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Rizwan Sharnez, PhD, is Scientific Director at Amgen and has more than 20 years experience in biopurification, pharmaceutical manufacturing, process development, and validation; firstname.lastname@example.org.
The author presents opportunities and challenges in implementing the product lifecycle approach.
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 FDA’s 2011 guidance on process validation.
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.
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 FDA’s 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 Design-The 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 Qualification-In 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).
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.
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.
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 factor-microbial proliferation or carryover of product residues-that 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 re-evaluate 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 re-evaluated 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.
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 FDA’s 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.
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 DetailsBioPharm International
Vol. 28, Issue 1
Citation: When referring to this article, please cite it as R. Sharnez, "Adopting the Product Lifecycle Approach," BioPharm International 28 (1) 2015.