Continued Process Verification (CPV): The often overlooked (but much needed) 3rd Stage of Process Validation
The FDA process validation guidance, Guidance for Industry: Process Validation- General Principles and Practices, outlines and separates process validation activities in three stages; Stage 1: Process Design (where Critical Process Parameters or CPPs and Critical Quality Attributed or CQAs are determined), Stage 2: Process Qualification, and Stage 3: Continued Process Verification (CPV). The first two stages (especially Stage 2) are the ones typically associated with the concept and application of process validation. Completion of Stage 2 subsequent to Stage 1 is a major milestone in the Process Validation Lifecycle as it confirms the process design and demonstrates the expected consistent performance of the manufacturing process. Additionally, the fact that completion of stage two is typically the gate that enables commercial manufacturing and distribution (other than regulatory approval of course) is part of the reason why these stages tend to get most (if not all) the attention when developing and commercializing pharmaceutical products. However, the third stage, Continued Process Verification, is the one that truly serves as the “guardian” of commercial product and its manufacturing process in order to identify and prevent out of specification results and avoid all the potential associated business and FDA compliance costs.
This stage encompasses a series of steps governed by a documented methodology (procedures and/or protocols) to collect and analyze end-to-end production components and processes data over the commercial lifecycle of a product to ensure product outputs remain within statistically determined control limits. These control limit ranges are by definition narrower than the approved product specifications, resulting in a systematic warning system to identify when a specific parameter is trending towards an out of specification event before it actually happens. Therefore, central to effective CPV is a methodology with which to identify unwanted process inconsistencies in order to execute corrective or preventive measures. This can take a number of forms, but at its core, it is a study plan with a list of parameters and attributes that must be regularly monitored and controlled during the complete lifecycle of the process. It must allow for statistical analytics and trend analysis of process consistency and capability as well as production variability. A correctly implemented procedure will minimize overreactions to individual production outlier events and guarantee genuine process inconsistencies across multiple batches are detected. Statistical tools must be used to quantitatively detect problems and identify root causes. Initially, continued process verification should be based on quality standards established in the design phase. After a period of time and a statistically meaningful sample size, variations can be detected by identifying deviation from historical data using statistical tools. Furthermore, these same tools can also be used to identify opportunities to optimize processes to increase quality reliability. Out-of-acceptance criteria and trends must be reviewed at regular intervals with experts from cross-functional disciplines such as engineering, manufacturing and quality to ensure that the process stays under control, in as close to real-time as possible. This is done over intervals of time that best correspond to the frequency of manufacturing.
Commercial Product Monitoring and Trending Across Batches
As stated above the CPPs and CQAs are established during the Process Design or Stage 1. The initial “control limits” (Upper Control Limit, UCL and Lower Control Limit, LCL) must be developed based on statistical analysis of the limited historical product data at this point, in order to trend CPPs and CQAs. These limits are by design tighter and different from the in-process/finished product specification criteria developed during Stage 1. One of the main particularities of Continued Process Verification study plans is that these DO NOT automatically call for an investigation if a deviation from the UCLs or LCLs occurs. Instead, CPV may call for initiation of a change request or the initiation of continuous improvement remediation initiatives in the case that specific trends are identified across multiple batches according to pre-established rules. It is not common that a single point outside of the pre-established UCLs or LCLs will trigger such actions. An evaluation might be called for depending of the criticality and the risk associated with the impacted parameters when agreed upon.
Additional periodic re-assessment of the validated status of a process is not required due to continued process verification (CPV). The findings or outputs of CPV include trend reports and documented evidence of CPPs, in-process and finished product CQA trend plots, as well as their analysis and recommendations. Instances where such parameters show a trend in an adverse manner must be evaluated in detail.
Continued Process Verification (CPV) is required and expected by regulatory agencies, therefore there are very tangible reasons from a regulatory FDA compliance perspective to implement CPV. To this point, 21 CFR 211.180(e) regulations require evaluating and determining the need for change in manufacturing or control procedures on an ongoing basis. ICH Q8 (Rev 2) recommends an enhanced Quality by Design (QbD) approach that is comprised of a process validation lifecycle with a process verification stage. The March 2012 EMA Guidance on Process Validation requires continued process verification during commercial manufacture. This ensures a continued state of process control throughout commercial production. A clear regulatory expectation exists to ensure that quality standards are set in place during Stage 1, Process Design, and that they must be monitored with regular frequency to confirm those parameters are being met. This is demonstrated by recent US FDA 483 forms and warning letters including deficient or non-existent CPV procedures and/or implementation.
Additionally, and on the more business friendly side of the spectrum, Continued Process Verification (CPV) not only helps protect consumers from production faults, but businesses also see benefits in implementing such programs. The reduction or elimination of process related failures makes business sense due to the resulting benefits, such as:
- Reduced cost of quality
- Reduced effort when investigating process events due to existing CPV data
- Improved process control and process understanding
- Continuous supply chain which will enhance client service levels
- Better manufacturing planning
- Possibility for addition of more products to the manufacturer’s portfolio
- Reduced regulatory and FDA compliance risk
In the end, Continued Process Verification (CPV) is not only necessary from a regulatory expectations perspective for pharmaceutical manufacturers in general, but actually beneficial and advantageous for the business side as well. Any system, such as CPV, that helps a manufacturer identify and prevent potential process problems before they happen with data that it’s already being collected by implementing the proper monitoring and trending methodology is worth looking into.