Electronic Data Review In Pharmaceutical Industry – Hybrid chromatographic data systems are the worst possible solution for any laboratory, regulated or unregulated, but they are common. Here is why.
Applications of hybrid CDS are common in analytical laboratories. However, they are the worst possible solution because you have to synchronize and manage two incompatible data formats: paper print and electronic records. We discuss why hybrid systems are the wrong approach and what you can do to clear up the doubt.
Electronic Data Review In Pharmaceutical Industry
Welcome to a new decade and a new collection of “Data Integrity Focus” articles for your reading pleasure. Let me start with brutal honesty: hybrid systems are the worst possible solution in any lab, regulated or unregulated. After such a bold statement, we will discuss what hybrid systems are and why I came to this conclusion. I’ll give you free advice: don’t use them! Since most of you will ignore this advice, I will also look at a possible solution that can help reduce the amount of paper printed and make the second review of the chromatographic data simpler and easier.
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Before starting the discussion about the disadvantages of the hybrid system (and it has no advantages), it is better to define what a hybrid system is. The best definition of a system or hybrid approach is found in the WHO guidelines on good data management practices:
It refers to the use of a computerized system in which there is a combination of original electronic records and paper records that constitute all the records that must be reviewed and stored (1).
An example of a hybrid approach is where laboratory analysts use computer-aided systems that create original electronic records and then print a summary of the results. A hybrid approach requires a secure link between all types of records, including paper and electronic, throughout the record keeping period. When hybrid approaches are used, appropriate controls should be available for electronic documents, such as templates, forms, and original documents that may be printed (1).
The problem with hybrid systems can be traced back 15 years to the Able Laboratories fraud case. Able was a New Jersey-based generic drug company that took a rather unusual approach to analysis, as shown in Citation #5 of Form 483 at the end of an investigation for this purpose:
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Data exchange was done by cutting and pasting chromatograms, changing vials, changing the weight of samples and changing processing methods… The weight of the samples was changed by the analyst until a transient result was obtained (4).
Worryingly for the FDA, they audited the company seven times without falsifying the data. The problem was that inspectors only focused on paper printouts and never looked at electronic CDS records and audit trail entries—that is, until a whistleblower called the local local office and the rest is history. This led to two updates of the 7346.832 Compliance Guide for Prior Authorization Inspections (PAIs) with a greater focus on data integrity in both editions (5-7).
After a hybrid system of both electronic and paper signed records is formed, how is this for CDS? Figure 1 shows a hybrid CDS controlling a single device. This system can be a stand-alone or networked system, as the principles of a hybrid system are the same regardless of the architecture. The color code of the figure is as follows:
You see there are two incompatible recording formats to manage. This combination of electronic records and paper prints that must be synchronized from creation to destruction during the record keeping period is what makes it the worst situation. Additionally, the WHO guideline goes so far as to state that looking at hard copy, problems with poor data management and falsification may be overlooked during second-party review:
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Data integrity risks can occur when individuals choose to rely solely on paper printouts or PDF reports from computerized systems without meeting applicable legal expectations for master records. Original records must be reviewed – this includes electronic records. If the auditor examines only a subset of the data provided in print or PDF, risks may go undetected and cause harm (1).
From the perspective of the WHO, this does not bode well for hybrid systems. This statement is also deja vu from the Able Laboratories fraud case discussed earlier. However, hybrids are very common in many laboratories. But could the situation get worse?
Figure 1 shows the most optimized version of a hybrid system where all system suitability tests (SST) and sample calculations are performed in the CDS program. Here, all electronic records are available for analysis in a computerized system, and there is only one printout of an analytical run.
But… there’s always Spreadsheet Siren, an easy-to-use-anywhere app for those lazy people who can’t be bothered to read the CDS manual. Additionally, although all CDS software vendors include a wide variety of SST parameters and calibration curve models in their software (with the added benefit of not having to print and retype peak areas on a spreadsheet), the lab is developing a spreadsheet template. Do the same I’ve often wondered if chromatographers are masochists, and here’s why.
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Now, I suggest you stand back and look at the spirit you have created, the spirit that will haunt you unless you change. Instead of the relatively manageable process shown in Figure 1, we now have a silly (insert your alternate adjective here) situation, where we’ve made the process more complex, error-prone, with increased record vulnerability. And not one but two hybrid systems! In addition, transcription error checking between the two systems has been added for free. I could not write such literature.
Figure 1 illustrates the fact that chromatographic data are dynamic and not static records. As you can see, after acquisition, there is automatic and manual integration (if the latter is allowed) for data processing and then post-integration calculations such as calibration and adjustment by factors such as purity and dilutions. What is the difference between dynamic and static data? The best description is found in FDA’s guidance on data integrity and cGMP compliance, where an edited version is provided below:
…static is used to represent a static data record such as a paper record or an electronic image, and dynamic means that the record format allows interaction between the user and the content of the record. For example, a dynamic chromatographic record may allow the user to change the baseline and reprocess the chromatographic data so that the resulting peaks appear smaller or larger…(8).
Here: Chromatographic data are dynamic records. As such, CDS and the data contained therein are in the crosshairs of regulatory authorities worldwide, as slight changes in base position in a sample chromatogram can turn a failed result into a transient one. These changes can be hidden if the article is under audit or review.
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Many documents (instructions and/or records) may exist in hybrid form, meaning that some elements are electronic and others are paper-based.
Appropriate controls must be in place to ensure record integrity throughout the retention period (9).
Here, it is necessary to identify both paper printouts and primary electronic records for each combined system and protect both types of records during the record retention period. However, identification of all records of any computer system is not always documented in many laboratories until the data integrity of the system is assessed.
Let me briefly and brutally return to the World Health Organization guidelines on hybrid systems. Here are two statements that are about as far as a regulator can go without saying, “Don’t use these systems!” There is:
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The use of hybrid systems is prohibited, but mitigation controls must be implemented when older systems await replacement.
Requirements for linking handwritten paper signatures to primary electronic records are found in CDS at 21.
Electronic signatures and handwritten signatures created on electronic records must be linked to their electronic records to ensure that the signatures cannot be extracted, copied, or otherwise transmitted to falsify an electronic record by normal means (10).
Regulation 11 applies only to electronic signatures, as it does to electronic records. However, it clearly states above that handwritten signatures apply to electronic records (please interpret this as
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) will be linked to the relevant electronic records. Therefore, paper printing must identify not only the key data files used to produce the printout or report, but also the key textual metadata involved in the production and processing of the data. Not all textual metadata needs to be identified in the report (typically, these are audit trail entries), but if the analytical approach is in CDS, then the remaining data should be easily accessible. The link signature of this record is a technical control that is the responsibility of the application provider. However, the lab