OR WAIT null SECS
This article uses case studies to explore the use and misuse of spreadsheet calculations in conjunction with a chromatography datasystem (CDS) in regulated GXP laboratories. What wonders of non-compliance will we find? How and when should spreadsheets be used in chromatographic analysis?
“It was the best of times, it was the worst of times, it was the age of wisdom, it was the age of foolishness...”. These are the opening lines of a book by that great chromatographer, Charles Dickens, and they serve as an excellent introduction to the subject of this column: spreadsheets. Is it the best application in the world? Are spreadsheets a fast track to regulatory non-compliance? The answer to both questions is YES! This column is focused on the use of spreadsheets for the post‑run calculation of reportable results in a regulated chromatography laboratory.
The title, abstract and introduction pose a number of questions that I will discuss and answer in this column. The examples quoted here are based on real examples and have been anonymised (mostly) to protect the guilty. If any examples come close to what you do in your laboratory, what are you going to do about it?
Enter the Dragon
Reader discretion is advised at this point as this is where the laboratory finds out the regulatory mess it is in. An inspector has arrived. They want to see some high performance liquid chromatography (HPLC) analysis records. As an auditor, I am a great believer in auditor’s (and inspector’s) luck: whatever records I ask for turn to dust in front of the audited (or inspected). Let us look at a recent FDA warning letter—I don’t have to write fiction, as real life is posted on the Agency’s warning letters “wall of shame” on their website.
Tismor Health and Wellness, an Australian company, received an FDA warning letter in December 2019 that did not do much for the company’s health or wellness. Apart from minor transgressions with the Chromatography Data System (CDS) such as analysts with administrator privileges, performing trial injections, aborting runs, repeating work to obtain passing results plus data deletion, there was also a citation for failing to control spreadsheets:
Your firm failed to validate the spreadsheet used to perform the assay calculation for your <redacted>. Your procedures lacked guidance on how to check and manually verify the calculation sheets. During the inspection, our investigator identified a calculation error within the spreadsheet. The incorrect formula for averaging the Internal Standard peak area was used… (1)
Let begin the non-compliance saga: no checks to verify the calculations and failure to validate the spreadsheet is bad. But then we plumb the depths: a calculation error was found by the inspector!
It goes from bad to worse as during the remediation:
During the review, you identified another error within your spreadsheets.
Please read the warning letter to see the list of remedial actions required by the FDA (1). This is not the best situation to be in and it could so easily be avoided if the CDS was used to perform the calculations.
Main Chromatography Data System Functions
Let’s set the scene for the rest of this column by listing the main functions of a CDS which are:
Looks simple and straightforward doesn’t it? All work can be performed in a single application. All chromatography files and associated contextual metadata are found in a single location. The only transcription checks that need to be conducted are when data are manually input from the sample preparation stage. Validated calculations can be performed automatically with the results signed and reviewed electronically.
Chromatographic and regulatory perfection! Why do anything else? Why even think about using a spreadsheet? Especially as many of the functions listed above cannot be performed by a spreadsheet:
However, when we come to post‑integration calculations, spreadsheets sometimes manage to get a foot in the door, a leg or even the whole body. CDS suppliers have gone to great trouble to include functions that enable a laboratory to work electronically, automatically calculate SST values, calculate results, adjust results with weights, dilutions and other factors,and perform custom calculations. This poses the key question: why on earth do laboratories use spreadsheets?
Seductive and Siren Spreadsheets
Enter stage left, the spreadsheet. Turn on any workstation in your laboratory or office, what is the one icon that you see consistently on each screen? The short‑cut to a spreadsheet. Spreadsheets are everywhere and they can be used and abused for a multitude of uses. We will focus on the parallel universe found in chromatographic analysis. The known universe is that of the CDS which can perform the majority of calculations as well as sign reports electronically, as described earlier. The parallel and dark universe is inhabited by the spreadsheet – a pervasive force with a seductive voice whispering in your ear saying, “I’m easy to use and you don’t need to read the CDS manual”. If listened to, the laboratory is now heading down the very slippery slope to transcription error checking hell.
The Great and Not So Good
Who is to blame for this? There are two key individuals who contribute to this debacle:
To this list of the great and the good, three more players are added:
The World’s Most Expensive Electronic Ruler
Enter stage right is our CDS in the hands of Dopey the lab manager. Seductive voices from Nerdy, the laboratory’s spreadsheet gnu—sorry guru—suggest that a quicker way of getting results would be to use spreadsheets to do all the post-integration calculations. If Dopey agrees, the laboratory can apply to the Guinness Book of World Records to see if they have created the world’s most expensive electronic ruler.
Dopey, aided and abetted by Nerdy, is now opening the door to a potentially uncontrolled and hidden software factory that appears at first glance to be a cheap solution. However, there are big hidden costs and great regulatory risks that can become unmanageable as we shall see later. Of course, a laboratory goes down the spreadsheet route in the full knowledge that a spreadsheet has a full audit trail (no it does not) and is technically Part 11 compliant (no it’s not) and is also a hybrid system that are not recommended by WHO (5).
Skis at the ready? This will be a rapid descent down the slippery slope to spreadsheet hell.
A Case Study of Analytical Incompetence
Let’s see how this works in practice in a QC laboratory working to Good Manufacturing Practice (GMP). Sloppy, the analyst analyses the samples as normal but the only data entered into the CDS is the sequence of vials and their corresponding identities, for example, standard, sample, blank, etc. There is no input from the sample preparation phase of weights, dilutions, etc. as these are saved for the spreadsheet extravaganza later in the process. Post-analysis, Sloppy checks the peak integration and when acceptable, the chromatograms and peak areas are printed out.
Dumb Move Number 1:
Next, Sloppy transcribes the peak areas of the SST injections from the CDS printout into a spreadsheet to calculate the SST parameters to see if the run passes or fails the predefined acceptance criteria. As mentioned earlier, Sloppy has acquired a reputation for a lack of attention to detail.
Dumb Move Number 2:
The next stage is for Sloppy to calculate the analyte amounts or concentrations in the samples using the specific calibration model in the analytical procedure. Guess what, the laboratory uses another spreadsheet!
Dumb Move Number 3:
Who is Paying the Bill?
Here’s where Dopey’s laboratory picks up the bill for an amazingly abysmal and inefficient process. Enter Picky, the poor unsuspecting individual who is going to review all the records and data to see that work has been performed correctly under EU GMP Chapter 6 (9) and 21 CFR 211.194(a)(8) (6). Picky must check all records to ensure that no mistakes have been made, the data are complete and accurate and signed off. What does Picky have to review? Instead of the sample preparation records and all data in the CDS if you had designed the process well, Picky has a mess of records spread across two media: paper and electronic.
Figure 1 shows the process of chromatographic analysis and spreadsheet calculations in green. Below each task in the process are the records that are created: paper records are in yellow and electronic ones are in blue. Some observations:
This mess ensures that any properly conducted second person review takes longer than the actual analysis to perform. Now you are probably thinking that I’m making all of this up and no laboratory works this way. I wish I was but this description is based on a real laboratory. I have only changed the names of the people involved; the names used here are much better and far more appropriate.
What is missing from Figures 1 and 2 is the instrument log book. The entries in the log must also correlate with analysis record sets generated either from the spreadsheet or electronic processes.
Do It Right: A Spreadsheet Free Zone
What should have happened when an inspector dropped in for a cozy fireside chat is that they should have been presented with the records generated from a streamlined electronic chromatography process, as shown in Figure 2 and based on the process described at the start of this column. The advantage for the inspector and the laboratory is that all the records are in the CDS database and the inspector can review them on-screen by directing a skilled CDS user where they want to look. As all appropriate technical controls are in place and the process is validated, there should be no issues and the inspector can go and terrorise—I mean inspect—somebody else.
Key Review Areas of the Electronic Process
Consider the situation where we have an electronic process with validated calculations and electronic signatures in the CDS, as described at the start of this column. Where are the main problem areas? Manual data input of weights, factors, and dilutions as well as the entry of sample identities in the sequence file and placement of the vials in the corresponding order in the autosampler. Picky’s job as a reviewer is focused on these areas as these are critical data entered manually that require a check as required by EU GMP Annex 11 (10), plus checking that peaks have been integrated correctly. The remaining part of the process is fixed and validated and should not require much review scrutiny. Comparing the spreadsheet-driven process in Figure 1 with the streamlined electronic process in Figure 2, shows the simplicity of an electronic process.
But the process in Figure 2 is not just to keep an inspector happy. They may only see the process every two years or so with regular facility audits. What about the staff in Dopey’s laboratory who will operate the process daily?
OK, job done? Not always.
Interface the CDS!
An earlier Questions of Quality column discussed a laboratory information management system (LIMS) interfaced with a CDS (11). Here sample identities and weights for an analysis are transferred from the LIMS to the CDS reducing the manual data input to the sequence file of factors and dilutions. This limits Sloppy’s data input activities and consequentially reduces Picky’s workload as the integrated process is validated and under control.
Alright, There Are Exceptions
Having spent the whole of this column until now saying that spreadsheets should be exterminated from the face of all chromatography laboratories, there are inevitable exceptions to this rule. In some situations where an experiment requires data from more than one chromatographic run, then a spreadsheet is one way that can be used to collate the data and perform the calculations with current CDS applications. However, the spreadsheet does not have an audit trail and is a hybrid system which are not great attributes to boast about in the current data integrity environment.
One way to overcome this is to use an electronic laboratory notebook (ELN) or similar application where data from the CDS can be imported and used to automatically populate the spreadsheet for performing the required calculations; in this way manual input is avoided and the associated transcription error checking. The ELN has the security, audit trail, and the ability to work electronically, enhancing the compliance of using a spreadsheet. The use of spreadsheets in this way should be a minority of cases in a chromatography laboratory.
Let’s revisit the words I quoted from Dicken’s Encyclopedia of Chromatography at the start of this column:
Need I say more?
I would like to thank Chris Burgess and Paul Smith for their constructive comments in the preparation of this column.
Bob McDowall is Director of R.D. McDowall Limited, Bromley, UK. He is also a member of LCGC Europe’s editorial advisory board. Direct correspondence to: firstname.lastname@example.org