|Email Newsletters from Pharmaceutical Technology and Pharmaceutical Technology Europe|
Providing the latest business, scientific, and regulatory news for the pharmaceutical and biotech industries.
News from Europe's pharmaceutical manufacturing industry coupled with upcoming events, and exclusive articles and interviews from industry experts.
Standards-Setting Activities of USP's Council of Experts
The US Pharmacopeial Convention (USP) was founded by volunteer physicians who met in 1820 with the goal of producing the United States Pharmacopeia (1, 2). Convention members continued to meet at 10-year and later at 5-year intervals to monitor revision of the original publication by the Committee of Revision, now known as the Council of Experts. USP acquired the National Formulary (NF) in 1975, with conversion of the latter into a book of excipient standards. Both compendia are official compendia of the United States and are continuously revised with a yearly publication, followed by two supplements. The first USP (USP 0) is now entering its 34th presentation and is combined with NF, now in its 29th presentation, with an official date of May 2011. USP-NF standards are public standards for medicines legally marketed in the US and are enforceable by FDA. They can be referenced by manufacturers and regulatory and compendial authorities throughout the world either in law or in private regulatory filings. Associated USP reference materials are distributed in more than 130 nations.
In recent years, USP's compendial offerings have expanded to include USP's Dietary Supplements Compendium, Food Chemicals Codex (FCC), and the USP Pharmacists' Pharmacopeia for compounding pharmacists. USP is also working to consolidate monographs for medicines legally marketed outside the United States through a Web-based publication termed the USP Medicines Compendium, which builds on and expands USP's work for non-US monographs intended for neglected infectious diseases.
USP s compendia and reference materials are made available through decisions of elected volunteer experts who form the Council of Experts and work closely with USP staff in the revision process. USP plans to publish the work plans of the Council online and to update them frequently during the current 2010-2015 revision cycle (www.usp.org/goto/CoEWorkPlans). This article presents an overview of the work of the Council in the 2010-2015 revision cycle as its moves through its first year. The publication will be linked to a finalizing report of the work of the Council at the April 2015 USP Convention.
The 2010-2015 revision cycle
USP delegates met in April 2010 and elected the 20 volunteer members of the Council of Experts' Expert Committees. Each member of the Council of Experts serves as chair of an Expert Committee. Expert Committee members are elected by the Council members in accordance with USP Rules and Bylaws (3). As needed, a new Expert Committee maybe formed during a cycle by the USP Board of Trustees, and this occurred in the current revision cycle when the Board created the 21st Expert Committee of the cycle to execute monographs for the USP Medicines Compendium.
As USP moves through the first year of the 2010-2015 revision cycle, Expert Committees are working with staff liaisons and stakeholders to finalize and disseminate their work plans. These work plans build on and extend the legacy work plans of the Expert Committees from the 2005-2010 revision cycle. The overall work plan is designed to enhance and strengthen standards in all of USP's compendia, including USP-NF, FCC, the Dietary Supplement Compendium, and the USP Pharmacist's Pharmacopeia. All compendia require extensive and continuing work to ensure a full cohort of up-to-date monographs with allied reference materials (i.e., official USP reference standards).
Nomenclature, Safety, and Labeling Expert Committee
The Nomenclature, Safety, and Labeling Expert Committee has responsibilities that span all Expert Committees. This Expert Committee reviews and approves USP-NF monograph titles for drug products, biologics and biotechnology products, excipients, and dietary supplements. In the 2010-2015 cycle, USP also added the focus on safety and labeling topics, formerly addressed by the Safe Medication Use Expert Committee in previous cycles.
USP has responsibility in law to create established (non-proprietary) names for drug products and to determine proper names for biologics [Section 502(e) of the Food, Drug, & Cosmetic Act (FD&C Act); FDA's policy on established names is set forth in 21 CFR, §299.4]. Along with FDA, the American Medical Association, and the American Pharmacists Association, USP participates in the US Adopted Names Council (USAN) and publishes the USP Dictionary of USAN and International Drug Names (6). USP's monograph naming approaches are outlined in general chapter Nomenclature <1121>. Additionally, a nomenclature guideline is being developed to provide supplemental information to the general approaches outlined in general chapter <1121>. The Nomenclature, Safety, and Labeling Expert Committee plans to revise general chapter <1121> to accommodate the new guideline and to make minor changes to the "Monograph Naming Policy for Salt Drug Substances in Drug Products and Compounded Preparations" (7).
The Nomenclature, Safety, and Labeling Expert Committee also has responsibility for the Medicare Model Guidelines (8) development activities, and to achieve that has appointed the Model Guidelines Expert Panel.
The Work Plan of the Nomenclature, Safety, and Labeling Expert Committee for the 2010-2015 cycle includes the following:
Naming activities. Naming activities include:
Safety and labeling activities:
Model guidelines activities: An Expert Panel of the NSL Expert Committee is charged with concluding recommendations for Versions 5.0 (2011) and 6.0 (2014) of the Medicare Model Guidelines (9). The recommendations will be considered and acted upon by the NSL Expert Committee with delivery thereafter to the Centers for Medicare and Medicaid Services.
Monograph development expert committees
Chemical Molecules. Four Expert Committees focus on developing monographs for chemical molecule ingredients and their associated drug products. These Expert Committees face a backlog as a result of missing monographs and monographs that require modernization. In addition, the number of missing monographs increases as FDA approves drugs. Assuming that each new molecular entity is associated with three or four dosage forms, USP estimates that the number of missing monographs increases each year by approximately 100. Collectively, these Expert Committees are responsible for approximately 3600 official monographs, and an additional 1500 monographs are absent. Monographs are distributed among the committees according to therapeutic categories. In addition to the monograph content, these Expert Committees are also responsible for approving the use of USP reference standards in their assigned monographs.
Following is a list of key initiatives affecting each of these Expert Committees:
New monograph development. This work involves an ongoing effort to establish new standards for drug substances and drug products in support of USP's public health mission. These Expert Committees are responsible for new monograph development for USP and the pending monographs initiative. USP posts pending monographs on its website for drug substances, drug products, and excipients that have been submitted or soon will be submitted to FDA for marketing approval but have not yet received this approval (10).
Monograph modernization . A key initiative in this cycle, modernization of monographs is needed to replace outdated tests or procedures with updated methodology and to add critical quality tests such as impurities. Focus areas include impurities and nonspecific identification and assay tests. To date, USP has identified at least 700 drug substance and drug product monographs for prescription and over-the-counter (OTC) medications that require modernization. The Expert Committees will collaborate with Expert Committees in other areas (e.g., general chapters), Expert Panels, USP staff, regulators, and stakeholders to outline strategies and implement tactics for monograph modernization.
OTC monograph development. This is a relatively new area as USP begins to address the absence of or inadequate public standards for OTC products. USP includes monographs for OTC ingredients and some drug products, but in several OTC product categories USP includes only a minimum number of monographs or, in some cases, none. Expert Committees plan to work with manufacturers and regulators to consider strategies for OTC product monograph development and revision.
Monograph redesign. As a result of the recall of USP 33-NF 28, most of the monographs remain in the old format. The conversion of monographs to the new format is expected to be complete by the close of the revision cycle (2015). Beginning with USP 35-NF 30, each annual edition will introduce a portion of the monographs (those without revisions) in the new format. USP 33-NF 28will be the primary publication for the migration of unrevised monographs in the new format. All new USP and pending monographs, revision proposals, and accelerated revisions will be published in the new format (11).
Expert Committee goals for this cycle include:
Chemical Molecules 1. Explore options for converting micro-bial assays to high-performance liquid chromatography (HPLC).
Chemical Molecules 2. Develop strategies for OTC monograph modernization and new monograph development. Although each of the four Expert Committees has monographs for OTC drugs and products, the majority are with Chemical Molecules 2, so USP anticipates that this Expert Committee will be a focal point.
Chemical Molecules 3. Collaborate with the Expert Panel associated with the Dosage Forms Expert Committee on the solubility criteria for veterinary drugs.
Chemical Molecules 4. Collaborate with the Expert Panel associated with the General Chapters—Physical Analysis Expert Committee on the revision of Radiopharmaceuticals for Positron Emission Tomography—Compounding <823>.
Biological expert committees. Two Expert Committees focus on monographs for biological medicines, including those arising from recombinant technologies. These Expert Committees concentrate on the development of new monographs and the revision of existing monographs. Both Expert Committees will support biosimilar biologics through monographs and also through general chapters, working with the General Chapters—Biological Analysis Expert Committee.
Biologics and Biotechnology—Monograph Committee 1. This Expert Committee develops and revises monographs for peptide, protein, glycoprotein, glycosaminoglycan therapeutics, and monoclonal antibodies. The Expert Committee sponsors several Expert Panels on unfractionated and low molecular weight heparins, as well as on therapeutic enzyme preparations. The Unfractionated Heparin Expert Panel currently is working in close collaboration with FDA on the stage-3 revision of the heparin sodium monograph. The low molecular weight heparin panel is addressing both monographs and procedural chapters for this class of therapeutic product. The Therapeutic Enzyme Expert Panel will continue to address the modernization of monographs for pancreatic enzyme products as well as enzymes in several other therapeutic areas. The Expert Committee is also cosponsoring an Expert Panel that will develop the chapter, Quality Attributes of Therapeutic Monoclonal Antibodies <129>.
Biologics and Biotechnology—Monograph Committee 2. This Expert Committee develops and revises monographs for a diverse area of biological products that include plasma-derived blood products, vaccines, and gene, cell, and tissue therapies. An Expert Panel has already been formed to address tissue-based products, an area of growing importance in the portfolio of this committee. Modernization and expansion efforts also will be devoted to the area of blood coagulation factors for which a second Expert Panel will initially focus on a monograph for plasma-derived Factor IX. Because of the challenge of developing full-length vaccine monographs, the Expert Committee hopes to collaborate with the General Chapters—Biological Analysis Expert Committee to explore the concept of class chapters for vaccines.
General chapters expert committees
Several Expert Committees are dedicated to the development and maintenance of the nearly 250 general chapters in USP-NF. The general chapters have been written over many years and by many different Expert Committees.
Each chapter's style, information content, and state of the art depends in part on when it was last updated. Goals for this
cycle spanning all the general chapters' committees include:
Chemical Analysis Expert Committee.
The charge of the General Chapters—Chemical Analysis Expert Committee is to revise and create general chapters that provide
standards and guidance to help USP-NF users when a chemical analysis is performed. This Expert Committee is responsible for more than 80 general chapters, including
those involving spectroscopy, chromatography, and metals analysis. In addition, this Expert Committee handles general chapters
related to dietary supplements. Some of the key initiatives for this group include:
Physical Analysis Expert Committee.
The charge of the General Chapters—Physical Analysis Expert Committee is to initiate and develop general chapters that help
users of USP-NF when a physical analysis is performed. This Expert Committee supports, updates, and develops general chapters concerned with
physical characterization of excipients and drug substances general chapters that provide standards and guidelines for users
concerned with regulatory sciences. Plans for the current cycle include:
Biological Analysis Expert Committee. The charge of the General Chapters—Biological Analysis Expert Committee is to initiate and develop documentary standards when a biological analysis is performed. This Expert Committee also reviews and approves reference standards used in a particular chapter. In this cycle, the committee will focus on product class general chapters for biologics. Biological products can be divided into different molecular classes based on their structure and function (e.g., polypeptides including proteins and peptides, enzymes, glycosaminoglycans, im-munoglobulins, and others). For many of these molecule classes, established platform approaches exist in terms of manufacturing, regulatory expectations (often reflected in FDA guidance to industry), and consequently, analytical characterization and quality control.
Approaching characterization and control by product class as much as possible affords important advantages: It gives the opportunity to establish and define acceptable assay approaches in important areas like potency determination, detection of common process impurities, or characterization of known, class-specific post-translational modifications. These approaches in turn are linked to general and public (compendial) procedures that do not rely on a single manufacturer's experience. These procedures then clearly establish the baseline for what is analytically acceptable. The class approach helps define and establish critical quality attributes that are common to a class of molecules rather than an individual product and hence can help focus and delineate scientific discussions around product identity and uniqueness.
The Expert Committee is establishing an Expert Panel to create Quality Attributes of Therapeutic Monoclonal Antibodies <129> to apply these principles to this biologic product class. In the area of low molecular weight hepa-rins, the existing USP Expert Panel is working on chapters for Anti-Factor IIa and Anti-Factor Xa Assays for Low Molecular Weight Heparins <208> and Low Molecular Weight Heparin Molecular Weight Determinations <209>, which are class-specific procedural general chapters that will establish consistency in how low molecular weight heparin products are analyzed in terms of potency and molecular-weight distribution, two critical product attributes. Other activities will focus on the review and updating of key information chapters, such as Biologics <1041> and Biotechnology-derived Articles <1045>.
Dosage Forms Expert Committee. The General Chapters-Dosage Forms Expert Committee initiates and develops general chapters that provide standards for dosage form performance, physical characterization, default conditions, and development. For dosage form performance, this Expert Committee is developing product quality and product performance chapters for drug products associated with each of the five routes of administration (i.e., oral, skin [topical and transdermal], aerosol, mucosal, and parenteral). The initial step is finalizing the topical and transdermal product quality general chapter <3> and its corresponding product performance chapters <724> and <1724>, followed by similar efforts for the other routes of administration. The Expert Committee is also working on general chapters that describe the product quality and performance characteristics of soft gelatin capsules and is beginning work via an Expert Panel on solubility criteria for veterinary drugs.
Microbiology Expert Committee.
The General Chapters-Microbiology Expert Committee develops public documentary standards and allied reference materials that
help ensure, where needed, sterility and related quality attributes of medicines. The Expert Committee will develop and update
chapters relevant to achieving microbiologically safe articles such as sterile and nonsterile manufactured ingredients and
dosage forms. This Expert Committee also is responsible for biological indicators used in the evaluation of sterilization
processes. Key initiatives for this committee include development or updating of:
In addition, the Expert Committee will contribute to the further development of Antibiotics—Microbial Assays <81>, along with the development of a workshop on rapid microbiological methods to help set USP's direction in this area.
The Expert Committee also provides microbiology support for committees dealing with food ingredients (FCC), dietary supplements, and excipient issues.
Packaging, Storage, and Distribution Expert Committee.
The General Chapters—Packaging, Storage, and Distribution Expert Committee develops and updates USP standards for container-closure
systems (i.e., glass, plastic, and elas-tomeric materials). General chapters developed by this Expert Committee define product
storage conditions and requirements and provide guidance for good packaging and repackaging practices. In addition, the Expert
Committee develops chapters providing guidance for issues related to pharmaceutical supply chain and product distribution.
Current key initiatives for this committee are:
Statistics Expert Committee
The charge of the Statistics Expert Committee is to initiate and develop general chapters to help USP-NF users with statistical treatment of data in support of USP's documentary and reference material standards. This Expert Committee
provides support to other Expert Committees regarding statistics and biostatistics. The Statistics Expert Committee is:
Toxicology Expert Committee
The Toxicology Expert Committee develops and revises general chapters in which toxicology plays a pivotal role, including biocompatibility. This Expert Committee will provide toxicology support to other committees in, among others, metal toxicity, genotoxic impurities, extractables and leachables, and residual solvents. The committee will lead the revision of general chapters Biological Reactivity Tests, In Vitro <87>, Biological Reactivity Tests, In Vivo <88>, and Biocompatibility of Materials Used in Drug Containers, Medical Devices, and Implants <1031>. The committee will also provide toxicology support for committees dealing with food, dietary supplement, and excipient issues.
USP Reference Standards
The charge of the Reference Standards Expert Committee is to guide the policy and processes by which USP tests, characterizes, assigns value to, packages, and releases reference materials for monographs in all of USP's compendia. The Expert Committee members provide guidance about related topics such as harmonization, continuing suitability for use, and metrological principles related to the development of reference materials (2).
Reference Standards Expert Committee.
The work plan of the Reference Standards Expert Committee includes the following (note that many of these activities will
be accompanied by an explanatory Stimuli article in USP's online journal of standards development, Pharmacopeial Forum (www.usp. org/USPNF/pf/):
National Formulary: Excipients Expert Committee
The Excipients Expert Committee concentrates on the development of new monographs and the revision of existing monographs in Pharmacopeial Forum. The Expert Committee also works with both the General Chapters—Physical Analysis and Chemical Analysis Expert Committees in the development of general chapters related to excipients. In addition to monograph content, the Expert Committee is also responsible for approving USP reference standards used in their assigned monographs. Following is a list of key initiatives for the Excipients Expert Committee:
New monograph development. This work is an ongoing effort to establish new standards for excipients in NF.
Monograph modernization. A key initiative in this cycle is modernization of monographs to replace outdated tests or procedures with updated methodology and to add critical quality tests such as identification and impurities. Focus areas include nonspecific identification and assay tests and impurities. USP has identified at least 150 excipient monographs that require modernization. The Expert Committees will collaborate with Expert Committees in other areas (e.g., general chapters), Expert Panels, USP staff, regulators, and stakeholders to outline strategies and implement tactics for monograph modernization.
Monograph redesign. As is the case with monographs published in USP, after the recall of USP 33 -NF 28 most NF monographs remain in the old format. For both USP and NF, the conversion of monographs to the new format will be accomplished during several years, and USP-NF will be the primary publication for the migration of unrevised monographs in the new format. In addition, 149 excipient monographs will be published in the USP Dietary Supplements Compendium Second Supplement.
Harmonization via the Pharmaceopeial Discussion Group (PDG). Harmonize current and future excipient monographs and excipient-related general chapters via the defined work processes of the PDG.
Specific goals for the Excipients Expert Committee during this cycle include:
Food Chemicals Codex: Food Ingredients Expert Committee
The charge of the Food Ingredients Expert Committee is to increase the number of monographs for food ingredients together with their associated USP reference standards, to develop relevant chapters about general tests and assays, and to modernize and revise all existing monographs and general tests and assays in Food Chemicals codex (FCC). All text in FCC is authorized (in distinction to official text, which is enforceable by regulators). FCC is recognized to various degrees as legally binding by the governments of the United States, Canada, Australia, New Zealand, Israel, and others.
The workplan of the Food Ingredient Expert Committee for the 2010-2015 cycle includes the following:
Dietary Supplements Compendium: Dietary Supplements Expert Committee
The Dietary Supplements Expert Committee revises monographs and general chapters that appear in the Dietary Supplements section of USP-NF and, with additional authorized material, in a line extension named the USP Dietary Supplements Compendium.
Members of the Dietary Supplements Expert Committee participate in a variety of joint subcommittees with the General Chapters
Expert Committees to develop general chapters for dietary supplements.
USP Pharmacists'Pharmacopeia: Compounding Expert Committee
The charge of the Compounding Expert Committee is to increase the number of evidence-based USP-NF compounding monographs—and to develop new chapters and to keep key general chapters up-to-date and relevant. These monographs appear in USP, and also, with additional authorized material, in a line extension named USP Pharmacists' Pharmacopeia. The Expert Committee reviews and revises existing compounding chapters if needed and develops new general chapters as appropriate. Text may be both official and authorized: official text is enforceable by FDA according to the FD&C Act, and authorized text is not yet approved as official or is informational.
Standards in USP-NF for compounded preparations may be enforced by both the states (pharmacy practice/compounding traditionally is regulated by state boards of pharmacy) and by FDA (compounded preparations are subject to the adulteration and misbranding provisions of the FD&C Act, which requires conformance to USP-NF standards).
The work plan of the Compounding Expert Committee for the 2010-2015 cycle includes the following activities:
This report presents the initial work plan of the USP Council of Experts for the 2010-2015 revision cycle. As noted, specific Expert Committee work plans will be posted on the USP website and will be periodically updated. This publication will be allied with a final report to the Convention, which oversees the work of the Council of Experts, continuing a time-honored process begun in 1820. USP encourages comments and questions from the scientific community and other stakeholders.
1. L. Bhattacharyya et al., Pharm. Res. 21 (10) 1725-1731 (2004), pmid:15553215.
2. R.L. Williams, Project Team 4, The 2000-2005 Reference Standards Committee of the USP Council of Experts and Its Advisory Panel, and USP Staff and Consultant, J. Pharm. Biomed. Anal. 40 (3) 3-15 (2006), doi:10.1016/j.jpba.2005.07.017.
3. USP, USP Bylaws, www.usp.org/pdf/EN/members/2010-2015-Bylaws.pdf.
4. USP, USP Council of Experts—Overview, www.usp.org/abou-tUSP/governance/councilOfExperts/ .
5. USP, Rules and Procedures of the 2010-2015 Council of Experts, www.usp.org/pdf/EN/members/2010-2015-Bylaws.pdf.
6. USP, USP Dictionary of USAN and International Drug Names (Rockville, MD, 2010).
7. USP, USP Nomenclature Policy, www.usp.org/USPNF/notices/generalChapter1121.html.
8. USP, Medicare Model Guidelines, www.usp.org/hqi/mmg/.
9. USP Model Guidelines Expert Committee, USP Staff, Ann. Intern. Med. 145 (2006) 448-453.
10. USP, USP Pending Guidelines, www.usp.org/standards/pending/.
11. T.L. Cecil, PharmacopeialForum 34 (6) 1638-1640 (2008).