In January 2011 the FDA issued the New Process Validation Guidance. The modern definition of Process Validation has abandoned the concept of a one-off activity where success consists of obtaining three commercial batches of product. Instead, the new guidance describes Process Validation as a continuous lifecycle founded upon the principles of scientific understanding, and divides it into three stages.
Stage 1 tackles product and process development by identifying critical process parameters and critical material attributes, to establish the Processes Proven Acceptable range (PAR) and Normal Operating Range (NOR). Stage 2 is the closest thing to the old concept: demonstrating process predictability. But it is Stage 3 that introduces the most significant departure from the 1987 concept: that is, Continuous Process Verification throughout a product’s lifecycle. This article will examine the components of a successful Stage 3 Continuous Process Verification program and discuss a framework for integrating this new activity as part of an organization’s current Quality Management System (QMS).
A Stage 3 Framework
To understand the Stage 3 methodology, it is important to understand the activities that comprise the total PV lifecycle. Figure 1 summarizes the major tasks that constitute the three stages.
Continuous Verification and the APR Process
All pharmaceutical Quality Management Systems include an Annual Product Review (APR) process. The GMPs require an annual evaluation of the quality standards of a drug product to determine the need for adjustments in drug product specifications, manufacturing and control procedures. Subpart J of 21 CFR 211.180 mandates establishing a written procedure for the APR process and recommends review of a representative number of approved as well as rejected batches.
The concept behind the APR process is a regular periodic analysis exercise to evaluate the overall performance of a product based upon its Critical to Quality Attributes (CQAs). The concept behind the Stage 3 Continuous Monitoring process is to extend the same philosophy to those factors within a process that affects product performance. The challenge with the Stage 3 portion of the new process validation guidance is two-fold; how to acquire the data from the shop floor and what rules to apply in terms of adjustments to the process. The four activities of establishing a continuous verification system will be discussed as follows.
Shop Floor and Process Control Strategy
Implementing an effective verification and control strategy to ensure process and product performance is the heart of the new Process Validation Guidance. Prior to Stage 2, the CPPs that drive product performance variability and the control strategy for those parameters that affect process predictability should be clearly identified. Similarly, critical material attributes (CMAs) should have been identified and measurement tools implemented in Stage 1 to capture the appropriate attributes. The goal of Stage 3 is to ensure the validated process remains in a state of control that translates to analyzing the behavior of any CPPs and CMAs identified against the process understanding derived from Stages 1 and 2.
Specifically, for new products and processes, Stage 3 builds upon the process knowledge gained in Stage 1 and Stage 2. For legacy products, process understanding is a hybrid of historical control and performance data and Stage 2 confirmation data. The APR process is a good place to obtain historical product performance data as well as any discussion regarding Out of Specification( OOS) and Out of Trend (OOT) results.
When designing the sampling and testing approach for the control strategy it is important to consider the Stage 3 data acquisition component. Many organizations have limited or no Statistical Process Control (SPC) programs in place. Capturing documentation within the batch record is typical. However, the systems for extracting that data for use as part of a Continuous Verification Program do not typically exist.
Beyond the Stage 3 compliance component of this activity, the benefits of enhanced visibility to in-process data are many for most manufacturing operations. SPC allows manufacturing to identify and address potential sources of variability within a particular step, unit operation, phase, etc., of the manufacturing process. Another advantage of SPC is that it helps to prioritize sources of variability within a process so that efforts are put toward controlling the correct process inputs.
Several critical pieces to SPC:
• Setting up a variables and an attributes control chart
• Stabilizing an out-of-control process
• Process improvement and control charts
• Identification of key unit operations and products
• Preparing for a capability study
• Determining the process output
• Comparing the process output to the specification
• Taking action to improve the process
• Identification of area to display data on the factory floor by each unit operation
Through the evaluation process, the control limits can serve to provide immediate feedback to the operators if the process begins to stray.
Defining Organizational Responsibilities
Defining the roles and responsibilities within the organization is essential to ensuring that the designated data is captured so it can be analyzed and reported. When developing the process for data capture a cross-functional team with representatives from Manufacturing, Quality Assurance, Technical Services and Engineering should convene to define how data is to be captured and communicated without adding additional burden to the organization. Considerations for establishing an effective process start with identifying where in the process the designated data will be generated, then establishing the following:
- A GMP record that is consistent with the current or proposed in-process control program
- Procedure for reviewing the data for accuracy
- Process for communicating data to the appropriate quality function
- The statistical tests to be applied to the data and defining how the data can be used. Possible applications include troubleshooting, complaints support and continuous improvement activities through Change Control.
Finally, if an organization is going to reap the maximum benefit from this activity, the data must be used by all functions in charge of product performance. The Continuous Process Verification program is not solely the responsibility of the PV or Quality organization. There are responsibilities required from a cross-functional team. Up front costs to establish the program and training for the organization may initially seem steep but these costs can be modulated depending on the maturity of the organization, the process knowledge and historical performance of the products, and the maturity level of other established QMS programs at the site.
The new guidance departs significantly from the 1987 guidance specifically in terms of the concept of revalidation. Since the 1987 guidance was issued the industry has viewed validation as the end of the development process, i.e. the last step to commercial introduction. If a significant change were introduced into the process the result would typically trigger a revalidation of the process. As a result, the threat of having to revalidate a process was the excuse for not implementing improvements that could affect the process predictability, yield or efficiency. The new guidance considers that the purpose of Stage 3 is to allow quality and manufacturing organizations to leverage process understanding as a basis for calibrating the risk of process variation. As data are gathered and analyzed, it becomes possible to understand the natural process variation based upon the identified CPPs and CMAs. Six Sigma professionals call this the common cause variation, which is intrinsic to the process. After sufficient data are captured it will be possible to establish alert and action limits that can be used to diagnose process drift or variability caused by factors that are no longer in control in the process.
The new guidance allows adjustments to be made to the process based upon the process understanding derived in Stages 1 and 2. However, the new guidance does not give carte blanche to the manufacturing or engineering organization to make changes as it sees fit. The most important component of the Continuous Verification program is defining how adjustments can be made to the process before it is no longer in control.
Continuous Improvement & Change Control
The biggest benefit to manufacturing operations is the ability to improve the process via the change control process. Organizations with an established Operational Excellence program can now take advantage of process and operational improvements by defining their impact based upon the process understanding derived in Stages 1 and 2. Highlighting statistically justified sampling plans and acceptance criteria within the guise of historical performance will provide the framework for implementing improvement. This reduces the quality risk associated with process improvements and provides a sound basis for evaluating any potential regulatory impact.
There is no doubt that the concept of Continuous Verification of critical process parameters is a significant departure from the classical requirements defined in the 1987 FDA guidance. If properly designed, the program can provide significant benefits to an organization by providing the ability to intervene in a process before it drifts out of a state of control. In addition, the investment in time and money made in establishing process understanding in Stages 1 and 2 can be recouped by allowing process and operational improvements to be made without the need to revalidate, thus achieving the end result of enhanced process predictability and product performance.