A pharmaceutical manufacturing process usually consists of a series of unit operations to produce the desired quality product. Unit operations may be executed in batch mode or in a continuous manufacturing process.
A process is generally considered well-understood when:
(1) all critical sources of variability are identified and explained
(2) variability is managed by the process
(3) product quality attributes can be accurately and reliably predicted.
Process parameters are referred to as the input operating parameters (e.g., speed and flow rate) or process state variables (e.g., temperature and pressure) of a process step or unit operation.
A process parameter is critical when its variability has an impact on a critical quality attribute (CQA) and therefore should be monitored or controlled to ensure the process produces the desired quality.
Under this definition, the state of a process depends on its CPPs and the CMAs of the input materials.
Process robustness is the ability of a process to deliver acceptable drug product quality and performance while tolerating variability in the process and material inputs.
The effects of variations in process parameters and material attributes are investigated in process robustness studies.
The analysis of these experiments identifies CPPs that could affect drug product quality and establishes limits for these CPPs (and CMAs) within which the quality of drug product is assured.
Steps to establish process understanding are very similar to those of product understanding and include the following:
- Identify all possible known process parameters that could impact the performance of the process
- Use risk assessment and scientific knowledge to identify potentially high-risk parameters
- Establish levels or ranges of these potentially high-risk parameters
- Design and conduct experiments, using DoE when appropriate
- Analyze the experimental data and, when possible, determine scalability and apply first principle models to determine if a process parameter is critical.
- Link CMAs and CPPs to CQAs when possible.
- Develop a control strategy.
- For critical parameters, define acceptable ranges.
- For noncritical parameters, the acceptable range is the range investigated.
When more than one process parameter or material attribute is involved, these defined acceptable ranges may be termed process design space
ICHQ8 (R2) defines design space as the multidimensional combination and interaction of input variables (e.g., material attributes) and process parameters that have been demonstrated to provide assurance of quality.
Parameter movements that occur within the design space are not subjected to regulatory notification. Movement out of the design space is considered to be a change and would normally initiate a regulatory postapproval change process.
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