Science & Research

Volume IV - 3.3 Methodology

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Orientation and Training Food and Drug Administration

Section 3 - Drug Analysis
REVISED: 02-14-13

A. Introduction

Modern pharmaceutical analysis has evolved from partitioning an active ingredient into a volatile solvent and performing a titration or gravimetric analysis, to techniques that include almost every known analytical procedure. Spectrophotometry is performed in the three most accessible regions of the spectrum - the ultraviolet, visible, and infrared. Atomic absorption, fluorescence, flame emission, and mass spectrometry (GC/MS and LC/MS) are also used. Pharmaceutical analysis now relies heavily on chromatographic techniques, especially high performance or pressure liquid chromatography (HPLC), since these techniques provide rapid, accurate, qualitative, as well as quantitative analysis. These techniques are also used to detect degradants and contaminants.

This section serves not only to review the methods, but more importantly, to understand where methods can be obtained for analyzing assigned drug samples. The analyst always considers two questions before beginning an analysis. Is the method the correct one? Is the method valid? This assignment will set the groundwork for answers to these questions.

B. Methodology Sources

  1. Official Compendia

    An "official compendium" is one that is officially cited in the FD&C Act (See Section 3.5 References 3). The United States Pharmacopeia (USP) (now combined with the National Formulary (NF)) is the major official compendium (See Section 3.5 References 9). The Homeopathic Pharmacopoeia is seldom used and is relatively obsolete. ORA Lab Manual, Volume IV, Section 1.3 Analytical Methods provides additional information on official compendia.

    The USP/NF, published annually, is cited in the Food Drug and Cosmetic Act, 201, (g)(1), 201(j), 501(b).

    The USP/NF contains valuable information. Analysts should become familiar with the location of the following sections found in the Table of Contents: "General Notices", "Monographs", "General Chapters", "Reagents"," Tables", and the sections of the NF. The General Chapters contains general tests and assay information, scientific principles and theory, as well as drug regulations and laws.

    The Monographs section, comprising a major part of the USP/NF, serves as a definition and as a standard for a given drug substance, drug product, or drug ingredient. It is recommended that the analyst read the ‘General Notices and Requirements' and several monographs noting their organization and content.

  2. Petition Methods (NDAs and ANDAs)

    Each New Drug Application (NDA) (PAC 46.832) or Abbreviated New Drug Application (ANDA) (PAC 52.832) includes a method for analysis of the final dosage form and in many cases the Active Pharmaceutical Ingredient (API). This is the control method used by the manufacturer, and it has been shown to be usable for regulatory purposes after review by the FDA. 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).

    All of the material in these NDA and ANDA submissions are confidential and subject to the protection required by the FD&C Act, sections 301(j) and 303(a) (5). The analyst may not cite NDA or ANDA methods in a publication, or discuss them with persons outside FDA. The documents require secure storage; the analysts are to be careful in how they handle the documents. Further document security and confidentiality information can be found in the following : the Supervisory Staff Manual Guides, FDA F:2280.2, "Physical Security in Field Activities," Part 8, "Document Security", and 21 CFR Part 31.14 (See Section 3.5 References 2), "Confidentiality of Data and Information in a New Drug Application (NDA) File."

    For more information about the Method Validation samples refer to Compliance Program CP7346.832 (most current version) and "Supplement to CP7346.832 Pre-approval Inspections/Investigations, 7/8/96."

  3. AOAC Official Methods

    The AOAC INTERNATIONAL (AOAC) Official Methods of Analysis of the AOAC (see Section 3.5 References 10) is specified in the Code of Federal Regulations, 21 CFR Part 2.19). Supplements, containing a cumulative index between editions, are published annually.

    Sections to review in the AOAC include the following: "Definitions of Terms and Explanatory Notes," page xv, "Microchemical Methods," Chapters 18–22, Drugs I-V, and "Vitamins and Other Nutrients" During the review, note the presentation style and content found in these segments.

  4. Pharmacopeial Forum

    The Pharmacopeial Forum is a periodical issued six times a year by the United States Pharmacopeial Convention. It contains proposed new methods, updated lists of official reference standards and general comments on matters of interest in drug analysis and on use of the compendium.

  5. Compliance Programs

    Many Drug Compliance Programs, especially surveillance sample programs (PAC 56008) contain analytical directions, methods or modification of methods to analyze products. The analyst needs to review the compliance program prior to analysis. The Compliance Program Guidance Manual (CPGM) is available on the intranet at:

  6. Code of Federal Regulations

    Title 21 of the Code of Federal Regulations (CFR) provides labeling requirements for a large number of pharmaceutical products. The CFR requirements frequently include official methodology to analyze the products. An example is "ANTACID PRODUCTS FOR OVER-THE- COUNTER (OTC) HUMAN USE" found in 21CFR 331.

  7. Journals and Other Literature

    When methods are not located in the conventional sources mentioned above, there are applicable procedures found in the literature.

    The Laboratory Information Bulletin (LIB) is a popular source of unofficial methodology in FDA published by the Office of Regulatory Science. The LIBs are an excellent source for methods and resolution to problems the analyst may encounter with a method. Consult the latest LIB cumulative index to see if another FDA analyst has already solved the problem. If there is a related LIB method, it may be advantageous to discuss the problem with the author. The LIB index is available on the intranet at:

    The Journal of Pharmaceutical Sciences (J. Pharm. Sci.) and the Journal of AOAC INTERNA-TIONAL (J. AOAC Int.) are useful references. An annual index is found in the last journal for the year.

    International Pharmaceutical Abstracts, which contains abstracts from the two journals found above, is an excellent key to the entire pharmaceutical literature.

    The Analytical Profiles of Drug Substances/Analytical Profiles of Drug Substances and Excipients, containing a series of monographs found in over thirty volumes, is another excellent reference. The first set of twenty volumes is edited by Klaus Florey of Squibb Institute; the remaining volumes are edited by Harry G. Brittain of Ohmeda Pharmaceutical Products Division, Inc., and published by Academic Press. A table of contents and cumulative index is included in each volume; approximately two volumes per year have been issued since 1996.

    Other useful materials for completing the exercises that follow are given in Section 3.5 References (14-27).If a non-official method is used and the sample is violative, the check analysis must be performed using an official method or a Center approved method.

  8. Links to Scientific Sites: : American Chemical Society. Find journals, articles of scientific interest, new trends in chemistry, and links to suppliers and vendors. : Association of Official Analytical Chemists. AOAC Publications, quality assurance issues, journal abstracts, approved method abstracts, and more. : International Federation of Pharmaceutical Manufacturers Associations is a channel to exchange information within the international industry and various international organizations. Find International Conference on Harmonization (ICH) guidelines and related issues. : Material Safety Data Sheets, Toxicology Reports, and other safety information. CDER Medical Library web site includes e-journals, FDC Reports, and WebLERN site that includes the USP current version with monographs, American Drug Index, Physician's Drug Reference, Drug Facts and Comparisons, and other useful information.

C. Questions

  1. What are the five most significant items of information in the USP "General Notices?" Compare the "General Notices" with the introductory chapter in the Official Methods.
  2. Using the current USP, find the Dissolution procedure for Ascorbic Acid Tablets and how does it differ from most other Dissolution procedures?
  3. Where in the USP is the listing for column types used in HPLC and GLC? How are they designated?
  4. Locate the USP Reference Standards in the USP. What information is included here? What important information is missing and where is it found?
  5. Obtain an NDA method and review it as one might review a research paper. Is it complete, specific, and unambiguous? Does it meet the requirements of the Code of Federal Regulations?
  6. What does the term "Official Compendium" mean? Name the three major types of "official" methods used by FDA.

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