Continued Process Verification for Biopharma

Manufacturing
The authors discuss complications of implementing continued process
verification and provide recommended approaches.
Oct 01, 2014
By Robin Payne, Jeff Fleming
BioPharm International
Volume 27, Issue 10
Continued process verification (CPV) is the
activity that provides ongoing verification of
the performance of a manufacturing process.
Guidance issued by FDA in 2011 (1)
emphasized the importance of manufacturers
undertaking CPV as an integral part of the
process validation lifecycle. CPV will provide
the manufacturer with assurance that a
validated process remains in a validated state
during the routine manufacturing phase of the
product lifecycle.
A group of more than 20 companies
collaborated on this topic, using the facilitation
services of the BioPhorum Operations Group
(BPOG), to generate a detailed example of how
CPV for a biopharma manufacturing process
might be implemented and explaining the
cogal/E+/Getty Images
thought process behind the development of a
CPV plan (2). Its recommendations are based
on a typical cell culture production process for making a fictitious monoclonal antibody
(mAb) product (3). Although this model plan does not provide examples of all aspects that
may be included for other types of processes, the concepts and principles upon which the
content was derived should help with CPV implementation for any real product. Preparation
of the CPV plan has provided a basis upon which to build and share knowledge and initiate
further clarifying discussion across the industry.

What is Continued Process Verification?

CPV is fundamentally a formal means by which the performance of a commercial

manufacturing process is monitored to ensure consistently acceptable product quality. In
its entirety, CPV includes: preparation of a written plan for monitoring a biopharmaceutical
manufacturing process, regular analysis of
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results, documentation of the data collected,
analysis of data, and actions taken based on
the results of monitoring the process. Some
elements of CPV overlap with existing GMP
Ensuring the Safety, Quality,
systems such as the generation of data for
and Identity of
batch release (BR) decisions, annual product
Biopharmaceutical Raw Materials
review (APR), and change control.
In general, the nature and extent of CPV
should be aligned with the outcomes of
process qualification by focusing attention on
Applying GMPs to the BioPharma
aspects of processing that are most important
Supply Chain
to determining the quality attributes of the
product. Limiting the focus of CPV to product
quality attributes is important to assure that
the burden of data collection and analysis
Feature articles
does not grow too large. Simply put, if a
measurement cannot be associated with one or more product quality attributes, it is not
essential for CPV. A manufacturer may also wish to include measures of process efficiency,
but beyond these two categories, adding additional measures to those taken during
processing will not add significant value to the performance monitoring task.

Table I is a sample showing the review of variables for inclusion in the model CPV plan for

the A-mAb (the conceptual mAb described in references 2 and 3) production-scale

bioreaction step. Only some of the variables considered for this step in the model CPV plan
are shown in Table I. As indicated, some variables were not selected for CPV or were made
optional because it was felt the variables selected for CPV are sufficient to assess process
performance and consistency, while other variables may not be appropriate for monitoring
process performance and/or consistency. In practice, the selection of variables for CPV
should be determined on a case-by-case basis by those with expertise in the process and
with statistical evaluations. For the complete set of tables for this process, see Reference 2.

Table I: Continued process verification recommendations for the production

culture bioreactor step

Variable

Culture duration

Class

CPP

CQAs impacted

CPV recommendation & justification

Aggregates,
glycosylated glycans,
HCP, DNA; can also
impact turbidity at
Included to establish SPC capability and verify
harvest, yield variation large tolerance for variation

Maximum
(dissolved) pCO2 CPP

Glycosylated glycans,
deamidated isoforms;
also product yield

(Bioreactor) pH

CPP

Glycosylated glycans,
deamidated isoforms

Included to establish SPC capability and

establish correlate with in-vitro cell age (IVCA)
Included to demonstrate that appropriate
monitoring and automated adjustments are
properly established

Afucosylated
glycans,
Galactosylated
glycans

CQAs

Not Applicable

Included to verify process consistency

Product yield
(titer at harvest)

KPA

Not Applicable

Included to verify process consistency

Antifoam lot

CMA

Residual antifoam C

Optional, may be included to track lot changes.

If included, test clearance at bulk drug
substance for 3 different lots

(Medium)
osmolality

CPP

Glycosylated glycans,
deamidated isoforms

Unnecessary, since large tolerance for variation

has been shown.

Time of glucose
feeds
(hrs since
inoculation)

KPP

Not Applicable

Optional, may be included to verify process

consistency

While a CPV plan will include analysis of data related to BR, CPV operates independently
from the BR process and should not have any impact on batches that have been previously
released. Data and analyses provided by CPV should be used to meet APR requirements,
eliminating redundancy between these GMP systems.

CPV and Quality by Design

Quality by design (QbD) means scientifically building quality into a product and the process
by which it is developed and manufactured. QbD is based on the systematic identification
of the risks involved in manufacturing the product and mitigation of those risks. QbD
recognizes that scale-up and industrial-scale commercial manufacturing experience provide
knowledge about the process and the suitability of raw materials used. FDAs January 2011
process validation guidance emphasizes the need for companies to organize and use
acquired knowledge and continually improve throughout the process lifecycle by making
adaptations to correct root causes of observed manufacturing problems (1).
By providing the mechanism for ongoing acquisition of process knowledge, CPV provides an
optimal mechanism for achieving the goal of measuring process performance and,
therefore, fits well within the QbD framework. CPV provides the essential link in the
product lifecycle chain by augmenting knowledge gained during the product development
phase with that acquired during commercial product manufacturing phase. CPV serves to
provide ongoing verification of the process design and aids in enhancement of process
understanding providing the vital link shown at the left side of the inner circle in Figure 1.

Figure 1. Elements of the product lifecycle (4). The pink zone indicates where
continued process verification plays its part.
While in some cases data from QbD may be available and advantageous, preparing and
executing a CPV plan does not necessitate a manufacturing process is developed using a
QbD approach. Indeed, there may be times when limited development history (e.g., as may
be the case for some legacy and in-licensed products) makes it necessary to create a CPV
plan without a QbD background. The CPV plan can be tailored to focus mostly on
performance of the process at the time of qualification/validation, the manufacturing
history to the time a CPV plan is created, and expectations for the process from that point
forward.

Initial and Long-term Control Limits

Control limits for CPV should be based on process data. Depending on the extent of
experience with the process, different limits for both an initial monitoring period and longterm manufacture may be advisable for CPV. For a newer process, because it is unlikely
that there will be a statistically robust set of data at the scale of commercial manufacture,
it is recommended that an initial phase of CPV be established. Initial limits will typically be
based on prior process experience (e.g., from the process validation campaign, even if this
is limited) and data from the development phase. Data gathered during the initial
monitoring period will then help to establish limits that represent the performance of the
process at the commercial scale.
In general, statistical control limits should be set at the centerline plus and minus three
sigma, which approximates to three standard deviations. Sigma may be estimated from
short-term or long-term variation using the established formulae.
The long-term variation version of sigma is preferred for two reasons. First, it is more likely
to include all the sources of variation for the process. This provides more realistic control
limits that will be better able to distinguish between expected and unusual instances of
variation in results. And secondly, during initial production, when relatively few results are
available for calculating sigma, the long-term estimate stabilizes more quickly than the
short-term estimate. For independent, normally distributed results, the long-term and
short-term formulas for sigma will provide similar values.
After the initial phase of CPV, control limits should be established against which the
performance of the process can be assessed for the longer term. These control limits are
expected to be more statistically reliable and should not be changed without recorded
justification. As a rule of thumb, 30 batches worth of data might be expected to reflect all
sources of variation in the process, but this must not be regarded as a hard and fast rule.

When sources of variation occur over extended timeframes, more than 30 results may be
needed to reflect all sources of variation. And, there are some sources, like raw material
changes, that occur quite infrequently, making it important to monitor data on an
appropriate frequency at different levels in the organization. Typically, operators will
monitor data during manufacture and review the data at the end of a campaign for
infrequently manufactured products or weekly/monthly for frequently manufactured
products, with a quarterly report that contributes to the annual product report (APR).
A CPV plan should be regarded as a living document that is updated accordingly, as
process changes are made. For instance, when a process change or improvement shifts the
mean or changes the variability, control limits should be re-set based on an appropriate
number of results following the change.

The Rewards of Process Performance Monitoring

CPV provides the opportunity to identify and control sources of variation and, therefore,
improve process robustness and increase assurance of reliable supply to the market.
Adopting or building on an existing system of monitoring manufacturing process
performance is likely to involve collection of considerably more data over the lifetime of the
product than may have occurred previously. Analysis of data and reporting for CPV may
also involve examination of existing process measurements and improved methods for
data tracking and analysis beyond what is typically done for process validation. The reward
for this additional data collection and analysis is that CPV will provide information from
which to improve process understanding, risk assessment/mitigation, and the control
strategy (CS), and will generate an established foundation for justifying process
improvements throughout the lifecycle of the product. Of course, having and following a
CPV plan should also put the manufacturer in more favorable standing with GMP regulatory
inspectors.
One of the main struggles to resolve when implementing CPV will be to determine the
types and quantity of data to be captured and analyzed. CPV can err on the side of
providing too little data to the manufacturer, or can lead to the over-collection of
unimportant data that masks the valuable stuff and adds to the costs incurred in
interpretation. Decisions on data capture and analysis will always have to be determined
on a case-by-case basis. But with careful forethought, CPV can fulfill both regulatory needs
and provide value to the manufacturer.
The implementation and ongoing execution of a CPV Plan is likely to require additional
effort beyond what is typically needed to prepare the APR, because CPV reports are issued
more frequently than the APR. The data presented in a CPV report will have a degree of
overlap with that for the APR, but a direct relationship in the data contained is unlikely, as
these reports meet somewhat different purposes. Additional cost may be incurred due to
the need for quality risk assessments to define the scope and frequency of data collection
and the time and effort needed to collect and analyze more data. The frequency of
collection and analysis will depend on several factors, including: whether production is
campaigned or continuous; variability relative to process control limits an statistical
capability (e.g., high capability for a parameter can justify reduced monitoring of the
parameter); whether risks to product quality (and thus product disposition) and process
consistency are sufficiently mitigated; and the intended use of the reported data (e.g., use
in continuous improvement may mean collecting and analyzing certain data for each batch
produced).

Future Efforts and Improvement

The BPOG CPV example plan prepared by the collaborative team does address some of the
complications of implementing CPV and provides recommended approaches, but questions
related to information technology (IT) systems are not dealt with in any detail. The case for
IT systems (including their design, introduction, and possible efficiency advantages) is the
subject of ongoing collaborative efforts facilitated by BPOG; results of that work may be
published in the future.

References
1. FDA, Guidance for Industry, Process Validation: General Principles and Practices (CDER,
2011).
2. BPOG, Continued Process Verification: An Industry Position Paper with Model Plan,
accessed Sept. 16, 2014.
3. CMC Biotech Working Group,A-Mab: a Case Study in Bioprocess Development(Oct. 30,
2009), accessed Sept. 16, 2014.
4. From presentation at 10th APIC/CEFIC meeting, FDAs Quality InitiativesAn Update by
Moheb M. Nasr

About the Authors

Jeff Fleming is an independent writer with over 30 years of experience in pharmaceutical

manufacturing.
Robin Payne is facilitator at the BioPhorum Operations Group, robin@biophorum.com .