By Bikash Chatterjee CEO, Pharmatech Associates, a USP company
Continuous manufacturing processes promise shorter manufacturing cycle times without the need for intermediate storage, sampling testing and release of intermediate process steps, and shorter product release times through the intelligent application of in-line and at-line testing strategies. For continuous processes, the general testing strategy is designed to decrease the probability of critical quality attribute (CQA) failure through control of critical material attributes (CMA) and critical process parameters (CPP).
Continuous manufacturing process design and development starts with a risk assessment to determine each unit operation’s characterization studies. As with batch processes, critical material attributes are evaluated by their impact on process predictability and variability. Risk assessments look at parameters used in each unit operation and consider the impact of material variability for API and excipients and the impact of process dynamics, startup and shutdown on the consistency of material being produced. That is why a clear analytical strategy is essential as the process moves from development to implementation.
Understanding the process dynamics as material moves through each unit operation within a continuous process is an essential characterization requirement for supporting the establishment of a control strategy and supports the development of sampling and diversion strategies. One approach to addressing this requirement is to measure the residence time distribution for all material throughout the process. In simple terms, the RTD is a reflection of the time it takes for material to move through each unit operation. Method development focuses on the resolution and sensitivity of each test with validation subscribing to the core requirements as defined in ICH Q2 and USP <1220>. Understanding where comparability and correlation can be used to move to in-line or at-line testing should be part of a deliberate strategy at the outset of analytical method development, considering the equipment capabilities of in-line testing equipment such as Near-Infrared (NIR) and Raman spectroscopy and also the data management and integrity considerations from inline monitoring and decision making. One of the great advantages of continuous manufacturing is the promise of real-time or near real-time measurement and control that results in less process excursions and waste. Building the models and logic for process correction and addressing process drift requires a clear understanding of the tools being used to separate the signal from noise in the measurement.
While the decision to pursue real-time release testing (RTRT) can be made at any time in the development of a continuous process for the finished drug product, integrating RTRT as a potential process design output as the analytical method development and process development move through characterization and control strategy development will allow drug sponsors to leverage development data and avoid costly additional studies. Getting feedback from FDA on the scientific and comparability arguments as the analytical testing moves from off-line to in-line will help realize the savings from limited or no additional release testing. Ultimately, a flexible analytical development strategy that can be aligned with different process designs and stages of control strategy can allow a drug sponsor to move efficiently from method development to demonstrating in-line control.
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