USP Headquarters Maryland, USA

Europe/Middle East/Africa Basel, Switzerland

USP–India Private Ltd. Hyderabad, India

USP–China Shanghai, China

USP–Brazil São Paulo, Brazil

QUA L IT Y S TA NDA RDS f or Me dic ine s , Die t ar y Supplement s , and Fo o d Ing re dient s WO RL DWIDE

ISO 9001:2008 Certified

CEO Column2 Message from the CEO

The Importance of Public Documentary Standards and Reference Materials

USP Science4 USP Workshop Focuses

on Excipient Performance

5 USP Advancing Standards for Tablet Scoring

6 General Chapter <1>Transformed to Focus on Product Quality Tests for Parenteral Medicines

7 USP Releases Standards to Guide Content, Appearance of Prescription Container Labels

8 Workshop Focuses on Quality of Global Heparin Supply

International12 Global Pharmacopoeias Explore

Potential Collaborations on Medicines Quality Standards

12 USP Welcomes Guests from the Jiangsu Province

Global Health Impact Programs14 African Labs Work toward

Establishing an Independent Professional Association

Inside USP16 USP Awards Recognize Volunteer

Experts

17 USP Achieves Continued ISO 9001:2008 Certification

In This Issue

VOL. 10 | ISSUE 2 | FALL/WINTER 2012

USP Symposium Explores New Standards for Functional Foods and Dietary Supplements The choices for consumers are nearly endless, as are the promises: Improved bone health. Increased energy. Enhanced focus. Better digestion. So-called “functional” ingredients represent not just a passing fad, but a fast- (and by some accounts, the fastest-) growing segment of the food and di-etary supplement industries as consumers increasingly seek products that they consider beneficial to their health, appearance, athletic performance and more. The science behind many popular ingredients, however, is still emerging, with little consensus on the validity of claims among industry, regulators, consumer representatives and other key parties. With this premise, more

than 200 attendees gathered in Boston September 18–20 for the 2012 USP Science and Standards Symposium, to consider opportunities and challenges posed by func-tional ingredients—and the future direction for public standards in this area.

The symposium opened with an evening keynote address from Dr. Paul Coates, direc-tor of the Office of Dietary Supplements (ODS) at the National Institutes of Health. Dr. Coates explained the

regulatory landscape governing dietary supplements in the United States as laid out in the 1994 Dietary Supplement Health and Education Act (DSHEA), in which dietary supplements are regulated as foods. Since DSHEA’s passage, supplement sales rose from $8.6 billion in 1994 to $28.1 billion in 2010. Dr. Coates noted that roughly 50 percent of the domestic population uses these products. He spoke about ODS’ work on evidence-based reviews of dietary supplements such as ephedra (now banned in the U.S.), omega-3 fatty acids, soy, probiotics, vitamin D and cal-cium; concerns about and current limitations of research in this area; and other ODS initiatives, including its Analytical Reference Chemicals program with the National Institute of Standards and Technology and consumer education programs.

In a morning plenary session on the second day of the symposium, Dr. Robert Buchanan of the University of Maryland and a member of the USP Board of Trustees spoke about the science behind regulation of functional foods. He explained three intersecting activities: science, science policy and food law. Dr. Buchanan presented dictionary definitions of a functional food, but noted that there is no current legal definition, “nor is there likely to be.” He said that the U.S. Food and

Continued on page 19. See Symposium

(From left to right): Drs. Gorecki, Ebert, Buchanan and Susana Socolovsky of Argentina’s Pentachem answer audience questions during a plenary session.

In This Issue Continued

The Standard Fall/Winter 20122

USP Science9 USP Announces Change in Labeling

Requirement for Total Strength of Heparin

10 New Monograph Naming Policy Brings Clarity, Consistency to Drug Names

11 USP Initiates Spectral Library Project

11 New Reference Material Offerings for Novel, Natural Sweeteners

International13 WHO–FIP Meeting Focuses on Future of

International World of Pharmacopoeias

13 Brazil Conference Provides Opportunity to Educate on USP Food Standards

Global Health Impact Programs14 Voice of America Television Features

USP in Discussion on Counterfeit Medicines

15 New PQM Initiative Looks to Build a Pool of Experts to Improve Regional Regulatory Enforcement

Inside USP17 USP Granted Observer Status by Codex

Alimentarius Commission

18 USP Receives National Recognition for Employee Benefits Program

18 Three Students Receive 2012–2013 Global Fellowship Awards from USP

Message from the CEO

The Importance of Public Documentary Standards and Reference Materials

Roger L. Williams, M.D. I have written before about the importance of science-based, widely available public standards to help ensure good-quality medicines, foods and their ingredients. I reprise this theme now, driven by the fragmented state of global public health measures—particularly regarding compendial standards. To this end, USP posted public statements on its standards-setting activities at www.usp.org/about-usp/our-impact/statements-usp-standards. A more detailed vision is advanced in a Stimuli article to be published in Pharmacopeial Forum in January 2013. In this smaller space, I offer a brief overview.

In the world of public monographs for drugs, foods and their reference materials, the policy elements and opportunities are clear. A USP article in Pharmaceutical Research explains:

For medicines and foods, a national or regional or even global goal might be a comprehensive collection of public documentary and reference material standards that can be used…to test for quality. …An even more ambitious goal might be a single collection of documen-tary standards and reference materials to support testing of medicines and foods. (1)

Attempts at harmonization among world pharmacopoeias have moved slowly, but a new approach has emerged that offers a path forward. Again, from USP’s Pharmaceutical Research article:

With availability of monographs where multiple accept-able procedures might be allowed (and one reference procedure designated for purposes of compliance), coupled with certified reference materials (CRMs) and other reference materials as needed, it is possible to imagine that a full cohort of public procedures and reference materials may become available…to help ensure the quality and benefit of medicines and foods.

The importance of this vision is underscored when one considers USP–NF, the most comprehensive of the world’s pharmacopoeias. USP estimates there are a total of 11,477 medicines, excipients, dietary supplements, food ingredients and their components marketed in the U.S. Of this universe, half are missing from USP compendia. Despite the efforts of dedicated scientists, the growing demands of global public health need to be better served.

Barriers and Challenges to Public StandardsHistorically, USP’s documentary standards and reference ma-

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terials have come from donations by manufacturers, and these are greatly valued. But too many times manufacturers’ concerns about intellectual property issues or perceived lack of cost/bene-fit justification prevent donations. Additionally, it is argued that there is no need for a public standard until generic entry, with multiple companies manufacturing a product. Recently, there also has been an increased focus on current Good Manufactur-ing Practices (cGMPs) approaches (e.g., Quality by Design) and a correspondingly decreased emphasis on end-product testing requiring monographs and reference materials.

Rationale for a Public MonographDuring the 1930s, USP leader James Beal observed that Congress had chosen to recognize the USP as a standard of measurement against which to compare drug products, making the USP “…no different from the legal system of weights and measures.” (2) This perspective remains compelling today. USP has advocated for a global system of public “weights and measures” for medicines beyond the extent that it already does through World Health Organization (WHO) initiatives, e.g., International Unit and Système International d’Unités.

Public monographs and reference materials remain part of the complex and imperfectly integrated actions needed to ensure a medicine’s quality, safety and efficacy. For example, cGMPs are critical, as are many other manufacturer, regulatory and com-pendial standards. These standards are subject to conformity assessments by first (sellers), second (buyers) and third parties (those independent of buyer and seller—regulatory agencies, compendia and others). The role of third parties on behalf of the practitioner and patient (or consumer) is especially impor-tant, because they are not ordinarily part of the manufacturing process. While one cannot test quality into a product, better design processes and product testing are essential. It is perhaps easier to recognize this when looking at developing countries where well-designed products are too often degraded by adul-teration or poor storage and shipment conditions. In such cases, post-market surveillance and testing are essential.

Even in developed countries, public standards help stakeholders maintain confidence in the quality of medicines. Regulators have their greatest influence at the time of the market-access decision, when manufacturers agree to many regulatory controls. After this, regulatory oversight can diminish rapidly. Based on this, USP believes public compendial monographs and reference materials should be available from the time of market entry for all medicines, innovator and generic.

Lessons from the USP Medicines CompendiumThe initial motivation for the USP Medicines Compendium (MC) was to expand the availability of public monographs and

reference materials in view of the challenges that face USP–NF in having a full complement of current monographs with allied reference materials. USP had no expectation that the MC would solve the deficiencies of USP–NF. It simply was a way to create standards for articles approved in any country. USP’s experience since the MC launch in 2011 has provided compelling insights. For example, USP can create a monograph based on procedures (Reference Procedures), as well as allowing optimized, man-ufacturer-specific procedures to be recognized as Acceptable Procedures. This creates a reference procedure that theoreti-cally can be a single global testing standard for all articles under the same name. Additionally, USP can independently identify impurity reference materials needed to support a monograph and can create these materials in USP laboratories—a departure from USP–NF ’s use of manufacturer-specific procedures.

Toward a Global System, Working Collaboratively Despite progress by international bodies, we still lack a global solution. Instead, there are many non-harmonized monographs, supplemented at times by the WHO International Pharmacopoeia. USP’s MC may be seen as complementary to all pharmacopoeias, and this is enhanced by MC’s open-access character and rapid, web-based approach to allow public comment. Relevant to manufacturers, the MC approach suggests that a pioneer’s donation of a drug substance could be used across all procedures in any pharmacopoeia. Ultimately, this leads to global har-monization. In some ways, MC accords with the notion of the “ideal pharmacopoeia” as articulated by the pioneer industry, because it can provide a single ICH-based global standard that can apply across markets and manufacturers. For ministries of health, regulatory bodies and pharmacopoeias, the value of a good monograph with reference material rarely needs defense in resource-poor countries where borders are porous, regulatory control is weak and capacity is limited. Even where regulatory resources and market control are strong, however, arguments in favor of public standards gain traction with rising concerns about counterfeit and substandard medicines. For patients and consumers, while concepts discussed here might be unfamiliar, these parties might benefit from clear statements about the value of independent standards.

Moving forward, USP is well positioned to work with all stake-holders. Our present vision embraces the concepts embodied by James Beal’s arguments many decades ago, while extending them to the globalized world in which we find ourselves today. u

REFERENCES

(1) USP Council of Experts, USP Reference Standards Committee, Hauck WW. Primary and secondary reference materials for procedures to test the quality of medicines and foods. Pharm Res. 2012; 29(4):922–931. doi: 10.1007/s11095-012-0687-7.

(2) Anderson L, Higby GJ. The Spirit of Voluntarism: A Legacy of Commitment and Contribution: The United States Pharmacopeia 1820–1995. Rockville, MD: USP; 1995:275–276.

The Standard Fall/Winter 20124

USP Science

USP Workshop Focuses on Excipient PerformanceUSP held its first “Workshop on Food Ingredient Functional-ity and its Correlations with Pharmaceutical Excipient Perfor-mance” in conjunction with its Science and Standards Symposium in Boston, Mass. It is the first workshop to highlight the paral-lels and contrasts between pharmaceuti-cal excipient and food ingredient quality. A consistent workshop theme was variabil-ity—its inevitability

in excipients and food ingredients, how to detect and measure it, why and when it matters, and how to manage it. While excipi-ents are sometimes called the “inert” ingredients in a regulated product, such as flavors, fillers, binders, colors, preservatives, etc., in reality no ingredient added to a medicine or food is fully “inert.” This is a complex environment that can be altered by, for example, a change of suppliers, equipment, processes, or even personnel or their training regimens.

With the traditionally disparate worlds of pharmaceutical, food ingredient and dietary supplement manufacturing increas-ingly overlapping, the use of excipients and the need for shared understanding of how to define and asses their quality provided the impetus for the workshop. While each industry is regu-lated differently in the United States, a single pharmaceutical excipient supplier might have all three types of manufacturers as customers. This makes common understanding increas-ingly necessary in a time of global markets, multiple regulatory requirements, limited resources and the growing adoption of Quality by Design (QbD) as well as compendial approaches. The workshop was intended, stated opening speaker Dr. Gregory Amidon, chair of USP’s Physical Analysis Expert Committee, to provide an overview of food ingredient functionality, raw material variability, the role of USP’s General Chapter <1059> Excipient Performance and the Food and Drug Administration (FDA)’s views, and to facilitate discussion among all parties.

Dr. Amidon observed that the food ingredients and pharmaceu-tical industries have much to learn from each other in dealing with excipients. Excipient manufacturers and suppliers most accustomed to supplying food processors must become familiar with how pharmaceuticals are regulated, and with current Good

Manufacturing Practices (cGMPs) applied by FDA to excipi-ents intended for use in medicines. On the pharmaceuticals side, manufacturers could benefit from the food ingredients industry’s familiarity with ingredient variation in composition, process efficiencies and flexibility in materials sourcing.

There was much discussion about functions in foods, in the contexts of chemistry, regulation and—importantly—market expectations and economics. Dr. Grady Chism, vice chair of USP’s Food Ingredients Expert Committee, noted that “functional foods” is a term gaining popularity but not well understood. Dr. Chism observed that, from industry’s perspec-tive, the two most important functions of food ingredients are lower cost and improved accessibility/acceptance by consumers. In contrast, pharmaceutical manufacturers’ emphasis is on excipient variability and how that impacts drug product perfor-mance (i.e., safety and efficacy as well as cost).

Functions in foods are generally complex and are products of an ingredient’s interactions with water, air, lipids, carbohy-drates, ions, proteins—or with nothing. While most ingredients have more than one function, manufacturers may not always know what those are or how they affect the finished product. Food functions include appearance, nutrition, stabilizers, pre-servatives, texture and flavor (economically the most important, and the most diverse in terms of the number of compounds and structure)—and many others. Dealing with such a range of variables inevitably involves trade-offs. For instance, consumers are demanding foods that are “natural,” and without preserva-tives—but they also want products to last in the refrigerator and taste good. In the pharmaceutical world, there is a greater emphasis on excipient ingredient performance and what ingredi-ent variations in composition are appropriate to achieve required performance (“functionality”). Functionality in an excipient is a broad, qualitative and descriptive term for the purpose an excipi-ent serves in a formulation. Of greater importance, however, are the quantitative performance requirements (e.g., critical material attributes) of excipients that must be evaluated and controlled to ensure consistent performance throughout the product life cycle (General Chapter <1059>). Properties such as quality and safety are important to both industries, but where food manufactur-ers are focused on rapidly shifting consumer trends and are less tightly regulated, pharmaceutical manufacturers are concerned with medical efficacy and side effects, multiple regulatory agen-cies and oversight, and ICH QbD principles.

An overarching consideration for both is a robust approach to risk management. Drs. Brian Carlin (Monographs—Excipients Expert Committee) and Bruno Hancock (General Chapters—Physical Analysis Expert Committee) in particular addressed the

Dr. Bruno Hancock, a member of USP’s General Chapters—Physical Analysis Expert Committee, speaks about critical material attributes for excipients in formulations.

Continued on page 15. See Excipient Workshop

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USP Advancing Standards for Tablet ScoringAs pharmaceutical tablet splitting has become more common among patients, often on the recommendation of practitioners or manufacturers, the U.S. Food and Drug Administration (FDA), USP and others are collaborating to bring consistency and clarity to this practice.

There are a number of reasons patients subdivide tablets—to adjust (halve) the dose, to ease swallowing and to save money. Tablets intended for oral use are the most common dosage form in the United States and many bear score marks. There is an expectation on the part of some patients that if tablets have score marks, they will get a proportionate dose when tablets are split.

At present, there are no standards for the performance of subdivisions of scored tablets. However, this has been a long-term concern for USP. At an August 9, 2012, FDA meeting of the Advisory Committee for Pharmaceutical Science and Clinical Pharmacology addressing the topic, Dr. Anthony DeStefano, senior vice president of general chapters and healthcare quality standards for USP, provided background on this issue from the organization’s perspective. USP first discussed this publicly in the March/April 2002 Journal of the APhA, publishing a piece titled Lack of Medication Dose Uniformity in Commonly Split Tablets, in which a trained analyst used a single-edge razor blade to split tablets from 11 products and the resulting uniformity was studied. USP concluded that there was a strong suggestion that split tablets (scored or unscored) generally fail to meet expecta-tions for weight variation.

A more recent discussion of the topic occurred in Pharmaco-peial Forum 35(6) [November–December 2009] with the Stimuli article, Pharmacopeial Standards for the Subdivision Character-istics of Scored Tablets. Among the top-line observations from this piece was that scored tablets can be difficult to break and often display large variations in the mass of subdivided parts, as shown in extensive literature. Additionally, USP noted that in a Dutch study, 39 percent of patients dissatisfied with subdivision characteristics and poorly functioning score lines perceived these as quality defects—which could lead to reduced patient compliance with the medication.

FDA proposed a draft guidance for industry—Tablet Scoring: Nomenclature, Labeling and Data for Evaluation—in August 2011. This was a focus of the August 2012 advisory commit-tee meeting. The document provides guidance and criteria for assessing characteristics of scored tablets during development;

proposes the nomenclature “functional score” for tablets meet-ing the criteria; and provides a pathway for manufacturers to demonstrate functionality of scoring. At the committee meet-ing, FDA’s Russell Wesdyk explained that the agency is using a Quality by Design (QbD) approach. Mr. Wesdyk also stated that FDA is working with USP on a general chapter that builds on other compendia such as the European Pharmacopoeia (EP).

As explained by Dr. DeStefano, USP’s role is to develop post-release testing requirements for tablets labeled as having a “functional score” to show they perform as expected throughout

their shelf life. This would include pro-viding a means to confirm the quality of functional scoring via specific tests and acceptance criteria. USP’s standards will align with FDA’s guidance, and will look to the existing resources from EP, which presents standards for accuracy of subdivision but not ease of subdivi-sion or loss of mass.

The new standards are being developed under the USP General Chapters— Dosage Forms Expert Committee.

The Expert Committee is considering some key questions as it develops the new general chapter, such as whether the standard should address all subdivided tablets (including those that are not scored); whether it would be a general chapter intended to be applied, or for information only; and whether the full mono-graph standard is applied to the split tablets.

The importance of accuracy in scoring tablets depends in large part on the individual tablet, according to Dr. DeStefano. “For a drug with a wide therapeutic index, like a statin, considerable variation in daily dosage can be tolerated without seriously im-pacting the therapeutic effect. This is in stark contrast to a drug like warfarin, which has a narrow therapeutic index. If someone gets that wrong, the consequences could be severe or perhaps even life threatening.”

He further noted, “Patients and practitioners assume that a split tablet will behave like two halves, and that it will be of the same quality, safety and efficacy of the whole tablet of the equivalent dose. FDA’s draft guidance says in a drug’s develop-ment phase, a manufacturer should demonstrate that is true if the tablet is scored.”

The FDA guidance, as well as new USP standards, are anticipat-ed to apply to new products that are labeled functionally scored, and not those already on the market. It is anticipated that draft USP standards will be proposed in the first half of 2013. u

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USP Science

General Chapter <1>Transformed to Focus on Product Quality Tests for Parenteral Medicines

As part of a larger effort to develop overall product quality chapters based on the five routes of adminis-tration for medicines, USP recently proposed a revised General Chapter <1> Injections and Implanted Drug Products (Parenter-als)—Product Quality Tests. Parenteral drug products encompass both injections and implants, and allow the direct administration of the active drug substance(s) into blood vessels, organs, tissues or lesions.

USP groups all dosage forms based on five routes of admin-istration: injection, oral, topical-transdermal, mucosal and inhalation. To support individual drug product monographs, USP has divided the tests of a monograph into two categories: product quality tests and product performance tests. Product quality tests assess product quality attributes, which for paren-teral products include identification, sterility and particulate matter, among others. Product performance tests assess, for example, in vitro release of the drug substance (active phar-maceutical ingredient) from the drug product. For each route of administration, USP intends to or has created two general chapters—one that provides product quality tests and one that provides one or more product performance tests. The approach was detailed in a Stimuli article in Pharmacopeial Forum (PF) 29(5) [September–October 2003].

Based on these considerations, General Chapter <1> has been completely revised. The revised general chapter groups tests into three categories. The first is universal tests, which apply to all parenteral dosage forms. These tests include descrip-tion, identification, assay, impurities, foreign and particulate matter and sterility, among others. The next category of tests is specific tests, which may be considered on a case-by-case basis and are referenced in particular monographs. These include physiochemical properties, container content, water content and residual solvents. The third category is product quality tests

for specific dosage forms. Dosage forms covered include sterile powders for injection, suspensions, in situ gels, implants, drug-eluting stents and more.

A new informational General Chapter <1001> Product Perfor-mance Tests for Injections and Implanted Drug Products, will be prepared to provide information on potential product per-formance tests.

According to Dr. Desmond Hunt, senior scientific liaison for USP, “We are looking at this general chapter as a road map for parenteral drug products. It provides the fundamentals to help ensure product quality, and then points the user to the appro-priate locations within USP–NF for more detail on the required testing. Since this is a major revision of a frequently referenced chapter, we encourage people to pay close attention to the structure, dosage form grouping and methodology, and provide comments. USP has already rolled out the product quality chap-ter model with General Chapter <3> Topical and Transdermal Drug Products: Quality Tests, which is already official, and this is similar. When finalized, we anticipate these general chapters will allow for clearer understanding of expectations regarding potential testing and specifications for these products.”

Standards previously in General Chapter <1> that do not pertain to product quality tests have been removed from the revised general chapter and relocated to other general chapters. This information falls into the areas of 1) nomenclature and definitions, 2) labeling and 3) container content and packag-ing and storage. References to this material remain in General Chapter <1> to minimize the impact that changes to this general chapter will have on previously submitted regulatory filings.

No new tests have been incorporated into the revised general chapter for dosage forms currently in the pharmacopeia. Dosage forms for which monographs do not currently exist in USP–NF (e.g., implants) have been added, clarifying compendial expecta-tions for such products. Methods and procedures specific to these dosage forms but not yet established as compendial tests remain to be developed.

The revised general chapter was published in PF 38(6) [Novem-ber–December 2012], which is accessible at www.usp.org/usp-nf/pharmacopeial-forum. u

Join the Conversation. Follow USP on

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With medication misuse resulting in more than one million adverse drug events per year in the United States, new standards published in November 2012 in USP 36–NF 31 for the first time provide a universal approach to the format, appearance, content and language of instructions for medicines in containers dispensed by pharma-cists. Wide variabil-ity in prescription container labels exists today across indi-vidual prescriptions, pharmacies, retail chains and states. The USP standards provide specific direction on how to organize labels in a “patient-centered” manner that best reflects how most patients seek out and understand medica-tion instructions.

“Lack of universal standards for labeling on dispensed pre-scription containers is a root cause for patient misunderstand-ing, non-adherence and medication errors,” said Dr. Joanne G. Schwartzberg, director, aging and community health for the American Medical Association and a member of the USP Nomenclature, Safety and Labeling Expert Committee, which is responsible for the new standard. “With an aging and increas-ingly diverse population, and people utilizing a growing number of medications, the risks are more pronounced today than ever. These USP standards will promote patient understanding of their medication instructions, which is absolutely essential to preventing potentially dangerous mistakes and helping to ensure patient health and safety.”

Studies have found that 46 percent of patients misunderstood one or more dosage instructions on prescription labels. The problem is particularly troublesome in patients with marginal literacy, and in patients receiving multiple medications that are scheduled for administration using unnecessarily complex, non-standardized time periods. However, even patients with adequate literacy often misunderstand common prescription directions and warnings.

USP Releases Standards to Guide Content, Appearance of Prescription Container Labels

USP’s efforts to create these new standards emanated from an Institute of Medicine (IOM)-led initiative to improve health literacy, which is defined as the degree to which people can obtain, process and understand the basic health information and services they need to make appropriate health decisions.

According to IOM, 77 million Americans have limited health literacy, and a majority of Ameri-cans have difficulty understanding and using currently available health information and services.

Elements of the new standards, contained in General Chapter <17> Prescription Container Labeling, include:4Emphasize instructions and other information important to patients. Prominently display infor-mation that is critical for patients’ safe and effective use of the medi-cine. At the top of the label specify patient name, drug name (spell out full nonproprietary and brand name) and strength, and clear direc-tions for use in simple language.

Less critical information (e.g., pharmacy name, drug quantity) should not supersede critical information and should be placed away from dosing instructions.

4 Improve readability. Labels should be designed and formatted so they are easy to read. Typography should be optimized by using high-contrast print; adequate white space between lines of text (i.e., 25–30 percent of the point size); simple uncondensed familiar fonts (Times Roman or Arial are specifically recommended); and large font size (e.g., minimum 12-point Times Roman or 11-point Arial) for critical information. Older adults, in particular, have difficulty reading small print.

4 Give explicit instructions. Instructions for use should clearly separate the dose itself from the timing of each dose. Do not use alphabetic characters for numbers. For example, write, “Take 2 tablets in the morning and 2 tablets in the evening” rather than “Take 2 tablets twice daily.” Dosing intervals such as “twice daily,” “3 times

Continued on page 9. See Labeling Standards4

Dr. Thomas Reinders, chair of the USP Nomenclature, Safety and Labeling Expert Committee, explains the impetus for and aspects of the new standards.Video with Dr. Reinders is available at www.youtube.com/uspharmacopeia.

The Standard Fall/Winter 20128

USP Science

Workshop Focuses on Quality of Global Heparin SupplyUSP co-hosted the “Fifth Workshop on the Characterization of Heparin Products” at its U.S. headquarters in Rockville, Md., August 14–15, 2012. Since 2008, USP’s workshop on heparin products has provided a forum for manufacturers, regulators and other stakeholders dedicated to disseminat-ing information on methods and practices for testing heparin quality and analyzing its components. Co-organized by the National Institute for Biological Standards and Control (NIB-SC) and the European Directorate for the Quality of Medicines and Healthcare (Council of Europe)—which publishes the European Pharmacopoeia (EP)—the workshop brought together participants from around the world.

In 2008, the U.S. heparin supply came under close scrutiny from the Centers for Disease Control and Prevention (CDC) and the U.S. Food and Drug Administration (FDA) when adverse health events in 2007 and 2008—including more than 200 deaths—associated with the use of adulterated or coun-terfeit heparin prompted an investigation of this commonly used blood thinner. The investigation led to the discovery of an adulterant, oversulfated chondroitin sulfate (OSCS), in heparin sourced from China. OSCS is a less costly substance than heparin, and was used for economically motivated adulteration because it can mimic properties of heparin when using older, less-sensitive quality tests.

In response to the immediate public health crisis, USP worked with FDA and manufacturers to develop more sophisticated test methods related to its heparin standards, which were further strengthened in a second stage of revisions. A third stage, including new proposed methods for molecular weight determi-nations and nucleotidic impurities detection as well as improved tests for identification and protein impurities, was a featured topic at the workshop, along with updates on upcoming revi-sions to labeling requirements for heparin (see associated article on page 9). USP’s revised monographs with the new methods and improved tests will become official on May 1, 2014. Updates to heparin standards in the EP and the Japanese Pharmacopoeia also were presented.

A session on the sourcing and production of unfractionated heparin active pharmaceutical ingredients (APIs) featured per-spectives from industry, regulatory and international speakers. Dr. Christopher Bryant of Fresenius-Kabi North America, who is a member of USP’s Low Molecular Weight Heparins (LMWHs) Expert Panel, discussed the complexities of global supply chains and the need for more integrated supplier quality oversight into drug product manufacturers’ quality systems. Providing input from the regulatory realm, Dr. Ali Al-Hakim of FDA described how the use of risk assessment

management within a Quality by Design (QbD) ap-proach can play a role in the development of control strategies and the identification of critical quality at-tributes, which can ultimately lead to higher quality prod-ucts. Dr. Patricia Aprea of the Administración Nacional de Medicamentos Alimentos y Tecnología Médica (ANMAT) in Argentina discussed the split between bovine and porcine sources of heparin in the Latin American marketplace and Argentina’s efforts to create separate standards for each. With a focus on good manufacturing practices related to crude heparin manufacturing in China, Ms. Xiaoxia Wang of Changzhou Qianhong Bio-pharma gave an overview of her company’s integrated approach of requiring good manufacturing practices throughout all stages of crude heparin manufacturing and supporting all stages of upstream and downstream manu-facturing within one enterprise.

Presentations by representatives from NIBSC, Sanofi-Aventis (France), Baxter, Kings College London, Fresenius Kabi (USA), Gland Pharma (India) and Momenta Pharmaceuticals (USA) were featured in a session dedicated to the implementa-tion of new and revised monographs for heparin and lessons learned. Assessments of validity, potency bioassays, molecular weight determination, nucleotidic impurities determina-tion and analytical methods related to impurities in heparin sodium were among the topics addressed.

A session focused on LMWHs included presentations on the use of proton nuclear magnetic resonance (1H NMR) for heparin product identification and control; NIBSC’s efforts to identify a replacement for the international standard for LMWH potency; structure-function relationships for LMWHs; and other modern approaches for analyzing LMWHs.

The workshop concluded with a final session on regulatory and dossier requirements, which featured industry feedback to FDA’s draft guidance on heparin and as well Europe’s evolv-ing regulatory requirements related to unfractionated heparin. Overviews were also presented by the Institute for Public Health and the Environment (the Netherlands); the Brazilian Phar-macopeia Commission; the National Administration of Drugs, Foods, and Medical Devices (Argentina); the Pharmaceutical and Medical Devices Agency (Japan); and FDA. u

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USP Announces Change in Labeling Requirement for Total Strength of HeparinTo address safety concerns about the expression of drug strength on labels for heparin sodium injections and heparin lock flush solutions, USP has revised its current standards for these prod-ucts. Heparin is a widely used anti-coagulant agent, or blood thinner. Medication errors related to misunderstanding of the expression of total strength on multi-dose product labels have the potential to result in serious consequences to patients. The revised standards will become official on May 1, 2013.

The labeling sections of the currently official Heparin Sodium Injection and Heparin Lock Flush Solution monographs in USP–NF are being revised to ensure that labels comply with General Chapter <1> Injections. General Chapter <1> requires that the label reflect strength per total volume as the primary expression of strength, followed in close proximity by strength per milliliter (mL). An example of an expression of prod-uct strength as articulated in General Chapter <1> would be “30,000 USP Units/30 mL (1000 USP Units/mL).”

In a July 2010 letter from the U.S. Food and Drug Adminis-tration (FDA) to USP, the agency referred to data indicating that containers labeled only with product strength statements written as “mg per mL” are often misunderstood by healthcare practitioners as total drug content statements. Such errors could result in improper dosing with serious outcomes, including death. FDA’s concerns were evaluated by the 2005–2010 USP Safe Medication Use Expert Committee, composed of 18 patient safety experts representing multiple health professions including medicine, nursing and pharmacy (now part of the USP Nomen-clature, Safety and Labeling Expert Committee). FDA was also represented by liaisons to USP’s Expert Committee.

“USP is committed to developing standards that help to ad-vance public health, “ said Dr. Roger L. Williams, USP’s chief executive officer. “It is our goal to ensure that USP standards aid practitioners in their delivery of quality care to patients. Particularly in light of the public health emergency involving adulterated heparin in 2008, USP and FDA are continuing to work closely together to help ensure that drug delivery is as safe and accurate as possible.”

The process to change the labeling requirement began with posted Interim Revision Announcements for Heparin Sodium Injection and for Heparin Lock Flush Solution on May 1, 2012, and September 4, 2012, respectively, for public comment in Pharmacopeial Forum. The revised monographs will become official on May 1, 2013, at which time all drug products affected by this change will need to be in compliance with the standard. Posting of the official monographs in the “Official Text” section of USP’s website (www.usp.org/usp-nf/official-text) will occur on January 25, 2013.

Healthcare professionals must be vigilant during the transition period when old labels and revised labels for heparin sodium in-jections and heparin lock flush solutions both may appear in the marketplace. Old heparin labels may only display “strength per mL,” whereas the revised heparin labels will display both total drug content as “strength per total volume (total mL)” followed in close proximity by “strength per mL.”

For additional information, go to http://uspgo.to/heparin-labeling-revisions. u

daily,” or hourly intervals such as “every 12 hours” should be avoided because such instructions are implicit rather than explicit, may involve numeracy skills, and patient interpretation may vary from prescriber intent. Ambiguous directions such as “take as directed” should be avoided without clear supplemental information.

Include purpose for use. If the purpose of the medication is included on the prescription, it should be included on the label unless a patient prefers that it not appear. Confi-dentiality and FDA approval for intended use (i.e., labeled vs. off-label use) may cause some to constrain its inclusion on labels. Current evidence supports inclusion of purpose-

Labeling Standards Continued from page 7.

for-use language in clear, simple terms (e.g., “for high blood pressure” rather than “for hypertension”).

Other elements of the standards include addressing limited English proficiency and visual impairment.

Enforcement of the standard will be the decision of individual state boards of pharmacy, which may choose to adopt it into their regulations. At its 2012 annual meeting, the National Association of Boards of Pharmacy passed a resolution sup-porting state boards in requiring a standardized prescription container label. u

The Standard Fall/Winter 201210

USP Science

New Monograph Naming Policy Brings Clarity, Consistency to Drug NamesTo provide greater clarity and consistency in naming practices for medicines, a new drug naming policy established by USP will become official on May 1, 2013. The policy will apply prospectively to drug product and compounded preparation monographs that appear in USP–NF. USP has worked closely with the U.S. Food and Drug Administration (FDA) and industry stakeholders over a number of years to develop the new policy.

According to the Monograph Naming Policy for Salt Drug Substances in Drug Products and Compounded Preparations (Monograph Naming Policy), a drug product or compounded preparation formulated with a salt of an acid or base will use the active moiety—the portion of the molecule responsible for clinical activity—in the title of a monograph. The Monograph Naming Policy also stipulates that the strength of the product or preparation will be expressed in terms of the active moiety. This means that the name of the drug and its strength should be based on the active moiety, not its salt form.

“The development of USP’s Monograph Naming Policy is designed to provide concise and consistent names for drug products,” said Dr. Roger L. Williams, chief executive officer of USP. “This consistency in drug product names ultimately will benefit manufacturers, regulators, practitioners and, most importantly, patients.”

Under the Federal Food, Drug and Cosmetic Act, if there is a USP monograph for a drug product, the monograph title must be used as the nonproprietary name of that product. If a monograph does not exist at the time the product is approved, then FDA can designate an “Interim” name that may be used unless USP later designates a different name. USP monographs are often developed years after the product approval, which along with other factors has led at times to inconsistencies in naming, including mismatches of the name and strength of the drug product.

The Monograph Naming Policy was posted to USP’s website in 2007 as a revision to General Chapter <1121> Nomenclature,

so that stakeholders would have time to prepare for the May 2013 official date. The USP Nomenclature, Safety and Label-ing Expert Committee—the Expert Committee responsible for monograph title approvals—will generally apply the following implementation principles: For products with an existing USP monograph, the policy

will not be retroactively applied unless there is a justifiable need.

Prior to May 1, 2013, FDA-approved products with no existing USP monographs will be considered on a case-by-case basis. USP generally will accept Interim drug names approved by FDA for USP dosage form monograph titles that are proposed or implemented before May 1, 2013. The Expert Committee will work to avoid retrospective changes to approved product names, and will consider input from industry and other stakeholders regarding retrospective application of the policy.

After May 1, 2013, the policy will apply to FDA-approved products with no existing USP monographs. Deviations from the policy may continue to occur, and will be consid-ered on a case-by-case basis.

With regard to products not yet approved by the FDA, applicants are encouraged to contact the FDA early in the application process to consider implications of the policy.

Exceptions to the policy will include: Cases in which the strength of the drug product is

expressed for historical reasons in terms of the salt; When the inclusion of the specific salt form of the active

moiety provides vital information from a clinical perspective (e.g., when the salt form affects the absorption, distribution, metabolism and/or excretion [ADME] of the drug in a man-ner that influences a clinician’s product selection); and

Attempts to maintain consistency with other dosage form monographs in a particular “monograph family” (e.g., new approval for an additional dosage form of an existing product line).

“Because of the prospective nature of the policy,” said Dr. Williams, “we do not anticipate many changes in the names of existing products, which would be confusing to patients and practitioners. Rather, the changes will occur prospectively over time.”

A proposed revision to General Chapter <1121> describing the monograph naming policy appears in the November– December 2012 issue of Pharmacopeial Forum. To access additional information on USP’s monograph naming policy, go to http://uspgo.to/monograph-naming. u

This consistency in drug product names ultimately will benefit manufacturers, regulators, practitioners and, most importantly, patients.

Dr. Roger L. Williams, chief executive officer, USP

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USP Initiates Spectral Library ProjectIn recent years, USP has been exploring the feasibility of building an authoritative and comprehensive food and drug informat-ics database, known as the USP Spectral Library. Once fully developed, such a library would have the potential to be used not only in the development of quality standards, but as a tool for material identification and rapid screening for counterfeit and substandard food and drugs in the field.

Every food and pharmaceutical ingredient and formulated product, together with its packaging materials, has a set of unique physical and chemical properties, and generates charac-teristic signals or leaves a “fingerprint” within various regions of the electromagnetic spectrum of wavelengths that can be probed and captured using appropriate analytical instrumen-tation and advanced informatics. A vast collection of spectral “fingerprints,” also called a “spectral library,” can aid regulatory authorities, law enforcement agencies, hospitals, pharmacies, manufacturers and distributors worldwide to screen for poten-tial counterfeit and substandard food and drug substances and products in any part of the world via Internet access.

An authoritative spectral library of reference standards can also help compendial laboratory scientists and quality control personnel in food and drug industries confirm the identity of a substance in question by providing access to reference spectra of any global pharmacopoeia that is available through the library. As a scientific and independent standards-setting organiza-tion, USP is well positioned to serve the role of being a central repository of reference spectra from sources throughout the world, also making the library potentially useful in global efforts related to the harmonization of standards.

USP has begun working with stakeholders to explore the

feasibility of establishing such a spectral library with a goal of providing the public with the most authoritative and compre-hensive spectral information for material identification. USP envisions that the spectral library also will capture any known or likely adulterants for drugs and contaminants for foods.

To fully characterize a substance, USP has adopted an orthogo-nal methodology for the development of the library. This uses multiple analytical technologies including, but not limited to, gas chromatography-mass spectrometry (GC-MS); near infrared spectroscopy (NIR), nuclear magnetic resonance (NMR) spec-troscopy, X-ray fluorescence (XRF) and X-ray diffraction (XRD), and Raman technology to gather spectral information. Advances in many of these technological areas have enabled the develop-ment of hand-held or portable versions of these instruments. USP has engaged several global scientific instrumentation companies that are market leaders in hand-held and portable devices, and is incorporating their expertise on these instruments in the spectral library project. One concept being explored is the creation of a USP SmartLab®, a portable “lab in the field,” which would include key analytical devices needed to con-duct orthogonal analysis and to access the database. Through wireless connection, one could conceivably employ the relevant hand-held devices and be able to perform real-time data search and analysis from anywhere in the world.

USP has recently completed a proof-of-concept activity for the spectral library with a European-based informatics group and continues to build its consortium of partners for the project. Industries, pharmacopoeias, government agencies and other stakeholders interested in learning more about USP’s spectral library project may contact Ms. Bei Ma at bm@usp.org or +1-301-230-6356. u

New Reference Material Offerings for Novel, Natural SweetenersAs USP’s standards-setting activities for food ingredients evolve via the Food Chemicals Codex (FCC), a major focus area is novel ingredients that are of high interest to consumers and manufacturers. These include a number of plant-derived sweeteners, which are now being used increasingly in beverages and a variety of other foods as more consumers seek out “natural” products. Many of these sweeteners also fall into the low-, or no-, calorie category—making them particularly attractive in product formulation.

Such plant-derived ingredients, however, are often difficult to characterize and present unique quality challenges. Additionally, as with all ingredients du jour, they command a higher price—putting them at a potentially higher risk for economically motivated adulteration and making standards particularly important in the global supply chain. USP has published a number of FCC monographs for ingredients falling into this category, and now has reference standards available for ingredients including Monk Fruit, Stevia (high-purity Rebaudioside A as well as a mixture of Steviol Glycosides) and Mogroside V. These can serve as an invaluable tool for finished-product manufacturers as they source their ingredients, ingredient suppliers who want to demonstrate the quality of their substances and regulatory agencies worldwide. For a full list of food ingredient reference standards available from USP, visit http://www.usp.org/sites/default/files/usp_pdf/EN/fccRefStandards.pdf.

The Standard Fall/Winter 201212

USP International

Global Pharmacopoeias Explore Potential Collaborations on Medicines Quality Standards

Representatives of pharmacopoeias from around the world par-ticipated in the Second Global Summit of the Pharmacopoeias on September 7, 2012, in Xi’an, China. Hosted by the Chinese Pharmacopoeial Commission (ChP) and USP, the Global Summit is a forum for participating national, regional, and international pharmacopoeias to share information about their standards-setting activities and to discuss the potential for harmonized standards for medicines. At this year’s summit, pharmacopoeial representatives from 11 countries participated, including Brazil, China, Germany, Indonesia, Japan, Kazakh-stan, Russian Federation, Thailand, the United Kingdom and the United States.

“We hope this Global Summit promotes understanding and pro-vides a long-term platform for exchanges of mutual experiences and information in terms of standards for medicines,” said Mr. Wang Lifeng, director general of the ChP, in his opening state-ment. “Our shared mission is international collaboration that will ultimately benefit the health of patients in the world.”

Dr. Roger L. Williams, USP chief executive officer, noted that USP is pleased to be a part of this important initiative. “The globalization of medicines requires global solutions,” he said. “It is critical to learn and share experiences with each other and to pool our expertise to create globally harmonized standards.”

Because pharmacopoeial standards can differ from country to country, one aim of the Global Summit is to explore ways in which pharmacopoeial standards can be more broadly harmo-nized. An outcome from the first Global Summit was a proposal from the ChP to develop an index of pharmacopoeias, and the initial work was presented at this meeting. “This index coalesces information about standards from seven pharmacopoeias, and shows the similarities and differences in those standards,” said Mr. Wang Ping, deputy director general of the ChP. “We hope this index becomes an important technical reference on the development and revision of drug standards to achieve more globally harmonized standards.”

USP Welcomes Guests from the Jiangsu ProvinceIn September 2012, USP welcomed to its Rockville, Md., head-quarters a delegation of 23 leaders from the Jiangsu Province in China. The delegation was led by Ms. Zhang Mei, deputy director-general of the Jiangsu Institute for Food and Drug Control, and had representatives from the Jiangsu Food and Drug Administration, Jiangsu Province Medical Instrument Testing Institute, Xuzhou Pharmaceutical Vocational College, Nanjing Institute for Food and Drug Control, Wuxi Institute for Drug Control, Changzhou Institute for Drug Control, Suzhou Institute for Drug Control, Nantong Institute for Drug Control,

Lianyungang Institute for Drug Control, Yangzhou Institute for Drug Control, and Taizhou Institute for Food and Drug Control.

The delegation was in the United States to learn more about the U.S. food and drug market and to establish a relationship with USP. The delegation was provided with an overview of USP and its activities in China, and conversations focused on USP refer-ence standards and their importance in promoting the safety of foods and medicines. The delegation was taken on a tour of the USP facilities. u

Continued on back cover. See Global Pharmacopoeias

Pharmacopoeial officials from 11 countries participated in the Second Global Summit of the Pharmacopoeias.

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Brazil Conference Provides Opportunity to Educate on USP Food StandardsAt a São Paulo conference titled “U.S. & Brazil: Navigating New Frontiers in Pharmaceutical, Medical Device & Food Law & Regulation” held September 10–11, 2012, and organized by the Food and Drug Law Institute (FDLI), Mr. Luiz Rogerio M. Silva, laboratory director for USP–Brazil, presented on Brazil-ian regulations governing the food industry and USP’s role and relevance as publisher of the Food Chemicals Codex (FCC).

As noted by FDLI, Brazil, which is the sixth largest economy in the world, is experiencing unprecedented growth and regula-tion in the pharmaceutical, medical device and food industries, dramatically affecting the operations of both multinational and Brazilian companies. USP opened its site in Brazil in 2008. The September event featured top U.S. Food and Drug Administra-tion (FDA) and Brazil National Health Surveillance Agency (ANVISA) officials, multinational and Brazilian manufacturers, legal experts, and international trade and import experts.

FCC—along with the Joint FAO/WHO Expert Committee on

Food Additives’s Codex Alimentarius—is recognized as an of-ficial compendium under Brazilian law, and according to Dr. Silva, “We have seen increasing awareness of FCC in the past few years in the country. People want to know more about it, and how they can utilize it to test materials and check specifications.”

Mr. Silva’s presentation encompassed the definition of food in Brazil; the relevant governmental organizations overseeing the industry; the main regulations, including microbiological standards and food additives; the history and scope of FCC; and the value of an FCC monograph.

The USP–Brazil site organizes speaking and other outreach opportunities to generate broader understanding of USP’s standards and how they can be a resource in the area of food ingredients, as well as pharmaceuticals and dietary supple-ments. USP staff from the Brazil site and U.S. headquarters have spoken at various conferences, academic institutions and in other forums in the country. u

Continued on page back cover. See WHO–FIP Meeting

WHO–FIP Meeting Focuses on Future of International World of PharmacopoeiasAs a next step following the World Health Organization (WHO)-organized “International Meeting of World Pharma-copoeias”—which was held in March 2012 and brought together representatives from 23 pharmacopoeias for the first time in a decade—officials from pharmacopoeial bodies, regulatory agencies, industry groups and WHO convened October 7–8, 2012, in Amsterdam to discuss the future role of international pharmacopoeias and a path forward for global collaboration. The meeting occurred in conjunction with the “International Pharmaceutical Federation (FIP) World Centennial Congress of Pharmacy and Pharmaceutical Sciences.”

The meeting opened with an overview of WHO’s International Pharmacopoeia from Dr. Sabine Kopp. Professor Alan Nich-ols of the French Pharmacopeia followed with a summary of conclusions from the March 2012 meeting, which included an emphasis on modern monographs, new analytical methods and interchangeability of reference materials. Dr. Mike Morris, representing the International Conference on Harmonisation (ICH), presented on the topic of multinational harmonization of compendia. A spirited discussion among participants about what has worked well and what has not in this area followed. Industry participants noted their support for harmonization

through the Pharmacopoeial Discussion Group, but suggested including all of the pharmacopoeias and focusing on prospective harmonization rather than retrospective harmonization, which has proven to be a slow process.

In a session on good pharmacopoeial practices, each of the individual pharmacopoeias provided updates on current initia-tives and suggestions for international cooperation. Dr. Roger L. Williams, USP’s chief executive officer, emphasized the need for the pharmacopoeias to work together, and explained the science behind the innovative approaches advanced by the new USP Medicines Compendium (a performance-based monograph with a Reference Procedure). He also spoke about the efforts to harmonize pharmacopoeias, which began in 1865 and continue to this day.

In the closing session, Professor Saleh Bawazir, chair of the 47th meeting of the WHO Expert Committee on Specifications for Pharmaceutical Preparations and vice president of the Saudi Food and Drug Regulatory Authority, presented his perspec-tives of the future role of WHO in international pharmacopoeial harmonization. He began with a quote from Dr. Williams on

The Standard Fall/Winter 201214

Global Health Impact Programs

African Labs Work toward Establishing an Independent Professional Association

In September 2012, 11 countries of sub-Saharan Africa joined together to establish the Network of Official Medicine Control Laboratories-Africa (NOMCOL-Africa) with the goal of be-coming an independent association. What began as an activity supported by USP’s Promoting the Quality of Medicines (PQM) program is moving forward to become a self-sustaining profes-sional organization. At a three-day meeting held at the recently opened Laboratório Nacional de Controle de Qualidade dos Medicamentos in Maputo, Mozambique, the NOMCOL-Africa representatives and facilitators developed a mission statement, vision and objectives, and drafted a charter to guide the net-work’s future.

To facilitate south-south collaboration on common issues and to provide a forum for sharing best practices, the directors of the national quality control laboratories of Ethiopia, Ghana,

Mali, Senegal and Uganda originally formed the Network of African Medi-cines Control Laboratories (NAMCOL) in 2009. PQM provided the group with hands-on training in Good Laboratory Practices and proper use of compendial analytical methods—tools that can be used to detect substandard and coun-terfeit medicines—and supervised their participation in inter-laboratory testing to improve the labs’ operations.

Due to the success of the network, invitations were extended to six addi-tional countries—Kenya, Nigeria, Sierra

Leone, Tanzania, Zambia and Zimbabwe—to participate in the meeting and join the network. The meeting in Mozambique provided an opportunity for NAMCOL members to renew their commitment to advancing medicines quality control, welcome new ideas and learn from the experience of the countries represented. One goal of the meeting was for the network to determine how it could become a professional organization; subsequently, the expanded membership voted to change their designation from NAMCOL to NOMCOL-Africa.

The PQM team will play only an advisory role in the coming year, guiding the newly formed secretariat of NOM-COL and supervising the drafting of bylaws. PQM expects to hand over operations of the network to the African coun-tries involved, ensuring better long-term sustainability of the program. u

Representatives from 11 countries came together to advance medicines quality control.

Voice of America Television Features USP in Discussion on Counterfeit MedicinesDr. Patrick Lukulay, vice president of global health impact programs for USP and director of USP’s Promoting the Quality of Medicines (PQM) program, spoke to Voice of America health reporter Ms. Linord Moudou about counterfeit medicines on the TV2Africa daily magazine In Focus on October 4, 2012. Voice of America is a multimedia broadcaster funded by the U.S. government that reaches an international audience. While in the studio, Dr. Lukulay discussed what constitutes a good-quality medicine; the scope of the problem of substandard/counterfeit medicines; and how developing countries in particular can combat this problem, with the need for a multi-faceted approach encompassing policy, technology and public education. Earlier that week, Dr. Lukulay was a panelist addressing the public health and economic aspects of poor-quality medicines at the conference “Counterfeit Medicines: Impact and Potential Solutions,” hosted by The World Bank. u

Video of Dr. Lukulay’s VOA appearance is available at http://uspgo.to/YS6twp.

w w w.u sp.org 15

New PQM Initiative Looks to Build a Pool of Experts to Improve Regional Regulatory EnforcementUSP’s Promoting the Quality of Medicines (PQM) program convened a regional meeting to kick off its new initiative, “Building Regional Expertise in Medicines Regulation, Information-sharing, Joint Investigation and Enforcement” (BREMERE). Held in Bangkok, Thailand, on August 28–29, 2012, BREMERE aims to strengthen regional cooperation between and among the medicines regulatory authorities and law enforcement agen-cies in the Greater Mekong Subregion to improve the quality of medicines in the area.

Representatives of the relevant authorities (medi-cines authorities, police, enforcement agencies and customs) from Cambodia, Laos, Thailand, Vietnam, Philippines and Indonesia as well as a wide range of international and scientific organizations and academia participated in the meeting. During two days of discussions, the group drafted the Terms of Reference (TOR) that would encompass BREMERE’s governance, coordination, implementation and complementary activities with other similar efforts. By the end of the meeting, participants successfully reached a consensus on the TOR and leadership of the initiative, and prepared a timeline for future activities.

The BREMERE initiative aims to build capacity in all member countries by sharing regional expertise, and providing training

and technical/financial support. In the long term, it will create a regional “pool of experts” who will share information and expertise in medicines regulation, registration, post-marketing surveillance and enforcement. In order to reach the objectives included in the TOR, support and collaboration will need to be strengthened between political bodies in the field of medicines quality and regulation, and improvements will need to be made in the processes among regulatory/technical agencies and other sectors, such as customs and INTERPOL, at national and regional levels. u

At the first BREMERE initiative meeting in Bangkok, groundwork was laid for future collaboration.

Excipient Workshop Continued from page 4.

topic. Dr. Carlin provided an overview of ICH Q9 risk assess-ment and its application to excipients, noting that collaboration among suppliers, industry, academia, and regulators is essential to identifying and understanding the impact of raw materials variability and approaches to eliminating failures. Dr. Hancock outlined a systematic risk management strategy, noting that comprehensive studies of excipient properties are needed only when they are expected to impact the drug product’s critical quality attributes. While there are challenges to a systematic risk management approach—e.g., it takes time to do it properly—benefits are tangible and extend to the manufacturer as well as to patients.

Discussions of risk management raised several key ideas, all tied to the variability of excipients. First, it is essential to know your

suppliers, without which quality cannot be assured. Second, while compendial approaches are necessary, they are often not sufficient—pharmacopeial compliance is not a guarantee of fitness-for-purpose. The emergence of QbD approaches is an essential next step beyond adherence to a monograph (elaborated on by keynote speaker Dr. Robert Iser from FDA). General Chapter <1059> draws a more direct link between excipient properties not necessarily identified in compendial monographs and product performance. (A recent revision appearing in Pharmacopeial Forum 38(5) provides a framework for apply-ing QbD principles to excipient quality and performance.) And finally, attendees were urged to beware the unknowns, which abound and are often not recognized. Continual monitoring is essential to tracking unforeseen changes in the variable realm of excipients. u

The Standard Fall/Winter 201216

Inside USP

USP Awards Recognize Volunteer ExpertsAt its annual Science & Standards Symposium held in Boston, USP recognized the exceptional contributions of two of its volunteer bodies to improving the health of people worldwide through public standards as part of its Awards and Recognition Program for USP Expert Volunteers. The 2012 USP awards were presented to its Food Ingredients Expert Committee and Joint Expert Panel on General Chap-ter <1059> Excipient Performance in a ceremony on September 18, 2012.

“These two groups embody the volunteer spirit that has guided USP since its founding nearly 200 years ago,” said Dr. Roger L. Williams, chief executive officer of USP. “Their com-mitment and creativity in developing standards that address the complex challenges facing the global pharma-ceutical and food industries benefits manufacturers, regulators, and above all, patients and consumers.”

The Food Ingredients Expert Com-mittee, chaired by Dr. Andrew Ebert, received the 2012 USP Award for an Innovative Response to Public Health Challenges. It was selected for its outstanding work and lead-ership in transitioning the Food Chemicals Codex (FCC) from the Institute of Medicine to USP (USP acquired the compendium of food ingredients in 2006) as well as spe-cifically addressing the public health challenge of food adulteration. The Expert Committee not only provided its expertise and guidance for the transition of FCC to USP, but ensured its growth and continuity as an international compendium of food ingredients standards. Further, the Expert Committee guided USP staff in a significant expansion of the scope of FCC to include new and novel ingredients essential to keeping FCC relevant to parties worldwide.

As noted in the awards ceremony, the Expert Committee faced serious challenges soon after it was formed by USP to work on FCC in 2006. As it was becoming acquainted with USP’s standards-setting processes and transitioning FCC to a regular publication cycle of every two years with interven-ing supplements, a number of food and drug crises occurred worldwide and increased the urgency and broadened the scope of the Expert Committee’s work. Specific to foods, episodes of economically motivated adulteration involving pet food (in which wheat gluten was replaced with melamine) and infant formula and other milk powder products (in which melamine

was used as a low-cost replacement for protein) led to adverse health events and deaths in humans and companion animals, and demanded development of new, more specific analytical methods that could not be “tricked” by such replacements. The Expert Committee worked to identify at-risk ingredients and potential adulterants, and developed a USP Food Fraud Data-

base to serve as a free resource and risk management tool globally. In addition, USP held an Adulteration Workshop at USP’s headquarters in Rockville, Md., to consider new testing strategies and future direc-tions for standards, with follow-up workshops now planned in Chile, China and Israel.

The Joint Expert Panel on General Chapter <1059> Excipient Perfor-mance, a collaboration between the General Chapters—Physical Analysis and Monographs—Excipients Expert Committees that is co-chaired by Drs. Gregory Amidon and Eric Schmitt, received the 2012 USP Award for an Outstanding Con-tribution to the Standards-setting Process. Due to the Expert Panel’s efforts, General Chapter <1059> provides an overview of critical material attributes for many excipi-ent functional categories along with a toolbox of procedures that may be useful in evaluating and controlling excipient critical material attributes

that are not typically included in compendial monographs. The general chapter also provides a framework for applying Quality by Design principles to excipient quality and performance. USP Expert Panels are formed to provide additional expertise with advisory input on a particular scientific topic, thereby supple-menting Expert Committee expertise.

As detailed in the awards ceremony, this general chapter has a long history—with talk about such a resource beginning more than 20 years ago at a USP-convened meeting in 1991 in Orlando, Fla. At this meeting, the International Pharmaceutical Excipients Council was formed, and discussions about the need for standards focused on excipient functionality first took place. USP has advanced many general chapters addressing excipient quality in the intervening years, but General Chapter <1059> is the first focused on excipient function and performance.

Video interviews with Drs. Ebert and Amidon may be viewed at http://youtu.be/gyUMykO5h4M. u

Ms. Angela Long, with Drs. Williams and Duane Kirking, present USP’s volunteer awards to Drs. Amidon (top) and Ebert on behalf of their Expert Panel and Expert Committee, respectively.

w w w.u sp.org 17

USP Achieves Continued ISO 9001:2008 CertificationReflective of the organization’s continued commitment to the highest standards of quality, USP headquarters was recom-mended for continued certification of its quality management system in accordance with ISO 9001:2008 based on a successful surveillance audit by the BSI Group in August 2012. The ISO 9001:2008 certification demonstrates that USP’s quality man-agement system is evident under the standard and provides effective management of internal processes to meet interna-tional quality requirements.

USP first achieved ISO 9001 certification in 2004 for its quality management system. It also first achieved ISO 17025 accreditation in 2004 for competence in laboratory testing and calibration. All USP’s global sites are audited against ISO standards.

USP’s ISO 9001:2008 accrediting body is the independent registrar, the BSI Group. Additionally, USP’s ISO 17025:2005

accrediting body is ACLASS, one of three ANSI-ASQ National Accreditation Boards.

“As an organization that sets quality standards for use around the world, we feel it is imperative that we, too, adhere to the highest quality of standards in all the work that we do,” said Dr. Roger L. Williams, USP’s chief executive officer. “I com-mend the staff for their diligence in helping to ensure USP’s internal processes are up to par with this rigorous interna-tional standard.”

To achieve this accreditation, auditors looked at USP’s informa-tion technology security plan, the implementation of tools for improved reporting in finance/accounting and organizational operation manuals, among others. USP headquarters passed the ISO 9001:2008 continued accreditation with zero non-con-formities and zero opportunities for improvement, which are the best results that can be achieved from the surveillance audit. u

USP Granted Observer Status by Codex Alimentarius CommissionJoining an international community dedicated to protecting the health of consumers and ensuring fair practices in the food trade, USP was granted observer status by the Codex Alimen-tarius Commission in August 2012. In this capacity, USP will provide expert information, advice and guidance to the Com-mission, along with other international governmental and non-governmental organizations (NGOs).

The Commission was established by the Food and Agriculture Organization of the United Nations (FAO) and the World Health Organization (WHO) in 1963. Today, it has more than 180 members, and more than 200 inter-governmental and international non-governmental organizations are accredited as observers. The Commission’s main work is the development of international food standards, guidelines and codes of practice. The Commission also promotes the coordination of all food

standards work undertaken by international governmental and non-governmental organizations.

“The increasingly globalized food industry, the associated supply chain complexities, consumer interest in new, complex ingredients with purported health and nutritional benefits, economic pressures to keep food costs low—all call for strong international standards,” said Dr. Roger L. Williams, chief ex-ecutive officer for USP. “USP’s mission and work in the area of food standards align closely with those of the Commission, and we are honored to now serve in an accredited NGO capacity. Food ingredients, which represent a key component of the food supply, are particularly important and remain our focus.”

Through its Food Chemicals Codex (FCC), USP develops inter-nationally used standards for the identity, quality and purity of food ingredients including colorings, flavorings, emulsifiers, nutrients, preservatives and processing aids. FCC standards are developed by the Food Ingredients Expert Committee (FIEC), chaired by Dr. Andy Ebert. The work of the FIEC aligns closely with manufacturers innovating and marketing foods throughout the world and with the work of the U.S. Food and Drug Admin-istration’s Center for Food Safety and Applied Nutrition. u

The Commission’s main work is the development of international food standards, guidelines and codes of practice.

The Standard Fall/Winter 201218

Inside USP

USP Receives National Recognition for Employee Benefits ProgramIllustrating its strong commitment to the long-term well-being of its employees, USP recently earned national acclaim for its benefits program. An independent judging panel of employee benefits experts named USP as one of the 2012 winners of The Principal® 10 Best Companies for Employee Financial Security in August 2012.

Judges selected USP because of its dedication to its employees through a focus on employee benefits, such as retirement and wellness programs, designed to improve both physical health and financial security.

“USP and other Principal 10 Best winners continue to set the standard for improving employee financial security; they realize an investment in their employees constitutes an investment in their own future well-being,” said Mr. Luke Vandermillen, vice president at the Principal Financial Group®. “Winning companies offer a number of ways to impact the long-term physical and financial health of their employees and understand the direct connection between well-rounded ben-efits, a healthier workforce and a better bottom line.”

The Principal Financial Group sponsors the national program, which is now in its 11th year. It honors growing companies (five–1,000 employees) for their commitment to their employ-ees’ financial security.

USP offers a core basket of fully paid benefits, with numer-ous options for upgrades at minimal employee expense. These

benefits include a three-tiered healthcare plan offering compre-hensive coverage, with the organization paying the total cost of its base “silver” plan for employees and their families; a 401(k) retirement savings plan in which the organization contributes 10 percent of the employees’ total cash compensation (including salary and bonus) per year after one year of service; and tuition assistance of up to $10,000 per calendar year, among others.

“We are proud and gratified to receive the tremendous honor of being named to Principal’s 10 Best list,” said Ms. Susan Bach, vice president of human resources for USP. “In keeping true to our mission of improving the health of people worldwide, we seek to provide the best-possible benefits to our own employees as they work to advance our mission.” u

As part of The Principal® 10 Best Companies award, USP received a $2,500 donation to a charity of its choice. Here, USP and Principal representatives deliver a check to The Reginald S. Lourie Center.

Three Students Receive 2012–2013 Global Fellowship Awards from USPFor the 2012–2013 academic year, USP awarded three global fellowships that focus on various detection methods of counterfeit and substandard drugs, analysis of pharmacopeial reference standards, and methods of excipient identification and adulteration detection. The goal of the USP Global Fellowships is to advance new research that contributes to innovative or updated quality standards for medicines, food ingredients and dietary supplements, and to support the work of early career scientists in these fields. The $50,000 Global Fellowship Awards recognize research that directly address a specific USP scientific or research need. All Global Fellows will present their work at a future USP event. Since the program’s inception in 1981, USP has invested nearly $4 million in 235 Fellowship awards.

Recipients of the 2012–2013 USP Global Fellowships are:

Darash Desai, Ph.D. candidate, Boston University, Department of Biomedical Engineering. His area of research is Pharmacheck: Counterfeit and Substandard Drug Detector for the Developing World.

Jose Napolitano Farina, Ph.D., University of Illinois at Chicago, College of Pharmacy, Department of Medicinal Chemistry and Pharmacognosy. His area of research is New Generation of 1H NMR Fingerprints for the Rapid Analysis of Pharmacopeial Reference Standards.

Ting Wang, Ph.D. candidate, University of Maryland at Baltimore, School of Pharmacy. His area of research is Developing the Scientific Basis for the Application of Spectroscopic and Chemometric Methods to Excipient Identification and Adulteration Detection. u

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The Standard

Drug Administration (FDA) simply considers these products “food” and not a separate entity. Dr. Buchanan explained that the lack of a legal definition means functional foods may be regulated under a variety of categories, depending on what a manufacturer is trying to claim and the group/population for which the product is intended.

USP Chief Executive Officer Dr. Roger L. Williams offered USP’s vision and strategy in the area of food ingredients and dietary supplements, and efforts to identify (and ultimately develop quality standards for) all articles moving in global commerce. He described USP’s current offerings—the Food Chemicals Codex (FCC) and USP Dietary Supplements Com-pendium (DSC)—as “textbooks” of standards in these areas. Dr. Dennis Gorecki, chair of the USP Dietary Supplements Expert Committee, detailed various USP initiatives for dietary supple-ments, including new monograph development, monograph modernization, safety reviews of dietary supplements and a planned Herbal Medicines Compendium for ingredients used in Traditional Chinese Medicine, Ayurvedic medicine and more. Dr. Andrew Ebert, chair of the USP Food Ingredients Expert Committee, provided a corresponding overview of food standards initiatives and explained how USP has transformed FCC since acquiring the compendium from the Institute of Medicine in 2006. He also spoke specifically about USP efforts to help prevent economically motivated adulteration of food ingredients via its Food Fraud Database and other work.

Providing attendees a glimpse into the future, Ms. Nirvana Chapman of the global market research firm Mintel discussed functional ingredients poised for growth, which fall in line with key consumer trends. These trends include an aging population seeking brain health, body health and “cosmeceutical” products, as well as a growing preference for “natural” products (with no artificial ingredients). From a consumer watchdog perspective, Mr. Chuck Bell of Consumers Union (publisher of Consumer Reports) presented concerns with these products and the claims they make, as well as questions they advise consumers to ask themselves: 1) should I be eating this? 2) how meaningful is the claim on this product? 3) do I need this additive (i.e., is my diet balanced enough without supplementation)? and 4) am I overdosing on a nutrient?

Presenting on oversight and governance of an increasingly complex “food-scape,” Ms. Diane McColl of Hyman, Phelps & McNamara, P.C. and a member of the USP Food Ingredients Expert Committee provided more detail on legislation guiding the industry, including the Nutrition Labeling Education Act of 1990 and DSHEA. She also explained the Generally Recog-nized as Safe (GRAS) path to food ingredient use, noting that while this system has come under criticism of late for perceived lack of scientific rigor, the food safety problems that dominate

today are related to foodborne pathogens. She stated that there have not been public health issues related to GRAS ingredients, and “this is not a coincidence.” From a food industry perspec-tive, Dr. Janet Collins of DuPont and incoming president of the Institute of Food Technologists spoke about the challenges in meeting sometimes conflicting consumer preferences for foods that, on the one hand, do not contain long lists of ad-ditives (particularly ones they can’t pronounce), but on the other, provide an increasing number of functional benefits. She described this as a “catch-22” for industry.

The remainder of the sessions fell into two break-out tracks, one focused on food ingredients and the other on dietary supplements.

The function of food ingredients, and the degree to which function is tied to identity, were discussed in multiple food sessions—including one on functional assays. Topics included challenges and opportunities for Fourier Transform Infrared Spectroscopy to authenticate food ingredients and screen for adulteration; Nuclear Magnetic Resonance (NMR) for quanti-fication and identification; a contract laboratory perspective on mistaken identity; and NMR to characterize reference materials. Other sessions looked at emerging ingredients from traditional sources. Topics included antioxidants in food: an evidence-based approach to understanding, sustaining and promoting benefits; functional oils; identity and authenticity testing of fruit juices; and more.

On the dietary supplements side, multiple presentations addressed identity testing for these products, including orthogo-nal methods for identity; NMR; and DNA bar code techniques. Other sessions looked at standards supporting dietary ingredi-ent structure/functional claims and quality initiatives from USP, including how USP standards can be utilized by industry in complying with current Good Manufacturing Practices and efforts regarding authenticating geo-authentic botanicals. Dr. Tieraona Low Dog of the University of Arizona and a member of the USP Dietary Supplements Expert Committee offered a unique viewpoint, presenting a clinician’s perspective on dietary supplements. While personally supportive of their use, she laid out the complexities physicians face in counseling patients on these products. These include contradictory research on ben-efits/risks and inconsistent dosing recommendations.

Throughout the meeting, many challenges regarding these ingredients were presented. Despite this, food and dietary supplement products incorporating these novel ingredients are currently in widespread use, and manufacturers are forging ahead—presenting a compelling need for public standards. Look to future issues of The Standard for updates on how this work is evolving. Interviews with some Symposium speakers are available at http://uspgo.to/Zulx2z. u

Symposium Continued from front cover.

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WHO–FIP Meeting Continued from page 13.

Global Pharmacopoeias Continued from page 12.

the critical importance of a public monograph and reference material for every medicine, which allows regulatory authorities to check for adulterated, counterfeit, or substandard medicines and their ingredients. Professor Bawazir’s recommendations included WHO formation of a new “Global Pharmacopoeial Group” that champions prospective harmo-nization and considers a performance-based monograph approach. He noted the need for paradigm shifts from information sharing to active engagement, regional thinking to considering the global picture, medicines quality to broader regulatory issues, and competitiveness to collaboration—saying there should be no competition in the area of product safety. u

Mr. Mark Wiggins, compendial affairs associate director of Merck USA, was invited to give a presentation about harmonization from an industry perspective. He indicated that it is difficult for manufacturers to work separately with all the pharmacopoeias in the world to achieve harmonized standards because individual pharmacopoeial approaches may vary widely. Instead, he suggested that it would be better, from his company’s perspective, to have a single prospectively harmonized standard that is developed through partnerships with the pharmacopoeias, and is therefore consistent and globally applicable. “The keys to the success of this approach are good pharmacopoeial practices, pharmacopoeial collabora-tion and regulatory acceptance of those standards,” said Mr. Wiggins.

His proposed approach includes working with a lead pharmacopoeia on a particular standard that would be submitted earlier than has historically been the case. Sharing of information with other pharmacopoeias throughout the standard development process would then enable all other pharmacopoeias to adopt the same standard. He acknowledged that pharmacopoeias must work with their regulatory authorities, and that sometimes approvals vary from country to country, which adds complexity to the creation of harmo-nized standards.

Dr. Williams provided an update on the USP Medicines Compendium (MC), a new online-only, freely available source of public standards. “There are many medicines in the world for which there are no public standards,” said Dr. Williams. “As a result, USP has created a way to develop standards based on International Conference on Harmonization approaches, literature searches and material analyses. MC monographs include multi-source procedures that may be used to test articles from multiple manufacturers. The MC is compatible with Mr. Wiggins’ proposal in that it offers a framework for a monograph as well a more comprehensive set of procedures that can look across comparable articles, up to and including substandard, spurious, falsified and counterfeit medicines.”

Other Global Summit discussion focused on spectral imaging technology and pharmaco-poeial standards, the importance of reference standards to pharmacopoeias, impurities, prioritization criteria, and Quality by Design approaches to pharmacopoeial standards. Updates from the Brazil, British, China, European, Japanese, Russian Federation, and U.S. pharmacopeias were provided. Concluding the Global Summit, Mr. Wang Lifeng observed, “It is important that we continue to work collaboratively on these critical issues.” u