What is Continued Process Verification (CPV) ?
Continued Process Verification (CPV) is part of the FDA guidelines on Process Validation with a product lifecycle concept. The guideline is also an integration of the International Conference on Harmonisation (ICH) guidance for industry Q8 (Pharmaceutical Development), Q9 (Quality Risk Management) and Q10 (Pharmaceutical Quality Systems)
The lifecycle concept links product and process development, qualification of the commercial manufacturing process, and maintenance of the process in a state of control during routine commercial production
Process Validation is defined as the collection and evaluation of data, from the process design stage through commercial production, which establishes scientific evidence that a process is capable of consistently delivering quality product. The FDA guidance describes process validation in three stages:
• Stage 3 CPV is the process by which we verify that our product control strategy remains capable and in its qualified state during routine commercial manufacture
• It is how we demonstrate that our processes can deliver products at highest quality on a consistent basis
• It is the way in which we monitor both our process variation through routine data trending and periodically assessing our process capability
• Helps define the actions required to maintain a state of control and identify process improvement opportunities. Helps us shift from “fire-fighting” or reactive to proactive mode.
• It is applicable to both new and existing products
Regulatory Expectations On CPV ( Continued Process Verification)
• Continued Process Verification (CPV) is now a requirement of many, if
not all, of the world’s regulatory agencies and WHO.
• FDA , Process Validation: General Principles and Practices, guidance for industry, January 2011 (Section D. Stage 3 – Continued Process Verification):
– “Production data should be collected to evaluate process stability and capability.”
– “We recommend that a statistician or person with adequate training in statistical process control techniques develop the data collection plan and statistical methods and procedures used in measuring and evaluating process stability and process capability.”
– “If properly carried out, these efforts can identify variability in the
process and/or signal potential process improvements.”
• In 2018 and 2019, about 23% of the FDA Inspection observations were related to gaps in CPV ( Continued Process Verification) whereby 9-10% was attributed to lack of “control procedures to monitor and validate performance” (source: https://www.fda.gov/ins pections-compliance- enforcement-and- criminal- investigations/inspection-references/inspection- observations)
•The goal is to provide continual assurance that the process remains in a state of control (the validated state) during commercial manufacturing.
•Regulatory agencies require the use of data to support the development and manufacture of drug products
•Good manufacturing practices must be followed when collecting and evaluating the data needed to assess product performance
Why is CPV important?
Through CPV, we are able to ensure the effective
execution of our robust Product Control Strategies and •Build trust with our patients and consumers by consistently delivering products of the highest quality • •Detect, Understand, and control the sources of variation in our processes •Improve Process and quality performance, to eliminate defects and waste • •Build trust with our regulators by demonstrating continual assurance that our processes are maintained in a state of control
CPV Implementation
When does CPV occur?
•CPV can begin at different phases in the product lifecycle depending on whether it is a new product or an existing product (also known as legacy product)
•New product will always begin as Stage 1 and follow the normal cycle into Stage 3 CPV.
•For existing or legacy products, most will begin at Stage 3 CPV unless there’s a significant process change requiring revalidation, which will then put you back into Stage 1 Process Design or Stage 2 Performance Qualification.
Who is involved in CPV?
•Continued process verification is a cross-functional responsibility, requiring individuals from different business groups. Some of the typical business groups involved in CPV are
–Technical
–Engineering
–Quality
–Production
–Statistics
–Informatics
–Analytical
How is Stage 3 CPV Implemented?
•Stage 3 CPV is consists of two phases: –Phase 1 is the “continued monitoring and sampling of process parameters and quality attributes at the level established during the process qualification stage until sufficient data are available to generate significant variability estimates” –Phase 2 is the “routine sampling and monitoring which is adjusted to a statistically appropriate and representative level” –
•For ease of discussion, we will refer CPV Phase 1 as Stage 3A and Phase 2 as Stage 3B. It’s worth noting that the Stage “3A” and “3B” terminology are not specifically used in the FDA Guidance, but the two phases are described.
How to transition from Stage 2 PQ to Stage 3 CPV?
•Upon completion of Stage 2 – PQ there are two options that can be followed when moving to Stage 3 (CPV)
•The first option is to move into Stage 3A where higher sampling/monitoring of a process/product is performed prior to moving to routine manufacture and sampling routines coupled with periodic data trending and review.
•The second option moves directly from Stage 2 to Stage 3B without the need for heightened sampling or monitoring.
•But when are these stages applicable?
Stage 3A CPV Monitoring Plan
•Number of batches to be trended- typically the first 30 batches after Stage 2 are subjected to Stage 3A as this is considered a “statistically significant number/population” which will provide an accurate representation of the voice of the process (VoP)
• Sampling and monitoring requirement- this includes the number of sampling points/location, sampling interval, and how many samples will be collected
• Critical Quality Attributes and Critical Process Parameters- the critical quality attributes or process parameters that can be trended are those which are impacting efficacy, safety, and compliance such as API assay, preservative assay, etc
• Data trending frequency- this will depend on the level of risks identified, it can be weekly, monthly, etc
•Action tracking and escalation- actions identified must be logged and closely monitored. Escalation route must also be clearly defined. This should also include procedure on how to manage any atypical or out of trends which will sometimes trigger investigation or root-cause analysis to identify process improvement initiatives
Statistical Process Control Charts, Process Capability, and Alert Limits
•Control charts are used to evaluate process stability. The Alert Limits are determined from the data and express the inherent routine variability of the process. The alert limit provide a means to identify atypical or out of trend performance from a statistical quality control (SQC) perspective
•There are several control charts that can be used for the data trending as part of Stage 3A CPV.
–Trend plots
–5 point moving average
–Cu-sum analysis
–Histogram
Process capability measures how well the “voice of your process (VOP)”
matches up with the “voice of the customer (VOC)”. It compares the variability
of a process to specifications
•Alert limits can be defined in different ways, depending on the risks and product understanding.
-Use of historical data- most often than not, legacy products have alert limits which are based on historical process performance, traditional approach is to use the minimum and maximum value from previous data
-Use of Standard Deviation- alert limits based on ± 3 standard deviation are commonly used
-Use of stability data- there are quality attributes which tend to increase or decrease throughout the product shelf-life. Stability analysis are conducted for those quality attributes in order to predict the appropriate alert limits which will minimize risk of out-of-specification during stability
How do we identify atypical or “out-of-trends (OOT) ?
Atypical data or out-of-trends are breakages in your statistical process control charts. Identifying this breakages provide a potential early warning to process shift or drift that may indicate a change in performance over time.
•Below are the control chart rules which can help in identifying atypical data or
OOT.
•Commonly used rules are Rule 1, 4, and 5.
What is CPV Governance?
•CPV governance
–formally assess product and process performance
–It confirms, prioritizes, and manages process risk areas
–It drives process performance improvement
–Should include all applicable functions (e.g. Production, Engineering, Technical, Informatics, Quality)
•Regular meetings help drive the governance process, and include a review of data trends, which drive actions and decision making
•Typical agenda includes review of data trends, identification and updating of actions, sharing of success stories, and escalations or support needed.
Link Between CPV and PQR
•Product Quality Review (PQR) is the over-all review of your product including assessment of different quality indicators such as deviations, change control, complains, out-of-specifications, etc
•Data from the CPV is an input to the PQR.
KEY LEARNINGS
•CPV provides an assurance that products are manufactured with highest quality on a consistent and continuous manner
•It verifies that control strategies remains capable and its qualified state
•It helps identify process improvement opportunities and shift the approach from reactive to proactive
•Applicable to new and existing products
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