Paula Brown06.01.09
Product specifications are critical quality standards that are proposed and justified by the manufacturer. They are composed of a list of tests, references to analytical procedures and appropriate acceptance criteria (numerical limits or ranges) for the tests described. For dietary supplements in the U.S. FDA says it is not enough to simply have specifications, but that your products must conform to the specifications you set. "Conformance to specification" means that the product, when tested according to the analytical procedure listed within the specification, will meet the acceptance criteria of the specification.
Product specifications represent one part of a total strategy designed to ensure product quality and consistency. While it may seem obvious that a manufacturer would have an expected product outcome and be able to measure whether success had been achieved, there are also internationally recognized reasons for mandating specifications and testing. The setting of specifications for products and the demonstration of conformance to those specifications provides a basis for legitimate commerce and law enforcement according to the International Committee on Harmonization (ICH).
Section 21 CFR Part 111.70 of the US Dietary Supplement cGMP states that the manufacturer is responsible for establishing specifications for identity, purity, strength and composition related to incoming components as well as limits on those types of contaminants that may adulterate or lead to adulteration of the finished product. Furthermore, Section 21 CFR Part 111.75 compels the manufacturer to then verify through appropriate, scientifically valid testing or examination that these specifications have been met.
The necessity of testing implies that a specification must be testable and FDA has very concrete ideas about testing product conformance to specifications. Unfortunately, the guidance provided in the final regulation is uncured concrete, so if you don't know what you're doing you can get yourself stuck. Section 21 CFR Part 111.320 ("What Requirements Apply to Laboratory Methods for Testing and Examination?") says: (a)You must verify that the laboratory examination and testing methodologies are appropriate for their intended use; and (b) You must identify and use an appropriate scientifically valid method for each established specification for which testing or examination is required to determine whether the specification is met.
What does FDA mean by "scientifically valid method" and how does one verify that the method built into the product specification is "appropriate for intended use"?
Sir Isaac Newton suggested that to be termed scientific a method of inquiry must be based on observable, empirical and measureable evidence subject to specific principles of reasoning. In terms of Section 21 CFR Part 111.320, a method that cannot be tested or informed by the collection of data, through observation and experimentation is not scientific. ICH states that products must meet acceptance criteria when competently tested according to the listed procedures in locations other than the originator's. The analytical procedures must be transferable.
The validity of methods listed in the product specification must be tested, and if you want to accept ICH's recommendations the performance criteria must include a measure of reproducibility (i.e., repeatable in somebody else's laboratory). The burden is placed on the manufacturer to prove testing is done correctly and to ensure the method is scientifically valid. Although there are many established protocols for determining the scientific validity of a method, for performing an in-house determination the AOAC Guidelines for Single Laboratory Validation of Chemical Methods for Dietary Supplements and Botanicals (http://www.aoac.org/dietsupp6/Dietary-Supplement-web-site/slv_guidelines.pdf), are very detailed, easy to follow and available at no cost. To demonstrate that a method is transferable would require additional experiments that address reproducibility such as peer-verified or collaborative studies.
In addition to the method standard operating procedure (SOP), which is a written step-by-step guide or set of instructions that directs users through proper method use, documentation should be developed around the rationale for method selection and its fitness for purpose. This documentation, to support the method as scientifically valid and appropriate for intended use, will have a number of common elements. A useful way to organize such a document is to consider it as a scientific publication.
Just as you would start a publication with the background or introduction, your document should begin with the method purpose, objective and scope and applicability. What are you trying to measure and why? At what levels and in what? This should be followed by a brief summary that describes the instrumentation used, the types of compounds and matrices to be investigated.
The "materials" section should list all chemicals, reagents, reference standards and quality control (QC) samples that will be used along with the purity, grade, source and detailed instructions for their preparation. The safety precautions necessary for handling all the materials must also be described. Procedures for quality checks of standards and chemicals used should be detailed; in fact, verification of reference standards is mandated in Parts 111.35(b)(3)(iii) and 111.315(d).
The "method" section of the file should include your protocol for method transfer from the development laboratory into routine analysis. This section outlines the method parameters including a statement that identifies specific parameters that are critical to the method's success, as determined from robustness testing. There should be a detailed list of equipment with functional and performance requirements, (e.g., column type, cell dimensions, baseline noise, column temperature range, etc.). Finally, a detailed description of how the experiments are conducted, including sample preparation and instrument settings must be provided.
The "results" section should include statistical procedures and representative calculations, along with procedures for laboratory quality control in routine analyses (e.g., system suitability tests). Representative chromatograms, spectra, calibration curves, method acceptance limits, performance data and expected uncertainty of measurement results are all necessary. Finally, you can state the results of the test and whether or not the results indicate pass or fail.
If the method employed to demonstrate product conformance to specifications is from a current revision of recognized standard references (e.g., USP, National Formulary, AOAC International) and the referenced method is not modified, a statement indicating the method and reference will suffice. A key consideration in the documentation is to describe the point at which you cross over from adjusting to modifying the test method, and at what point the laboratory needs to conduct a revalidation because the procedure is no longer the method defined in the reference. The criteria for revalidation should also be clearly stated so that a change-such as fine-tuning to accommodate a new product formulation-does not result in ambiguity over whether the method change has rendered your product specification objectionable.
The purpose of setting specifications is to establish the set of criteria to which a product or material should conform to be considered acceptable for its intended use. The ability to create a high quality dietary supplement is dependent on both the quality of the raw materials and the manufacturer's ability to test the final product to its specifications. Commonalities among collections of specifications, such as those provided in the USP, include parameters and tests for identity, potential impurities and valuable constituents (assay).
The performance parameters that are investigated when determining whether or not a test is scientifically valid are mandatory if the test is to be used for one purpose but become less important if the test is to be used for a different purpose. For example, a specification for impurities is generally seeking to assure that the consumer is exposed to as little of a substance as possible, thus a test must be sufficiently sensitive to detect and quantitate very low levels of the impurity. Hence a method that is not sufficiently sensitive, as determined by evaluating its lower limit of quantitation (LOQ), is not fit for the purpose of measuring impurities and would not be acceptable.
There has been much discussion in the dietary supplement industry about "scientifically valid method" versus "method validation." The bottom line is that the quality of products is reliant on test methods, and the way to ensure a method is working as it should, when it should (i.e., is fit for purpose) is to engage in a series of experiments called a validation. The big question is which experiments do you have to do?
This is really a brief introduction to fit for purpose, a topic that requires a lengthier discussion. Practices around method selection and use are sure to be addressed in future columns.
Product specifications represent one part of a total strategy designed to ensure product quality and consistency. While it may seem obvious that a manufacturer would have an expected product outcome and be able to measure whether success had been achieved, there are also internationally recognized reasons for mandating specifications and testing. The setting of specifications for products and the demonstration of conformance to those specifications provides a basis for legitimate commerce and law enforcement according to the International Committee on Harmonization (ICH).
Section 21 CFR Part 111.70 of the US Dietary Supplement cGMP states that the manufacturer is responsible for establishing specifications for identity, purity, strength and composition related to incoming components as well as limits on those types of contaminants that may adulterate or lead to adulteration of the finished product. Furthermore, Section 21 CFR Part 111.75 compels the manufacturer to then verify through appropriate, scientifically valid testing or examination that these specifications have been met.
Testing Protocols Are Built into Product Specifications
The necessity of testing implies that a specification must be testable and FDA has very concrete ideas about testing product conformance to specifications. Unfortunately, the guidance provided in the final regulation is uncured concrete, so if you don't know what you're doing you can get yourself stuck. Section 21 CFR Part 111.320 ("What Requirements Apply to Laboratory Methods for Testing and Examination?") says: (a)You must verify that the laboratory examination and testing methodologies are appropriate for their intended use; and (b) You must identify and use an appropriate scientifically valid method for each established specification for which testing or examination is required to determine whether the specification is met.
What does FDA mean by "scientifically valid method" and how does one verify that the method built into the product specification is "appropriate for intended use"?
Sir Isaac Newton suggested that to be termed scientific a method of inquiry must be based on observable, empirical and measureable evidence subject to specific principles of reasoning. In terms of Section 21 CFR Part 111.320, a method that cannot be tested or informed by the collection of data, through observation and experimentation is not scientific. ICH states that products must meet acceptance criteria when competently tested according to the listed procedures in locations other than the originator's. The analytical procedures must be transferable.
The validity of methods listed in the product specification must be tested, and if you want to accept ICH's recommendations the performance criteria must include a measure of reproducibility (i.e., repeatable in somebody else's laboratory). The burden is placed on the manufacturer to prove testing is done correctly and to ensure the method is scientifically valid. Although there are many established protocols for determining the scientific validity of a method, for performing an in-house determination the AOAC Guidelines for Single Laboratory Validation of Chemical Methods for Dietary Supplements and Botanicals (http://www.aoac.org/dietsupp6/Dietary-Supplement-web-site/slv_guidelines.pdf), are very detailed, easy to follow and available at no cost. To demonstrate that a method is transferable would require additional experiments that address reproducibility such as peer-verified or collaborative studies.
Supporting Information ('Proof') for a Test Method Must Be Documented
In addition to the method standard operating procedure (SOP), which is a written step-by-step guide or set of instructions that directs users through proper method use, documentation should be developed around the rationale for method selection and its fitness for purpose. This documentation, to support the method as scientifically valid and appropriate for intended use, will have a number of common elements. A useful way to organize such a document is to consider it as a scientific publication.
Just as you would start a publication with the background or introduction, your document should begin with the method purpose, objective and scope and applicability. What are you trying to measure and why? At what levels and in what? This should be followed by a brief summary that describes the instrumentation used, the types of compounds and matrices to be investigated.
The "materials" section should list all chemicals, reagents, reference standards and quality control (QC) samples that will be used along with the purity, grade, source and detailed instructions for their preparation. The safety precautions necessary for handling all the materials must also be described. Procedures for quality checks of standards and chemicals used should be detailed; in fact, verification of reference standards is mandated in Parts 111.35(b)(3)(iii) and 111.315(d).
The "method" section of the file should include your protocol for method transfer from the development laboratory into routine analysis. This section outlines the method parameters including a statement that identifies specific parameters that are critical to the method's success, as determined from robustness testing. There should be a detailed list of equipment with functional and performance requirements, (e.g., column type, cell dimensions, baseline noise, column temperature range, etc.). Finally, a detailed description of how the experiments are conducted, including sample preparation and instrument settings must be provided.
The "results" section should include statistical procedures and representative calculations, along with procedures for laboratory quality control in routine analyses (e.g., system suitability tests). Representative chromatograms, spectra, calibration curves, method acceptance limits, performance data and expected uncertainty of measurement results are all necessary. Finally, you can state the results of the test and whether or not the results indicate pass or fail.
If the method employed to demonstrate product conformance to specifications is from a current revision of recognized standard references (e.g., USP, National Formulary, AOAC International) and the referenced method is not modified, a statement indicating the method and reference will suffice. A key consideration in the documentation is to describe the point at which you cross over from adjusting to modifying the test method, and at what point the laboratory needs to conduct a revalidation because the procedure is no longer the method defined in the reference. The criteria for revalidation should also be clearly stated so that a change-such as fine-tuning to accommodate a new product formulation-does not result in ambiguity over whether the method change has rendered your product specification objectionable.
Suitable for Its Intended Purpose
The purpose of setting specifications is to establish the set of criteria to which a product or material should conform to be considered acceptable for its intended use. The ability to create a high quality dietary supplement is dependent on both the quality of the raw materials and the manufacturer's ability to test the final product to its specifications. Commonalities among collections of specifications, such as those provided in the USP, include parameters and tests for identity, potential impurities and valuable constituents (assay).
The performance parameters that are investigated when determining whether or not a test is scientifically valid are mandatory if the test is to be used for one purpose but become less important if the test is to be used for a different purpose. For example, a specification for impurities is generally seeking to assure that the consumer is exposed to as little of a substance as possible, thus a test must be sufficiently sensitive to detect and quantitate very low levels of the impurity. Hence a method that is not sufficiently sensitive, as determined by evaluating its lower limit of quantitation (LOQ), is not fit for the purpose of measuring impurities and would not be acceptable.
There has been much discussion in the dietary supplement industry about "scientifically valid method" versus "method validation." The bottom line is that the quality of products is reliant on test methods, and the way to ensure a method is working as it should, when it should (i.e., is fit for purpose) is to engage in a series of experiments called a validation. The big question is which experiments do you have to do?
This is really a brief introduction to fit for purpose, a topic that requires a lengthier discussion. Practices around method selection and use are sure to be addressed in future columns.
