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Volume IV - 1.3 Analytical Methods

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Orientation and Training

Food and Drug Administration

DOCUMENT NO.:

IV-01
VERSION NO.: 1.3

Section 1 - Laboratory Orientation

EFFECTIVE DATE: 10/01/2003REVISED: 02/14/2013

The analyst will use methods from a number of sources to determine regulatory compliance. These include methods described in official compendia, in manuals relating to analytical categories, and in FDA compliance manuals.

 1.3.1 Official Compendia 

The FD&C Act and regulations cite publications that contain methods to determine if a product conforms to legal requirements. The compendia cited have gained official status within the Federal judicial system as methods of choice. Most commonly used in the laboratory are the United States Pharmacopeia (USP), National Formulary (NF) and Official Methods of Analysis of AOAC International (formerly the Association of Official Analytical Chemists). These books are referred to here as USP, NF, and AOAC. Note that the USP and NF are now combined into one publication, and that we use the acronym AOAC to refer to both the compendia and the professional organization.

Official methods are those in compendia specified in the Food, Drug & Cosmetic Act and prescribed in the Code of Federal Regulations. Official methods are used, whenever found, or unless otherwise specified, for either original or check analysis, when regulatory actions are based on analytical findings.

Four common sources of methodology, and their citation in the Act or CFR, are listed below.  Review the citations for pertinent information.

  • AOAC [21CFR 2.19]
  • United States Pharmacopeia (USP) [FD&C Act, 201 (g)(1), 201 (j), 501 (b)]
  • Pesticide Analytical Manual (PAM) [40 CFR 180.101 (c)]
  • Food Chemicals Codex [21 CFR 170.30]

Methods in manufacturer’s Applications and Petitions that have been approved have “official” status. These include New Drug Applications (NDA), Abbreviated New Drug Applications (ANDA), New Animal Drug Applications (NADA), Food Additive Petitions (FAP), and Pesticide Petitions (PP).

Official methods always have higher status and are preferred over non-official methods. However, the method is only official for the product matrix and performance range specified for the method. 

Non-official methods may be used for determining compliance. Method validation will be submitted when a non-official method is used for a sample recommended for regulatory action. See section ORA Lab Manual, Volume IV, Chapter 1.3.4.

 1.3.2 Specialized Manuals 

In addition to official compendia, FDA also relies on a large number of analytical manuals that pertain to analytical categories. These manuals contain both official and unofficial methods and are generated by FDA, other agencies, professional associations, and trade associations. 

The FDA-produced manuals are a collection of the most reliable methods for program areas. They may include official and unofficial methods and be compiled from methods from other agencies, professional associations, and trade associations.  Two of the most widely used analytical manuals are the Bacteriological Analytical Manual (BAM) and the Pesticide Analytical Manual (PAM). Both the BAM and PAM are found on the Internet.

 1.3.3 Other Method Sources

In addition to official compendia and specialized manuals, certain methods may be directed for use by sources other than the CFR and the Act. The Compliance Program Guidance Manual, Compliance Policy Guides, Import Alerts, and special Assignments may dictate a particular method to be used.  Before embarking on a long search for methodology for a particular sample be sure to check these sources (especially the compliance programs) for methods which may be specified. Choosing another method could have adverse impact on the regulatory decision.

Often unofficial methods are specified, and these commonly come from scientific journals and the Laboratory Information Bulletins (LIB). LIBs are a popular source of unofficial methodology in FDA published by the Office of Regulatory Science, ORA. Peer-reviewed scientific journals are found for all areas of analytical science. One of the most used is the Journal of the AOAC International, which is geared toward analytical chemistry. This journal is unique in that the AOAC organization was originally sponsored by (and for) the federal government, and it was under the auspices of the FDA until its independence in 1979.

The specified methods may or may not be official and have been chosen because they have been deemed the best method for the job. Consistency in method selection is important, as more than one laboratory may perform the analysis. Proper method selection is the responsibility of the analyst, with concurrence from the supervisor.

 1.3.4 Method Validation

Validation of a method is the planned and documented procedure to establish its performance characteristics. The performance characteristics or the validation parameters of the method determine the suitability for its intended use. They define what the method can do under optimized conditions of matrix solution, analyte isolation, instrument settings, and other experimental features. Method validation often includes the determination of the following: system suitability, linearity region, accuracy, precision, specificity, detection limit, ruggedness, and recovery. Comparison of the results to another method, the use of blank reagent and matrix runs, and independent runs performed by another analyst are also used.

Sometimes an alternative method source may not need validation. Examples include "non-standard" methods that a lab would not have to validate if the validation data was in existence and performed by a collaborative study or some other formal protocol which evaluated the methods performance (accuracy, precision, ruggedness, specificity, linearity, detection, etc). These methods need proof of validation from a recognized certification process such as AOAC Peer Verification or Performance Testing. Certification of method validation is essential when using test kits as an additional method source.