THE LIFECYCLE OF PROCESS VALIDATION:

AN INDUSTRY CASE STUDY ON CONTINUED

PROCESS VERIFICATION (CPV)
OUTPUT FROM BIOPHORUM OPERATIONS GROUP (BPOG)
COLLABORATION OF BIOTECH COMPANIES

Stefanie Pluschkell, Ph.D., Pfizer Inc.

Presenting to the CASSS CMC Strategy Forum Japan, Dec 2014
on behalf of the BPOG CPV Workstream

CMC Strategy Forum Japan, Tokyo, December 2014

09-Dec-2014
What are the Messages we like to convey?

Bioidentical
expectations Non-comparables
Science and Risk should are unrealistic are unacceptable
Drive Decisions

Not all CMC Changes are

created equal
Fit for Purpose is
better than trying to do
Everything

Changing the Address

Does not cause Mutations
Repetitious Testing or Inspecting
Does not change the result

Innovation and
Continuous Improvement
benefit from
Harmonized standards Pfizer Confidential 2
 INDUSTRY CASE STUDY: CONTINUED PROCESS VERIFICATION (CPV) FOR A
BIOTECH PRODUCT
OUTPUT FROM BIOPHORUM OPERATIONS GROUP (BPOG) COLLABORATION OF BIOTECH COMPANIES

Summary
Continued Process Verification (CPV) encompasses a written plan for monitoring a licensed biopharmaceutical
manufacturing process, then documenting and reporting the results. CPV reporting provides a basis from which to
improve process understanding, and hence risk assessment, control strategy, and ultimately process improvement.
This presentation describes one of the first cross-company efforts to be compiled on CPV in response to the FDAs
2011 process validation guidance. It has been created by representatives from 20+ biopharmaceutical companies,
sharing and building knowledge, with support and facilitation from the BioPhorum Operations Group (BPOG)
(www.biophorum.com). We describe general approaches to implementing CPV and offer some specific
recommendations on the content of a CPV Protocol, along with associated rationale. These recommendations are
based on a typical cell culture production process for making a fictitious monoclonal antibody product described in
the A-Mab Case Study. Consequently, these recommendations may not apply directly to specific products or
processes, but the principles and concepts described can be considered where applicable.

CMC Strategy Forum Japan, Tokyo, December 2014

09-Dec-2014
Outline Case Study on Continued Process Verification

1. Background on BPOG and CPV Working Team

2. Why CPV?

3. Case Study Paper

4. CPV Plan Construction

5. CPV Execution and Application Example

6. CPV Costs and Benefits

7. Conclusions and Future Opportunities

CMC Strategy Forum Japan, Tokyo, December 2014

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 1. Background
BioPhorum Operations Group (BPOG)

CPV Team

CPV Informatics
BioPhorum Team
BioPhorum
Development Group

The BioPhorum Operations Group (BPOG) is an industry-wide collaboration to

enable networking and to share best practice in the area of Operations.
Beginning in 2008, it now has 26 member companies with over 600
participating representatives.
The community primarily consists of experts from biopharmaceutical drug
substance operations, who meet and work together at face-to-face meetings
in the USA and Europe, on regular teleconferences and via web meetings.
The group has established best practice on a wide range of quality,
engineering and organizational topics considered central to the challenge of
mastering effective biotech drug substance operations.
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BPOG CPV Team and Operating Company Affiliations
Aaron Goerke Roche / Genentech Kerry Hawitt Shire
Abel Hastings FDB Kevin Legg Genzyme
Alekhya Gummaregula Merck & Co Kevin Pipkins Janssen
Angela White Onyx Kyle Langham GSK
Anneli Niemi Pfizer Lada Laenen Genzyme
Bert Frohlich Shire Lilong Huang Biogen Idec
Beth Junker Merck & Co Madeline Roche Gallus
Brett Hanna Janssen Marcus Boyer BMS
Christian Menzel Merck Serono Mark DiMartino Amgen
Christopher Taylor Shire Mark Smith Roche / Genetech
Cillian McCabe Eli Lilly Martha Rogers Abbvie
Cynthia Ball AstraZeneca Mike Doremus Abbvie
Dan Baker GSK Nicole Jackson Pfizer
Darren Whitman BPOG Otmane Boussif Sanofi Pasteur
Derek Mak Pfizer Pamela O'Brien Eli Lilly
Eric Hamann Pfizer Paul McCormac Pfizer
Gareth Priestley Shire Paul Wong Bayer
Graham McCartney Eli Lilly Rajesh Ahuja Regeneron
Graham McCreath FDB Rajesh Beri Lonza
Jenny McNay Regeneron Ranjit Deshmukh AstraZeneca
Joerg Gampfer Baxter Healthcare Vijay Chiruvolu Amgen
John Grunkemeier Bayer Healthcare
Julia O'Neill Merck & Co
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 2. Why CPV?
Moving Towards the FDAs Desired State!!

Desired State for the Pharmaceutical Sector

Maximallyl efficient, agile, flexible pharmaceutical manufacturing sector that produces
reliable high-quality products without extensive regulatory oversight.*
This state would encourage:
A regulatory process that is consistent, transparent and science-based
A regulatory process that allows for efficient and effective continuous improvement
A pharmaceutical sector that understands its products and the processes, uses risk
assessment/mitigation tools and modern effective quality systems, and takes full ownership of
the product

Control Strategy!!
A planned set of controls, derived from current product and process understanding, that assures process
performance and product quality. The controls can include parameters and attributes related to drug
substance and drug product materials and components, facility and equipment operating conditions, in-
process controls, finished product specifications, and the associated methods and frequency of monitoring
and control. (ICH Q10)

CMC Strategy Forum Japan, Tokyo, December 2014 * Janet Woodcock, CDER, FDA
09-Dec-2014
 2. Why CPV?
Control Strategy a Regulatory Expectation!
Controlling Variability..
ICH Q8(R2): PHARMACEUTICAL DEVELOPMENT; Current Step 4 version; August 2009
A comprehensive pharmaceutical development approach will generate process and product understanding and
identify sources of variability.
.control of the process such that the variability (e.g., of raw materials) can be compensated for in an
adaptable manner to deliver consistent product quality.
ICH Q11: DEVELOPMENT AND MANUFACTURE OF DRUG SUBSTANCES (CHEMICAL ENTITIES AND BIOTECHNOLOGICAL/
BIOLOGICAL ENTITIES): Current Step 4 version dated 1 May 2012
Every drug substance manufacturing process, whether developed through a traditional or an enhanced approach
(or some combination thereof), has an associated control strategy.
Regardless of whether a traditional or enhanced process development approach is taken, the use of upstream
controls should be based on an evaluation and understanding of the sources of variability of a CQA.

CPV an integral part of Control Strategy

ICH Q10: Pharmaceutical Quality Systems
Sect. 3.2.i .execute a system for the monitoring of process performance and
product quality to ensure a state of control is maintained. An effective monitoring
system provides assurance of the continued capability of processes and
controls to meet product quality and to identify areas for continual improvement.

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 2. Why CPV? PDA Technical Report #60

Lifecycle Approach to Process Validation Lifecycle approach to Process

Validation
PROCESS &
FDA: Guidance for Industry, Quality Systems Approach to Pharmaceutical CGMP Stage 1 ANALYTICAL
Regulations. U.S. Department of Health and Human Services, Food and Drug Process Validation: DEVELOPMENT
Administration, September 2006 Process Design

Building in quality from the development phase and

throughout a products life cycle
PROCESS & ASSAY
Stage 2 IMPLEMENTATION
Process Validation:
Process Performance
Qualification
FDA: Guidance for Industry, Process Validation. U.S. Department of Health
and Human Services, Food and Drug Administration, September 2011
The goal of the third validation stage is continual assurance
that the process remains in a state of control (the validated COMMERCIAL
Stage 3
state) during commercial manufacture. Process Validation:
MANUFACTURING
A system or systems for detecting unplanned departures from Continued Process
& LIFE CYCLE
MANAGEMENT
the process as designed is essential to accomplish this goal. Verification

Adherence to the CGMP requirements, specifically, the

collection and evaluation of information and data about the
performance of the process, will allow detection of Commercial Product
undesired process variability. PRODUCT
DISCONTINUATION

CMC Strategy Forum Japan, Tokyo, December 2014 9

09-Dec-2014
 2. Why CPV?
Reasons to Pursue a Common Approach
Gain consensus of interpretation of CPV requirements as third stage of
process validation lifecycle in response to new regulatory guidelines

Establish consistency of approach within the BioPharm industry.

Convenient and clear way to share perspectives across the industry and with
regulators

Gain efficiencies across companies to conserve resources. Share the Load!

Resource intensive effort affecting several functions and disciplines
Cross-functional and complex and impacting GMP systems

An efficient way of obtaining collective feedback from government

regulators.

To identify and ultimately realize the benefits of implementing CPV as soon

as possible for industry and regulatory agencies alike!
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 3. CPV Paper
Purpose of Case Study Paper

New Business Process for Biopharmaceutical Industry

o Very few articles on the topic and most literature covers only some aspects of the topic
o Little experience within Industry in submitting new license applications under these
guidelines
o To exemplify implementation of Continued Process Verification (CPV)
Leverage Collective Experience and Expertise
o Very few articles written by actual practitioners
o Includes perspectives from wide cross-section of biotech industry participants
Case Study Format to Include Realistic Examples
o Comprehensive industry mock example to illustrate CPV program implementation
o Embedded detailed available process design and process development information from
widely available prior case study
o Convenient and clear way to share perspectives across the industry and with regulators
Provide Groundwork for further useful discussion on implementation

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 3. CPV Paper
Concept and Basis of Case Study

Process description and development taken from industry generated:

A-mAb: A Case Study in Bioprocess Development,
CMC Biotech Working Group. 2009 (Available free download at ispe.org)
[Exception: Although A-mAb claims a design space, this case study does not
address CPV concepts associated with design space implementation]
Assumes product development based on a QbD approach
(ICH guidelines Q8, Q9, Q10 and Q11).

Case study focuses on Drug Substance

Drug Product effort planned (with analogous DP Biophorum group)
Broad input and contributions from all participating member companies

Free of charge access to full case study

http://www.biophorum.com/page/123/BPOG-CPV-Case-Study.htm

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3. CPV Paper - continued
What does the Case Study contain?
Selected Outline
Purpose and Scope
Roles and Responsibilities
References (as used in CPV Plan)
Product and Process Description
Development of a CPV Strategy
Scope of Data Collection and Analysis Plans
Establishing Initial Control Limits
CPV Execution Plan
Process Desccription based on:
A-mAb: A Case Study in Bioprocess
Development
Assumes a QbD approach But!.....
Regardless of whether a traditional
or enhanced process development
approach is taken, the use of
upstream controls should be based
on an evaluation and understanding
of the sources of variability of a CQA.
Requires risk evaluation to identify
Critical Quality Attributes (CQAs) and
classification of process parameters
linked to product quality (i.e. Critical
Process Parameters - CPPs)

- Including Lifetime Limits and Other Monitoring

- Change control decision tree
Sampling and Data Management
- Sample Plans/Templates
Data Entry and Verification
Data Analysis Methods and Responses
Discretionary Elements of Guidance
External
CPV Document Slide Packreferences
V5.4
18-Feb-15 13
4. CPV Plan Construction:
Objectives and Considerations
Objectives of CPV
Demonstration of consistent robust production within validated parameters
Addresses long-term variability (can not all be captured during development cycle)
Identify special-cause variation
Monitor process changes

Objectives of CPV Plan

Written plan to examine data that establishes process capability and control limits that account for normal
process variability
Provide justification for what is included/not included. Explain why included items sufficient to meet CPV plans
objectives
Should be risk-based (To focus attention on areas of greatest risk)

Considerations for Plan:

Product history and knowledge
Frequency of production
Not required to include every CQA, CPP, CMA, etc. in CPV plan, but provide justification for what is included/not
included (why included items sufficient to meet CPV plans objectives)
May be possible to aggregate some data sources to establish highly sensitive multivariate performance
indicators. PLS model utilized in A-mAb for production bioreactor

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 4. CPV Plan Construction
QbD Work Flow Leading to Control Strategy and CPV
PRODUCT PROCESS & ANALTICAL PROCESS & ASSAY MANUFACTURING
DEVELOPMENT DEVELOPMENT IMPLEMENTATION & LIFE CYCLE
MANAGEMENT
QTPP P&A
TPP CQA PIA VMP SDM PC Class Eng Intro Com PPQ CPM CPV CPI
CS

TPP Target Product Profile Control Strategy

QTPP Quality Target Product Profile (QTPP)

CQA Product Quality Attribute Assessment (Identification of CQAs) CQAs

Process Parameter Impact PIA VMP Process Development and Validation Master Planning
Assessment
SDM Scale-down Model Development and Characterization

PC Process Characterization PARs/MARs

Class Parameter (Criticality) Classification CPPs
Product-specific Control Strategy PCS IPCs
Engineering Design Eng

Process Introduction Intro

Process Performance
Equipment Commissioning/Validation Com PPQ
Qualification
Continuous Process Monitoring CPM

Continued Process Verification CPV

CMC Strategy Forum Japan, Tokyo, December 2014 Continuous Process Improvement CPI
09-Dec-2014
4. CPV Plan Construction:
Selection of Parameters
CQAs, Risk Assessment CPV Plan
Process Impact Potential?
Parameters and Controllability?
Attributes

Example: Production Culture Bioreactor Step - CPV Recommendations

Variable Class CQAs impacted
CPV Recommendation & CPV Plan
Justification
Aggregates, glycosylated glycans, HCP,
Included to establish SPC capability and verify
Culture duration CPP DNA; can also impact turbidity at harvest,
large tolerance for variation
yield variation

Maximum (dissolved) Glycosylated glycans, deamidated Included to establish SPC capability and
CPP
pCO2 isoforms; also product yield establish correlate with in-vitro cell age (IVCA)
Included to demonstrate that appropriate
Glycosylated glycans, deamidated monitoring and automated adjustments are
(Bioreactor) pH CPP
isoforms properly established

Afucosylated glycans,
CQAs Not Applicable Included to verify process consistency
Galactosylated glycans
Product yield
KPA Not Applicable Included to verify process consistency
(titer at harvest)
Optional, may be included to track lot changes.
Antifoam lot CMA Residual antifoam C If included, test clearance at bulk drug
substance for 3 different lots
Glycosylated glycans, deamidated Unnecessary, since large tolerance for variation
(Medium) osmolality CPP
isoforms has been shown.

Time of glucose feeds Optional, may be included to verify process

KPP Not Applicable
(hrs since innoculation) consistency

16
 4. CPV Plan Construction On-floor tests QC Micro Product Quality Tests

Sampling Management

Truncated impurity
Product variant
Affinity ligand
Methotrexate
product conc.
Conductivity

Charge Variants

Aggregates
CQA/IPCs/KPAs

Endotoxon
Bioburden
A280 conc

Antifoam
Potency
Retain

DNA
HCP
Sample Plan Matrix

pH
Sample volume 10 mls
Sampling/Testing Template Storage temp <-40 C
Testing offsite N
Testing onsite Y
Method SOP 42
Step 4: Affinity chromatography
Legend Load post hold period
Routine Sample Load flow-through U
Elution pool n
Strip flow thru
Non-routine Sample
Step 9: UFDF
i
Load pool post hold period t
Retain Permeate during concentration o
Retentate pool post diafiltration
Step 10: Bulk filtration and Freezing
p
post hold period, prior to filter s
Bulk sample prior to freeze

Sample plan and frequency

Routine test ROUT
Routine monitoring Retain RETN
Non-routine monitoring (Baseline monitoring, time-based periodic monitoring,
Non-Routine test NROU or special event / change based monitoring)
Stability STBL
Other sampling (Intermediate stability/hold time,
Reuse Lifetime Performance resin reuse, cleaning verification)
LFTM
Specific / representative sampling
Cleaning Verification location and collectionCLNV

Sample container and container size

Sample volume, aliquots, and retains; Sample labelling ; Sample storage temperature and transport conditions
Follow existing SOPs and batch records for collection
Tests to be performed (including additional samples such as reference solutions)
Testing limits or ranges of expected results 17
 5. CPV Execution
Execution Plan (Short-term plan develops into a long-term plan)
PROCESS &
PV1 ANALTICAL Initial limits informed by
DEVELOPMENT
clinical or scale up batch
PROCESS & ASSAY data
IMPLEMENTATION
PV2 MANUFACTURING & LIFE CYCLE MANAGEMENT
PPQ
(Process Validation Stage 3)

PV3 Continuous Process Monitoring

Stage 3a: Initial, Short-term: Prior to Statistical Process Control (SPC)

Stage
Accumulate ~30 batches to set limits Preliminary limits set as alert triggers (not acceptance
3a criteria) based on PPQ data
based on statistical significance
(CPV) Review parameters and update risks
Stage 3b: Long-term:
Once sufficient data gathered, introduce SPC w/ rules Stage 3b (CPV)
for alerts
Understand variation and trends Routine CPV
Avoid limit updates that mask drift or special cause
variation. Track limit history in case reset needed.
Identify opportunities to continuously improve process Continuous Process
Change Improvement (CPI)
Continuous Improvement: Reset
For cause evaluation (change-based)
Planned process change triggers (e.g. cell bank,
modified controls)
CMC Strategy Forum Japan, Tokyo, December 2014
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5. CPV Execution
Decision Path to Control Strategy and CPV Plan Revisions
Unexpected Incident INVESTIGATE
(Based on Risk Level)
CPV Out-of-trend
Determine if due to special
CONTROL STRATEGY
Detected cause variation RISK REVIEW
Impending Change Risk Levels 1, 2, 3
Notification
Parameter No
Risk Level 1 (Low) little Included in CS
risk in exceeding an in-
?
process specification,
release specification or in-
process acceptance range Yes
in a subsequent batch. An
evaluation may or may not Control
be deemed necessary by No Strategy Needs Yes CONTROL STRATEGY
the CPV Team. CPV PLAN REVIEW Adjustment REVISION
Risk Level 2 (Medium) ?
increased risk in exceeding
an in-process specification,
release specification or in-
process acceptance range
in a subsequent batch. An
evaluation may or may not No Add to CPV Yes
be deemed necessary by Plan
the CPV Team. ?
Risk Level 3 (High):
High risk in exceeding an
in-process specification,
No Change to Implement
release specification or in- CPV Plan CPV Plan Change
process acceptance range
in a subsequent batch. An

evaluation will always be
necessary. CMC Strategy Forum Japan, Tokyo, December 2014
09-Dec-2014 19
5. CPV Execution
Risk Levels of Actions for Trend Investigations
Risk Level 1 (Low) represents little risk in exceeding an in-process specification,
release specification or in-process acceptance range in a subsequent batch.
An evaluation may or may not be deemed necessary by the CPV Team
An example may include a shift in the mean of a specific parameter where the magnitude of
the shift is small in comparison to the distance to the nearest specification limit.

Risk Level 2 (Medium) is an increased risk in exceeding an in-process specification,

release specification or in-process acceptance range in a subsequent batch.
An evaluation may or may not be deemed necessary by the CPV Team.

Risk Level 3 (High) represents a high risk in exceeding an in-process specification,

release specification or in-process acceptance range in a subsequent batch. An
example includes a shift of a specific variable towards one a limit which is now
indicative of the potential failure of a subsequent batch in meeting its specification
or in-process acceptance range. An evaluation will always be necessary.

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5. CPV Execution
Example Incident.
High Protein A leachate observed in chromatography eluate, step 5

Incident:
A PPQ batch contained 123 mg of protein A/g A-mAb in Protein A pool, which
exceeded in process control limit, but not DS release specification, for this process-
related impurity.

Investigation revealed:
Protein A ligand released from the chromatography resin (Resin A from Supplier A) and
entered process stream during product elution. R&D and Supplier A confirmed that
elevated amounts of Protein A can leach from bead surface during an initial elution after
extended resin storage-- even when storing under recommended conditions.

Extended storage can cause increased Protein A leaching in the next use cycle. The
resin storage time of more than 12 months between last clinical manufacturing batch
and first PPQ batch was longer than previously experienced and was not represented in
small scale trials used to establish PPQ limits.

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5. CPV Execution
Example Incident - continued
High Protein A leachate observed in chromatography eluate, step 5

Strategy developed:
Risk analysis of the level measured in eluate was orders of magnitude below impurity
safety limit for final drug product.
Downstream clearance of Protein A below detectable level was demonstrated for this
batch, which is consistent with small-scale observations that subsequent
chromatography steps capable of removing leached Protein A.
Additional Design of Experiments (DOE) study conducted after PPQ to determine
potential for Protein A leaching relative to storage time, resin age (use cycles) and
storage conditions.
Spiking study confirmed downstream clearance capabilities and identified new CPPs to
control clearance which then were updated in control strategy

CPV impact
For an initial period, in-process testing of Protein A content performed to assess
process capability
Newly identified CPPs monitored for a set of 3 batches, then consider addition to plan
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6. Cost and Benefit
Costs of CPV
Costs highly dependent on the product/process scenario

Costs can vary considerably based on data retrieval system

Example Estimate Cost for Manual System

Scenario & Assumptions:
o Effort required to create CPV based on A-mAb process
o 3 CPV reports (excluding APR)
o 20 attributes/parameters trended
o For mostly manual system, working assumptions per data set: 3 hrs to retrieve; 1 hr to create control chart;
4 hrs to analyse / investigate
Estimate for multi-site Effort:
o indicates about 10 additional person-weeks of effort each year (~ $50 K at $200 K/person/year)
o For 3 sites each executing 5 CPV plans, manual implementation costs ~$250k/year

Example Estimate - Multi-site Automated Data Management System Return on Investment

System Hardware + Software costing ~ $1.25 MM
expected to reduce effort by ~ 50% or $125k/year
System takes ~ 3 years to pay for itself
Shorter payback if consider costs of losing one batch (~ 1 MM)
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 6. Cost and Benefit
Benefits of CPV
Intangible and tangible (eg, monetary) benefits highly dependent on the
product/process scenario

Compliance with FDA guidance

Raise the standard of reporting at APRs

Enhance transparency internally and with regulators

Improve process control

Clarify opportunities for process improvement

Reduce operating costs and cost of goods ultimately increasing access to

products

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 7. Conclusions and Future Opportunities
Conclusions
Differences in regulatory histories of biotech companies lead to different
perspectives on response(s) to regulatory guidelines

With a common purpose, differences can be recognised and accounted

establishing a consistent position (or else clear reasons for divergence!)

Establishing a CPV plan is complex, requiring a team with a range of knowledge

working together to be comprehensive and deliver real results

Need for initial short term control limits before setting (or re-setting) lifetime
long-term control limits after implementation of changes

Expertise in statistical analysis required for an effective program

Simple and cost-effective IT solutions are needed to support CPV

implementation

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7. Conclusions and Future Opportunities
Future Opportunities and Topics for Further Discussion
Provide additional guidance/rationale for decisions on what parameters are trended
and which are excluded.
o Well-controlled variables not subject to random variation or performance drift
o Attributes/parameters related to understanding/improving process consistency (eg, titer, yield, intermediate
stream quality measures, cycle time, etc.)
o Relationship to ongoing PPQ protocols (eg, resin / membrane reuse)

Setting formalized acceptance criteria, control chart rule triggers or limits in an

approved plan without triggering excessive investigations
Clarify differences and boundaries between CPV and routine monitoring
Further and more sophisticated application of statistics, especially for non-normal
data
Automation of data compilation, statistical analysis, and alert notification
Development of multivariate real-time control
Provide guidance on application of CPV to licensed products with extensive
manufacturing experience. BPOG planning another paper dedicated to legacy
manufacturing processes
CMC Strategy Forum Japan, Tokyo, December 2014
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Thank You!

27