P.A. Smith

Analysis of 47 FDA Form 483 observations and warning letters for infrared spectrometers reveals a spectrum of data integrity problems and a lack of laboratory procedures for the technique. Is this your laboratory? 

	Since the Able Laboratories data falsification case in 2005 (1), there has been a regulatory focus on the lack of data integrity with chromatography data systems. This scrutiny has focused on inappropriate access privileges with conflicts of interest, deletion of data files, failure to configure the application, testing into compliance, and failure to review audit trail entries (2). More recently, inspection focus has moved to the use of peak integration to integrate into compliance and masking potential impurities (3). There have been many warning letters as a result of these noncompliances and poor data management practices; this is due to chromatography being a major technique that can comprise between 40–70% of a laboratory's workload. You may ask, "Why the focus on chromatography in a publication on spectroscopy?" Just think of chromatography as sample preparation for spectroscopy!

	In contrast, there are relatively few FDA warning letters involving spectroscopic techniques. An analysis of FDA warning letters citing infrared spectrometers was published in 2014 (4).

	Originally, we were going to write a column looking at some of the data integrity issues that could occur with Fourier transform infrared spectroscopy (FT-IR) analysis, with a few regulatory citations to illustrate each point. However, given the bonanza of Form 483 observations and warning letters that have been issued by the FDA, we realized that an analysis of these would provide a great overview of the current regulatory problems facing the technique, before discussing specific topics in the future.

	In this column, we present an analysis of 47 Form 483 observations and warning letters issued between 2012 and 2018 (5–51). It should be noted that many of these Form 483 observations are not generally available publicly. Therefore, these observations, the regulatory focus on infrared, and the conclusions we have drawn may be new to laboratories that only review FDA warning letters. We have taken each citation or observation and broken it down into one or more data integrity areas; therefore, a single observation can have one or more data integrity noncompliances. For example:

		The application does not have an audit trail. This is a single 483 observation and a single data integrity issue.

		In contrast, here is a more complex citation: System audit trails are not available on the two FT-IR instruments, and quality control (QC) operators have the option of not saving the IR data. This citation will be classified into two entries; one of no audit trail, and another of application software design because data are not automatically saved. This is a simple example of compound data integrity problems, but some citations can be far more detailed and complex.

	Therefore, there is not a one-to-one correlation between all non-compliances analyzed and the data classification presented here.

	The noncompliances have resulted in a total of 104 separate citations for IR analysis that have been classified and discussed below. Some of these are self-explanatory, and will not be discussed in part due to space considerations and because the solution is obvious (such as no software validation, for example). In the references, we have included the FDA Facility Establishment Identifier (FEI), which is the way the FDA identifies a specific site in a company. Where there are different FEI numbers for the same organization, this means that two sites or facilities were inspected.

	Our main challenge in this analysis is to interpret a regulatory citation, because we don't know all the circumstances at the time of the observation by an inspector. For example, we don't know the functionality of the application software, so the observation of no system audit trails available as shown above could be a true software design limitation, or, more likely, it could be that the users did not enable this function. We have used our experience and best judgement in classifying each citation in this analysis.

	We do not claim that this noncompliance review reflects the total number of 483 observations issued, but, based on the significant number, it is reasonably comprehensive to draw firm conclusions on regulatory gaps involving IR analysis. Enjoy reading about the calamities of others. If any noncompliance mentioned here applies to your laboratory, what are you going to do? We suggest that you remediate the problem before you are included in a future update of this article!

Citations Before the Operational Use of the Instrument 

	One of the surprises of our analysis is that 42% of the 483 citations occur before the instrument and the associated software application are supposed to become operational. You may doubt this statement, but look at both Table I and Figure 1 and you will see two main areas: inadequate software architecture, and design and failure to qualify, calibrate, or validate the system. The interpretation of these nonconformance data is based on the wording of the 483 observations.

	The biggest area, at 37% of the total noncompliances, appears to be due to inadequate architecture and design of the application software that has been purchased by the regulated laboratories. The main problems with the application software are that, as implemented, there are inadequate controls for ensuring data integrity, no audit trail, and the architecture where data files are stored in directories within the operating system and users can delete data without any record in the data system. Again, this is based on the wording inspectors included in each Form 483 report, which represents a high level conclusive summary of the inspection findings, and not a detailed analysis of the root cause associated with each observation. In particular, this represents the inspector's interpretation of what was found about how software was implemented, and not the full compliance capabilities of each software package. In line with FDA warning letters, in many instances, the manufacturer and name of the software was included in many of the examples we reviewed, but we have redacted these in this column.


	Figure 1: Infrared spectroscopy Form 483 citations occurring before operational use of the instrument and software.

	Some of the citations for poor software design are:

		The UV and FT-IR analytical instruments are both equipped with commercial software that does not prevent accidental or intentional deletion of files containing data.

		QC operators have the option of not saving the IR spectra.

		With the FT-IR instrument (QC/FT-IR/201), it was noted that the redacted software had an option to enable or disable automatic saving of measurement available to the chemist.

		FT-IR spectrophotometers used in identity testing were observed to have a "delete" option available to the user.

		The lack of an audit trail was one of the largest number of citations; there was no audit trail in 16 out of 104, or 15%, of all citations.

	The use of directories in the operating system for data storage where a user can delete spectral files without any record in the application software (assuming there is a function capable of this) gave rise to 17 citations out of 104, or 16%.

		There were no controls to prevent deletion of data and deleted FT-IR data was observed in the computer recycle bin.

		Data can be deleted off the FT-IR used in the testing of active pharmaceutical ingredient (API). The data can be deleted off the computer systems hard drive, outside of the system software, and therefore not captured by the systems audit trail.

		Laboratory personnel can change and save changes to the date and time setting in the Windows operating system.

	The first problem is that regulated laboratories are purchasing IR application software that appears not to have any or inadequate data integrity controls. For example, all data should be saved, and there must be an audit trail built into the system which, once implemented, cannot be turned off. However, suppliers are market driven, and if users don't ask for these features, or help into how to implement them, then they won't be delivered. The responsibility of the supplier to help customers implement a compliant solution is becoming increasingly important. There is also the overall market that a supplier is developing its software for both regulated and unregulated industry sectors. What should occur is that suppliers should be selling configurable software, and also providing assistance in the form of white papers informing users how to configure the software or providing professional services to help implement compliant solutions. The second issue is the overall architecture of the system: Almost all IR software is designed for standalone operation, or can be implemented as a standalone system. Many standalone systems involve files storage in directories in an operating system, and not a database. If the software is designed to support networked implementation, using database storage on a secure network server, this should be implemented. This would remove many of the limitations of standalone systems, such as backup, as this would be performed by the IT department.

	Part of the problem is that many software applications require a range of expertise to implement compliant solutions, so that an expert in the analytical technique, someone with a detailed understanding of the software capabilities and strong IT and Part 11 knowledge, is required. From the number of Form 483 observations, it is clear that this multidisciplinary collaboration has not occurred.

What are Performance Qualification Tests for IR Instruments?

	The second area for noncompliance before operational use of the instrument (6%) is due to failure to qualify or calibrate the instrument or validate the software. This is a fairly straightforward area, and we were not going to discuss this, with the exception of two citations about the performance qualification of an IR instrument, one of which is:

	No Performance Qualification (PQ) is required before use to ensure the performance of the <redacted> FT-IR; only the . . . operation qualification is performed. In addition, the SOP # <redacted> does not require such a test.

(USP) general chapter <1058> on Analytical Instrument Qualification (AIQ) was recently updated (52), and contains new requirements compared with the 2008 version. The key issues are that:

		Users must write a user requirements specification (URS) that contains the operating parameters for the IR spectrometer and the instrument software.

		These parameters are verified in the Operational Qualification (OQ).

		Performance Qualification (PQ) needs tests that either directly or indirectly confirm that the instrument continues to operate in compliance with the operating parameters in the URS (52).

	The difference between an instrument OQ and PQ is typically the area of greatest discussion when considering analytical instrument qualification. It is important to first understand that, because an OQ and PQ test different attributes of instrument performance, both are required.

	Uniquely for FT-IR, the subject of calibration also needs to be considered because of confusion that can arise around interpretation of this word. First, in simple terms, the instrument performance attributes that are associated with an OQ and PQ are:

		OQ: Documents how the instrument satisfies user requirements before operational release and at regular intervals, typically after an annual preventative maintenance service.

		PQ: Demonstrates the instrument continues to work under actual conditions of use as documented in the user requirements specification.

	The reader must consider what these terms mean for an FT-IR instrument, and be able to defend this interpretation during regulatory inspections.

	For an FT-IR instrument, apart from replacing the internal desiccant that removes water vapor from sealed instrument enclosure, there are typically no user serviceable components. Therefore, it would be more appropriate to label regular testing of instrument as performance verification checks for wavelength accuracy, resolution, and signal-to-noise, rather than calibration. However, for an FDA inspector, calibration is most likely to be the name used for instrument performance checks, because this is specified in the Good Manufacturing Practice regulations in 21 

	Tests performed on analytical instruments during qualification typically fall under the following categories:

		metrology-based tests (not needed for an FT-IR instrument, unless temperature controlled)

	We will return to this topic in a later "Focus on Quality" column, where we will address OQ and PQ requirements for FT-IR in more detail.

	The main citations for IR systems found by FDA inspectors during the operational phase are listed in Table II, and shown diagrammatically in Figure 2. In general, these citations mirror those found with chromatography data systems (CDS) such as:


	Figure 2: Infrared spectroscopy Form 483 observations as found by FDA inspectors during operational work. 

		Poor Security and Access Control: This is the biggest problem with issues identified such as no security, all users have the same identity, and password thus making attribution of action impossible and conflicts of interest where all laboratory users have administrator rights. Some people will never learn! This is especially true when these citations against CDS have been made for the past 10–15 years. What is interesting in this case is that some laboratories have been cited because management had administrator access, confirming a requirement for application administration to be independent of the laboratory.

		Data Falsification/Testing into Compliance: This is another classic area for citations that is not limited to CDS, and are also found with IR systems. Citations here include data deletion, and retesting until a passing result is obtained. Some people never learn.

		No Audit Trail Review: Even when you have an audit trail in the application, it is ether turned off or if it is turned on the entries are not reviewed. There is even one citation where the audit trail is stored on a secure network, but the laboratory and QA staff cannot access it!

		Failure to Backup Data: This is a major problem when a laboratory is left to backup its own GMP records, and fails to do so. It is always better to get the IT department to back the data up on secure network drives.

	In addition, there are the following gems of noncompliance:

		Work Not Scientifically Sound: A variety of novel and unscientific approaches to charm FDA inspectors, such as use of IR analysis for cleaning validation where lack of sensitivity to detect an analyte was the issue (for example, using an identification algorithm to compare spectra of cleaning wash samples with pure solvents). On the bright side, every cleaning validation passes.

		Inadequate Instrument Log Book Entries: The instrument log book was featured in an earlier "Focus on Quality" column (54); here there were five citations for inadequate log book entries, including the failure of a second person to review them.

		Lack of Procedures: Another evergreen classic of noncompliance. No procedure or work instruction available, and naturally no training records, either-two citations for one noncompliance! Come on, how easy do you want to make it for an auditor or inspector?

		Failure to Maintain Complete Data: Although closely associated with data falsification, the writing of the citations indicate that this is due to a laboratory error, such as losing rather than deleting electronic records. Also, there are signed paper printouts, but no accompanying electronic records-oops!

		Raw Data Defined as Paper: One of the main data integrity messages is that paper cannot be raw data when a computerized system is involved (55); unsurprisingly, this message has not got through to some laboratories, who then receive a 483 observation.

		Inadequate OOS Investigations: Invalidated OOS results are a key quality metric that the FDA have selected for GMP laboratories as part of their quality metrics program (56), and it is the lack of root cause analysis or finding a scientifically sound assignable cause for invalidating an OOS result that gains an inspector's attention.

	Some of the factors that contributed to the observations reported in this article are:

Articles

Analysis of FDA Form 483 observations and warning letters for infrared spectrometers reveals a range of data integrity problems and a lack of laboratory procedures for the technique. Is your laboratory in the same situation?

P.A. Smith

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Analysis of FDA Infrared 483 Citations: Have You a Data Integrity Problem?