Continued Process Verification (CPV)

Signal Responses in Biopharma

Syama Adhibhatta
 
Mark DiMartino
 
Richard Falcon
 
Eric Haman
 
Kevin Legg
 
Robin Payne
 
Kevin R. Pipkins
 
Abdelqader Zamamiri

This paper was written by members of the BioPhorum Operations

Group CPV and Informatics team and widely reviewed across the
BPOG collaboration. As such, it represents the current consensus
view of process verification subject matter experts in the
biopharmaceutical industry, but does not represent the procedural
details of any individual company. It is designed to be informative
for industry members, regulators, and other stakeholders. It does
not define statistical methods in detail, as these definitions are
readily available elsewhere.
This paper describes how signals can be developed and evaluated in support of
CPV in the biopharmaceutical industry. Implementation of CPV, in addition to meeting
regulatory expectations, can also provide a basis for continuous improvement of
production processes and hence greater consistency of product quality and assurance
of supply.

CPV involves gathering data related to CQAs and CPPs, as well as analyses that reveal
any statistical signals that become evident over time. It is designed to detect variation
within specifications. Thus, CPV is about maintaining control within specification and so
does not normally lead to a formal investigation. This paper provides several examples
of signal response and escalation within the quality system where necessary as a model
of a risk-based approach to CPV.

In 2011, the FDA introduced guidance on the process validation life cycle, including
continued process verification (CPV).1 While implementation is becoming a regulatory
expectation, CPV can provide benefits beyond compliance by identifying opportunities
to improve production processes and ultimately, the reliability of drug quality and supply.

CPV is the third stage of the process validation life cycle. It is a continued assessment
of the parameters and attributes within the control strategy identified in Stage 1 (process
design) and refined at the end of Stage 2 (process qualification). Its principle objective is
to detect variability in the process and associated quality attributes that may not have
been evident when the process was characterized and introduced. CPV provides
continued verification that the control strategy remains effective in maintaining product
quality.

Additional parameters and/or attributes not considered critical to quality or otherwise not
specified in the control strategy may also be included in the CPV program (or an
associated process monitoring program) to enhance process learning and support
investigations to identify the root cause and source of unexpected variability.

CPV can also identify opportunities to improve process performance and/or optimize
process control. Using statistical methods, data from historical manufacturing or
characterization studies are evaluated during CPV implementation to define signal
criteria, set limits, and implement appropriate response procedures for ongoing
operations. Signals are thus selected to identify process behaviors of interest and
indicate when statistically meaningful variation may be affecting the process.

A critical aspect of CPV is establishing a procedure that provides a consistent response

to these signals as they become evident. Ideally, perhaps, signals would be detected as
soon as they occur, but this is not practical in most cases. Practically, the signal should
be detected and a response mounted before the indicated trend leads to a true process
deviation or out-of-specification (OOS) event. Good practice is to respond as soon as
possible based on risk assessment.
The purpose of this document is to provide best practice guidance for responses to CPV
signals that occur within the process’s acceptable control space.

There are five main steps in establishing CPV signals and associated response
procedures.

1. Define parameters and signal criteria

2. Establish monitoring and evaluation frequency
3. Establish signal evaluation criteria and actions
4. Escalate actions if necessary
5. Document signals and response

Although this paper is focused primarily on responses, some discussion of signal

selection is required since the magnitude of the response should be commensurate with
the severity of the signal.

SIGNAL SELECTION
Define parameters and criteria

In general, CPV signals assess predicted performance based on previous process

experience. The development and effectiveness of these signals depend on statistical
techniques sensitive to the size and inherent variability of the existing data set. While
not ideal, some signals will be due to existing and acceptable variation that was not fully
captured and characterized in the initial data set. This is a common occurrence in
biopharma, given the complexity of manufacturing processes and raw materials.
Although these are sometimes referred to as “nuisance signals” or “false positives,”
such signals may prove to be useful learning opportunities over time and used to
augment the data set.

Definitions

Identify variation

The focus of CPV signals should always be to identify variation within specified limits
defined in the control strategy. This applies when critical quality attributes (CQAs) are
maintained within specifications and critical process parameters (CPPs) are maintained
within proven acceptable ranges. Signals that are outside the control strategy (i.e.,
OOS) are investigated primarily within the quality management system (QMS).

This paper is concerned primarily with evaluation of responses to CPV signals within the
design space. There would be benefit, however, in capturing and integrating lessons
learned from both formal investigations and CPV-related evaluations for improved long-
term process control.
Establish monitoring and evaluation frequency

As stated previously, the ideal scenario for CPV monitoring is to identify signals in real
time during manufacturing and react accordingly. This scenario is not always practical,
however, since that many signals require multiple data points (i.e., signals for drift or
shift) and specific data-capture and analysis technologies are required to perform the
calculation. Given that these signals are by definition within the specified limits defined
in the control strategy, the risk inherent in disassociating the identification and reaction
to signals from batch release is low, allowing for a more periodic review.

The review frequency should be established with the monitoring plan and should
consider:

 Relative risk of a parameter or attribute deviating from its acceptable range

 Manufacturing frequency
 Level of historical process knowledge
 Manufacturing plant’s technological capability to collect and analyze the data

Establish evaluation criteria and response

A CPV signal is designed to identify potential new variation or unexpected patterns in

the data. Because these conditions are within the control strategy, signals should not
automatically be considered formal good manufacturing practice (GMP) deviations.
There may be cases, however, in which a signal is significant enough to indicate a
product quality or validation effect that requires tracking and resolving within the QMS.
When this happens, a cross-functional data review and escalation procedure should be
in place to ensure the signal is addressed appropriately.

This paper provides an example of a procedure that can be used or adapted for
responses to CPV signals using risk-based decision-making to determine when a signal
should be escalated. The procedure has four key elements that should ideally be in
place as prerequisites (Table A).

Table A: Prerequisites for an effective response to signals procedure

Element Description
CPV plan with signal Plan outlines the parameters analyzed for CPV and rules for identifying signals. This prov
criteria identified guidance on what process behaviors merit further analysis.
Default responses to Default responses are predetermined actions for each parameter/signal combination. Thes
signals and based on the criticality of the parameter and the nature of the signal to ensure the response
parameters commensurate with the level of risk being signaled.
Signals and their default responses should be reviewed periodically by a cross-functional
Data signal review
of SMEs to evaluate the appropriateness of the default response and determine if alteratio
and escalation process
(escalation or de-escalation) is needed.
Documentation
Signal response and rationale must be documented and approved.
system
Table A: Prerequisites for an effective response to signals procedure
Element Description
Table B: Signal-response action terms
Action Description
No response required. This response is associated with signals that are not considered sign
No action enough to warrant further root cause analysis and require no corrective or preventive actio
(CAPA). Document the decision and rationale per approved procedures.
This response is associated with signals of unexpected variation from historical processing
experience that are considered significant enough to warrant a technical evaluation to und
the cause of variance; it is not significant enough, however, to warrant a product quality im
Evaluation assessment. A subsequent CAPA may be required. Evaluations can span a wide spectrum
complexity, from a simple review of a batch record or starting raw materials to a complex
collaborative, cross-functional evaluation. The size of the evaluation is based on the techn
input of process SMEs.
This response is associated with signals of unexpected variation from historical processing
experience that are considered significant enough to warrant a technical evaluation to asse
potential product/validation impact and establish a root cause. A subsequent CAPA may b
Escalation to QMS
required. The signal response is tracked within the QMS and requires a product/validation
impact analysis, root cause identification, and any associated CAPAs within the timelines
mandated by the relevant quality procedures

CPV PLAN
At the completion of Stage 2—process performance qualification (PPQ) 2 —a CPV plan
shall be established with the following components, including a rationale for each:

 Parameters and attributes to be monitored

 CPV limits for each parameter and attribute combination
 Frequency of trend evaluations
 Statistical signals to be evaluated
 Default responses for each parameter-signal combination

The rationale can be risk based and should include an explanation of which process
behaviors may merit further analysis. Ideally, each default response should be
determined from a risk-based strategy that considers the criticality of the parameters,
the nature of the signals, and the performance/capability of the process parameters.

The CPV plan should reference company-specific procedures that specify reporting
formats, designate escalation procedures, identify roles and responsibilities for CPV
trending, and define terms.3 For illustration, this paper uses the signal-response action
terms shown in Table B.

Default responses to signals

Table C provides an example of a risk-based strategy that could be used to determine
minimum default responses for each parameter and signal in the CPV plan. The
example uses classic signals, which indicate departures from established behavior for
normally distributed, independent data. Actual strategies may vary by CPV plan. The
default response assigned for an individual parameter-signal combination may vary
from the proposed default if a proper justification is provided in the plan.

Table D illustrates how default responses and modifications can be presented in a CPV
plan.

Escalation process

During CPV plan execution, data is collected and analyzed at a predefined frequency.
Once a signal is identified, a cross-functional team (CFT) of subject matter experts
(SMEs) with knowledge of the process, manufacturing operations, quality control, and/or
quality assurance reviews the signal to determine the appropriate response. Others,
such as quality control laboratories, regulatory sciences, or continuous improvement
and process development may also participate.

The CFT reviews the signal against the default response, and determines if escalation
to a higher level or de-escalation to a lower level of response is appropriate. Factors
that may be considered when altering the default response include (but are not limited
to) the CFT possible review outcomes shown in Table E.

When product is manufactured at more than one site it is advisable to have a system to
share CPV data and or observations. In all cases alteration of any default response to
signals requires justification and proper documentation.

Document signals and responses

Once the CFT triage is complete and outcome aligned, the team will perform the
recommended actions or ensure they are done. If the action is to escalate, the
appropriate quality system document will be initiated and procedures that govern it will
be followed. If the action is evaluation, additional analysis or experimentation will be
required to determine the cause of the signal.

Results of any evaluations should be documented following GMP principles. If no action

is taken, that decision and rationale must also be documented, but no further action is
required.

Signal and response documentation typically falls within one of the types described in
Table F.

Any changes to control limits, signals, or processes that result from evaluation should
be managed by the system most appropriate for the change (i.e., change control or
CAPA). Quality approval is required to close out a response to signal for all three
categories (escalation, evaluation, no action).

Table C: Classic signals

Signal Signal Type CQA* CPP N
Nelson Rule 1: 1 point outside of a control If process capability is
limit acceptable,† evaluation N
Outlier Evaluation
Western Electric Rule 1: 1 point outside of If process capability is a
a control limit marginal, escalation
Nelson Rule 2: 9 consecutive points on same If process capability is
side of center line acceptable, evaluation Evaluation if process N
Shift
Western Electric Rule 4:  8 consecutive If process capability is capability is marginal a
points on same side of center line marginal, escalation
Nelson Rule 3: 6 consecutive points, all If process capability is
increasing or all decreasing acceptable, evaluation Evaluation if process N
Drift
Western Electric Rule 5:  6 consecutive If process capability is capability is marginal a
points, all increasing or all decreasing marginal, escalation

* Where existing procedures require formal quality investigations, those procedures supersede this strategy
(e.g., OOT/OOS). Where possible, CPV plans should be aligned with OOT procedures.

† Acceptable and marginal process capability can be defined in a procedure, in statistical terms.3 ,4

Table D: Default response examples

CPV plan response
Parameter Comment
Outlier Mean shift Drift
NCP1 No action No action No action N/A
No impact to quality. Evaluate shifts and drifts to limit bu
NCP2 No action Evaluation Evaluation
impact.
CPP1 No action Evaluation Evaluation No action for outliers due to high process capability.
CPP2 Evaluation Evaluation Evaluation Marginal process capability
CQA1 Escalation Escalation Escalation Escalate all signals due to marginal process capability
No action for drift signals due to inherent drift in the proc
CQA2 Evaluation Evaluation No action Escalation not required for outliers or mean shifts due to
acceptable process capability.
Table E: CFT review potential outcomes
Factor Potential outcome
Escalate if the data is significantly different from historical data
Compare signal to historical performance
unusual based on SME knowledge of process performance
Proximity of the data point to specifications Escalate if the CFT concludes there is a risk of OOS
Recurrence of similar signals Escalate to determine the cause
Signals for multiple parameters and/or attributes Escalate to determine the cause and any potential process impac
Table D: Default response examples
CPV plan response
Parameter Comment
in the same lot highlighted by CPV trending
De-escalate if an attributable cause has been identified and
Related events within the quality system
investigated in the quality system
De-escalate if the signal is attributed to the related study. Excee
Related planned deviation, technical study, or
an existing time limit, for example, as part of validating an exte
validation protocol
of a unit operation’s hold time.
Table F: Documentation used to record signals and responses
Document
Description
Type
Can be used on a lot-to-lot basis to explain special causes and document their effects on the produ
Form and/or process. Form comments can also be summarized in CPV reports. Information may also be
captured in a database, typically outside the QMS.
Used to document periodic reviews of CPV trends, signals, and discussions of the CFT responsibl
Meeting
the reviews. If part of the established periodic CPV review, meeting minutes should be approved b
minutes
and stored in a formal document control system.
Technical May be used to document an evaluation, as directed by the CFT. A report is typically used to docu
report additional data gathering and/or analysis outside the scope of a periodic CPV report.
Used to summarize all signals and attributable causes. May include brief discussions for readily
CPV report
explained signals that do not require evaluation in a technical report or a quality record.
When the CFT decides to escalate to QMS, a record within the quality system is initiated to track t
Quality root cause investigation and product quality impact assessment. This record may involve differing
system record as a result of the root cause investigation and the outcome of the product impact assessment. This
should be referenced in the CPV report.

SAMPLE RESPONSES
The following scenarios, frequently encountered while performing CPV activities, offer
guidance on assessing and responding to observed signals under similar
circumstances. They are classified into three categories:

 Default response vs. modulated response

 Addressing long-term special cause variations during control chart setup
 Signals indicating improper control chart setup

Default response vs. modulated response

In these three examples the CFT, after routine review, must decide whether to proceed
in accordance with the prescribed default response or modulate the response.
Example 1: Default response
The CFT is monitoring a noncritical process parameter (NCP) using a control chart. By
definition, NCPs have no effect on any critical quality attribute over a wide range of
operation. They may be step yields, in-process hold durations for stable intermediates,
or final cell density in seed steps. Typically, NCPs are monitored as performance or
process consistency indicators that could have practical or financial implications. While
trend signals of such parameters have no effect on quality, monitoring them offers an
opportunity to learn and collate process knowledge. Observed signals for NCPs may
indicate suboptimal operation or undesirable process changes.

Figure 1: NCP experiencing infrequent outlier signals

In this scenario, the control chart shown in Figure 1 indicates that the monitored NCP is
typically within the control limits, with a few exceptions where outliers are observed. The
CFT believes that this NCP is well understood and all previous excursions were
explained. According to the CPV plan, the default response for the observed outlier
signals is no action.

The CFT wants to decide whether to escalate the response for the most recent outlier
signal. Examining the figure, and considering SME’s input, a member of the CFT argued
that neither the magnitude of the excursion is exceedingly alarming nor does the
frequency of the outlier signals seem to have increased. Given this conclusion, a
reasonable course of action in this case was to follow the default response of “no further
action is required.” An additional consideration is that the noted excursion may be
considered part of common cause variation, therefore a reassessment of control limits
may be warranted.
Example 2: Escalated response
In this scenario (Figure 2), a well-behaved NCP is monitored for outliers, shifts, and
drifts. An outlier signal was observed for the latest batch manufactured. Upon review,
the CFT concluded that the magnitude of this excursion was of significance, compared
to recent manufacturing experience. The CFT was also concerned because outliers
were not frequently encountered for this parameter, so there was little process
knowledge with respect to the impact of this one, especially considering its magnitude.
While the default response for outliers of this particular NCP is no action, the CFT
determined that such a significant outlier signal should be escalated to evaluation to
determine its cause. Escalation to QMS was not deemed necessary since the
associated critical parameters were well within the control strategy.

Example 3: Reduced response

In this example, a CPP is being monitored for outliers, shifts, and drifts. The control
chart in Figure 3 shows that the CPP experienced an outlier signal for the third-most-
recent batch produced. However, the dominant observation from the chart is that this
CPP is very well behaved from a statistical perspective.

Figure 4 shows that the process capability for this parameter is marginal (1.00–1.33).
Because the direction of the excursion is away from the closest specification limit (the
lower specification limit or LSL), however, it does not signify a risk to process capability.

According to the CPV plan, the default response for outliers of this CPP is evaluation.
To determine if the default response is appropriate, the CFT considered several factors:
the magnitude and frequency of outliers, the direction of the excursion in relation to
process capability, and the lack of similar outlier in the next two batches. The CFT
determined that this single outlier with relatively small magnitude is well within the
specification limits and poses low risk to product quality. Therefore, the team decided
that further evaluation is not necessary, reducing the response in this case to no action.

Figure 2: NCP experiencing a large outlier signal

Figure 3: CPP with marginal capability and a single outlier

Figure 4: Process capability analysis for a CPP with marginal capability

Addressing long-term special cause variations

Many parameters and attributes experience long-term variation due to special causes;
these include changes in raw materials over time, aging equipment, campaign-to-
campaign variation, and cumulative process, equipment, material, and test method
changes. Addressing such long-term variations depends on the nature of the variation,
its frequency, and the ability to identify or predict it.

Treatments generally fall into one of two categories: If the special cause can be
identified and doesn’t change too frequently, the control chart can be stratified at the
different levels of this special cause, otherwise, a relatively large data set should be
used when setting control chart limits. It should be large enough to fully express the
voice of the process, including the effect of special causes on long-term variation.

Control chart stratification is desirable when the special causes for the long-term
variation are easily identified and have low frequency. This allows for a statistically
meaningful number of data points within each stratum. Examples of special causes that
can be treated through stratification include (but are not limited to): variations due to
campaign manufacturing; variations caused by the introduction of significant changes to
the manufacturing process, equipment, or test methods; and variations due to changes
in materials (such as chromatography resins) that affect a number of subsequent
batches.

If, on the other hand, the materials changes are too frequent or the long-term variation
is gradual due to small cumulative changes, stratifying the control chart becomes
impractical and challenging. The best approach in the case of too-frequent changes is
to build a robust control chart with relatively large data set that demonstrates these
variations. Temporary control limits are initially established and then recalculated at
some frequency by introducing additional data until the SMEs feel that the data set
expresses the true voice of the process, including long-term variation. The CFT may
also consider “no action” for shift signals since these are expected for parameters that
are sensitive to long term variation.

Example 4: Control chart stratification

In this example, a CPP for a product that is manufactured in campaigns is monitored for
mean shifts, drifts, and outliers. Figure 5 shows a control chart of the CPP over three
10-run campaigns (A, B, and C in the top axis). In this case, it is typical that several
months may elapse between successive campaigns. Different products/processes are
often run in the interims.

Signals for multiple mean shifts and outliers became evident with continued production.
Because the parameter was a CQA, the signal was triaged against a default response
of “evaluation.”

The important consideration is the existence of subtle shifts from one campaign to the
next. These can be the result of different raw material batches, new column packs, etc.
All are considered normal process variables, but when viewed on a campaign basis
they can display marked shifts in the process. To account for the campaign effect on the
CPP and avoid false signals, the most appropriate treatment for the control chart was to
stratify it per campaign, as shown in Figure 6.

Important considerations:

 All data are within specifications (0.84–1.60). This can be qualified via capability
analyses or simply checked relative to specifications.
 Data within each campaign are considered “in-control” or stable. There are no
violations to the run rules as described in previous sections.
 Variation within each campaign is similar. Homogeneity of variance can be
checked across all campaigns using various statistical tests. The most important
consideration is that the process variation is not getting worse (i.e., wider control
limits) with each successive campaign.
 Any shifts between campaigns should be acknowledged and documented in CPV
plans and/or more formally in a QMS.

Figure 5: CPP over three 10-run campaigns

Figure 6: CPP stratified by campaign

Example 5: Accounting for long-term variation in setting control chart limits

In this scenario, a CPP was found to be sensitive to a number of known and unknown
long-term special-cause variations. The top half of Figure 7 shows a scatter plot of the
CPP with a line representing a moving average. The figure is also segmented into three
parts representing three different column packs. The moving average for this CPP
shows slow and somewhat alternating variation within and across the three segments.
In addition, the variation within each segment appears to be of the same magnitude, if
not larger than the variation between segments. In this case, control chart stratification
may help avoid some false positive signals, but will not eliminate them.

Given the long-term dynamics of this CPP, setting control chart limits with a limited data
set would create excessive false positives. In cases like this, therefore, it’s a good idea
to use the largest practical data set when calculating limits that take into account the
natural long-term variation of this CPP. The long-term standard deviation should also be
used when calculating limits. The lower part of Figure 7 shows a control chart with limits
calculated using the entire data set and without stratification.

Figure 7 indicates that despite the long-term variation observed for this CPP, it is
actually a well-behaved parameter. There are few trend signals and the process
capability is markedly high, considering the width and location of the control chart with
respect to the specifications.

Figure 7: Long-term variation in setting control chart limits

Signals that indicate improper control chart setup

When calculating control chart limits for trending, the idea is to collate a statistically
significant data set that captures the common cause variation expected to persist in the
future. In practice, though, most CPV plans for new products are created with limited
number of batches. Control limits, therefore, may need to be updated once a sufficiently
large data set is available.

Even for legacy products, there are cases where the historical data set is not
representative of current manufacturing due to cumulative process, equipment,
materials, or test-method changes. While it is not advisable to continually and arbitrarily
modify the data set baseline and recalculate control limits, applying control limits that do
not represent the current manufacturing process is not any better. A balanced approach
is preferred, where control limits are assessed periodically and updated when
necessary.

Both the mean and variance of monitored parameters and attributes are subject to
change; they can also be purposefully introduced as the result of process optimization
or continuous improvement. Ideally, the mean should move in the direction of a
predetermined target and the variance should diminish over time, in accordance with
process knowledge gained and the addition of controls fed back through active
monitoring.

One of the advantages of control charts is that signals within them can alert
practitioners to changes in mean or variance. One valuable control chart run rule not
frequently exploited in the industry is 15 data points in a row, all within ±1 standard
deviation of the mean, which indicates that the variance has decreased over time. This
behavior is often observed as a wide space between control limits and the mean.

Persistent outlier signals in one direction and/or persistent shift signals can also indicate
long-term shifts in the mean. In this case, the parameter in question should be
examined to determine if the change is acceptable and new control limits are needed, or
if the change is not acceptable and further action is needed to bring the mean back to
target. The following two examples illustrate these types of situations.

Example 6: Variance reduction over time

In this example, while monitoring a CPP, the CFT observed a wide space between the
control limits and the data, which was clustered around the mean as shown in Figure 8.
The signals highlighted on the chart indicate that 15 or more data points are within ±1
standard deviation of the mean.

Figure 8: Wide space between control limits and data

Figure 9: Updated limits due to variance reduction

Figure 10: Correcting control limits due to process improvement, before (top) and
after (bottom)
Such a scenario can result from one of two things: 1) A phenomenon called
“stratification,” wherein the samples are systematically pulled from multiple distributions,
or 2) the process variation has narrowed, indicating a significant process shift. Both
require that control limits be re-evaluated.

Upon further assessment, the CFT ruled out stratification. Reviewing the history of this
chart indicated that the control limits were established using a limited data set when the
process was first transferred to the site. Documented evidence showed that a number of
process improvements and tighter controls were implemented over time. The CFT
concluded, therefore, that the current limits were inappropriate and new limits were
needed.

Figure 9 displays the same data set, using control limits that reflect the true nature of
the data. In this case, control limits were recalculated to reflect the process
improvement that led to the improved (narrowed) control limits.

Example 7: Mean recentering and variance reduction over time

In this example a process had undergone an improvement project to optimize
performance and reduce variation. While implementing the changes, the project team
decided to maintain existing limits and monitor performance for 15 to 20 lots to see if the
change was successful.

Figure 10 shows data from this process where the change was implemented around lot
58. At around lot 70, the CFT reviewed the data and assessed the change as
successful. At lot 110, after a period of time that encompassed additional variance
factors, such as equipment maintenance and critical raw materials, the control limits
were recalculated and are now considered appropriate for future production.

SUMMARY
CPV is an important initiative for the biopharmaceutical industry. Compliance means
that statistical signals revealed from CQAs and CPPs should be addressed
appropriately. CPV helps maintain product quality, but it is distinct from batch release.
Since CPV’s primary purpose is to protect the product from longer-term sources of
variation, escalation to the QMS is likely to be rare.

Good practice related to CPV signals involves defining the attributes and parameters to
be monitored, along with their associated signal criteria. A set of default responses can
be defined, but it is important that signals be reviewed by a CFT familiar with the
product and the process. This allows the complexities of the manufacturing process to
be considered. Signals may be escalated or de-escalated from their defaults; the
rationale for these decisions must be recorded. The review process also provides
opportunity for an organization to understand its manufacturing process in greater depth
and improve it over time.

ACKNOWLEDGEMENTS

Andrew Lenz (Biogen), Martha Rogers (Abbvie), Bert Frohlich (Shire), Parag Shah
(Genentech/Roche), Ranjit Deshmukh (AstraZeneca), Sinem Oruklu (Amgen), Susan
Ricks-Byerley (Merck), and Randall Kilty (Pfizer).

REFERENCES

 1a b U.S. Food and Drug Administration. “Guidance for Industry. Process Validation: General
Principles and Practices.” http://www.fda.gov/downloads/Drugs/.../Guidances/UCM070336.pdf
 22. Boyer, Marcus, Joerg Gampfer, Abdel Zamamiri, and Robin Payne. “A Roadmap for the
Implementation of Continued Process Verification.” PDA Journal of Pharmaceutical Science and
Technology 70, no. 3 (May-June 2016): 282–292.
 3BioPhorum Operations Group. “Continued Process Verification: An Industry Position Paper with
Example Protocol.” 2014. http://www.biophorum.com/wp-content/uploads/2016/10/cpv-case-study-
print-version.pdf
 4Oakland, John. Statistical Process Control, 6th ed. Routledge, 2007
 5International Conference on Harmonisation of Technical Requirements for Registration of
Pharmaceuticals for Human Use. “Development and Manufacture of Drug Substances (Chemical
Entities and Biotechnological/Biological Entities): Q11.” 1 May 2012. http://www.
ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q11/Q11_Step_4.pdf