11 USP REFERENCE STANDARDS.doc

11 USP REFERENCE STANDARDS美国药典对照品USP Reference Standards are highly characterized specimens of drug substances, excipients, reportable impurities, degradation products, compendial reagents, and performance calibrators.They are explicitly required in many Pharmacopeial assays and tests and are provided solely for such use. Assessment of the suitability for use in other application(s) rests with the purchaser.AUTHORITY FOR ESTABLISHMENT AND RELEASE USP Reference Standards are established and released under the authority of the USPC Board of Trustees upon recommendation of the USP Reference Standards Expert Committee, which approves each lot as being suitable for use in its compendial applications. For some Reference Standards a preliminary review and approval is sought from other Expert Committees of the Council of Experts.The distribution of controlled substances is subject to the regulations and licensing provisions of the Drug Enforcement Administration of the Department of Justice.Industry Advisory Panels and other expert groups (such as Project Teams) may be assembled to advise USP on various aspects of the Reference Standards Program.HISTORY Future availability of the first USP Reference Standards was announced in 1926 (USP X) “ in order to facilitate the adoption of the biological assay standards of the Pharmacopoeia, and to provide a greater degree of uniformity in their application.” The list of USP Reference Standards that in 1936 comprised 6 items has grown to almost 1650 in 2004, and the collection has tracked the progress in pharmaceutical sciences: The first vitamins (Cod Liver Oil) and the first enzyme (Pepsin) in 1936; the first sulfonamide (Sulfanilamide) and the first hormones (Insulin; Posterior Pituitary) in 1942; the first performance standards (Melting Point Standards) in 1947; the first penicillin (Penicillin G Sodium) in 1950; the first recombinant-DNA technology protein (Insulin Human) in 1985, etc.The continuous increase in the number of USP Reference Standards (over 100 new standards are being developed yearly) reflects not only the increase in the number of monographs and General Chapters, but also the development and extensive use of modern analytical methodology (such as chromatography, spectrophotometry, biological and biochemical assays, etc.) which require measurements relative to a reference standard.NOMENCLATURE Standards designated as USP Reference Standards (USP RS) are, with a few exceptions, required for use in USPNF monographs or General Chapters. The exceptions include current lots of USP and NF Reference Standards for which uses are no longer specified in the current USP or NF but for which sufficient demand remains (upon depletion of the current lots, future lots will be designated as Authentic Substances), Reference Standards specified in monographs developed by USP that are not intended for publication in the USPNF, Reference Standards specified in the current edition of the Food Chemicals Codex (labeled with an additional designation “FCC”), and Fluoride Dentifrices (evaluated and distributed by agreement with the FDA and the Cosmetics, Toiletries, and Fragrances Association). A USP Reference Standard required in a monograph or General Chapter proposed in Pharmacopeial Forum may be released in advance of the official date of the proposed PF revision.Reference Standards currently labeled as “NF Reference Standards” will eventually all be designated and labeled as “USP Reference Standards” pursuant to the consolidation of USP and NF within the USPC as of January 2, 1975. Meanwhile, where a USP Reference Standard is called for, the corresponding substance labeled as an “NF Reference Standard” may be used.As a service, the USPC tests and distributes additional Authentic Substances (designated by AS) not currently required for use in a USP monograph or General Chapter. These also are provided under the supervision of the USP Reference Standards Expert Committee. They are highly characterized samples of chemicals, including substances of abuse, which are collaboratively tested and made available as a service primarily to analytical, clinical, pharmaceutical, and research laboratories. Such materials may be used for identification, method development, evaluation of method performance, or other applications as found suitable and validated by the user.Authentic Visual References Unlike chemical reference standards, Authentic Visual References (AVRs) are not used in chemical analyses. Instead, the AVRs are visual images used by analysts to compare certain test articles to ensure that they meet compendial requirements and are incorporated by reference into the monograph. Approval of AVRs for use in a monograph is the decision of the Expert Committee that approves the specific monograph.DIVERSITY AND IMPLICATIONS The USP Reference Standards collection is very diverse in terms of appearance, chemical structure, composition, and uses. This diversity has significant implications for the way the materials are tested, packaged, stored, and utilized.The USP Reference Standards may be crystalline or amorphous powders, volatile or viscous liquids, solutions or suspensions, gels or pastes, plastic sheets, etc. In chemical structure they vary from simple inorganic salts to proteins produced by recombinant DNA technology. Some are highly-purified single components, while others are complex mixtures (in most cases extracted from plant or animal sources).USES OF USP REFERENCE STANDARDS The official and authorized uses of USP Reference Standards are specified in the USP monographs and General Chapters and they include the following: quantitative uses in assays for drug substances and formulations, limit tests, or blanks and controls qualitative uses, such as identification tests, system suitability tests, chromatographic peak markers, etc. performance standards and calibrators, such as dissolution calibrators, melting point standards, the particle count set, etc. As discussed under Nomenclature, USP also establishes and distributes standards not specified for use in a USP monograph or General Chapter.The most frequent applications of USP Reference Standards (USP RS) are in chromatographic and spectroscopic methodologies. However, they are also widely used in biological and biochemical applications, such as microbial assays for antibiotics, enzymatic reactions, cell-culture tests, whole-animal tests; in thermal analysis for polymers; and in titration, etc. Some of the most frequently used USP RS are those utilized in General Chapters tests such as Dissolution 711, Bacterial Endotoxins Test 85, Total Organic Carbon 643, and Particulate Matter in Injections 788.STEPS IN ESTABLISHING A USP REFERENCE STANDARD The establishment of a new USP Reference Standard is triggered by the proposal of a new monograph or of a revision of an existing monograph by the inclusion of a test requiring a new USP RS. The need for a new lot of an existing USP Reference Standard is identified when its inventory reaches a pre-established threshold. The new lot is designated as a “replacement lot” if a new bulk material is to be procured or as a “continuation lot” if the candidate material is another portion of the bulk used for the existing official lot.USP scientists generate a set of documents including procurement specifications and a testing protocol. A bulk material is obtained, generally from a major manufacturer of the article. The material is tested and characterized in an inter-laboratory collaborative study organized according to the protocol designed at USP Headquarters. The results are evaluated by USP Staff, additional testing or investigations are performed when necessary, and a report is compiled and presented for review and approval to the USP Reference Standards Expert Committee. After approval the material is subdivided (if not packaged prior to the collaborative study), labeled, quality checks are performed, and the standard is made available for distribution. If a candidate material is found to be unsuitable by USP scientific staff or by the Reference Standards Committee, a new bulk is procured and tested.COLLABORATIVE STUDY FOR THE EVALUATION OF A USP RS CANDIDATE MATERIAL The goals of the evaluation study are to confirm the identity and assess the purity of the material, to determine its suitability for use in the official applications, to provide the user with all the necessary information and directions for use, and to acquire time-zero information for future continued-suitability-for-use studies.USP scientists design a detailed testing protocol that includes the following elements: types of tests, number of tests, number of collaborators, number of replicates, and references to the procedures to be used.The following factors are considered when designing the study protocol: the compendial status of the standard, its official uses, the history of the standard, its composition and complexity, the characteristics of the methodology, and the availability of material and of competent laboratories.The testing protocol may comprise visual and microscopic evaluation; identification tests (more elaborate for first-time standards); determination of physicalchemical constants (e.g., melting range, specific rotation, refractive index, specific gravity, etc); chromatographic and electrophoretic purity tests; inorganic contaminants determination; volatile tests (water, solvents); functional group analysis (such as titrations, UV absorptivity, elemental analysis); thermal analysis; and assays against another well-characterized standard (a previous lot, an international standard, etc). Specialized testing is implemented where appropriate, such as for dissolution calibrators and the particle count set, for standards that define an attribute (negative and positive bioreaction, ion-exchange capacity, permeability diameter), and for biological standards that define a Unit of activity (heparin, endotoxin, enzymes, complex antibiotics). Vapor sorption analysis may also be performed to assist in determining packaging and storage conditions, and directions for use. For lyophilized single-use USP RS, acceptable vial content reproducibility and stability of the lyophilized form are demonstrated.The number of collaborators is generally not less than three (two outside of USP); but it can increase significantly, especially when the methodology is complex or does not have a high level of precision or when potential users express an interest in participating in the evaluation of the candidate. (Participation in all evaluation studies is open to all competent, interested parties.) Where appropriate, statistical control is exercised in the design of the evaluation study and in the analysis of the results. The USP Reference Standards Laboratory and the FDA laboratories participate in almost all evaluation studies. Other collaborators include Health Canada, the USP Research and Development Laboratory, and industrial and academic laboratories from the United States and from abroad.BIOLOGICAL REFERENCE STANDARDS The World Health Organization, an agency of the United Nations, manages a program providing International Standards for biological materials.USP collaborates closely with the WHO in the harmonization of analytical methodology, in the definition of the units of potency, and in some cases to share in the preparation of a reference standard. In many cases the USP Units and the International Units of potency are identical.SUITABILITY FOR USE AND PURITY ASSIGNMENT The data collected in the collaborative evaluation study are analyzed to determine whether the material is suitable for its monograph-designated use. Characterization data and results must be considered as a whole when evaluating suitability for intended use, assignment strategy, and assigned value. For Reference Standards used in quantitative applications, this includes the determination of a calculation value to be used in the compendial utilization of the standard. The method of choice in computing the assigned value is a mass balance analysis using independently determined components such as moisture, solvent residues, inorganic residues, chromatographic impurities, and ion content. The assay results against a previous lot or against another validated standard and the results of the functional group analysis are for confirmatory purposes only. Exceptions to the mass balance approach include many biological Reference Standards, especially those which define the Unit of activity.The number of significant figures in the labeled calculation value is a function of the use of the standard and the number of significant figures in the acceptance range or limit. Generally, Reference Standards used in assays are labeled with three significant figures and standards used in limit tests with two significant figures. Reference Standards having multiple applications in different methodologies may require separate assay-specific assignments.The assigned value is labeled without any associated uncertainty. However, for calibration standards, the labeled value is a range, determined by a statistical analysis of the results.Previous approaches used a purity threshold above which the content was no longer labeled, and the analyst was directed to use a default value of 100.0%. This approach is no longer in use, but older lots of standards have not been re-labeled, and users should continue to apply the default 100.0% value for compendial quantitative applications.For antibiotics, the designation “g/mg” is sometimes used as a unit of biological activity, and values greater than 1000 g/mg may be assigned to some of these standards. This can happen when the first standard is assigned a value higher than its actual purity and subsequent standards of higher purity are defined relative to the previous lot. A relatively overstated assigned value can also result when less selective separation techniques are replaced with more selective modern methodologies. As a result, the original content might have been assumed to be higher than the actual level.No value is assigned to standards having only qualitative applications.A report compiling the results of the evaluation study and including the proposed label text is submitted for review and approval to the USP Reference Standards Expert Committee.LABEL TEXT The label text is designed to provide the user with all the information needed for the correct storage and usage of the Reference Standard in monograph application(s). The label includes directions for use, safety warnings, required information for controlled substances, and a calculation value for standards with quantitative applications. For calibrators, acceptance ranges are provided. Where necessary, USP Reference Standards are accompanied by additional documentation, such as Technical Sheets or Typical Chromatograms. USP generally does not provide Certificates of Analysis because all the information that the user needs for the official or authorized applications of the standard is provided in the label text and, where necessary, in the additional documentation provided.Directions for use are lot-specific, and they take precedence over any other indication in the compendium.Material Safety Data Sheets are generated for every standard that USP distributes. They are available on the USP website.USP REFERENCE STANDARDS EXPERT COMMITTEE The USP Reference Standards Expert Committee comprises professionals from industry, government agencies and academia from the United States and abroad. It is organized in groups and may be assisted in the review of the evaluation studies by an Industry Advisory Panel. The approval of the evaluation report has to be unanimous.PACKAGING The USP Reference Standard production process operates under a registered ISO 9001:2000 Quality System and appropriate cGMP principles.USP Reference Standards are packaged in individual units designed to maintain the integrity of the contained Reference Standard material. The packaging and storage conditions for USP Reference Standards provide protection for all materials even though the material may not need such exceptional protection due to its inherent stability. The most common packaging configurations are vials for solid materials and ampuls for liquids. The packaging environment is determined by the sensitivity of the material to light, oxidation, or atmospheric humidity, and by its toxicity. Where appropriate, containers are filled in a glove box under inert gas and in conditions of controlled low residual humidity. (The need to store such standards under inert gas protection is indicated on the label.) They may also be sealed in a foil bag as an added protective barrier. Ampuls are filled and sealed on an automated device and are typically purged with an inert gas. The most common ampul sizes are 2 mL and 5 mL. Vials may be filled by manual, semi-automated, or fully automated operations. Vials may be of different sizes depending upon the amount of material. The amount of material per individual container depends on the compendial application of the standard and is generally sufficient for several replicates. Larger amounts are provided when additional experiments are required (such as a titrimetric determination of the water content at the time of use). In general, Reference Standard containers are slightly over-filled so that the user can retrieve the labeled, nominal amount of material. Vials are closed with Teflon-lined stoppers and secured with aluminum crimps and a USP-logo tamper-evident seal. Lots using prior vial closure configurations may still be in distribution.Various considerations may determine the need to provide the standard in single-use containers, mainly for materials with significant handling issues or for t