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[[File:Food Safety Lab (Gibson).jpg|right|300px]]
{{raw:wikipedia::Detection limit}}
'''Title''': ''What do Laboratory Accreditation for Analyses of Foods (LAAF) labs require out of a LIMS?''
 
'''Author for citation''': Shawn E. Douglas
 
'''License for content''': [https://creativecommons.org/licenses/by-sa/4.0/ Creative Commons Attribution-ShareAlike 4.0 International]
 
'''Publication date''': December 2023
 
==Introduction==
 
 
==Food and beverage labs and the LAAF program==
The Food Safety Modernization ACT (FSMA) was signed into law in January 2011, giving the U.S. [[Food and Drug Administration]] (FDA) broader authority to regulate how the country's food supply is grown, harvested, and processed. The FSMA gives the FDA additional powers towards the prevention of food-borne risks, the inspection of food-related facilities, the enforcement of compliance controls and violations, the response to food supply threats, and the imposition of stricter controls on imported goods. The FSMA was largely born out of "high-profile outbreaks related to various foods" in the 2000s<ref name="FDAFoodBill10Arch">{{cite web |url=https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm237758.htm |archiveurl=https://web.archive.org/web/20101226031457/https://www.fda.gov/ForConsumers/ConsumerUpdates/ucm237758.htm |title=Food Bill Aims to Improve Safety |author=U.S. Food and Drug Administration |publisher=U.S. Food and Drug Administration |date=23 December 2010 |archivedate=26 December 2010 |accessdate=06 December 2023}}</ref> and recognition that "a breakdown at any point on the farm-to-table spectrum can cause catastrophic harm to the health of consumers and great disruption and economic loss to the food industry."<ref name="HamburgFood11Arch">{{cite web |url=http://www.foodsafety.gov/news/fsma.html |archiveurl=https://web.archive.org/web/20110107124402/http://www.foodsafety.gov/news/fsma.html |title=Food Safety Modernization Act: Putting the Focus on Prevention |author=Hamburg, M.A. |work=FoodSafety.gov |date=January 2011 |archivedate=07 January 2011 |accessdate=06 December 2023}}</ref> The FSMA was amended in December 2021 to include the Laboratory Accreditation for Analyses of Foods (LAAF) rule, mandating that "testing of food in certain circumstances" be performed by LAAF-accredited laboratories<ref name="FDALabAccred21">{{cite web |url=https://www.fda.gov/about-fda/economic-impact-analyses-fda-regulations/laboratory-accreditation-analyses-foods-final-regulatory-impact-analysis |title=Laboratory Accreditation for Analyses of Foods, Final Regulatory Impact Analysis |publisher=U.S. Food and Drug Administration |date=03 December 2021 |accessdate=06 December 2023}}</ref>, as part of the overarching goals of the FSMA. (However, the FDA notes that these testing scenarios represent "certain tests that are already occurring" in the food industry and aren't new.<ref name="FRLab21">{{cite web |url=https://www.federalregister.gov/documents/2021/12/03/2021-25716/laboratory-accreditation-for-analyses-of-foods |title=Laboratory Accreditation for Analyses of Foods |author=U.S. Food and Drug Administration, Health and Human Services Department |work=Federal Register |date=03 December 2021 |accessdate=06 December 2023}}</ref>) The FDA emphasizes that testing of food includes "the analysis of human or animal food, as well as testing of the food growing or manufacturing environment (i.e., 'environmental testing')."<ref name="FRLab21" />
 
The "certain circumstances" of LAAF-mandated testing include when<ref name="FRLab21" />:
 
* growing, harvesting, packing, or holding environments for sprouts test positive for ''Listeria'' species or ''L. monocytogenes'' as part of normal mandated environmental testing;
* egg producers of 3,000 or more laying hens, who have have already mandated tests on molting and non-molting pullets and hens, reveal ''Salmonella enteritidis'' during environmental testing;
* bottled drinking water facilities reveal ''Escherichia coli'' in their approved product and operations water sources as part of mandated environmental testing;
* the FDA issues a directed food laboratory order to any owner or consignee, specifying a particular food product or environment be tested for an identified or suspected food safety problem;
* the FDA conducts evidence-based hearings prior to a mandatory food recall order;
* the FDA reviews the corrective action plan for a registered food facility ordered to be suspended;
* the FDA examines submitted evidence as part of an administrative detention appeal process;
* a food article (that has arrived to the U.S., or has had an FDA-approved representative [[Sample (material)|sample]] submitted prior to arrival) is submitted for admission of import or being offered for import into the U.S., to better ensure that the food article meets or exceeds the applicable requirements; and
* a food article impacted by an import alert (that has arrived to the U.S., or has had an FDA-approved representative sample submitted prior to arrival) requires successful consecutive testing in order to be removed from the import alert.
 
For each method of food and beverage testing that is or will be LAAF-accredited, laboratories seeking LAAF accreditation must be able to demonstrate compliance with [[ISO/IEC 17025|ISO/IEC 17025:2017]] and show that each method has also successfully passed a proficiency test or comparable program within the last 12 months. It must also show that it uses appropriate reference materials or [[quality control]] samples for each sample batch tested under the LAAF rule. Of course, the lab must also comply with other obligations laid out by LAAF (e.g., conflict of interest requirements, documentation of qualifications and conformance, analytical requirements, records and reporting requirements, etc., addressed in the next section).<ref name="FRLab21" />
 
LAAF accreditation is voluntary, and labs from both the United States and outside the U.S. are able to participate in the LAAF program.<ref name="KlemmLab23">{{cite web |url=https://blog.ansi.org/anab/laboratory-requirements-fda-laaf-accreditation/ |title=Laboratory Requirements for the FDA LAAF Accreditation Program |author=Klemm, K. |work=ANSI Blog |date=26 April 2023 |accessdate=06 December 2023}}</ref> As of the beginning of December 2023, there are 24 accredited laboratories and seven accreditation bodies.<ref name="FDALAAFDash23">{{cite web |url=https://datadashboard.fda.gov/ora/fd/laaf.htm |title=Laboratory Accreditation for Analyses of Foods Program |work=FSMA Data Dashboard |publisher=U.S. Food and Drug Administration |date=2023 |accessdate=06 December 2023}}</ref> The number of accredited labs is expected to grow (though the list of "certain circumstances" is limited, in turn likely limiting the number of labs finding it worth accrediting to the LAAF program), as the LAAF program won't come into effect until well after "there is sufficient LAAF-accredited laboratory capacity for the food testing covered by the final rule."<ref name="FDALabAccLAAF23">{{cite web |url=https://www.fda.gov/food/food-safety-modernization-act-fsma/laboratory-accreditation-analyses-foods-laaf-program-final-rule |title=Laboratory Accreditation for Analyses of Foods (LAAF) Program & Final Rule - Frequently Asked Questions |publisher=U.S. Food and Drug Administration |date=26 October 2023 |accessdate=06 December 2023}}</ref> That capacity number isn't known, but as more labs become LAAF-accredited, they will increasingly wish to ensure their informatics systems (e.g., [[laboratory information management system]]s [LIMS]) can not only help them continue to meet ISO/IEC 17025 requirements (which are referenced in LAAF and likely already in place for most high-level food and beverage labs) but also the additional requirements placed on the lab by the LAAF program itself.
 
==LIMS requirements for labs accredited to LAAF==
A food and beverage laboratory accredited to ISO/IEC 17025 is already likely to use a LIMS within their operations. That LIMS ideally addresses numerous standard user requirements for ISO/IEC 17025-accredited food and beverage labs, including tools for the provision of preloaded and configurable sample types and analytical test methods of the food and beverage industry; the management of documents, images, and attachments, with versioning and release controls; development of regulatory-driven safety plans, including building Hazard Analysis and Critical Control Points (HACCP) steps into laboratory workflows; and improvement of reaction time to non-conformances, including automatically messaging suppliers and re-prioritizing or pausing related activities. (For more on this, see ''[[LIMS FAQ:How can a LIMS assist food and beverage industry compliance with ISO 22000 and ISO/IEC 17025?|How can a LIMS assist food and beverage industry compliance with ISO 22000 and ISO/IEC 17025?]]''.) But what more does LAAF ask of the accredited lab, and what can a LIMS do to better address those LAAF requirements?
 
LAAF's extra requirements are largely tied to sampling, analysis, reporting, and record keeping.<ref name="FRLab21" /> A quality LIMS solution should already address most of the following requirements, but the vendor may need to make a few minor adjustments to ensure better support for the LAAF-accredited lab.
 
===Sample acquisition and client management===
Product and/or sample registration should be able to accurately capture submitted information and product state. Assuming the product is submitted for sampling, this includes product identifier(s), lot number, shipping container, client name and street address, and observations about the status of the received product. Whether the lab samples the product or a third party does the sampling, reception should also include sampling time and date, sample size, sample identifier(s), sample quantity, sample collection procedures and preparations, and chain of custody. Some of these details may be captured as part of a client management module of the system, though most will be documented at registration. However, LAAF also requires additional sampling documentation to be captured and sent by the lab. Can the informatics solution attach qualifications documents to a client record? Can sampling plans, sample collection reports, and advance notice of sampling documentation be captured, stored, and linked to registered products or samples, scheduled analyses, or analytical reports? Can a received product and/or sample be designated as LAAF-related in the system?
 
===Analyses===
 
As the LAAF rule notes, analyses can be either food-related or environmental in nature. As such, the informatics solution should be flexible enough to address the subtleties of these types of analyses and the sample matrices associated with them. The well-designed system will likely come preconfigured with multiple test types for food and environmental testing. However, the system will need to be configurable in its tests and workflow management to allow for the addition of new and customized tests and method-related workflows. This prompts a few questions. Can an existing or new test or workflow be flagged as being LAAF-specific and marked as validated for LAAF? Or is there some other means to ensure a LAAF-related sample can only be connected with a LAAF-accredited test method or workflow? Can a custom, FDA-approved method outside the scope of LAAF-accreditation be entered into the system and marked as being LAAF-useable? The system also should ensure an analyst assigned to a LAAF-specific product, sample, or test is qualified to conduct a LAAF analysis (which, by extension, means the system should be able to flag an analyst as LAAF-qualified). Finally, the entire analytical process that runs through the system should be capturing all the necessary details for what the FDA considers a "full analytical report" (see next section).
 
===Reporting and information packet submission===
 
A quality informatics system will capture information and data from reception to final archiving of results. The LAAF rule highlights the importance of ISO/IEC 17025:2017 and its demands for reporting results. While the informed vendor will already address those requirements in its solution, the vendor will still want to ensure or re-verify their solution's reporting module is able to address the needs of ISO/IEC 17025:2017. For reference, the report components addressed in sections 7.8.2.1 and 7.8.3.1 of ISO/IEC 17025:2017 and required by the LAAF rule include<ref name="ISO/IEC 17025">{{cite web |url=https://www.iso.org/standard/66912.html |title=ISO/IEC 17025:2017 General requirements for the competence of testing and calibration laboratories |publisher=International Organization for Standardization |date=November 2017 |accessdate=18 February 2022}}</ref>:
 
* report title
* name and address of the laboratory
* location of activity performed (even at a mobile or third-party location)
* unique identification of report components as being part of a complete report
* clear identification of the end of the report
* customer name and contact information
* method used
* unique identification, description, and condition of a sample and container
* sampling date and reception date
* dates of laboratory performance activities
* date report is issued
* reference to a sampling plan, methods, or other sources relevant to the validity and application of the results
* statement of exclusive relation between the items tested, sampled, or calibrated and the actual results
* results, with units of measurement
* deviations from, additions to, or exclusions from the method
* identification of the individual authorizing or finalizing the report
* identification of results from external providers
* specific test conditions (e.g., environmental conditions)
* statement of conformity with requirements or specifications
* measurement uncertainty presented in a same unit as or in a term relative to the measurand
* opinions and interpretations of the results
 
However, there's more that the rule requires a LAAF-accredited lab to report. These additional requirements can be met more readily with a reporting tool that allows for highly configurable reports. This would allow for elements such as U.S. Customs and Border Protection entry and line numbers, references to the analytical method used, name and signature of the analyst(s), calculations made, certificates of analysis, and the many other elements mentioned prior. (See the bullet points in the section on LAAF reporting and submissions requirements for more.) Given that LAAF-accredited labs, under certain conditions, are able to submit abridged analytical reports to the FDA, a configurable reporting module will allow the lab to select either a full or abridged analytical report based on their current FDA-approved status with LAAF.
 
Finally, the LAAF rule currently indicates electronic reporting of the full submission package, though details on how this is to be done are sparse as of February 2022. The FDA will likely update submission rules, which the vendor should be attentive to in case a special electronic submission type is mandated.
 
===Records management===
 
As mentioned prior, the LAAF rule imposes some records requirements on the laboratory, requiring document management, archiving, retention, and versioning tools to allow the lab to more readily meet those requirements. The LAAF-accredited lab will inevitably collect many documents as part of becoming accredited and enacting tests under the LAAF rule, beyond just test results. Does the system have the ability to manage multiple document formats? Is there sufficient secure storage? Can emails and other externally-generated documents be fed into and stored in the system? Given the five-year retention rule, the system should be flexible enough to handle retentions of that length, even if the documents and data are compressed and archived. It should be relatively painless to be able to retrieve all those records, in a timely fashion for regulatory purposes. Documents also need to be version-controlled should "significant amendments"<ref name="FRLab21" /> need to be made. Can the system retain all version of a document or dataset? Does the versioning procedure include the date of a change and identify the personnel responsible for the change? Can a "conspicuous" notice be added to the original document indicating a change has been made and where to view that changed document?
 
 
==Conclusion==
 
 
==References==
{{Reflist|colwidth=30em}}

Latest revision as of 18:25, 10 January 2024

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Template:Short description

"LOQ" redirects here. For the company listed as LOQ on the London Stock Exchange, see Lo-Q. For the airport in Botswana with IATA code LOQ, see Lobatse Airport.

The limit of detection (LOD or LoD) is the lowest signal, or the lowest corresponding quantity to be determined (or extracted) from the signal, that can be observed with a sufficient degree of confidence or statistical significance. However, the exact threshold (level of decision) used to decide when a signal significantly emerges above the continuously fluctuating background noise remains arbitrary and is a matter of policy and often of debate among scientists, statisticians and regulators depending on the stakes in different fields.

Significance in analytical chemistry

In analytical chemistry, the detection limit, lower limit of detection, also termed LOD for limit of detection or analytical sensitivity (not to be confused with statistical sensitivity), is the lowest quantity of a substance that can be distinguished from the absence of that substance (a blank value) with a stated confidence level (generally 99%).[1][2][3] The detection limit is estimated from the mean of the blank, the standard deviation of the blank, the slope (analytical sensitivity) of the calibration plot and a defined confidence factor (e.g. 3.2 being the most accepted value for this arbitrary value).[4] Another consideration that affects the detection limit is the adequacy and the accuracy of the model used to predict concentration from the raw analytical signal.[5]

As a typical example, from a calibration plot following a linear equation taken here as the simplest possible model:

where, corresponds to the signal measured (e.g. voltage, luminescence, energy, etc.), "Template:Mvar" the value in which the straight line cuts the ordinates axis, "Template:Mvar" the sensitivity of the system (i.e., the slope of the line, or the function relating the measured signal to the quantity to be determined) and "Template:Mvar" the value of the quantity (e.g. temperature, concentration, pH, etc.) to be determined from the signal ,[6] the LOD for "Template:Mvar" is calculated as the "Template:Mvar" value in which equals to the average value of blanks "Template:Mvar" plus "Template:Mvar" times its standard deviation "Template:Mvar" (or, if zero, the standard deviation corresponding to the lowest value measured) where "Template:Mvar" is the chosen confidence value (e.g. for a confidence of 95% it can be considered Template:Mvar = 3.2, determined from the limit of blank).[4]

Thus, in this didactic example:

There are a number of concepts derived from the detection limit that are commonly used. These include the instrument detection limit (IDL), the method detection limit (MDL), the practical quantitation limit (PQL), and the limit of quantitation (LOQ). Even when the same terminology is used, there can be differences in the LOD according to nuances of what definition is used and what type of noise contributes to the measurement and calibration.[7]

The figure below illustrates the relationship between the blank, the limit of detection (LOD), and the limit of quantitation (LOQ) by showing the probability density function for normally distributed measurements at the blank, at the LOD defined as 3 × standard deviation of the blank, and at the LOQ defined as 10 × standard deviation of the blank. (The identical spread along Abscissa of these two functions is problematic.) For a signal at the LOD, the alpha error (probability of false positive) is small (1%). However, the beta error (probability of a false negative) is 50% for a sample that has a concentration at the LOD (red line). This means a sample could contain an impurity at the LOD, but there is a 50% chance that a measurement would give a result less than the LOD. At the LOQ (blue line), there is minimal chance of a false negative.

Template:Wide image

Instrument detection limit

Most analytical instruments produce a signal even when a blank (matrix without analyte) is analyzed. This signal is referred to as the noise level. The instrument detection limit (IDL) is the analyte concentration that is required to produce a signal greater than three times the standard deviation of the noise level. This may be practically measured by analyzing 8 or more standards at the estimated IDL then calculating the standard deviation from the measured concentrations of those standards.

The detection limit (according to IUPAC) is the smallest concentration, or the smallest absolute amount, of analyte that has a signal statistically significantly larger than the signal arising from the repeated measurements of a reagent blank.

Mathematically, the analyte's signal at the detection limit () is given by:

where, is the mean value of the signal for a reagent blank measured multiple times, and is the known standard deviation for the reagent blank's signal.

Other approaches for defining the detection limit have also been developed. In atomic absorption spectrometry usually the detection limit is determined for a certain element by analyzing a diluted solution of this element and recording the corresponding absorbance at a given wavelength. The measurement is repeated 10 times. The 3σ of the recorded absorbance signal can be considered as the detection limit for the specific element under the experimental conditions: selected wavelength, type of flame or graphite oven, chemical matrix, presence of interfering substances, instrument... .

Method detection limit

Often there is more to the analytical method than just performing a reaction or submitting the analyte to direct analysis. Many analytical methods developed in the laboratory, especially these involving the use of a delicate scientific instrument, require a sample preparation, or a pretreatment of the samples prior to being analysed. For example, it might be necessary to heat a sample that is to be analyzed for a particular metal with the addition of acid first (digestion process). The sample may also be diluted or concentrated prior to analysis by means of a given instrument. Additional steps in an analysis method add additional opportunities for errors. Since detection limits are defined in terms of errors, this will naturally increase the measured detection limit. This "global" detection limit (including all the steps of the analysis method) is called the method detection limit (MDL). The practical way for determining the MDL is to analyze seven samples of concentration near the expected limit of detection. The standard deviation is then determined. The one-sided Student's t-distribution is determined and multiplied versus the determined standard deviation. For seven samples (with six degrees of freedom) the t value for a 99% confidence level is 3.14. Rather than performing the complete analysis of seven identical samples, if the Instrument Detection Limit is known, the MDL may be estimated by multiplying the Instrument Detection Limit, or Lower Level of Detection, by the dilution prior to analyzing the sample solution with the instrument. This estimation, however, ignores any uncertainty that arises from performing the sample preparation and will therefore probably underestimate the true MDL.

Limit of each model

The issue of limit of detection, or limit of quantification, is encountered in all scientific disciplines. This explains the variety of definitions and the diversity of juridiction specific solutions developed to address preferences. In the simplest cases as in nuclear and chemical measurements, definitions and approaches have probably received the clearer and the simplest solutions. In biochemical tests and in biological experiments depending on many more intricate factors, the situation involving false positive and false negative responses is more delicate to handle. In many other disciplines such as geochemistry, seismology, astronomy, dendrochronology, climatology, life sciences in general, and in many other fields impossible to enumerate extensively, the problem is wider and deals with signal extraction out of a background of noise. It involves complex statistical analysis procedures and therefore it also depends on the models used,[5] the hypotheses and the simplifications or approximations to be made to handle and manage uncertainties. When the data resolution is poor and different signals overlap, different deconvolution procedures are applied to extract parameters. The use of different phenomenological, mathematical and statistical models may also complicate the exact mathematical definition of limit of detection and how it is calculated. This explains why it is not easy to come to a general consensus, if any, about the precise mathematical definition of the expression of limit of detection. However, one thing is clear: it always requires a sufficient number of data (or accumulated data) and a rigorous statistical analysis to render better signification statistically.

Limit of quantification

The limit of quantification (LoQ, or LOQ) is the lowest value of a signal (or concentration, activity, response...) that can be quantified with acceptable precision and accuracy.

The LoQ is the limit at which the difference between two distinct signals / values can be discerned with a reasonable certainty, i.e., when the signal is statistically different from the background. The LoQ may be drastically different between laboratories, so another detection limit is commonly used that is referred to as the Practical Quantification Limit (PQL).

See also

References

  1. ↑ IUPAC, Compendium of Chemical Terminology, 2nd ed. (the "Gold Book") (1997). Online corrected version:  (2006–) "detection limit".
  2. ↑ "Guidelines for Data Acquisition and Data Quality Evaluation in Environmental Chemistry". Analytical Chemistry 52 (14): 2242–49. 1980. doi:10.1021/ac50064a004. 
  3. ↑ Saah AJ, Hoover DR (1998). "[Sensitivity and specificity revisited: significance of the terms in analytic and diagnostic language."]. Ann Dermatol Venereol 125 (4): 291–4. PMID 9747274. https://pubmed.ncbi.nlm.nih.gov/9747274. 
  4. ↑ 4.0 4.1 "Limit of blank, limit of detection and limit of quantitation". The Clinical Biochemist. Reviews 29 Suppl 1 (1): S49–S52. August 2008. PMC 2556583. PMID 18852857. https://www.ncbi.nlm.nih.gov/pmc/articles/2556583. 
  5. ↑ 5.0 5.1 "R: "Detection" limit for each model" (in English). search.r-project.org. https://search.r-project.org/CRAN/refmans/bioOED/html/calculate_limit.html. 
  6. ↑ "Signal enhancement on gold nanoparticle-based lateral flow tests using cellulose nanofibers". Biosensors & Bioelectronics 141: 111407. September 2019. doi:10.1016/j.bios.2019.111407. PMID 31207571. http://ddd.uab.cat/record/218082. 
  7. ↑ Long, Gary L.; Winefordner, J. D., "Limit of detection: a closer look at the IUPAC definition", Anal. Chem. 55 (7): 712A–724A, doi:10.1021/ac00258a724 

Further reading

  • "Limits for qualitative detection and quantitative determination. Application to radiochemistry". Analytical Chemistry 40 (3): 586–593. 1968. doi:10.1021/ac60259a007. ISSN 0003-2700. 

External links

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