Keeping control of a chromatography data system (CDS) is a never-ending task; but it is a task that must be done in order to adhere to good practice (GxP) and data integrity guidelines and to keep you audit-ready. Over the nine years Sterling has had the Thermo Scientific™ Chromeleon™ 7 Chromatography Data System, we have developed a comprehensive set of procedures that make it easier for us to maintain and demonstrate control of our system.
As is often the way, when Chromeleon CDS was first installed, none of our current control measures were in place. However, with the evolving regulatory guidelines and the assistance of Thermo Fisher Scientific, we have been able to gain an in-depth understanding of the Chromeleon software and the controls we need to have in place to not only maintain compliance, but also carry out routine self-inspections which help us to gather evidence to be able to demonstrate that we are in complete control of our systems and processes. These procedures also enable us to track key performance indicators (KPIs), monitor training requirements and identify any problem areas within our laboratories.
Beyond the regular reviews carried out on every batch release, our system control activities are primarily carried out on a monthly basis, meaning the CDS Admin team will perform at least one of these tasks each week. This ensures the admin team isn’t overrun with ‘control’ tasks, but they are more of a constant in the background.
The first step in maintaining control begins with the initial training that every new analyst goes through when they join the company. I have previously spoken about how we perform our training in my blog ‘Walking the training tightrope with Chromeleon CDS.’
This initial training gives the trainer the chance to explain and demonstrate the control measures that we have in place and the new starter can see what is going on behind the scenes in the system. We make sure they understand that the checks aren’t there to find fault with an individual’s work, but to provide a safety net to ensure the CDS is used correctly.
Second Person Checks: The Four-Eyes Principle
Second person checks are the norm in GxP environments - they are one of the fundamental ways of maintaining control.
Every reviewer is trained in how to properly review data so they can check the work and audit trails every time they sign a piece of work as reviewed. This allows the analyst to get real-time feedback on their work, whilst giving the opportunity to share tips and tricks for use of the CDS. For example, the simple act of saying ‘I would integrate this peak like that’ gives the other person a chance to learn and understand a different way, or even a better way, of using and controlling the CDS.
We have recently given our Operational Qualification (OQ) managers access to Chromeleon CDS along with training on how to inspect the sequences and audit trails. So now, if they have any questions, they can logon and review the sequences ‘live’ rather than relying on exported reports. This ensures we have multiple layers of control going beyond the CDS Admin team.
We have recently incorporated Chromeleon CDS incident/issue management into our existing IT helpdesk that we have on-site. This has been invaluable as we can internally track training requests, support requests, and any issues that users are experiencing allowing us to keep an overarching view of how our systems are functioning whilst also being able to track any subsequent escalation to Thermo Fisher for more support. Having this reporting system not simply a convenient approach for maintaining control, it is also a regulatory expectation that auditors will require to see in place.
Monitoring Electronic Signatures
Chromeleon software provides the functionality to electronically sign sequences and, while this is something that has been around a while, at Sterling we have only just started to implement it in our system for certain types of testing. Our current KPI for electronic signatures is to have 100% of the final product and intermediate testing being electronically signed. This KPI was put in place in December 2019, which required the whole analytical team to move from ‘wet’ signatures to electronic. Before this, we hadn’t enforced electronic signatures and there was something of a divide between those who liked the idea and those who preferred the old way, typically based on personal preference. But since the switch, the attitudes have changed and the site has come together to embrace electronic signing of the data. Of course, CDS Admin must monitor the usage of electronic signatures, so we created Chromeleon Queries to find sequences that should be signed and check if they have been electronically signed off.
[caption id="attachment_21613" align="aligncenter" width="2607"] Example of a Query to find sequences that should be signed electronically[/caption]
At the start, December’s sequences weren’t fully signed off until the end of January, which required significant effort from the CDS Admin team to run the queries multiple times each week and follow up with individuals to ensure compliance. Now, if we take April’s figures, on the 6th of May 2020, 78% of all the required sequences were already signed. This has significantly reduced the amount of checking CDS Admin has to do and shows that electronic signatures are now established as the norm while allowing us to show auditors that we are consistency electronically signing sequences and that we are in control of this.
[caption id="attachment_21615" align="aligncenter" width="2043"] Electronically signed sequence monitoring[/caption]
Manual integration is still a hot topic for auditors so it is of paramount importance that we keep control of the level of manual integration. Brian Alliston has spoken at length about how we monitor manual integration in his blog post, ‘What’s wrong with manual integration.’
We have a sitewide KPI target to ensure that monthly manual integrations are below 18%. Our first step is always method optimization to use automatic integration wherever possible. Obviously we would love to drive this figure lower but unfortunately, due to the age of some of our methods, this has not always been possible hence the 18% figure.
On a monthly basis, we perform a Query to discover the number of manually integrated injections which allows us to monitor our progress and identify any training issues. We can also find and investigate methods that have a consistently high level of manual integration, which could be due to the nature of the testing or the age of the method or something else. Either way, we can inspect that method and decide if there is a general need for manual integration on a routine basis and, if there is, we can detail that in our SOPs which in turn helps the analysts as they are given even more guidance on how to carry out the integration.
[caption id="attachment_21614" align="aligncenter" width="2607"] Example of a Query to identify manually integrated chromatograms[/caption]
Monthly In-Depth Audits
Every month I have the job of carrying out an in-depth audit of a sequence performed on Chromeleon CDS. We have a defined schedule so that each department will get audited three times a year.
One sequence is scrutinized from start to finish. Every audit trail is interrogated, each chromatogram is inspected, everything is examined to ensure every SOP and best practice is being followed. These in-depth audits are not about finding errors, they are a way for teams, including CDS Admin, to discover what works well and things that provide opportunities for improvement. I frequently have many questions about the sequence, for example, ‘What was the rationale behind this change?’ This can lead to a far wider conversation about how we can improve things, is there something missing from the method, is there a better way of data processing, is extra training required, etc. This is something that helps us to ensure we are always audit-ready.
Changes in Culture
Although some analysts may say that between Chromeleon CDS and our checks it can seem like big brother is always watching, we have found that these controls have influenced how people respond when using the CDS software. A great example is the recent transition to and acceptance of electronic signatures - in just five months the whole analytical team almost painlessly shifted to electronic signatures.
Before these regular checks, the audit trail comments often left a lot to be desired with entries such as ‘integrated’ being common. A few years on and we are getting full descriptions of the rationale behind the decisions that were made in that save, leading to much better clarity and audit readiness.
Also, since the analysts know we inspect everything, they are very willing to come to us and say ‘I made a mistake’ which makes everyone’s life easier. It’s much easier to deal with a problem then and there rather than have it found by an auditor two years later! It’s great that the analysts on our site seem willing to do whatever they need to ensure we are following the best practices.
As with all change, it takes a while but when it happens, it happens to the whole site.
Who doesn’t like it when life is made easier? That is a common theme I hear with Chromeleon CDS - there are multiple ways to make your life easier and the analysts enjoy using the software as much as possible.
My experience is that there is always some hesitancy when a new procedure is introduced but, once people get used to it and start seeing the advantages, they quickly come on board. Take automatic integration, for example, there was some resistance that this would take way longer to set up than manual integration, which is true for a single sequence but, when used across multiple sequences, the benefits become increasingly apparent. Once people got more comfortable with the parameters and how they work, integration has become far more automated and we have seen our manual integration figures reduce massively.
The ultimate in ease-of-use must be eWorkflow™ procedures. Our formulations team now exclusively uses eWorkflows, which they have found it to be easier and more efficient for routine analysis.
Finally, electronic signatures have allowed us to significantly reduce the amount of paper we use in printing reports, which has been gratefully received by staff. They also like the fact their sequences are locked and any accidental changes prevented.
Reduction in Admin Effort
Put all these things together and it makes the CDS Admin sound incredibly controlling and paranoid, which unfortunately is exactly what is expected of a GxP laboratory!
But, by utilizing these regular, scheduled checks, the CDS Admin team’s workload has actually reduced, allowing us more time to move the CDS forward rather than constantly firefighting or chasing people to sign sequences!
Also, as time has gone on, we have found a reduction in repeat audit findings. For example, in March 2019 we identified an issue with column numbers not being added to the sequence correctly and, after we reminded the analysts of the correct procedure, we have only had one reoccurrence of this issue in the last 12 months. So, now we can identify problems sooner and resolve them before they become an issue or cause us to receive findings during an audit.
These measures have revolutionized how we use and control our CDS and how we present it to auditors.