The Hidden Factory in Your Laboratory?

LCGC Europe, LCGC Europe-08-01-2021, Volume 34, Issue 8
Pages: 326–330

Columns | <b>Column: Questions of Quality</b>

There is a hidden factory in plain sight in many laboratories. Not many people know of its existence, yet it stares back at you when you work. What is the output from this hidden factory? Paper.

Ask any analyst what the function of a laboratory is and why they work there and you will get one of two answers. The first may seem frivolous but it’s true, and that is they to get to play with some amazing toys—sorry, analytical instruments. The second is to analyze samples, interpret the data, and generate results for people to make decisions—as well as play with some amazing toys. What nobody will ever say is that the function of a laboratory is to generate reams and reams of paper records, and that they just love clicking on a print button. Welcome to the hidden factory.

In many laboratories, paper constitutes most analytical records. Whilst there are electronic records generated and stored in instrument data systems, many laboratories still print paper out of custom and practice, or following an edict from the sadists in quality assurance (QA). Welcome to the nightmare world of paper and hybrid systems that make up the hidden factory.

Warning! Although this column focuses on paper printouts, don’t forget the electronic records sitting in computerized systems throughout your laboratory—protect and preserve them please.

This column will look at the advantages and disadvantages of both paper records and hybrid systems (there are not many of the former but plenty of the latter), with suggestions to reduce the amount of paper generated by the hidden factory. We will finish by discussing approaches to reduce paper storage volume and costs by scanning and destroying paper records that you have just created. I could not make this up, even if I tried.

Advantages of Paper Records

This is a very short section: what are the advantages of paper records?

Flexibility: A paper record is easy to establish and is infinitely flexible. If you modify a process, just redesign the associated paper form. No messing around with software configuration and no computer validation to worry about.

Visible Error Correction: Errors are easy to correct and a reviewer does not have to wade through all those annoying audit trail entries to see them. Corrections are in plain sight, although you may have to squint to read the reason for change with some individual’s handwriting.

Known Archive Properties: Paper is a relatively robust record medium with less likelihood of data loss, except when you attempt undocumented chromatography by spilling solvent on the pages. Paper has well understood archive properties as long as the environmental conditions are maintained and monitored.

That was quick—now let’s look at the problems with paper.

Disadvantages of Paper Records

Unsurprisingly, there are several disadvantages of paper records.

Blank Forms: Blank forms can be at the heart of data falsification and therefore they need to be controlled by uniquely numbering each form, allocating a form to an individual or group for use, and reconciling when the work is complete as required by data integrity guidance (1–4). For more information on how to implement controlled blank forms see the article by Burgess and McDowall (5).

Administrative Costs: Blank forms are expensive to administer, but the cost is hidden from management as it comes from general staff payroll, rather than a specific budget item. The cost of long-term record storage of records is expensive, either with on-site buildings and associated staff or off-site storage rental costs.

Record Access: Think about your laboratory notebook—anybody can read it when placed on the top of your desk, but nobody can if it is locked in a desk drawer. Look further to QC batch records from product analysis. There is only one copy of the paper record and it is difficult to share all the information with more than one person. Of course, your laboratory has never lost a batch record.

Limited Search Capability: Although there is a requirement for trending some analytical data in EU GMP Chapter 6.9 (6), this is very difficult to achieve with paper. It requires that information be abstracted from paper and entered into an informatics application over time to trend results. This is a slow, tedious, and error-prone process. Searching through paper records to extract data for annual product reviews (7) or product quality reviews (8) is the same.

Storage: It is obvious that paper is a physical record medium that, in large quantities, has bulk and weight, requiring much storage space within a controlled environment. While the days of loading copies of drug submissions into the back of a lorry with a forklift truck are long gone, the same can’t be said for analytical batch records. Typically, records are stored on-site for up to two years and then transferred to an off-site records management facility until the end of the retention period when they should be formally destroyed. If required for inspection, audit, or complaint, investigation records should be retrieved rapidly under the service agreement with the records management company.

Back to the hidden factory and its only product: printed paper records.

Sources of the Laboratory Paper Records

We need to examine which tasks in an analytical process generate most of the hidden factory’s paper. Figure 1 shows a typical analytical process involving chromatographic analysis in green and highlighting the paper records that are generated during the hidden factory’s operation in yellow. This figure focuses on the paper outputs from both manual processes, such as sampling and sample preparation, as well as the chromatographic analysis and post analysis calculation of results from sample aliquots and generation of the reportable result.

You can see that paper records are generated by virtually all tasks throughout this process. Typically, the second person review may also generate some paper by using a review checklist to confirm that work has been performed correctly. If there is an out of specification (OOS) investigation, the hidden factory can be working overtime or double shifts, producing even more paper records. The scope of any hybrid systems, for example, the chromatography data system (CDS), as well as any spreadsheet use, is shown at the bottom of Figure 1 in blue. This is where we will focus our discussion to reduce some of the hidden factory’s paper production, as well as simplifying the second person review process.

Hybrid Systems are the Worst Solution

Welcome to your worst nightmare: hybrid systems. We have signed paper printouts generated from electronic records in the CDS coupled with the regulatory requirement in 21 CFR 11.70 for record signature linking (9). Most hybrid systems print paper as if it is going out of fashion, helping the hidden factory production quotas. At a minimum, the paper printout needs to be initialled and dated at the beginning and end of the printout by both the analyst and reviewer. If the sadists in QA insist, each page must be initialled by the tester and again by the reviewer, which are yet two more error-prone and tedious tasks. The printouts must also be checked against the electronic records, including those that were created or used in the analysis. Never mind, just think of playing with the toys when you have finished moving paper around the laboratory. But wait!

The Gift that Keeps on Giving

There is a bonus from the hidden factory. If a reviewer finds that there is an error in any data in the CDS, the paper records are returned to the analyst to correct. After the correction, guess what? Some or all the corrected record set are printed again and added to the batch records. The hidden factory is the gift that keeps on giving.

Let me ask you a very simple question: are you lazy? Those answering no will be asked if they are masochists and condemned to an eternity of initialling and dating paper records in purgatory. Lazy people, please follow me to the sunlit uplands of simpler regulatory compliance—even with a hybrid system.

There is a Better Way!

A simple way to reduce the amount of paper printed from a hybrid system is outlined in appendix 1 of the WHO data integrity guidance (10). Figure 2 shows a controlled review form for documenting both the creation and review of the record set created during an analysis with a hybrid CDS system. The review form is linked to the analytical procedure as well as the standard operating procedure (SOP) for review of laboratory records and the audit trail review work instructions for the computerized system that has generated the electronic records.

At the start of the analysis, a uniquely numbered version of the form is issued to the tester. This person documents the start and end dates and times of the analysis (to help the reviewer search audit trail entries), as well as listing all records created, modified, and where they are stored. The only printout from the CDS is a summary of the reportable results and a list of the contextual metadata used, for example, the instrument control file, data acquisition, and processing methods. Nothing else is printed from the system. The tester signs both the results printout and review form.

A much lighter set of paper records is passed to a supervisor or peer who will conduct the second person review as follows:

  • All data files are reviewed on screen. This requires a large enough screen to have two windows open—the first to see the data and the second to review other files, such as the acquisition method or the audit trail. This approach avoids the check of the bulk of the paper printouts and makes the task simpler and quicker. It is also an opportunity to ask the boss for a high definition 55-inch screen for reviewing data; any other uses I’ll leave to your imagination.
  • The reviewer checks the CDS data and contextual metadata files generated by the performer of the test and documents these on the review form.
  • The applicable audit trail entries are also reviewed and documented. Two windows are very useful for correlation of data modifications in the data and contextual metadata with specific entries in the audit trail.
  • Checks for falsification of data are included in the form and will be checked during data integrity audits and, if applicable, data integrity investigations.
  • If changes are needed, these are documented and sent back to the tester to update.
  • When the review is complete, the reviewer then signs the form.
  • If required by laboratory procedures, there may be space on the form for an approval or QA signature.

System Backup is Critical

Regardless as to whether you implement the paper reduction process outlined above or not, all hybrid systems need the electronic records backed up. Many hybrid systems are standalone and the process owner is responsible for electronic record backup as required under EU GMP Annex 11 clause 7.2 (11) and 21 CFR 211.68(b) (7). Do not use USB devices for backup, as discussed in a recent Focus on Quality column (12). Instead, connect the workstation to the organization’s network, either using the existing network socket on the PC or by installing a network card, and then use an agent from the IT department’s backup system to regularly backup the system. Alternatively, IT should write and verify a script to perform the same function automatically after initiation by a user. Ensure that the backup process works by performing test restores on a regular basis.

Scan and Destroy?

Having spent time and effort generating a humongous amount of paper we come to the pièce de la résistance as we say in Britain. The increasing storage costs for the paper may be spotted by an eagle-eyed senior manager. This may generate a mastermind light bulb moment: “Let’s cut the costs of external storage by scanning all these records and then destroying the paper. Look at the cost savings!” At this point the initials MBA after their name simply mean Minus Brain Activity.

The more sensible option is investing in informatics solutions such as laboratory execution systems (LES), electronic lab notebooks (ELN), or laboratory information management systems (LIMS) to capture data electronically at point of origin and eliminate paper printing in the first place. Why spend a huge amount of money scanning and destroying paper? How dumb and stupid is this?

The UK regulatory authority, MHRA, published advice for scanning and destroying good manufacturing practice (GMP) records on their old website that, unfortunately, is no longer available publicly. I have a word version available that I have used as a basis to write this section. Outside of the GMP arena there is good laboratory practice (GLP) guidance from the AGIT, a Swiss regulator and industry collaboration (13), as well as Question 6 of an FDA draft good clinical practice (GCP) guidance that discusses scan and destroy (14) and Section 5 in an EMA GCP guideline (15). Even the German Federal Office for Information Security gets in on the act with an English version of guidance for replacement scanning (16).

The first task is to perform a risk assessment of the proposed process before starting work. We will assume that this risk assessment does not veto the approach. The overall process is described in Figure 3, which is divided into three phases as follows:

1. Define and Validate the Process

The first phase, shown in red in Figure 3, is to define how you will scan the paper records and the equipment to be used. This must have high capacity automatic document feeders for the defined make(s) and model(s) of the scanners. For the latter what resolution is adequate for the job? Does the scan need to be coloured or just black and white? Single or duplex scanning? Can you search the resulting file (typically a PDF file)? Will any software be used or will the embedded software in the scanners be used instead? How will scanned copies be verified? Will a separate application be used to electronically sign to verify that the scan is a true copy or will the scanning application have electronic signature capability?

Once the system is defined, the requirements can be written and tested. To complete this phase, a procedure for scanning and verifying the copies must be written and staff trained. How will the records be named? (A file naming convention must be agreed from the beginning.) Where and how will the scanned records be stored? If this is not done, how will you retrieve the records in a hurry?

2. Identify Records to be Scanned and How to Destroy Paper after Scanning

The paper records in the process are shown in yellow in Figure 3. Records for scanning must be checked for completeness before starting the process. After scanning, the records need to be assessed to see if they can be destroyed or if a legal hold should be placed on them due to any pending legal action. If there is no legal impediment the formal process for destruction should be signed off.

3. Scan and Verify the Records

The lost MHRA guidance stated adequate Quality Control (QC) checks are performed and documented during the transfer process (to provide assurance that unacceptable errors have not occurred during the transfer process).

In contrast, the AGIT guidance proposes a 100% check of all pages (13). I agree. You must know that if 100 pages went into the document feeder then 100 pages of scan came out. That is not the end of the story. Each and every page must be checked versus the original to ensure the whole page was scanned, there were no misfeeds, orientation is correct, the content is legible, characters have not been misinterpreted by the software, colour reproduction is correct, and that the resolution is adequate. Only then can an individual verify that the electronic file is a true copy by electronically signing the file. The act of signing must lock the file to prevent any post-scanning tampering and ensure the integrity of the contents. The file must be stored in a secure location for long-term retention.

Backups of the system storing the scanned records must be performed along with periodic checks to ensure that the data are still readable.

What a pain—all because there was not the foresight to implement an electronic solution in the laboratory in the first place. Instead, the laboratory creates Great Mountains of Paper (GMP) only to then scan and destroy it. You couldn’t make it up! Welcome to your laboratory’s hidden factory.

Summary

A laboratory’s hidden factory produces paper records in abundance. A simple way of reducing the amount of paper printed from a hybrid system is described to help both the analyst and reviewer and make both jobs easier. Laboratories may also consider scanning and destroying paper to reduce storage cost; this is only a sticking plaster and fails to address the problem of a lack of foresight and investment. Tackle the problem at source and invest in informatics solution(s) to stop printing paper. Then close the hidden factory in your laboratory.

References

  1. FDA Guidance for Industry Data Integrity and Compliance With Drug CGMP Questions and Answers (Food and Drug Administration, Silver Spring, Maryland, USA, 2018).
  2. PIC/S PI-041-3 Good Practices for Data Management and Integrity in Regulated GMP / GDP Environments (Pharmaceutical Inspection Convention / Pharmaceutical Inspection Cooperation Scheme, Geneva, Switzerland, 2021).
  3. MHRA GMP Data Integrity Definitions and Guidance for Industry 2nd Edition (Medicines and Healthcare products Regulatory Agency, London, UK, 2015).
  4. MHRA GXP Data Integrity Guidance and Definition (Medicines and Healthcare products Regulatory Agency, London, UK, 2018).
  5. C. Burgess and R.D. McDowall, LCGC Europe 29(9), 498–504 (2016).
  6. EudraLex, Volume 4 Good Manufacturing Practice (GMP) Guidelines, Chapter 6 Quality Control (European Commission, Brussels, Belgium, 2014).
  7. 21 CFR 211, Current Good Manufacturing Practice for Finished Pharmaceutical Products (Food and Drug Administration, Silver Spring, Maryland, USA, 2008).
  8. EudraLex, Volume 4 Good Manufacturing Practice (GMP) Guidelines, Chapter 1 Pharmaceutical Quality System (European Commission, Brussels, Belgium, 2013).
  9. 21 CFR 11, Electronic records; electronic signatures, final rule, in Title 21 (Food and Drug Administration, Washington, DC, USA, 1997).
  10. WHO, Technical Report Series No.996 Annex 5 Guidance on Good Data and Records Management Practices (World Health Organisation, Geneva, Switzerland, 2016).
  11. EudraLex, Volume 4 Good Manufacturing Practice (GMP) Guidelines, Annex 11 Computerised Systems (European Commission, Brussels, Belgium, 2011).
  12. R.D. McDowall, Spectroscopy 36(4), 14–17 (2021).
  13. Position Paper regarding: Is it acceptable to destroy the paper originals of raw data and re- lated study documentation, if an image of the paper is captured in an electronic form (e.g. scanned)? (Working Group on Information Technology [AGIT], Bern, Switzerland, 2014).
  14. FDA Draft Guidance for Industry: Use of Electronic Records and Electronic Signatures in Clinical Investigations Under 21 CFR Part 11 – Questions and Answers (Food and Drug Administration, Silver Spring, Maryland, USA, 2017).
  15. EMA Guideline on the content, management and archiving of the clinical trial master file (paper and/or electronic) (European Medicines Agency, London, UK, 2018).
  16. BSI Technical Guideline 03138 Replacement Scanning (RESISCAN) (Federal Office of Information Security, Berlin, Germany, 2017).

ABOUT THE COLUMN EDITOR

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: amatheson@mjhlifesciences.com