The pharmaceutical industry continues to evolve. New International Conference on Harmonisation (ICH; Q8, Q9, and Q10) guidelines provide science- and risk-based approaches to development, risk management, and quality systems that can empower manufacturers to manage continuous improvement and technical innovation throughout the product life cycle. New manufacturing technologies are being introduced, and increasingly sophisticated approaches to process analytical technology (PAT) are being developed.
Key factors drive this evolution, including industry competition, cost containment, and quality and regulatory considerations. New technology initiatives provide capabilities with potential to enhance productivity by improving the process—capability, control, and robustness—reducing cycle times, and improving consistency, while at the same time ensuring compliance.
New technologies and advances in PAT-enabled process control can, in combination with strategic use of design space and implementation of quality risk management, enable quality by design (QbD) to achieve a desired state of manufacturing. These new manufacturing paradigms can provide opportunities for significant regulatory flexibility, including real-time release (RTR) and post-approval continuous improvement.
The Value-Added Role of PAT
Historically, the pharmaceutical industry has applied PAT to further process understanding. Over time, as the technology has grown and become more sophisticated, the potential for PAT-based applications to add value has increased.
Pharmaceutical companies such as Pfizer have applied PAT to:
- enable process understanding;
- identify and remove sources of variability;
- monitor processes on line to provide real-time data for information purposes; and
- determine process endpoints in chemical reactions, drying, and so on, to allow better timing of the off-line release samples.
All of these approaches add value by furthering process understanding, but, like the sophistication of the technology and implementation of PAT, value rises exponentially as the list descends. The jump from process understanding to determining process endpoints is certainly significant, but new PAT-based control strategies can overcome traditional process control limitations, bring new definition to process consistency and efficiency, and extend process capabilities beyond what is possible with conventional control approaches.
Newly developed and emergent PAT-based approaches are pushing the boundaries of process design and redefining strategies for process control. As the reliability and performance of PAT systems improve, its potential to serve an integral role in pharmaceutical processes will increase. Within this context, PAT is increasingly used to replace off-line final product tests with at-line or on-line PAT-based release tests, to provide the basis for process control strategy, and to enable continuous quality verification (CQV) and RTR.
Traditional Process Control
Process control has traditionally been achieved through tight control of key process parameters at predetermined set points or ranges. The premise for this approach is the assumed or established relationship between process inputs—raw materials properties, process parameters such as temperature or pH, and so on—and critical and key product attributes such as process outputs. This control strategy, however, does not allow for mid-course correction to account for variation in starting materials or process upsets, nor does it allow flexibility within or between production runs to utilize the design space concept.
The set points for critical process parameters are commonly determined during development—typically in a design of experiment—and the process validated using a three-batch validation approach. Yet, in reality, after validation, the process will be subject to different sources of input variation that would be transferred directly to process outputs. Variability in quality attributes, therefore, is virtually inevitable.
Reducing common cause variation in such a traditionally controlled process can require significant effort. To ensure acceptable process capability, over-processing—over-drying, for example—is typically utilized, commonly resulting in increased costs and cycle times. Thus, control strategies that are based on fixed process parameters can result in higher variability of product attributes.
Advanced Process Control
No single definition of advanced process control (APC) exists in the literature, but the phrase as it is currently used describes mathematically advanced control algorithms that use predictive, adaptive, and optimization techniques to control multi-input, multi-output processes. A new concept in the pharmaceutical industry, APC is a mature technology that is commonly used in all other industrial sectors to improve quality, consistency, and process efficiency. Pfizer distinguishes APC as control strategies that utilize PAT, process models, or other techniques to manipulate process parameters (process inputs, Xs) within any required constraints, in order to actively control one or more active pharmaceutical ingredient (API) or drug product attributes (process outputs, Ys) at a set point or within a tight range.
PAT-based APC can overcome traditional control strategy limitations to enable capabilities that include:
- real-time monitoring of process outputs as well as process inputs;
- real-time prediction of process endpoints and product attributes to determine any potential deviation from desired range; and,
- calculation of the change needed in process inputs at each APC sample time to minimize the potential deviation in process outputs.
In a continuous process, outputs are typically controlled to reach and maintain steady state; thus, simpler steady state control strategies (time invariant) are sufficient. By comparison, in a batch process, outputs will typically follow a time-variant trajectory, necessitating more involved control strategies, including the use of multivariate controller models.
One PAT application uses near infrared (NIR) technology to monitor multivariate high shear wet granulation (HSWG) batch trajectory. (HSWG is a particle size enlargement process for maximizing powder handling and uniformity and minimizing dust hazards. Powder is mixed as the powder bed is simultaneously sprayed with binder solution.)
Figure 2 illustrates how the variation in raw materials and processing conditions results in separation of NIR trajectories. The performance of the granules during downstream processing can be predicted by the NIR trajectory, with the trajectory for Excipient 1 at X1 = M representing an optimal batch.
Figure 3, illustrates the use of PAT-based APC to control the real-time trajectory of a batch with non-optimal raw materials; it would follow the trajectory of the optimal “golden batch” that results in the required granule properties.
Benefits of PAT-Based APC
APC offers a new and promising paradigm for efficiency in pharmaceutical processes while providing tangible quality and business benefits. It can enable higher process capability, maintaining the process attributes close to specification. Improved quality, lower common cause variations, greater product consistency, improved yield, and cycle time improvements are among the benefits these advanced strategies can provide.
Currently, at Pfizer, there are a number of APC applications, involving both drug product and API processes and focused on large-scale manufacturing, at different stages of development. They utilize a range of APC technologies, including various latent variable model-based batch control strategies, non-linear APC with hybrid process models, soft sensing, and multi-loop optimal control using quality and business cost functions. These applications aim to address some of the most technically challenging problems in our industry with regard to chemical and physical attributes of API and drug products.
CQV (ASTM E2537) is a science-based approach to process validation in which manufacturing process performance is continuously monitored, evaluated, and adjusted as necessary (see Figure 4, below, right). This science-based approach verifies that a process is capable of producing and will consistently produce product meeting its predetermined critical quality attributes. PAT-based CQV provides real-time quality assurance; the desired quality attributes are ensured through continuous assessment during manufacture. Data from each batch are used to validate the process.
RTR is the ability to evaluate and ensure acceptable quality of in process and/or final product based on process data, which include a valid combination of material attributes and process control (ICH Q8 [R1]). RTR requires a high level of process knowledge to understand the impact of process parameters and raw materials on product critical quality attributes, as well as to identify and control the sources of variations. Process data composed of larger numbers of continuously gathered samples as compared to samples taken at the beginning, middle, and end of a process serve as the basis for real-time release of the final product. Measurement may be indirect, e.g., blend uniformity using on-line NIR coupled with unit dose weight variation control versus United States Pharmacopeia testing of tablets. Enhanced process understanding, larger number of process samples, and effective process control provide an increased level of quality assurance with RTR.
Next Generation Manufacturing Initiative
Pfizer defines QbD as designing and developing formulations and manufacturing processes to ensure predefined product quality and understanding and controlling formulation and manufacturing process variables that affect the quality of a product.
Pfizer’s Next Generation Manufacturing Initiative extends QbD principles to achieve continuous manufacturing of a drug product. Design space and PAT are combined to demonstrate and achieve process control; CQV is used for process validation. The combination of these approaches enables the RTR of a continuously manufactured product.
Continuous manufacturing is the combination of multiple unit operations in a manufacturing process into a single integrated system. In a continuous process designed based on QbD principles, sources of variation are defined and controlled, and end product variation is minimized by controlling the process within the design space.
The benefits of continuous manufacturing include:
- a smaller equipment footprint;
- minimized scale up and innovative, science-based regulatory approaches that can reduce regulatory filings for scale changes;
- reduction in engineering lead time;
- shortened time to market;
- lower inventory; and
- safer processes.
Reduced waste and increased containment capabilities are among the environmental, health, and safety benefits afforded by continuous management.
Driven by cycle time reduction and capacity enhancement, as well as reduced off-line analytical testing and minimized change over time, resulting efficiencies may be captured in capital and operating cost reductions. The integration of on-line PAT tools supports the development of more advanced process control strategies and CQV that can lead to real-time release.
Among the PAT applications enabling CQV and RTR is a PAT-based system for real-time monitoring of blend potency and uniformity in new continuous drug product manufacturing processes. The application utilizes sophisticated PAT signal conditioning, advanced chemometrics, and multivariate calibration models to accurately measure the potency of flowing blends. Apart from enabling CQV and RTR, PAT supports process control strategy by providing fast, real-time measurement that is used by the supervisory control system to maintain the process and the product within the required limits.
As the reliability and performance of PAT systems improve, their potential to serve an integral role in pharmaceutical processes will increase. Newly developed and emergent PAT-based approaches are pushing the boundaries of process understanding at Pfizer and redefining process control strategies in batch and continuous processes. Within this context, PAT is increasingly used to replace off-line final product tests with at-line or on-line PAT-based release tests, to enable CQV and RTR, and to provide the basis for advanced process control. n
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