Bringing Business and Data – Integrity Benefits to an Organisation

This white paper will demonstrate that an investment in an instrument data system including validation can bring substantial business benefits to both a laboratory and its parent organisation.

We will look at the regulatory landscape to see some of the business benefits of laboratory automation, such as:

• Business benefits obtained from automating chemical analyses in GMP regulated labs
• Cashflow benefits following from earlier release of products
• Compliance cost benefits by ensuring data integrity for chemical analyses

We will start our discussion from the last point as it provides a firm foundation for understanding the current regulatory environment as well as the position of regulatory authorities globally.

To fit into this publication, the white paper has been reduced in its content. To view the full white paper go to: www.mt.com/lab-business-data-integrity

Driver 1: Regulatory Push for Data Integrity

The major current emphasis in regulated GMP laboratories is data integrity. There is an implicit expectation, with the FDA and European regulatory authorities, that the pharmaceutical industry keep up to date. This is best illustrated with 21 CFR 211 on Current Good Manufacturing Practices (CGMP) for Finished Pharmaceutical Goods – the key word is “current”. The preamble to the 1978 CGMP publication states that the meaning of “current” is that industry should keep up-to-date with new advances where one contributes to drug quality.

Currently many GMP laboratories are paper based and working practices have hardly changed over last decades. In fact, the FDA Guide to Inspection of Pharmaceutical Quality Control Laboratories issued in 1993 is still relevant a quarter of a century after publication as many working practices in regulated laboratories have not changed substantially. Many laboratories still work using:

• Manual processes
• Blank forms
• Hybrid systems
• Spreadsheets to perform calculations

The problem is that these approaches do not enhance data integrity and also result in higher second person review and administrative overheads.

Paper Processes Can be Easily Manipulated or Falsified

The first thing to note is that under no circumstances may balance weighing be accepted by observation – the data are too critical. There must be independent evidence to corroborate the activity. An analytical balance must at the very least have a printer attached. However, a printer has the potential to be manipulated, as evidenced by this regulatory citation:

FDA Warning Letter, February 2014 (ucm386678):

As analytical balances are so critical, security must be in place to ensure that there is limited access to the clock to prevent time travel. However, post run fabrication of data can be difficult to detect, especially when spread- sheets are used to calculate reportable results and not a secure instrument data system.

Master Templates and Blank Forms Must be Controlled with Accountability

Since 2016, there have been increasing regulatory requirements for the control of master templates and blank forms i.e. forms that are used to record data to demonstrate that a procedure has been executed correctly. The high regulatory risk of blank forms is exemplified with this case:

FDA Warning Letter, January 2017 (ucm538068)

Hybrid Systems are Discouraged

When a computerised system is involved, most computerised systems in analytical laboratories are hybrid: electronic records maintained in the computerised system with signed paper printouts. Under 21 CFR 11 regulations, the signature on the paper must be linked with the applicable electronic records used to generate the report. Hybrid systems are also under increased regulatory scrutiny as synchronising the paper printouts with electronic records can be difficult. Another issue is that paper printouts can still be classified as raw data and the electronic records either ignored or deleted. Backup of standalone workstations in the laboratory can be a major problem. To illustrate one of the problems with backup of laboratory data from standalone workstations the following citation is relevant:

FDA Warning Letter, May 2016 (ucm502347):

Similarly, using other media such as a USB stick or external drive would result in a similar citation – data must be backed up automatically using software, preferably via the IT department.

Spreadsheets Used for GMP Calculations Are High Risk

Many laboratories use spreadsheets such as Excel for calculation of analytical data generated by analytical instruments. Typically data are transcribed from a paper printout, entered into the spreadsheet, where the final calculations are printed out. There are several regulatory compliance issues with this approach:

• The spreadsheet is a hybrid system
• The master template must be validated
• The completed spreadsheet must be saved to a secure location and backed up as it is part of the complete data for the analysis
• The resulting printout must be linked to the saved electronic spreadsheet record

FDA Warning Letter, January 2017 (ucm538068): FDA Warning Letter, October 2015 (ucm474013):

Although spreadsheets can be very useful in the laboratory, their misuse can bring serious regulatory consequences.

How Much Risk is Justifiable?

From practical and regulatory perspectives there is a high compliance overhead and high regulatory risk when continuing to work with paper or hybrid processes.

To illustrate this point, if blank forms (e.g. papers that show how a procedure should be executed and what data should be recorded) are used in a laboratory they must be controlled stringently. The reason is that they can be photocopied and there is no knowing how many times a procedure has been executed before a passing result has been obtained. As shown in the following citation:

FDA Warning Letter, January 2017 (ucm538068):

There must be a better way of working to improve the way laboratories fulfil their role efficiently and effectively.

Driver 2: Laboratory Business Efficiencies Pull

Here we discuss two processes for weighing an analytical reference standard, ensuring the solution is the right pH value for compatibility with the HPLC mobile phase. After preparing the reference standard, the standard concentration is entered into a CDS:

1. Manual operation of a balance and pH meter and manual transfer of the reference standard concentration into a CDS for calculation sample results
2. Automation of the process using Mettler Toledo’s LabX instrument data system with automated transfer of the standard concentration to the CDS

Common features of the processes are:

• There are two analytical balances in the laboratory, a four-place and a five-place balance but only the five-place balance is specified for use in this analytical procedure. For the manual procedure, there is a printer attached to document the work performed.
• Each time the balance is used it must be verified to have been calibrated and checked against acceptance criteria specified in the procedure.
• There is a single pH meter that also has a printer attached for use in the manual workflow.
• As per the GMP regulations, a second person review will be performed

The differences in the processes are summarised as follows:

• For the manual process, there is a controlled and uniquely numbered blank form for the work. Printouts from the balance and the pH meter are attached to this form and any associated information (metadata) written down by the analyst.
• The electronic process uses LabX software from Mettler Toledo; this is an integrated instrument data system that links multiple instruments in a single analytical workflow. The instruments have touch screen front panels that act as terminals for LabX, removing the need for a PC workstation to control the workflow and collection of data from an instrument. Any calculations performed are defined and validated as part of the workflow.

Manual Process Workflow

The process flow involving the analytical balance and the pH meter is shown in Figure 1. The process in Figure 1 is:

• Slow
• Manual
• Prone to transcription errors
• Calculator calculations are error prone and needs second person checks
• Qualification status of instruments are slow as information must be checked manually
• Uses controlled forms to record work that needs to be formally issued, tracked and reconciled after completion of the analysis

The workflow has high-risk data integrity issues:

• How many times has the measurement been done?
• Entering data into a computer system manually is error prone
• The second person reviewer must check:
• Correct analytical balance used
• All fields in the blank form completed correctly, nothing is missing, blank spaces and corrections are initialled, dated and a reason for change given
• The calculation of the analyte concentration – (calculator)
• Manual input of the concentration to the CDS – manually entered critical data

LabX: An Integrated Electronic Workflow

The workflow in figure 2 is simpler and there are the following advantages for both the analyst performing the work and the second person reviewer:

• The qualification status of both instruments are contained in the LabX database, and if not qualified, the analyst cannot use the instrument
• Date and time of the work comes from the network time server, which itself is linked to a trusted time source; therefore the contemporaneous documentation of the work is assured
• The LabX workflow includes a check to require that the weighing is performed only on a balance with correct readability. This is also documented in the records of the work
• The mass set and acceptance criteria are in the LabX workflow for this procedure and the workflow will stop if the limits are exceeded
• Calculation of the analyte concentration is also automatically performed using a validated workflow
• The workflow automatically links the two instruments via the LabX workflow
• The pH measurements required are the calibration solution (with acceptance criteria) and the reference standard to ensure that the solution injected into the chromatograph is compatible with the mobile phase
• The reference standard concentration is transferred automatically to the CDS using a validated process.

The advantages to the laboratory are:

• Speed of analysis
• Speed of review
• ALCOA principles for data integrity are assured using the technical controls within the LabX application
  Total elimination of paper
• Assured contemporaneous recording of data
• Enforced workflow that mirrors the applicable SOPs
• Automated checks that the correct instrument is used in the process, each one is qualified and correctly calibrated
• Validated calculations are used throughout the process
• Automatic transfer of the reference standard concentration to the CDS

The second person reviewer profits from the advantages that:

• Many required checks that were tedious in the manual process are eliminated with LabX automation
• Issues that arise are easily highlighted when the LabX audit trail is reviewed or results are annotated for assessment – the data come to the reviewer not the reviewer to the data

Driver 3: Return on Investment Pull

• Current situation: QC is at the end of the process and everybody waits until testing is complete before batch release. Caveat is that LabX only automates some assays, but these are the traditional wet chemistry analyses that can be rate limiting. Automation of other assays is required to achieve this.
• See the impact of this on company cash flow of earlier release to market
• Potential calculation – If a batch is worth $1m and it takes 10 days to release what would be the benefit to the company if the release was reduced to 9 days?

Conclusions

This white paper has demonstrated the advantages of transition from a manual, paper based process to an automated process using an analytical balance and a pH meter as an example. With LabX the principles can be expanded to other analytical techniques such as Karl Fischer, titration, UV-Vis, etc. The automation of the process and the time savings coupled with ensuring data integrity fully offset the purchase and validation costs of the system. Ultimately, combining LabX instrument control software to an LES or LIMS system brings the most benefit of workflow efficiency, data integrity support and total cost of ownership savings. After the short term pay back of the validated LabX system, and as the long term savings multiply in efficiency and batch release effort, an even the larger scale benefit is realised in the removal of the cost of ‘non-compliance’.

Acknowledgement

The authors gratefully acknowledge Bob McDowall, Ph.D. of R D McDowall Limited, and Gunnar Danielson of Mettler-Toledo Analytical GmbH, for their invaluable contribution to this article. We especially thank Bob McDow- all for sharing his considerable expertise on the topic of Data Integrity and implementation of automated laboratory systems, as well as his comments and critique during the writing process.