-Mab. In this example it is assumed that the PPQ campaign proceeded smoothly
and that the expected results were achieved. In particular, CPPs, WC-CPPs, KPPs and GPP are
defined and achievable and the process CS is appropriately established. The process CS is
assumed to include input raw material controls, procedural controls, process parameter controls
and monitoring, in-process testing, and product specification testing (see Figure 5.1.1). These
scenarios are accounted for in the CPV plan:
• Determining process and quality impact for the material change through the change control process was electively agreed to by process experts and quality representatives via verification testing of culture performance and the ability to operate within the established parameters and attributes;
• A study was thus completed in the small-scale model from thaw through the production bioreactor to provide additional process characterization data and establish confidence in expectations of process control when the new material lot is introduced into the commercial scale process;
• Minor but statistically significant differences for KPPs normal operating ranges and attributes (e.g. VCC, and cell density, titer and turbidity at the end of the bioreactor production) were identified at small scale; • Medium qualification attributes should be assessed in
the change control evaluation to determine if/ how these attributes may be impacted. The supplier was requested to demonstrate if a detectable mean shift in any of their output tests could be identified with respect to their change.
Small scale production bioreactor material was purified downstream. No structural modifications to the protein, or shifts in CQAs were observed. Based on the outcome of the small scale studies, a comparison should be made to evaluate the product quality obtained at full scale, to verify that no unexpected quality change has occurred and to provide further verification of process control ranges and performance outcomes.
A CPV plan is expected to take account of this type of scenario, providing the internal policies and procedures upon which decisions related to changes in process verification should be based. The change described in this scenario can be addressed through the change management system and does not require additional sampling in the CPV plan, as routine sampling is already in place to monitor the upstream cell growth impact of this scenario (Tables 7.1, 7.2, 7.3 and 10.1, 10.2, 10.3). Potential downstream impact could be included in the monitoring plan, e.g. the KPAs of inlet pressure to depth filters and duration of the broth clarification, which are suggested as optional items for CPV in Tables 7.4, 10.4.
Note: Attributes should only be considered optional after their impact on the process has been risk assessed and any lack of monitoring fully justified.
Scenario 2: High Protein A leachate observed
in chromatography eluate, Step 5.
A PPQ batch contained 123 mg of protein A/g A-Mab in the Protein A pool, which exceeded the control limit for this process-related impurity. Investigation revealed that: • Protein A ligand released from the chromatography resin
(‘Resin A’ from Supplier A) and entered the process stream during product elution. R&D and Supplier A confirmed that elevated amounts of Protein A can leach from the bead surface during an initial elution after extended resin storage, even when storing under recommended conditions;
• Extended storage can cause increased Protein A leaching in the next use cycle. The resin storage time of more than 12 months between the last clinical manufacturing batch and first PPQ batch was longer than previously experienced and was not represented in small scale trials used to establish PPQ limits;
• In-process testing of the Protein A clearance will be performed to further demonstrate downstream process capability of control of this product quality attribute (AEX Table 7.8, 10.8);
• The level measured in the Protein A step eluate for the batch implicated by this scenario was orders of magnitude below the impurity safety limit for final drug product. Also, at full scale in the affected PPQ batch, downstream clearance of Protein A below the detectable level was demonstrated which is consistent with small-scale observations that the subsequent chromatography steps are capable of removing Protein A (The possibility that limits or controls on extended storage time, conditions, and/ or resin treatments may need to be considered if data indicates the clearance capability of the process is not sufficiently high enough for the reader’s situation). An additional Design of Experiments (DOE) study was conducted after PPQ to determine the potential for Protein A leaching relative to storage time, resin age (use cycles) and storage conditions. Spiking study confirmation of clearance capabilities in the downstream process steps was achieved and is discussed in the amended CS revision completed after the PPQ experience, where the new CPPs to control clearance are clearly identified. Within CPV, results will be monitored to detect any departures from the expected behavior observed during development; monitoring tools such as ‘tool wear charts’ or ‘residuals charts’ may be useful, and consultation with a statistician is recommended. These tools are mentioned again in Section 12.4.
PAGE 26 – BPOG CONTINUED PROCESS VERIFICATION: AN INDUSTRY POSITION PAPER WITH EXAMPLE PLAN
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.
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.
Page 28 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
SECTION 7.0
7.0 CPV PLAN
RECOMMENDATIONS FOR THE
A-MAB PROCESS
This section describes, for each of the A-Mab process steps, what to include in the CPV plan and
the justification for its conclusion. This justification is primarily based on process knowledge
and process experience. A table is provided for each step to summarize the recommendations for
CPV. Discretionary items are also included that may be needed in a CPV program depending on
the assurance of process understanding or that provide additional depth to the monitoring plan.
No recommendation for including in-process product pool hold times in CPV is proposed, because the hold times were validated as part of the basis for controls within the Master BRc. In the event that a hold time is exceeded this one-off event would trigger a deviation within the Quality System, under which impact to product quality would be determined. In the steps with elution of product from resin beds (i.e. steps 5 and 7), several resin loading/ elution cycles are used to process each batch. No controls have been identified for resin regeneration operations in either of these steps. For these steps, concurrent validation of the resin use lifetime includes periodic sample testing of appropriate quality attributes for continued verification of packed resin effectiveness during its use lifetime. Effectiveness of resin regeneration conditions is included in the ongoing resin use validations. Therefore monitoring of CQAs for this purpose need not be included in the CPV plan. Continued monitoring, and further verification of effective process controls, should be considered for CPV when resin use lifetime monitoring ceases, if further data are needed for understanding of impurity clearance.
No recommendation for including in-process hold times in CPV is proposed because ongoing study of hold times during commercial manufacturing is conducted using a separate hold time qualification study.
Steps that have in-process quality attributes related to microbial control (bioburden, endotoxin) are sampled and
tested as routine in-process controls. The nature of test results in this case (approximately 0 cfu/ sample, and ≤ Limit of Quantification, LOQ, respectively) do not permit meaningful Statistical Process Control (SPC) analysis in CPV. QC microbiology laboratory review of these results against action and alert limits will provide appropriate monitoring for drift in microbial control of the process and management of deviations, so monitoring, data analysis and any response to bioburden and endotoxin results are not included under this CPV plan.
Note: It could be seen as best practice that the quality system for bioburden and endotoxin monitoring and the CPV system are connected, so that any deviations would be reflected in CPV Reports.
Statistical criteria that may be applied to analyses of data are discussed in section 12.
The A-Mab case study did not identify any critical raw materials or address CS or risk assessment for input material controls. However, as a result of a hypothetical culture medium change described in section 6, one monitoring recommendation related to material variability is provided as a recommendation for the CPV plan. Additional monitoring of materials used in the bulk drug formulation is also included as an option.
The process risk assessment established that steps 1 and 2 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, such as cell banks and media components, assure use of the intended genetic cell line to produce A-Mab and control introduction of endotoxins which could affect cell metabolism. CPV for this step should focus on process consistency and obtaining sufficient data to calculate long-term control limits (see Sections 9.0 and 10 for further discussion and examples of control limits, and Section 12 for information on the statistical basis for control limits. which account for normal process variability. As stated in the A-Mab case study and demonstrated in the PPQ, BR procedures, SOPs, automated process controls and use of alarms all ensure the
seed expansion steps are routinely monitored and operated 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 is shown in Table 7.1 below.
Environmental Monitoring (EM) is routinely performed for open (under appropriate ISO classified conditions) process manipulations (including use of Rodac and settling plates) to demonstrate microbial control and the existing QC laboratory program is established for reporting results and assessing trends. Therefore inclusion of this EM monitoring plan in the CPV plan is unnecessary. As noted previously, these systems need to connect as it would be best practice to ensure deviations are present in CPV Reports.
7.1
STEP 1, SEED CULTURE EXPANSION IN DISPOSABLE VESSELS –
CPV RECOMMENDATIONS
Table 7.1. Step 1 CPV recommendations
VARIABLE CLASS CQAS
IMPACTED CPV RECOMMENDATION & JUSTIFICATION DETERMINATION METHOD AND/OR SOURCE TYPE OF DATA EXPECTED/ ANALYTICAL APPROACH VCC
(each passage end) KPA
– Include, to verify process consistency
Routine batch documentation for each passage.
Discrete value, univariate
OPTIONAL ELEMENTS TO INCLUDE IN CPV Initial VCC/split ratio
(each passage) KPP
– Optional, to verify process consistency
Calculation from routine batch documentation for each passage, ratio of passage ending cell density over initial cell density of next passage.
Discrete value, multivariate
Culture duration
(each passage) KPP
– Optional, to verify process consistency
Routine batch documentation for each passage.
Discrete value, univariate
Culture viability
(each passage end) KPA
– Optional, to verify process consistency
Routine batch documentation for each passage.
Page 30 – BPOG Continued Process Verification: An Industry Position Paper With Example Plan
7.2
STEP 2, SEED CULTURE EXPANSION IN BIOREACTORS –
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 variability. Expansion culture conditions may impact cell biology which in turn can impact product quality during product expression. CPV for this step should focus on process consistency and obtaining sufficient data to resolve long-term control limits which account for normal process variability.
Inclusion of EM in the CPV plan is unnecessary because an existing QC program is established for reporting and trending of EM results.
VARIABLE CLASS CQAS
IMPACTED CPV RECOMMENDATION & JUSTIFICATION DETERMINATION METHOD AND/OR SOURCE TYPE OF DATA EXPECTED/ ANALYTICAL APPROACH
VCC
(each passage end) KPA – Include, to verify process consistency Routine batch documentation for each passage.
Discrete value, univariate
OPTIONAL ELEMENTS TO INCLUDE IN CPV
Initial VCC/ split ratio
(each passage) KPP – Optional, to verify process consistency Calculation from routine batch documentation for each passage, ratio of passage ending cell density over initial cell density of next passage.
Discrete value, multivar