Kaitlyn Vap, Life Sciences Lead Product Application Specialist, SUEZ
In 2004 the FDA published a guidance document on Process Analytical Technology (PAT). It contains non-binding recommendations and serves to encourage GMP manufacturers to deploy PAT to achieve process understanding, process control, and robust risk management. PAT allows for real-time measurements of desired quality attributes to optimize efficiencies. One of many benefits of obtaining real-time data is process understanding and demonstration of a validated state without manual sampling or laboratory analysis.
What is RTT?
Among other technologies, GMP manufacturers are leveraging PAT through the implementation of Real-Time Testing (RTT) in accordance with ASTM E2656 which provides standard practices for testing the Total Organic Carbon (TOC) attribute of pharmaceutical-grade water. There are different ways in which online TOC data can be used— process monitoring, process control, and process understanding. RTT is validated to provide process monitoring, process control, and process understanding to release water into production in real-time.
There are preparatory tasks, implementation procedures, and ongoing maintenance that are beneficial to be aware of when considering the integration of RTT into current manufacturing/production practices. Below outlines a stepwise approach to various phases of an RTT project that includes key elements for success within each phase.
Phase 1: Organize and Define
To initiate an RTT project requires a team, justification, and change control approval. Transitioning quality measurements from the lab to the production floor requires the collective contribution and consensus of a variety of functional areas to establish a risk-based, scientific strategy for implementing online TOC for real-time water release. It is highly recommended that management from all relevant functional areas be represented on the team including Quality Assurance, Quality Control, Validation, Manufacturing Engineering, Facilities/Utilities, Metrology, and Production.
From Phase 1 to final implementation, a change control committee will be involved reviewing, approving/disproving, and monitoring long term effects of the acquired changes. The function of a change control committee is to ensure process integrity and uphold regulatory requirements through the course of an RTT project.
Phase 2: Risk Assessment
When adopting any new technology, risk assessments need to be performed. For RTT, the two major risks that can be associated with the project are introducing a new technology and ensuring the measurements from the instrument of record are indicative of all Points-Of-Use (POU) along a water loop. The implementation phase incorporates a bridge study and a POU comparability study to account for these risks. Before these studies, a Failure Mode and Effects Analysis (FMEA) should be performed to evaluate the risk associated with transitioning to a new technology, identify placement of the instrument of record, and rank the risk of each POU in a water loop under consideration.
In preparation to perform an FMEA, it is necessary to evaluate the current vs. future state parameters that will undergo a change – sampling plans, Out-Of-Specification (OOS) reports, facility maps, Standard Operating Procedures (SOPs), water system design, POU criticality, etc. Defining these parameters and the change they will encounter will ultimately contribute to the FMEA.
When initiating an FMEA, the technology that will be introduced should be considered. To transition to RTT, current and future state instruments should be “like-for-like” or “like-for-kind” on the basis of instrument qualification and method validation. Method validation consists of accuracy, precision, robustness, sensitivity, specificity, system suitability, limit of detection, and limit of quantification protocols to determine whether the methods are suitable for their intended use.
Upon completion of an FMEA, placement of the instrument of record for RTT can be determined depending on the area along a water loop that will be most reflective of all POU. The return to tank POU is most likely to capture and record measurements indicative of all other POU as the water passes and returns to the reservoir. There are a few exceptions that may require a second instrument of record for RTT (e.g., chase-the-tail loop or heat exchanger); however, most often the return to tank instrument accurately encompasses an entire water system.
Phase 3: Implementation
The implementation phase appears a light orange in the RTT process outline as it is the only phase the end-user can/might outsource to the RTT solutions provider. The solutions provider will likely have a Validation Support Package (VSP) associated with the implementation phase that contains all the necessary instrument qualification, operational qualification, and performance qualification metrics as it applies to RTT validation. Other than the implementation phase, the end-user owns the elements and deliverables of Phase 1: Organizing and Defining, Phase 2: Risk Assessment, Phase 4: Reporting/Data Handling, and Phase 5: Maintenance, making the Implementation Phase unique to the process.
Migrating from current state laboratory grab sample practices to future state online monitoring and release of water for an RTT project first requires a standard Instrument Qualification, Operational Qualification, and Performance Qualification (IOPQ) to validate the future state instrument.
A bridge study helps to compare the performance of future state to current state per the ASTM E2656 requirement that the future state instrument must perform “equivalent or better” than the current state. The bridge study accounts for both the method transfer and method equivalency elements of the implementation phase by comparing the performance of the current state laboratory instrument to the future state online instrument.
Finally, the riskiest POU will be determined by the FMEA, and the TOC attribute on each POU will be compared to the permanently installed instrument of record. By doing so, this ensures the permanently installed instrument of record implemented for RTT outputs measurements reflective of all POU along a water loop and completes the POU comparability study.
Phase 4: Reporting/Data Handling
21 CFR Part 11 is the pinnacle of data integrity as it applies to the pharmaceutical, biotechnology, cosmetic, medical device, and food and beverage industries. Maintaining protected/unique logins, controlling data/metadata, and generating audit trails are just a few ways in which data integrity regulations are upheld.
In the case of RTT, remote logins and transferable data with an associated audit trail are valuable to limit the need to directly access the instrument of record. Having an internal IT department with the expertise to route data in this fashion relying solely on a SCADA system is one option; however, there are a few firmware and software packages that now allow users to isolate data from the online instrument of record and wire to a QC/QA lab for signoff while maintaining the necessary audit trail for ease of access and use for applications such as RTT.
Setting action and alert limits is also a key element to the reporting/ data handling phase. Starting by establishing a process capability index (Cpk) and process performance index (Ppk) will provide statistical insight on process performance over time. Cpk and Ppk quantify how many standard deviations the outer limits are from the center of the process. Defining action and alert limits with a known Cpk and Ppk will aid in identifying trends in RTT and establish procedures and responses in the case an action or alert limit is breached.
Phase 5: Maintenance
With any CapEx equipment, maintenance is necessary to achieve optimal instrument lifetime, but also plan for an event in which the instrument of record malfunctions. For RTT, redundancy, preventative maintenance, and Out of Specification (OOS) procedures should be considered.
Simply maintaining laboratory practice (current state) SOPs can be a form of redundancy in case an online instrument of record malfunctions. Preventative maintenance protocols should be defined by the RTT instrument vendor and routine maintenance visits can be scheduled. For OOS in the lab and during RTT, the FDA’s Guidance for Industry on Investigating OOS Test Results for Pharmaceutical Production details best practices for handling an OOS.
The Power of Process Control and Understanding through RTT
With pressure to meet today’s production demands, many companies are embracing PAT for operational efficiencies and lean processes. RTT offers processes understanding, process control, efficiency gains, and optimization all while ensuring precise, accurate, and robust data that stands up to data integrity requirements.
For example, in the scenario circled in the following figure, real-time monitoring would provide the data needed to make real-time decisions and provide insight into a contamination source. If TOC values and conductivity values were increasing out of normal range, while inorganic carbon levels were remaining in control, a contaminant such as citric acid could be the culprit. With validated and accurate data, RTT provides the ability to make important decisions, troubleshoot in real-time, and optimize efficiencies for a facility of the future.
Author Biography
Kaitlyn Vap is the Life Sciences Lead Product Application Specialist responsible for supporting Sievers total organic carbon (TOC) customers. She works with companies in the pharmaceutical industry to implement Sievers analytical instruments for the validation of laboratory water and drug products in accordance with global pharmacopeia regulatory standards. As an application specialist, she also explores new and/or developing applications to streamline the process of water and drug product testing. Kaitlyn holds a B.S. in Chemical Engineering from the University of Wyoming.
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