The FDA’s regulatory requirements for process validation highlights the need for defining Critical Process Parameters (CPPs) based on Critical Quality Attributes (CQAs). As described by the FDA, a CQA is a characteristic within a range that ensures a specified level of product quality. These requirements highlight the focus of QbD, or Quality by Design. The ICH describes this view of quality assurance that focuses more on validating the process through control parameters and less on defining quality based on product testing.
The ICH guide outlines the FDA requirements for process validation in three stages: Process Design where the manufacturing process is defined, Process Qualification where the process design is clarified and scaled for commercial production, and Continued Process Validation where the controls are monitored during production to ensure product quality. Identifying CQAs and CPPs occurs beginning with Process Design, based on information from the development stage and from historical data. Working through this and the Process Qualification process then provides the needed information for the Marketing application.
The challenge here is in determining the attribute as critical, and then to determine the acceptable variability. “Critical” could be based on the acceptance criteria defined for the product. The CQAs defined during development, and identified as critical to the manufacturing process, would be those that have a measured impact on product quality, but beyond just determining the impact of the attribute, the amount of impact should be considered, and the acceptable variables defined. Using risk analysis can help dene criticality based on the potential risk to the patient. The FDA describes using a lifecycle approach to process validation and employing risk-based decision making, which can show criticality as a continuum rather than as a binary state. Meaning levels of criticality can change through re-iterations of the lifecycle.
Defining the CPP might be easier. The process parameter is considered critical when its variability impacts the CQA, but the FDA and ICH are vague on the amount of impact, so common sense can be used in making the determination. For example, extreme temperatures could destroy a pharmaceutical product, but if the process
Search creating it can’t produce the extreme temp, then that parameter wouldn’t need to be identified as a CPP. The next step is determining the range of each CPP expected in routine manufacturing, and establishing the control.
After determining the CQAs acceptable variability, process studies can be used to dene the CPPs acceptable variability, and thus dene the ranges to be monitored for control.
By conducting tests, the manufacturer can determine the acceptable range limits of each CPP and use that in defining the allowable process variables. Operational conditions within this range would be acceptable for manufacturing operational standards. Anything outside the acceptable range would indicate issues within the process and may lead to substandard products.
The Process Design stage and the Process Qualification stage provide the information needed for the Marketing Application (figure 1). 3.2.S.2.6 and 3.2.P.2 would contain the explanation of the content components, providing the background and assessments used to determine the CQAs. The description for the Manufacturing Process would include the description of the CPPs, their relationship to the CQAs, and their acceptable ranges. CPPs with a higher impact on CQAs should be prioritized and held in a stricter state of control.
By dening the CPPs acceptable ranges, exibility is built into the application so that changes in the manufacturing process, such as new equipment or process improvements, can be accommodated without requiring additional approval.
|3.2.S.2.2||Description of Manufacturing||Description of proposed Design Space, for which supporting studies and justification are detailed in S.2.6|
|3.2.S.2.3||Control of Materials||Identify critical raw materials. Screen suppliers of critical raw materials to identify quality parameters and ranges for qualifying alternate suppliers. Link to the information is S.2.6 if applicable.|
|3.2.S.2.4||Controls of Critical Steps and Intermediates||Test and acceptance criteria performed at critical steps identified in S.2.2|
|3.2.S.2.5||Process Validation and/or Evaluation||Process Validation (PV)Commercial scale verification Continuous verification program|
|3.2.S.2.6||Manufacturing Process Development||Central location of QbD information. Could contain the following elements: Process development history to tie together the experience from non-clinical to clinical to commercialDefinitions for non-critical, criticalDetermination of CQAs and justification of acceptable boundaries (Cross reference P.2.3 and S.3.1)Justification of scaling. Determination of CPPs, including risk assessmentFunctional relationship between CPPs and CQAsDefine product quality control strategy including raw material specifications, and drug substance testing (cross reference to relevant sections for details)|
|3.2.P.2.1||Components of the Drug Product||Traditional|
|3.2.P.2.1.1||Drug Substance||Identify DS properties that can affect CQAs (e.g., physiochemical characteristics; degradation pathways). Provide appropriate cross-reference to DS section containing this information.|
|3.2.P.2.1.2||Excipients||Identify CQAs of excipients critical to DP performance. Screen suppliers of critical excipients to identify quality parameters/ranges for qualifying alternate suppliers|
|3.2.P.2.2||Drug Product||Provide introduction/executive summary of the strategy used to achieve the desired QTPPOverview of CQAs impacting product performanceProvide risk assessment per ICH Q9 identifying the formulation strategies for risk mitigationDescription of product quality control strategy|
|3.2.P.2.2.1||Formulation Development||Include data rich information from experimental studies to support risk mitigation strategy and TPP described in Section P.2.2|
|3.2.P.2.2.2||Overages||Justified based on risk mitigation strategy|
|3.2.P.2.2.3||Physiochemical and Biological Properties||Classification of product quality attributes as either critical or non-critical and justification thereof|
|3.2.P.2.3||Manufacturing Process Development||Include data rich information from experimental studies to support risk mitigation strategy described in Section P.2.2; determination of CPPs and risk assessment; use of PAT for in-process control of CQAs|
|3.2.P.2.4||Container Closure System||Extensive screening and qualification studies on packaging components (vial and stoppers) to identify critical quality attributes that could affect DP|
|3.2.P.2.6||Compatibility||Experimental data to support risk mitigation strategy|
The Marketing Application is critical for compliance and marketability, but more importantly, the information outlines the process that will ensure product quality. The manufacturer’s technical staff and quality managers should determine CPPs and CQAs to better hone the overall process, and to enable continuous re-evaluation. CPP variables and ranges should be reviewed and adjusted over time and after careful analysis of CPP data.
A well-established manufacturing process will contain a process control strategy that clearly identifies the CQAs and CPPs. Understanding these is critical to both patient safety and corporate good health.