Adopting the Product Lifecycle Approach

Jan 01, 2015

By Rizwan Sharnez
BioPharm International
Volume 28, Issue 1
The primary objective of process validation is to
provide assurance that the process consistently
delivers product of acceptable quality. FDA
recommends that manufacturers adopt a
product lifecycle approach to process validation.
Recommendations for implementing this
approach are delineated in the FDAs 2011
guidance on process validation.

Dan Ward

Opportunities and challenges in implementing

the product lifecycle approach are discussed in
this article. Case studies on the application of
this approach to cell culture, centrifugation,
chromatography, and other biopharmaceutical
unit operations will be presented in subsequent
parts of this series.

Background

FDA first published guidance on process validation in 1987 (1). Nearly a quarter of a
century later, FDA issued new guidance on the subject entitled Process Validation: General
Principles and Practices (the 2011 guidance) (2). The driver for revising the 1987 guidance
was articulated by a senior policy advisor at FDA: Poor quality of drugs on the market,
evidenced by recalls, complaints, and other indicators, from supposedly validated
processes, pointed to a lack of process understanding and adequate process control (3).
The 2011 guidance is consistent with the basic principles of process validation articulated
in the 1987 guidance and cGMP regulations enunciated in 21
Code of Federal Regulations (CFR) Parts 210 and 211 (4). It conveys FDAs thinking on
process validation based on more than 25 years of experience and regulatory oversight,
and the Pharmaceutical cGMPs for the 21st Century Initiative (5). The 2011 guidance
promotes a product lifecycle approach to process validation; it also provides
recommendations for concurrent release of process performance qualification (PPQ) lots,
documentation, and analytical methodologies.

Product lifecycle approach

The 2011 guidance describes process validation activities in three stages of the product
lifecycle:
1. Process DesignThe commercial process is defined during this stage based on
knowledge gained through development and scale-up activities. The objective is to design
a process that is suitable for routine commercial manufacturing and can consistently
deliver product that meets all quality attributes.
2. Process QualificationIn this stage, the process design is evaluated to determine if it is
capable of reproducible operation at commercial scale. There are two aspects to process
qualification: design of facilities and qualification of equipment and utilities, and PPQ.
3. Continued Process Verification (CPV)The performance of the process during routine
manufacturing is continually evaluated during this stage. The performance data are used to
identify problems and reduce process variability. The data are also used to determine
whether action must be taken to correct and prevent the observed issues so that the
process remains in a state of control.
For a detailed description of the product lifecycle approach and the stages of process
validation refer to McNally (3), and Katz and Campbell (6).

Regulatory expectations

Biopharmaceutical products are typically complex macromolecules (>100 kDa) that are
difficult to characterize analytically. As a result, the safety and efficacy of these products
cannot be adequately assured merely by in-process and finished-product inspection or
testing (2). In light of this limitation, FDA expects manufacturers to adopt the product
lifecycle approach described in the previous section. The goal is to provide assurance that
the process consistently delivers product of acceptable quality.

The opportunities the product lifecycle approach presents and the challenges in
implementing them are discussed in the following sections.

Opportunities

The product lifecycle approach provides industry with an opportunity to leverage better
process understanding to make sound, science-based process improvements. It also
provides manufacturers with a framework for implementing an integrated approach to
product quality. Industry for its part is encouraged to avail of this opportunity to improve
product quality and operational efficiency.
As manufacturers adopt the product lifecycle approach, they better understand how
process inputs and parameters impact the safety and efficacy of their products. This
knowledge better equips manufacturers to address questions from regulators, but more
importantly, it reduces the number of process deviations and out-of-specification results.
Consequently, there are fewer non-conformances, investigations, corrective and preventive
actions, complaints, and recalls, which in turn results in less rework and revalidation, better
utilization of equipment, and higher run rates. Furthermore, better process understanding
can be used to develop platform technologies for key unit operations. The development of
platform technologies can greatly reduce time and resources required for process
development, as well as equipment and qualification costs. Another benefit of the product
lifecycle approach is that manufacturers can reduce the risk of failures during PPQ and
thereby minimize delays to product launches.

Challenges

As discussed in the previous section, adopting the product lifecycle approach can provide a
constellation of benefits. Depending on the level of validation maturity of an organization,
however, implementing this approach may require substantial organizational change and
commitment of time and resources. Key functions such as clinical and commercial process
development, engineering, manufacturing, quality, and regulatory affairs need to
collaborate effectively and efficiently throughout the lifecycle of the product. Furthermore,
management needs to foster a culture of innovation, operational excellence, and risk
tolerance that is conducive to realizing meaningful change.
With the product lifecycle approach, materials, process parameters, and in-process controls
are not monitored in isolation; instead, they are statistically correlated to the associated
product attributes that they are meant to deliver. Operational strategies are designed to
monitor and control parameters that correlate well with critical quality attributes.
Furthermore, aspects of process design, validation, and monitoring that have proven to be
inadequate in the past are redesigned to ensure process consistency and product quality.
This integrated approach ultimately leads to better process understanding and higher
operational efficiency.
Number of PPQ runs
The traditional approach to process validation involves three consecutive successful runs at
commercial scale. With the product lifecycle approach, however, the number of PPQ runs
for a given molecule needs to be justified based on process and product understanding.
One approach to determine the appropriate number of PPQ runs is to develop a scoring
criterion based on pertinent risk factors. Each risk factor is assessed in terms of failure
modes, detectability, and potential impact to product quality. In addition to determining the
number of PPQ runs, the scores from the risk assessment can also be used to develop a
sampling and testing plan, and to set acceptable operating ranges for process parameters.
The following risk factors should be considered in the evaluation:
Are sources of variability (e.g., raw materials) and their impact on product quality
attributes well understood?
Is there prior experience with transferring the molecule at clinical or commercial scale?
Have high-risk issues been identified through formal risk assessments, and have the
issues been addressed?
Have new or modified unit operations been successfully run before at clinical or
commercial scale?
Are process changes being implemented at commercial scale?
Is there a well-defined process control strategy at commercial scale?
The objective of the evaluation is to show that the process and product understanding is
such that the number of PPQ runs will be sufficient to demonstrate that the process
performs as expected and is in a state of control. As more information about the product,
process, equipment, and facility becomes available, the level of confidence in the process
increases and fewer PPQ runs may be warranted. That can in turn expedite regulatory
approval and commercial distribution of the product.

Requalification of process performance following a process change

The risk-based approach described in the previous section can also be used to determine
the number of PPQ runs required to requalify process performance following a process
change. A process change to a validated system may not always warrant requalification.
For instance, if it can be demonstrated that relative to the new state, the validated state
represents a worst-case scenario from the standpoint of product quality, it may not be
necessary to requalify the performance of the process. This point is illustrated in the
following examples:
A manufacturing process for a buffer is validated for dissolution time, chemical stability,
and microbial control. The composition of the buffer is changed by reducing the
concentration of a growth-promoting ingredient.
A cleaning cycle is qualified to clean a process soil in a given circuit. Subsequently, a
process change that alters the properties of the process soil is implemented. A qualified
experimental model is used to demonstrate that under the operating conditions of the
cleaning cycle, the new process soil is easier to clean than the original process soil that
was used to qualify the circuit (7, 8).
In the aforementioned examples, the risk factormicrobial proliferation or carryover of
product residuesthat differentiates the new state from the validated state is mitigated by
the process change. Thus, from a scientific standpoint, requalification of process
performance is unwarranted.
Statistical evaluation of data
With the product lifecycle approach, manufacturers are expected to establish in-process
control limits for key performance parameters based on prior knowledge and process
characterization data collected during Process Design (Stage I). During Continuous Process
Verification (Stage III), the performance data are continually monitored, and process
consistency is evaluated using statistical process control. The performance data are
reviewed periodically to detect trends in product quality and determine whether corrective
action must be taken to reduce batch-to-batch variability.
The 2011 guidance (2) states:
We strongly recommend firms employ objective measures (e.g., statistical metrics)
wherever feasible and meaningful to achieve adequate assurance . . . The data should be
statistically trended and reviewed by trained personnel.
Good process design and development should anticipate significant sources of variability
and establish appropriate detection, control, and/or mitigation strategies, as well as
appropriate alert and action limits.
We recommend continued monitoring and sampling of process parameters and quality
attributes at the level established during the process qualification stage until sufficient
data are available to generate significant variability estimates. These estimates can
provide the basis for establishing levels of frequency of routine sampling and monitoring
for the particular product and process. Monitoring can then be adjusted to a statistically
appropriate and representative level. Process variability should be periodically assessed
and monitoring adjusted accordingly.
Criticality as a continuum
Another important change in the 2011 guidance is that the criticality of product quality
attributes and process parameters is not limited to a binary (critical or non-critical) state.
Instead, it recommends that manufacturers exercise control over attributes and parameters
commensurate with the risks that they pose to process consistency and product quality. It
also enunciates that these risks can vary over time, and that manufacturers should reevaluate the level of risk assigned to attributes and parameters as new information
becomes available and should modify their operational strategy accordingly. The guidance
states, With the lifecycle approach to process validation that employs risk based decision
making throughout that lifecycle, the perception of criticality as a continuum rather than a
binary state is more useful. All attributes and parameters should be evaluated in terms of
their roles in the process and impact on the product or in-process material, and reevaluated as new information becomes available. The degree of control over those
attributes or parameters should be commensurate with their risk to the process and
process output. In other words, a higher degree of control is appropriate for attributes or
parameters that pose a higher risk (2).
This expectation is consistent with the notion that process validation is an ongoing practice
that is tied to product and process lifecycle rather than a single event. Viewing process
validation in this light facilitates process improvements that in turn improve product
quality.

Conclusion

The 2011 guidance on process validation provides manufacturers with a framework for
implementing an integrated approach to product quality. It recommends that
manufacturers adopt a product lifecycle approach to process validation. With this
approach, process validation is viewed as an ongoing program that spans the entire
lifecycle of the product, rather than a discrete and isolated event.
The product lifecycle approach to process validation is consistent with FDAs risk-based
approach to process monitoring and control. It recommends the use of modern risk
management and quality system tools and concepts to enhance product and process
understanding. It also recommends that manufacturers continually detect, understand and
control sources of variability to consistently produce safe and effective drugs that meet all
quality attributes.
The product lifecycle approach provides industry with an opportunity to enhance process
understanding and product quality, realize higher operational efficiency, and expedite
regulatory approval. Depending on the level of validation maturity of an organization,
however, implementing this approach may require substantial organizational change and
commitment of time and resources.
With the product lifecycle approach, the number of PPQ runs is determined based on
process and product understanding. Another distinguishing feature of this approach is that
the criticality of an attribute or parameter can vary over the lifetime of the product. As new
information becomes available, manufacturers are expected to re-evaluate the level of risk
assigned to attributes and parameters and modify their operational strategy accordingly.
Manufacturers are also expected to use prior knowledge and process characterization data
to establish in-process control limits for key performance parameters. Performance data
are continually monitored and process consistency is evaluated using statistical process
control. The performance data are reviewed periodically to detect trends in product quality
and determine whether corrective action must be taken to reduce process variability.

References

1. FDA, Guidance on General Principles of Process Validation (FDA, May 1987).

2. FDA, Process Validation: General Principles and Practices (CDER, January 2011).
3. McNally, G., Process Validation: A Lifecycle Approach (FDA, May 6, 2011).
4. FDA, 21 CFR; Parts 210 and 211.
5. FDA, Pharmaceutical cGMPs for the 21st Century-A Risk-Based Approach (FDA, August
2002).
6. P. Katz and C. Campbell, J. of GXP Compliance 16 (4) (2012).
7. R. Sharnez, Journ. of Val. Tech., 14 (4) (2008).
8. R. Sharnez, American Pharm. Review 13 (5) p. 77-80 (2010).

Article Details
BioPharm International
Vol. 28, Issue 1
Pages: 32-34
Citation: When referring to this article, please cite it as R. Sharnez, "Adopting the Product
Lifecycle Approach," BioPharm International 28 (1) 2015.