Guidance for Industry: Analytical Procedures and Methods Validation

Draft guidance released August 2000. Available at: http://www.fda.gov/downloads/Drugs/GuidanceComplianceRegulatoryInformation/Guidances/ucm122858.pdf

Target audience

This guidance helps applicants who submit analytical procedures (a term that herein is interchangeable with method or test procedure), validation packages, and samples to FDA to document the identity, strength, quality, purity, and potency of drug substances and drug products. Thus the guidance is relevant to those who submit new drug applications (NDAs), abbreviated new drug applications (ANDAs), biologics license applications (BLAs), product license applications (PLAs), and supplements (collectively, applications, that are submitted by applicants or sponsors). In addition, the guidance helps those who submit Type II drug master files (DMFs). Although this guidance applies to all types of analytical procedures, it may not be suitable for certain unique analytical procedures for products like biological, biotechnological, botanical, or radiopharmaceutical drugs.

Laws, Regulations, and Related Guidances

• 21 CFR 58
• 21 CFR 211.165(e)
• 21 CFR 211.194
• 21 CFR 312.23(a)(7)
• 21 CFR 314.50(d)(1) and 314.50(e)
• 21 CFR 314.94(a)(9)(i) and 314.94(a)(10)
• 21 CFR 601.2(a) and 691.2(c)(1)(iv)
• 21 CFR 610.20
• 29 CFR 1919.1200(g)
• Food, Drug, and Cosmetic Act Section 501(b) and Section 502(e)(3)

• FDA guidances (eg, Validation of Chromatographic Methods—see References section of the guidance)
• International Conference on Harmonization (ICH) guidances
• Q2A Test on Validation of Analytical Procedures
• Q2B Validation of Analytical Procedures: Methodology
• Q3A Impurities in new Drug Substances
• Current US Pharmacopeia–National Formulary (USP–NF).

Summary

During drug discovery and development, formulation development, clinical studies, and manufacturing, applicants must ensure that they consistently control the identity, strength, quality, purity, and potency of drug substances and drug products (collectively, quality attributes). Sponsors demonstrate such attributes by reporting the results of suitable analytical procedures that can be verified in FDA laboratories using samples submitted by the applicant (and reference standards, as appropriate).

In many cases analytical procedures described in USP–NF are appropriate if they are performed on validated equipment by properly trained analysts who use samples and suitable reference standards. Alternative analytical procedures can be used only if they are shown to perform equally well or better than (“equal to or better than” in regulatory parlance) compendial (USP–NF) procedures. Applicants also must demonstrate via a stability-indicating assay that their products are stable during the period claimed on the label. That is, sponsors must submit stability-indicating assays that can detect degradation products, process impurities, and other potential impurities.

In all cases analytical procedures must be validated. As the guidance notes, “methods validation is the process of demonstrating that analytical procedures are suitable for their intended use.” Validation packages may vary depending on the nature of the application, but in all cases they must be sufficient to ensure the identity, strength, quality, purity, and potency (including bioavailability) of the drug substance and drug product. For an analytical method (compendial or noncompendial), typical validation characteristics may include:

• accuracy

• precision (repeatability, intermediate precision)
• specificity
• limit of detection
• limit of quantitation
• linearity
• range
• robustness.

These terms have specific, well-defined meanings in ICH guidances such as Q2A and Q2B.

Rationale

As noted, many factors may change during a drug’s life cycle and include modifications to drug product synthesis, formulation variables (including excipients), and manufacturing processes, among others. To ensure the quality attributes of drug substances and products, applicants perform and report the results of demonstrably suitable analytical procedures that can be repeated with similar results in different laboratories (intermediate precision). Demonstrating suitability and comparability is part of validation, the effort to show equivalence.

One aspect of equivalence is showing that the results in multiple labs with multiple analysts will yield results that are similar to a reference standard or sponsor’s drug product (including drug substance and drug product impurities). Manufacturers typically devote considerable resources to ensuring that their new drug substance is pure, consistent, and suitable for use from early tests through full-scale production following regulatory approval. Because of the effort required to quality a reference standard (see Note 1 below), manufacturers and regulators often rely on qualified reference standards from a compendial source such as USP. Reference standards from compendial sources by definition are pure, and tests performed on a sample can reliably be compared to the results obtained from the reference standard. Such comparisons involve standard statistical techniques.

Resulting Recommendations

When applicants develop drug substances and drug products, they must demonstrate the presence of suitable, predefined quality attributes. They can do so by presenting results of compendial procedures and measurements (see Note 2 below). When compendial procedures are not suitable or are not available or the applicant prefers a house method (one developed in house as opposed to taken from a compendial source), applicants can develop their own procedures. If a compendial procedure is available and the applicant submits a different method, the latter must yield results that are equivalent to or better than the results that would be obtained by compendial procedures. When reference standards are available, applicants and FDA should use them to establish equivalence. When such standards are not available, sponsors must submit highly qualified and characterized materials.

Section XI of the guidance reviews several analytical methods (chromatography, spectrophotometry, capillary electrophoresis, dissolution, and others) and makes specific recommendations about each, including validation and revalidation.

Impact

In this guidance FDA specifies the types of analytical procedures needed for submissions. To ensure drug quality and performance attributes during a drug’s life cycle, FDA expects applicants to provide an extensive body of analytical data obtained by validated procedures.

In most cases sponsors can provide data from validated USP procedures and comparison of results to compendial reference standards. When the latter are not available, sponsors rely on carefully characterized house standards. (Because house standards are available only to the sponsor and FDA, independent laboratories cannot fully test samples of the drug product, which may present public health concerns.)

Since the release of this guideline, FDA, sponsors, and USP have fine-tuned many aspects of compendial tests, and USP has published additional general chapters that outline a variety of procedures. Current regulatory research focuses on comparability and means to establish that a novel procedure is equivalent to or better than another (see Note 3 below).

Notes

1. For information about qualification of compendial reference standards, see:

Project Team 4, 2000–2005 Reference Standards Committee and Advisory Panel, USP Staff, and Council of Experts Chair. Official USP reference standards: metrology concepts, overview, and scientific issues and opportunities. J Pharm Biomed Anal. 2006;40(1):3–15.

2. If USP–NF includes the name of a drug or ingredient, manufacturers must comply with the tests, procedures, and acceptance criteria therein, whether or not the manufacturer uses the letters USP on the label. The Food, Drug, and Cosmetic Act specifies in Sec. 501 [21 USC §351] Adulterated Drugs and Devices:

A drug or device shall be deemed to be adulterated—

(b) If it purports to be or is represented as a drug the name of which is recognized in an official compendium, and its strength differs from, or its quality or purity falls below, the standards set forth in such compendium. Such determination as to strength, quality, or purity shall be made in accordance with the tests or methods of assay set forth in such compendium ... Whenever a drug is recognized in both the United States Pharmacopeia and the Homeopathic Pharmacopeia of the United States it shall be subject to the requirements of the United States Pharmacopeia ...

3 For more information about current concepts in comparability and demonstration of equivalence, see:

Hauck WW, DeStefano AJ, Cecil TL, Abernethy DR, Koch WF, Williams RL. Acceptable, equivalent, or better: approaches for alternatives to official compendial procedures. Pharm Forum. 2009;35(3):772–778.

Small Molecules Collaborative Group, Williams RL, Abernethy RL, Koch WF, Hauck WW, Cecil TL. Performance-based monographs. Pharm Forum. 2009;35(3):765–771.

— Stefan Schuber