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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.
2. Why CPV?
CPV Team
CPV Informatics
BioPhorum Team
BioPhorum
Development Group
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.
Process Performance
Equipment Commissioning/Validation Com PPQ
Qualification
Continuous Process Monitoring CPM
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
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.
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
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.
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
CMC Strategy Forum Japan, Tokyo, December 2014
09-Dec-2014 22
6. Cost and Benefit
Costs of CPV
Costs highly dependent on the product/process scenario
Need for initial short term control limits before setting (or re-setting) lifetime
long-term control limits after implementation of changes
27