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9 | ISSUE 3 | SPRING 2012

Global, Common Approach to Pharmaceutical Supply Chain Integrity the Focus of Workshop
The increasing globalization of the drug supply presents a host of public health challenges: theft and diversion of medicines, growth of illegal Internet pharmacies and insertion of adulterated medicines or ingredients into the supply chain. Pharmaceutical companies, regulatory authorities, lawmakers, healthcare practitioners and others all are working to determine the best approaches to securing increasingly complex supply chains and protecting patients from potentially dangerous products. With the goal of coordinating and facilitating these individual initiatives, USP convened a Supply Chain Integrity Workshop, May 2223, 2012, in Rockville, Md., to consider key issues, generate areas of agreement and solicit feedback on its newly proposed informational standard. Although it has been a perennial topic of the past few years, supply chain integrity proved a particularly timely one this spring, coming on the heels of recent problems in the United States with two counterfeit cancer medications (Avastin and Altuzan). AdMore than 200 people gathered to discuss critical issues ditionally, at the same time as the workshop surrounding supply chain integrity. was being held, the U.S. Senate was considering user-fee legislation incorporating new supply chain provisions and increased authority for the U.S. Food and Drug Administration (FDA) as it grapples with threats to the modern drug supply. Welcoming the more than 200 workshop participants, Dr. Mary Foster, chair of the USP General ChaptersPackaging, Storage and Distribution Expert Committee, stated that a more rigorous approach to safeguarding medicines for end-users is essential. Dr. Praveen Tyle, executive vice president and chief science officer for USP, laid out a broad charge for attendees, stating that the entire community of stakeholders needs to determine how it can divide and conquer as it addresses this multifaceted challenge. What is the role of the pharmacopeia? Of industry? Of FDA? We need to make sure there are no gaps as we all work to ensure a safe and effective supply of drugs to patients. Dr. Michael Eakins, vice chair of the USP General ChaptersPackaging, Storage and Distribution Expert Committee, presented USPs current work as proposed in its draft General Chapter <1083> Good Distribution PracticesSupply Chain Integrity. This informational chapter is designed to present a holistic approach to supply chain integrity, which involves minimizing risks that arise anywhere along the supply chain. At present, approaches vary by individual companies, and current guidelines consider specific aspects of this issue but not supply chain integrity as a whole. The USP standard covers key areas including importation, best practices to combat counterfeit drugs and medical devices, and diversion and theft.
Continued on page 11. See Supply Chain Workshop

In this Issue
CEO Column
2 Message from the CEO Matching Dollars to Aspirations

USP Science
4 4 New Standards Limit Elemental Impurities in Medicines Immunogenicity Testing Associated with Therapeutic Proteins the Focus of New USP General Chapter New General Chapter Developed Following Recalls Due to Glass Particles in Injectable Medications Improvements to Heparin Standards Announced USP on Compounding: A Guidebook for the Compounding Practitioner
More...

6 6

International
12 U.S., British Pharmacopoeias Collaborate on Proposed Standards 12 USP Hosts Indian Delegation under New Training Program 13 USP Staff Travel to China to Solidify Relations 13 Mutual Dedication to Quality Medicines in South Korea, U.S. Strengthened through MOU
More...

Global Health Impact Programs

16 USP Joins the Clinton Global Initiative
More...

Inside USP
3 USP Convention News
More...

Q U A L I T Y S TA N D A R D S f o r M e d i c i n e s , D i e t a r y S u p p l e m e n t s , and Food Ing redient s WORLDWIDE

USP Headquarters Maryland, USA Europe/Middle East/Africa Basel, Switzerland USPIndia Private Ltd. Hyderabad, India USPChina Shanghai, China USPBrazil So Paulo, Brazil

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USP Convention News

Message from the CEO
USP Welcomes New Convention Members
into the Clinton Global Initiative, whose mission is to alleviate poverty, create a cleaner environment, and increase access to health care and educationclearly aligned with USPs worldwide work for public health. Ultimately, the combined efforts may allow USP to do more perhaps far morebeyond its current development work, but for now, we are committed to giving start-up funds to these endeavors. I am especially proud that the USP Board earmarked $1.5 million in matching dollars to stimulate donor enthusiasm. During a trip to Ghana in May, Dr. Lukulay met with government officials and other leaders in the capital, Accra, to explore possibilities for land on which USP will build a Center for Pharmaceutical Advancement and Training (described in the Winter 2012 issue of The Standard). These landmark events are a strong start to making USPs new GHIP initiative a reality. Beyond this emerging stream of activity, USPs focus on core compendial work has expanded to include the USP Medicines Compendiumoff to a robust start as it concludes its first yearand a planned Herbal Compendium, currently expected to launch in the fall of 2012. These new compendia demand investment, of course, so the alert reader might wonder if USP is neglecting its existing compendia: the USPNF, the USP Dietary Supplements Compendium (DSC) and the Food Chemicals Codex (FCC). I can assure you that this is not the case. USP is devoting considerable and growing resources to these compendia, with significant new laboratory capability as well as scientific and administrative staff being added at a vigorous pace both at USPs headquarters in Rockville, Md., and in our facilities in India, China and Brazil. USP relies on sophisticated volunteers and excellent managers, as well as thoughtful stakeholder input, as it evolves a truly global strategy to support public health. Everything I say to you now and all that I will say in the coming year arises out of this intensive effort, now concluding for FY13, of matching dollars to organizational aspirations. Based on its independence and strong financial position, USP is able to move freely in the world to create and sustain core compendial standards with allied compendial programs and to offer these in increasingly effective ways to broaden access to good-quality foods and drugs. I am indeed privileged to be chief executive of such a distinguished organization and I thank all the many volunteers, staff and stakeholders who contribute to this endeavor. Academic Institutions and Associations Thereof North America Florida A&M University College of Pharmacy and Pharmaceutical Sciences Health Practitioner Professional and Scientific Associations and Organizations North America AACC-International Governmental Bodies, Divisions and Associations East Asia Indonesian Pharmacopoeia Commission Korean Pharmacopoeia Pharmacopoeia of Chinese Taipei (Taiwan) Philippine Pharmacopoeia Thai Pharmacopoeia Committee Vietnam Pharmacopoeia Commission South Asia Indian Pharmacopoeial Commission Ministry of Health and Family Welfare of India Middle East and North Africa Jordan Food and Drug Administration Manufacturer, Trade and Affiliated Associations South Asia Bulk Drug Manufacturers Association (India) Non-Governmental Standards-Setting and Conformity Assessment Bodies Latin AmericaCaribbean Chilean Pharmacopoeia Foundation

In this Issue
USP Science
7

Continued

Matching Dollars to Aspirations

As USP continues to grow, I have been struck by both the opportunities and the challenges presented by expansion in the global community. For a public health organization like USP, there is no shortage of needs to be addressed, collaborations to pursue, or science to deploy in the service of providing greater access to good-quality medicines and foods. Resource allocation is a sobering exercise; one in which, at this writing, USP is engaged for our fiscal year 2013 that starts on July 1. I often think of this process as a triumph of experience over hope. This seems especially true this year because USP has such hard-working volunteers and so many enthusiastic staff, all of whom want to do exciting things. Experienced managers know that the hope for resources is tempered by the experience that not all can be satisfied, given that resources are always constrained.

New USP Database Reveals Food Ingredients Most Prone to Fraudulent Economically Motivated Adulteration Scientic, Regulatory Issues Surrounding Probiotics the Focus of USP-IFT Workshop New Edition of FCC Offers Standards to Help Ensure Quality, Safety of Innovative and Widely Used Ingredients

Roger L. Williams, M.D.

10 USP Annual Science & Standards Symposium to Address Functional Ingredients in Food, Dietary Supplements 10 Resource Assists in Ensuring Quality of Dietary Supplements

International
14 Ambassador of Kenya Visits USP 14 Worlds Pharmacopoeias Come Together to Discuss Global Harmonization 15 USPs Visiting ScientistsWhere Are They Now?

There is no shortage of needs to be addressed, collaborations to pursue, or science to deploy in the service of providing greater access to quality medicines and foods.
Roger L. Williams, Chief Executive Ofcer, USP

Global Health Impact Programs

16 PQM South Korea Workshop Seeks to Make Affordable, Good-quality Tuberculosis Medicine a Reality 17 PQM Introduces Medicines Quality Monitoring Program to Burma

Inside USP
18 Inaugural Listening Tour Dinner Held in New Orleans 20 Student Pharmacists Compete in National Compounding Event

And we indeed have exciting new initiatives emerging for the new fiscal year. USP now has a global development and fundraising focus as a result of a Board of Trustees decision at its February 2012 meeting. This new function is headed by Ms. Reema Jweied-Guegel, who is building capability to gain funds separate from USPs traditional financing sources as a means of assisting those in developing countries who wish to promote access to good-quality medicines and foods. Coupled with a development and donations effort (see chief operating officer Brian Hendrixs guest Message from the CEO in the Summer 2011 issue of The Standard), USP has also advanced a new department titled Global Health Impact Programs (GHIP), headed by Dr. Patrick Lukulay, which is designed to channel these new resources into targeted initiatives designed for maximum impact. Additionally, USP has been admitted

New Convention Observers

South Asia Indian Pharmaceutical Association Bangladesh Ministry of Health and Family Welfare Directorate General of Drug Administration Bangladesh Association of Pharmaceutical Industries Association of Biotech Led Enterprises Middle East and North Africa Moroccan Board of Pharmacists Manufacturers Turkey Association of Research-Based Pharmaceutical Companies Latin AmericaCaribbean Federal Commission for Protection Against Sanitary Risks Chilean Institute of Public Health Perus National Center for Quality Control University of So Paulo Brazils National Academy of Pharmacy
Continued on page 19. See Convention News

The Standard Spring 2012

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New Standards Limit Elemental Impurities in Medicines

As part of its ongoing efforts to help ensure the quality of medicines, USP announced in April 2012 two new standards related to elemental impurities: General Chapters <232> Elemental ImpuritiesLimits and <233> Elemental ImpuritiesProcedures. The new standards provide procedures for the detection of selected impurities in drug products based on modern analytical methods, as well as acceptable limits for their presence based on toxicity data and exposure levels. The U.S. Food and Drug Administration (FDA) and other public health officials have monitored the presence of elemental impurities in products intended for human consumption for some time. Elemental impurities can occur naturally, be added intentionally or be introduced inadvertently (e.g., by interactions with processing equipment). Elemental impurities include catalysts and environmental contaminants such as lead or mercury that may be present in drugs. Until the development of General Chapters <232> and <233>, USPs standards for elemental impurities were included in General Chapter <231> Heavy Metals, and applied only to active pharmaceutical ingredients and excipients. The test methodology included in <231>, while widely used, is based on a longstanding technique not sufficiently sensitive to detect a number of impurities at levels known to be toxic. Once General Chapters <232> and <233> are implemented, all references to USP General Chapter <231> will be omitted from monographs in USPNF. Given the broad-reaching impact of these standards on multiple drug products, USP has established a clearly defined timeline for pharmaceutical manufacturers and regulators to prepare for these changes, said Dr. Anthony DeStefano, USPs senior vice president for compendial sciences. We feel that these new standards have struck a good balance between the need to maintain the quality of medicines for the protection of patients and rational testing procedures and limits that can be readily applied by industry. General Chapter <232> specifies limits for the acceptable amounts of elemental impurities in drug products. Of the 15 elemental impurities identified for testing in <232>, 11 are catalysts. As such, their presence in a given drug product would be known through an assessment of the manufacturing process. The remaining four elementsarsenic, cadmium, lead and mercuryare naturally occurring or environmental impurities, thus making it necessary to assess the likelihood of their presence. The analytical procedures in General Chapter <233> apply inductively coupled plasmaatomic (optical) emission spectroscopy (ICP-AES) or inductively coupled plasmamass spectroscopy (ICP-MS) to detect elemental impurities. The general chapter also describes criteria for validation/verification of the procedures and for the establishment of acceptable alternative procedures. General Chapters <232> and <233> will be effectively official December 1, 2012. However, the general chapters will have a deferred application date of May 1, 2014, at which time conformance to the new standards will be required. More information is available at www.usp.org/usp-nf/hot-topics/ elemental-impurities. The revised General Chapter <2232> Elemental Contaminants in Dietary Supplements appeared in the MayJune 2012 Pharmacopeial Forum (PF) 38(3). The comment deadline is July 31, 2012.

New General Chapter Developed Following Recalls Due to Glass Particles in Injectable Medications
Since 2010, the presence of glass particles in injectable medications has led to a number of product recalls. This issue is related to the durability of the inner surfaces of the glass containers storing these products. This is a serious quality problem that has led to the development of a new USP general chapter. A handful of specific conditions have been associated with a higher incidence of glass delamination (that is, the shedding of glass flakes from a vials interior walls). These include glass vials manufactured by the tubing process (and thus exposed to higher heat); drug solutions formulated with certain buffers; high pH drug products; and products that undergo terminal sterilization. FDA warned of this issue in a March 2011 advisory to drug manufacturers. Under the guidance of the USP General ChaptersPackaging, Storage and Distribution Expert Committee, the new informational general chapter recommends approaches to predict potential formation of glass particles and delamination. General Chapter <1660> Evaluation of the Inner Surface Durability of Glass Containers will be included in the JulyAugust 2012 Pharmacopeial Forum (PF) 38(4), and was posted on the USP website in May 2012. Glass, in the form of ampuls, bottles, cartridges, vials and prefillable syringes, is the container material most often used for injectable products, especially biopharmaceuticals. Three types of glass are defined by USP General Chapter <660> ContainersGlass for the purposes of pharmaceutical packaging. Type I glass (borosilicate glass) is typically used for parenteral drug products, and is the focus of the new chapter. We know that not all Type I glass is of the same quality, as evidenced by recent recalls, said Dr. Desmond Hunt, senior scientific liaison with USP. What do manufacturers need to do to ensure glass quality? How do we combat glass delamination? What are some predictive tests? These are the questions the proposed general chapter is seeking to help answer. Major areas covered by the general chapter include: Good Glass Supply-Chain PracticesProvides recommended steps for manufacturers in selecting a glass container vendor. Glass Surface ChemistryDiscusses surface glass chemistry and how a drug product formulation and glass treatment can impact glass durability. Factors that Influence Inner Surface DurabilityOffers information on factors that have the potential to influence the durability of the inner surface of glass containers. The general chapter also provides information on screening methods to evaluate inner surface durability. These expand upon what is included in General Chapter <660>, which outlines mandatory compendial requirements for glass pharmaceutical containers. Although tests in the general chapter provide an indication of glass durability, they do not take the drug product into consideration. The most important variable that affects surface durability is the interaction between the product and the container. This is why additional screening methods as outlined in <1660> are important. To read the draft general chapter, visit www.usp.org/usp-nf/ pharmacopeial-forum.

Immunogenicity Testing Associated with Therapeutic Proteins the Focus of New USP General Chapter
Providing manufacturers with some key recommendations for monitoring and measuring unwanted immunogenic activity related to the administration of therapeutic proteins, USP has recently proposed General Chapter <1106> Immunogenicity AssaysDesign and Validation of Immunoassays to Detect Anti-Drug Antibodies. The new general chapter appeared in the MayJune 2012 Pharmacopeial Forum (PF) 38(3). As a growing number of therapeutic proteins are used to fight complex diseases including certain cancers and autoimmune disorders, drug manufacturers and regulators continue to take a close look at how best to address immunogenic responses associated with their use in patients. The administration of a protein therapy can trigger an unwanted immunogenic response that may result in clinical effects ranging from a decreased therapeutic response to severe adverse events. Given that manufacturing process changes take place during the entire life cycle of a protein drug product, it is important to monitor immunogenicity during the development of that particular drug candidate as well as during post-market surveillance, according to Dr. Maura Kibbey, USP senior scientific liaison. Testing for immunogenicity is directly influenced by good assay design, assay reagents, how assays are executed and how assay data are analyzed. General Chapter <1106> focuses on the first critical step involved in immunogenicity testingscreening for anti-drug antibodies (ADA). At times, the body can confuse the presence of a large molecule drug such as a therapeutic protein with that of another foreign substance, thus raising a flag for the
Continued on page 5. See Immunogenicity

Immunogenicity Continued from page 4.

body to respond accordingly. In either non-clinical or clinical studies, different types of ADA responses can develop. In some cases, ADA can prevent the protein drug from binding to its therapeutic target in the body. This can cause the drugs eventual clearance from the body as well as a loss of efficacy. In other cases, an immune response to a therapeutic protein can involve a cross-reaction with native proteins in the body and potentially shut down biochemical processes that may be essential to life. General Chapter <1106> outlines proposed strategies for the design, development, validation and analysis of binding immunoassays that measure unwanted immunogenicity responses. This includes testing to confirm that the ADA screening assay is, in fact, caused by the presence of drugspecific antibodies, instead of other contributing factors. The general chapter also provides approaches to the validation of immunoassays. While several regulatory guidance documents and published studies related to immunogenicity testing currently exist, USPs newly proposed informational standard attempts to provide an inclusive set of detailed recommendations for manufacturers with regard to ADA screening. This general chapter is the first of several that USP hopes to develop to provide laboratories with best practices for immunogenicity testing associated with the use of therapeutic proteins, said Dr. Kibbey. The general chapter was developed by the USP Immunogenicity Testing Expert Panel. The comment deadline is July 31, 2012.

The Standard Spring 2012

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Improvements to Heparin Standards Announced

To help further secure a safe supply of the widely used blood thinner heparin, a third round of revisions to quality standards for the drug were advanced by USP in May 2012. The changes were recommended by USPs advisory Expert Panel on Unfractionated Heparin, which reports to the USP MonographsBiologics and Biotechnology 1 Expert Committee. The revised standards are scheduled to appear in the NovemberDecember 2012 Pharmacopeial Forum (PF) 38(6), with a comment deadline of January 31, 2013. In response to the public health crisis of 2008 in which heparin that was intentionally adulterated with over-sulfated chondroitin sulfate (OSCS) caused adverse effects and deaths among patients, USP and the U.S. Food and Drug Administration (FDA), working with manufacturers, initiated a multi-stage process to revise and modernize standards for heparin. OSCS is a less costly substance than heparin and was used for economic adulteration because it can mimic heparin when tested using older, lesssensitive methods. OSCS also was determined to play a role in clinical adverse events associated with contaminated heparin use. USP and its partners completed the first stage of revisions to the heparin standards in June 2008. Those changes consisted of validating and implementing procedures to detect OSCS. Stage two revisions to the standards were completed in October 2009 and included new Identification, Potency Assay and Impurities (e.g., Absence of OSCS) test procedures, with associated reference materials. Stage two also involved the harmonization of USP Heparin Units with International Units established by the World Health Organization. The third stage of revisions will bring even greater sensitivity and precision to the tests and reference materials used to help ensure heparin quality. In response to requests from FDA, USP has identified and plans to incorporate into the standards new and improved procedures and tighter specifications for detecting and deterring the presence of OSCS as well as improved control for protein and nucleic acid impurities. FDA also requested the addition of a heparin molecular weight procedure with allied reference materials, which will be included in the proposed revisions along with a related reference material for testing. The work on Unfractionated Heparin also impacts quality standards for Fractionated Heparin. USPs activities related to Unfractionated Heparin will be among the highlights of the Fifth Workshop on the Characterization of Heparin Products (http:// uspgo.to/heparin-workshop) taking place on August 1415, 2012, in Rockville, Md.

New USP Database Reveals Food Ingredients Most Prone to Fraudulent Economically Motivated Adulteration
A new database developed by USP is the first known repository compiling reports on food fraud and economically motivated adulteration. Available at www.foodfraud.org, the new USP Food Fraud Database provides baseline information to assist interested parties in assessing the risks of specific products. It includes a total of 1,305 records for food fraud based on a total of 660 scholarly, media and other publicly available reports. Records are divided by scholarly research (1,054 records) and media reports (251 records). Content from the database is also included in the Food Chemicals Codex (FCC), Eighth Edition, which was released in March 2012. The database was developed as part of USPs standards-setting activities for food ingredients. It provides information that can be useful in evaluating current and emerging risks for food fraud. In addition to providing a baseline understanding of the vulnerability of individual food ingredients, the database offers information about potential adulterants that could reappear in the supply chain for particular ingredients. Food fraud was recently defined in a report commissioned by the Department of Homeland Security and funded by the National Center for Food Protection and Defense (University of Minnesota) as a collective term that encompasses the deliberate substitution, addition, tampering or misrepresentation of food, food ingredients or food packaging, or false or misleading statements made about a product for economic gain. A more specific type of fraud, intentional or economically motivated adulteration of food ingredients has been defined by USPs Expert Panel on Food Ingredient Intentional Adulterants as the fraudulent addition of nonauthentic substances or removal or replacement of authentic substances without the purchasers knowledge for economic gain of the seller. Analyzing the records in the database, USP scientists published the report, Development and Application of a Database of Food Ingredient Fraud and Economically Motivated Adulteration from 1980 to 2010, in the April 2012 Journal of Food Science. Researchers were Drs. Jeffrey C. Moore (lead author) and Markus Lipp of USP, and Dr. John Spink of Michigan State University and USPs Expert Panel on Food Ingredient Intentional Adulterants. Their report highlighted the most fraud-prone ingredients in the food supply. Based on a review of records from scholarly journals, the top seven adulterated ingredients in the database are olive oil, milk, honey, saffron, orange juice, coffee and apple juice. While traditionally considered primarily an economic issue and less a consumer safety threat, the research defined empirically that in some ways food fraud may be more risky than traditional threats to the food supply. The adulterants used in these activities often are unconventional and designed to avoid detection through routine analyses. Melamine, for example, was considered neither a potential contaminant nor an adulterant in the food supply before the episodes of adulteration of pet food in 2007 and infant formula and other milk products in 2008 (with tainted products still appearing sporadically today, principally in China). Although, as records from this database indicate, melamine was used as an adulterant to mimic protein as early as 1979; however, this remained virtually unknown until 2007. Hence, testing for melamine was not included in routine quality assurance or quality control analyses. Additionally, current food protection systems are not designed to look for the nearly infinite number of potential adulterants that may show up in the food supply. Food ingredients and additives present a unique risk because they are used in so many food products and often do not have visual or functional properties that enable easy discrimination from other similar ingredients or adulterants throughout the supply chain, the report states. In addition to identifying specific food ingredients and food categories vulnerable to adulteration, the report examines the types of analytical detection methods used to discover the fraud, as well as the type of fraud using three categories: replacement, addition or removal. The authors found 95 percent of records involved replacementan authentic material replaced partially or completely by another, less expensive substitute. The report points to a key application of the new database, which involves analytical testing strategies to detect food fraud. A commonly used strategy at present is testing for the absence of specific adulterantsan approach that excels at detecting known adulterants at very low levels but has the critical limitation of not necessarily being able to detect unknown adulterants. An alternative strategy is compendial testing (via FCC and other sources) for the quality and safety of a food ingredient (i.e., what should be present and in what quantity instead of what should not be present). While this testing may not always be capable of detecting adulterants at trace levels, it is capable of detecting both known and unknown adulterants. Well-designed compendial testing approaches can be a very powerful tool for guarding against food fraud, said Dr. Moore. Their potential to detect both unknown and known adulterants is a significant benefit in an environment where no one knows what harmful adulterant criminals will use to create the next generation of fake food ingredients.

USP on Compounding: A Guidebook for the Compounding Practitioner

Over the past two decades, there has been an increased need for pharmaceutical compounding, resulting from a variety of factors: drug shortages, the need to access drugs or dosage forms withdrawn by manufacturers from the market and special patient needs for customized therapies. To meet the needs of compounding practitioners, USP has launched USP on Compounding, an electronic publication that includes all compounding-related general chapters from USPNF, as well as the General Notices and Requirements. USP on Compounding includes: <795> Pharmaceutical CompoundingNonsterile Preparations: Provides guidelines for applying good compounding practices in the preparation of nonsterile compounded formulations for dispensing and/or administration to humans or animals. <797> Pharmaceutical CompoundingSterile Preparations: Provides procedures and requirements for compounding sterile preparations. <797> describes conditions and practices to prevent harm to patients that could result from microbial contamination, excessive bacterial endotoxins, variability in intended strength, unintended chemical and physical contaminants and ingredients of inappropriate quality in compounded sterile preparations. <1160> Pharmaceutical Calculations in Prescription Compounding: Provides general guidance and assistance to pharmacists in performing the necessary calculations when preparing or compounding any pharmaceutical drug. <1163> Quality Assurance in Pharmaceutical Compounding: Describes a quality assurance program as a system of steps and actions that must be taken to ensure the maintenance of proper standards in compounded preparations. <1176> Prescription Balances & Volumetric Apparatus: Provides information about acceptable balances and volumetric apparatus (e.g., burets, pipets, cylinders, conical graduates, medicine droppers) used to weigh or measure medicinal and other substances required in prescriptions or in other pharmaceutical compounding. USP on Compounding is offered as a 12-month electronic subscription and will be updated with the release of each new USPNF edition and Supplement.

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Scientic, Regulatory Issues Surrounding Probiotics the Focus of USP-IFT Workshop

Regulators, manufacturers and academic researchers from around the world convened for a two-day workshop on the scientific and regulatory challenges posed by the use of probiotic ingredients in food products, May 910, 2012, in Rockville, Md. Co-sponsored by USP and the Institute of Food Technologists (IFT), the workshop was intended to guide USPs future work in this emerging area via its Food Chemicals Codex (FCC). amounts confer a health benefit on the host. Examining the live element of the definition, she noted factors that affect a microorganisms ability to survive, which include the food matrix in which they are being used (e.g., yogurt, bread), addition of ingredients (e.g., flavors, sugars), pasteurization/heating and others. Speaking to administered in adequate amounts, she stated that effective dose varies based on the individual strain of the microorganism as well as the health condition under study. Dr. Davis concluded that probiotics may have potential benefits, including some outside the gastrointestinal tract. She noted that studies are difficult to interpret based on significant differences in study design and duration, dosage forms and amounts, and many other factors, and laid out how future health studies can be better designed. Ms. Janet Balson of the International Food Additives Council and Chr. Hanson provided an overview of global regulations pertaining to probiotics. Underscoring the fluidity of regulatory thinking in this area, she noted that, Everything is in a state of flux; everyone is having a discussion, all across the world. Ms. Balson pointed to the regulatory commonalities that exist across countries, which include differentiation of the probiotic ingredient based on its intended use (i.e., as a food, drug or dietary supplement) and the requirement of evidence indicating the ingredients safety. Differences include whether pre-market approval is required, the types of claims allowed on products and specifics of safety evaluations. With regard to the claims, Ms. Balson explained that there are three categoriesefficacy, health and structure/function claimsbut noted that there is no global model for how such claims are handled. With regard to safety, Ms. Balson stated that some regulators recognize a safe history of use at the genus and species level of a microorganism, while others insist that safe history of individual microorganism strains is required. Dr. Anthony Cundell of the USP General ChaptersMicrobiology Expert Committee and Merck Research Laboratories provided information on various types of testing to help ensure quality and safety, including identification, enumeration and functional tests. He explained that identification can occur through microbial characterization, phenotypic identification, genotypic identification and strain typing. Dr. Cundell sought feedback on the types of testing that should be included in any standards developed by USP. Making a case for public standards for probiotics was Mr. David Keller of Ganenden Biotech, Inc., who presented a case study on the companys unique strain of Bacillus coagulans. He stated that clinical studies on an individual strain must show the amount
Continued on page 9. See Probiotics Workshop

Eighth Edition of FCC Offers Standards to Help Ensure Quality, Safety of Innovative and Widely Used Ingredients
The latest specifications for the identity, quality and purity of more than 1,100 food ingredients, test methods to verify specifications, key guidance on critical issues such as impurities testing for metals, and content from a new USP Food Fraud Database (see related story on page 7) are all included in the Food Chemicals Codex (FCC), Eighth Edition. Released in March 2012 by USP, FCC is a compendium of internationally recognized standards for the authenticity of a wide variety of food ingredients, including colors, flavorings, nutrients, preservatives and processing aids. The food industry is constantly innovating with new products and ingredients designed to meet consumer desires for healthful, flavorful and convenient foods, said Dr. Praveen Tyle, USP executive vice president and chief science officer. At the same time, manufacturers are increasingly sourcing their ingredients globally. Public standards provided by FCC can serve as a key resource for manufacturers in managing their supply chains by providing specifications to authenticate their ingredients, and can also help differentiate suppliers. FCC, Eighth Edition contains: More than 1,100 monographs, which include chemical formula and structure, chemical weight, function, definition, packaging and storage, labeling requirements, test procedures and more. Fourteen appendices, which detail more than 150 tests and assays, with step-by-step guidance for the analysis of enzymes, impurities such as metals and pesticides and markers for authenticity testing, among others. General information, which includes relevant information on a variety of topics including Good Manufacturing Practices (GMP) Guidelines for Food Chemicals, a compareand-contrast table of food and drug GMPs, a table of citations where FCC has been incorporated by reference in the U.S. Code of Federal Regulations, AOAC International/ International Organization for Standardization (ISO)/ International Union of Pure and Applied Chemistry (IUPAC) method validation guidelines, and helpful introductions into a variety of different analytical test methods. FCC is available in two-year print and online subscriptions. A subscription includes the main edition in addition to three supplements that publish every six months. More information is available at http://www.usp.org/food-ingredients/foodchemicals-codex.

NIH Li d Duffy NIHs Linda D ff spoke on k probiotics and the microbiome.

Dr. Praveen Tyle, USP executive vice president and chief science officer, opened the workshop with the central question the organization is seeking to answer: what can USP create in terms of standards to ensure the identity, quality and purity of these unique ingredientsnot only through their manufacturing processes, but through packaging, shipping and all the way to when individuals consume the final product. As probiotics are live microorganisms, this is a far more difficult proposition than in the case of a simple food chemical. Will the ingredient that ends up in the final product be what we intended it to be? How do we know this? Beyond surviving harsh processing conditions, will it survive the harsh environment in the human body? We need to make sure that any health claims are scientifically backed so what we are stating on the label makes sense to average consumers, and that they are receiving the products they expect, he said. The premise of the workshop was that proper identification of the particular strain of probiotic that is incorporated into a food product is central to safety and any health claims of these ingredients. Given the large number of strains being researched and optimized for use in foods, manufacturers must verify that the strain they are using is the one studied in the safety/clinical trial upon which their health claims and safety determinations were based. This is challenging because of the level of specificity needed to differentiate strains. Tests for identification as well as enumeration (microbe dose) are areas where public standards can provide benefit, according to Dr. Markus Lipp, director of food standards for USP. Presenting on behalf of the U.S. National Institutes of Health (NIH), Dr. Cindy Davis examined the strength of current evidence related to probiotics and health. Dr. Davis provided the joint Food and Agricultural Organization of the United Nations (FAO)/World Health Organization (WHO) Working Groups definition of probiotics, which was developed in 2001: Live microorganisms which when administered in adequate

Probiotics Workshop Continued from page 8.

needed for efficacy in target populations, and guarantee that the amount at the end of shelf life is sufficient to support claims. However, contract laboratories and others may struggle to accurately enumerate a strain they have never seen before, and there is a need for published protocols. He said that whether you believe it or not, someone else is testing your product. They may not be doing so correctly, and there are consequences. These may include someone going to a regulatory body or to the media with incorrect information. He urged attendees to raise the bar to publish protocols to let everyone know that what we claim is in there is indeed present. Perspectives of regulatory agencies were presented from the United States, Europe and Canada. Dr. Dan Levy of the U.S. Food and Drug Administration (FDA) described relevant laws and pertinent guidances to probiotics, including the draft New Dietary Ingredient Notification guidance. He also noted regulatory questions and challenges facing FDA, such as what exactly constitutes a new ingredient or strain? Dr. Renata Leuschner of the European Food Safety Authority (EFSA) described her groups tool for microbial safety assessments: Qualified Presumption of Safety (QPS). This is a list initiated in 2003 and implemented for use by EFSA in 2007 on safe species of microbial food cultures. However, she noted that the list does not go down to the strain level and also does not consider dose. Dr. Dan Buijs of Health Canada provided information on his agencys safety assessments of probiotics, as well as its new draft guidance on the labeling of natural health products. Ms. Kristie Laurvick of USP offered an overview of USPs current activities, including a new FCC appendix proposed in the December 2011 FCC Forum titled Microbial Food Cultures Including Probiotics, which offers general information to assist manufacturers and others. She explained that USP plans more specific monographs at the strain level, and the first of these is expected to be proposed in December 2012. Ms. Laurvick noted that USP is seeking cooperation from the probiotic industry in developing more individual monographs and test methods. Other presentations offering more details about presumptive modes of action of probiotics, the effect of various processing conditions and best practices from cell banks rounded out the program. The workshop offered a forum for much debate, and attendees provided guidance to USP on how it could play a helpful role in this evolving area.

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USP Annual Science & Standards Symposium to Address Functional Ingredients in Foods, Dietary Supplements
As consumers increasingly seek foods, beverages and dietary supplements with perceived health, nutritional and other benefits, the so-called functional ingredients that make up these products are of high interest to manufacturers. While this area represents a dynamic and rapidly growing segment of the food, beverage and dietary supplement industries, many fundamental issues regarding these ingredients remain unresolved. Chief among these are how to describe and determine the identity and verify the authenticity of these ingredients, and to what degree function (i.e., health claims) is tied to identity. To interactively address this cutting-edge topic, and to help define the direction of future public standards from USP, the 2012 USP Science & Standards Symposium will address the theme: Functional Foods and Dietary SupplementsGlobal Opportunities and Challenges. The USP Symposium will be held September 1820, 2012, in Boston. As functional ingredients are often naturally derived, they can have complex and variable compositions, which make the development of public standards challenging. At the same time, these novel ingredients are often sourced through long and complex supply chains. Public standards with stringent specifications for the purity and identity of ingredients are instrumental to maintaining the integrity of the supply chain and to ensuring that ingredients have not been altered without the knowledge of the purchaser, (i.e., have not been adulterated for illicit economic gain). Furthermore, knowledge of the authenticity, identity and purity of ingredients is the foundation of the development of a defensible claim of any benefits. Only when it can be demonstrated that the ingredient offered to the consumer is identical to the one that was used to demonstrate any benefit can public trust in such an ingredient be built and maintained. The USP symposium will assess the current science and regulatory landscape governing functional foods and dietary supplements; explore the overlap of nutraceuticals and dietary supplements and the implication for standards-setting organizations; and ascertain the need for functional standards, and when function and identity become intertwined. The symposium will fall into two tracks: one dedicated to food ingredients and the other to dietary supplements, with overlapping sessions. The food ingredients track will include sessions on regulatory perspectives on functional foods, functional assays and identity, chemical and functional definitions, and emerging ingredients. The dietary supplements track will include sessions on structure/function claims, identity testing and evidencebased reviews of dietary ingredients. Keynote speakers include: Dr. Paul M. Coates, director of the Office of Dietary Supplements at the U.S. National Institutes of Health; Ms. Deborah A. Duchon, nutritional anthropologist; and Dr. Herv This, global expert on the chemistry of cooking (invited). Early-bird registration is available through August 17, 2012. More information is available at http://uspgo.to/boston-s3-2012.

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A different perspective Dr. Ilisa Bernstein, director of the Office of on traceability in the Compliance in FDAs Center for Drug Evaluation supply chain was offered and Research, provided the workshops keynote by Dr. Prashant Yadav, address. She noted that with 130,000 importers of senior research fellow and FDA-regulated products to the United States last director of the Health year, and drug imports increasing by 13 percent anCare Research Initiative, nually, the opportunity for mischief in the supply William Davidson chain has increased. The more hands touching these Institute, University products and ingredients, she said, the greater the of Michigan. Dr. Yadav challenge for regulators and others in ensuring safe, invoked the example of authentic medicines. While no one really knows just the lunch box supply how many counterfeit drugs are in the United States Hear more from workshop keynote Dr. Ilisa Bernstein chain. This is the story of or globally, Dr. Bernstein noted, we are seeing on supply chain integrity in a video interview at Mumbai dabbawallasa them, and they are continuing to rise. Referring to http://uspgo.to/JbCcUs. service in which more than the diversity of the counterfeit drug cases that the one million homemade lunches are collected from the homes of agency finds, she explained that one case may involve a single workers around the city and delivered to their workplaces every person concocting these products in his or her garage, while day, via a system utilizing color, alphabetic and alpha-numeric another may represent a multinational scheme driven by coding, with 99.9 percent service level and the low cost of $1 organized crime. per month. The example (essentially a low-tech track-and-trace Dr. Bernstein pointed to regulatory challenges including limited system, he noted) underscored the two elements Dr. Yadav resources, an incomplete set of enforcement tools, and a complex argues are essential for a standard: that it is simple and that system of federal, state and foreign oversight of product safety. incentives are dispersed for all people in the system. He urged She provided an overview of FDAs approach to addressing USP to consider simplicity, especially since this standard may supply chain issues, including a new Office of Drug Security, be used not only in the United States but in countries around Integrity and Recalls. She and subsequent speakers from FDA the world. Referring to incentives, he said the business case said their ideal scenario is a national, uniform track-and-trace for supply chain integrity and uniform numerical identifier system with a unique serial number (license plate) on each standards is stronger than just for compliance with regulations. drug package. Dr. Bernstein also offered plans on how FDA Other benefits include reducing lead times, excess inventory and intends to transform itself from a domestic into a global agency, temporary stock-outs, and improving service levels, in addition as laid out in its recent report, Pathway to Global Product to patient safety and product quality benefits. Safety and Quality. This is accessible at http://www.fda.gov/ Mr. Charles Forsaith, corporate director of supply chain AboutFDA/ CentersOffices/OfficeofGlobalRegulatory security at Purdue Pharma Technologies and chairman of the OperationsandPolicy/GlobalProductPathway/default.htm. Pharmaceutical Cargo Security Coalition, presented on preventOther regulatory perspectives and approaches to supply chain ing cargo thefts. Recounting the largest burglary in U.S. history, integrity were presented throughout the workshop, including in which close to $80 million in pharmaceutical products were from the European Union, the Medicines and Healthcare stolen from a warehouse in Enfield, Conn., in 2010, Mr. Forsaith Products Regulatory Agency of the United Kingdom and Health said that, as an industry, we were somewhat nave. Much Canada. Dr. Virginia Herold from the California State Board of has been learned since then, he stated. Because of the potential Pharmacy presented the current status of the states e-pedigree payoff, those who target the pharmaceutical industry are not requirements, which call for full implementation of a track-andamateur criminals; they have an organized business structure trace system by 2017 for all drug products sold in California. that includes an array of specialized talent, such as surveillance Mr. Taha Yayci from the Turkish Ministry of Health offered a teams, alarm specialists, drivers, logistics experts and commodcase study on implementing track-and-trace technology in the ity brokers. He went through various anti-theft technologies country, and Ms. Monica Eimunjeze of the Agency for Food and factors that raise risk of theft in warehouse and transit and Drug Administration & Control of Nigeria explained how environments. the country is beginning to use SMS-text via cell phones to A host of other critical topics, including tamper-evident packallow citizens to effectively verify that the medicine they have aging, radio frequency identification technology and its effects is indeed authentic and not counterfeit. on biologics, and GS1 Standards rounded out the program. The viewpoints of manufacturers (Pharmaceutical Research Closing the workshop, Dr. Foster, presided over a spirited and Manufacturers of America), wholesalers (Healthcare discussion focused on how the proposed informational general Distribution Management Association), pharmacies (National chapter should evolve. USPs Expert Committee will consider Association of Chain Drug Stores) and others were also feedback in determining the next iteration of the general presented throughout the two-day program. chapter.

Resource Assists in Ensuring Quality of Dietary Supplements

As raw materials used in dietary supplements are sourced from around the world and global manufacturing of finished products accelerates, a resource released by USP in April 2012 can help ensure the quality of these ingredients and products. Among its applications, the 2012 USP Dietary Supplements Compendium (DSC) can assist dietary supplement manufacturers in developing quality specifications, testing new products, qualifying raw materials and protecting their overall supply chains. In addition to analytical methods and specifications, DSC includes essential information such as the regulatory framework for dietary supplements, industry guidance documents and tables of dietary intake levels. Other practical features for manufacturers, ingredient suppliers, contract laboratories and regulatory agencies include checklists for Good Manufacturing Practices audits used by the USP Dietary Supplement Verification Program; Good Agricultural Practices from the American Herbal Products Association; and U.S. Federal Trade Commission and U.S. Food and Drug Administration guidelines on appropriate labeling for dietary supplements. Now offered in a two-volume set, DSC contains: More than 550 monographs for finished products, dietary ingredients and other components common to dietary supplement manufacturing, derived from USP 35NF 30 and Food Chemical Codex, Eighth Edition. The 2012 DSC includes 64 new dietary supplement monographs and 178 excipient monographs. New and revised admission safety reviews for 23 dietary supplement ingredients including Black Cohosh, Melatonin, Maca and more. These reviews are conducted for the sole purpose of determining admission into USP compendia, and should not be relied upon as a determination of the intrinsic safety or effectiveness of a dietary ingredient under review. More than 300 pages of full-color illustrations, including macroscopic and microscopic photographs, diagrams, chemical structures, and TLC/HPTLC/HPLC/ GC chromatograms that exemplify the performance of compendial tests. For more information, visit http://uspgo.to/dsc-2012.

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U.S., British Pharmacopoeias Collaborate on Proposed Standards

In an innovative and informal harmonization endeavor, USP and the British Pharmacopoeia Commission (BP) developed two drug product quality standards that have been aligned in advance of inclusion in their respective compendia. The two standards involved in the effort are for prescription eye drop medications: dorzolamide hydrochloride ophthalmic solution and dorzolamide hydrochloride-timolol maleate ophthalmic solution. The proposals were included in the MayJune Pharmacopeial Forum (PF) 38(3). The proposals build on existing international harmonization activities by extending efforts to finished drug products and by reconciling monographs in a prospective manner. Harmonization has long been cited as an opportunity to promote public health through the advancement of consistent quality standards, recognizing the modern drug supply is becoming increasingly globalized, said Dr. Praveen Tyle, executive vice president and chief science officer for USP. It also may assist regulators, standards-setting bodies and pharmaceutical companies in saving resources, which may be re-deployed for other initiatives. Under this effort, we sought to explore how we can further cooperate with other pharmacopoeias and potentially expand upon existing harmonization work. The informal nature of the activity, in which we simply traded information on monograph procedures, allowed us to work in a nimble way and may provide a model for future projects with BP and other groups. In addition to harmonized standards, this collaboration may provide a new path to addressing some mutual challenges facing BP, USP and other pharmacopoeias, namely sharing resources to expedite the introduction of new monographs, said Mr. Richard Turner, principal pharmacopoeial scientist for BP. Given the success of this pilot project, we look forward to exploring future opportunities to strengthen both pharmacopoeias. USP engages in formal trilateral harmonization activities under the Pharmacopoeial Discussion Group (PDG) with representatives for the Japanese Pharmacopoeia (JP) and the European Pharmacopoeia (EP), with the World Health Organization as an observer. This effort covers specific general chapters and excipient monographs that already exist in the three compendia. PDG is driven by a formal workplan. Separately, USP and EP are engaged in a pilot project in which the groups are prospectively harmonizing monographs for four active pharmaceutical ingredients (drug substances). However, EP encompasses only drug substances and not finished drug products. Both BP and USP encompass both drug substances and drug products, supporting the new, informal approach. The draft standards took one year to reach the current proposal statusa relatively short timeframe for a harmonization activity. The harmonization is with respect to the analytical procedures only, and was initiated and conducted in cooperation with the sponsor of the monographs. USP is seeking comment through July 31, 2012. The proposals can be viewed at www.usp.org/ usp-nf/pharmacopeial-forum.

USP Staff Travel to China to Solidify Relations

Emphasizing the increasing importance that Asia plays in the global health community, a delegation of USP staff traveled to China in March 2012 to meet with representatives from government agencies and manufacturers, and to attend the first meeting of the USP Medicines Expert CommitteeEast Asia. USPs activities in the region stem from the USP-China site in Shanghai, which opened in 2007, and CEO-driven work to build relations with regional ministerial bodies. The USP-China site recently reached its capacity, and in 2011, the USP Board of Trustees approved a $25 million investment to expand operations at a new location, which is expected open in 2013.

USP staff and Excipients Expert Committee Chair Lawrence Block (bottom center) with the USP Medicines Expert CommitteeEast Asia.

Resulting from USPs relationship with the Chinese Pharmacopoeia Commission (ChP) is the opportunity for laboratory work and collaborative testing for both the USP Medicines Compendium and a planned Herbal Compendium in association with Chinas provincial drug control institutes and USP-China site staff. To advance this collaboration, USP staff visited the Guangdong Provincial Institute for Drug Control, where state-of-the-art facilities for excipient standards are being developed. At the meeting of the USP Medicines Expert Committee East Asia, members were welcomed by Dr. Lawrence Block of the USP MonographsExcipients Expert Committee and USP CEO Dr. Roger L. Williams, and given an overview of what is

expected of the Expert Committee. The Expert Committee will first support work on excipient monographs for the USP Medicines Compendium with the intention that these monographs will assist with updating current monographs and adding new monographs to the Chinese Pharmacopoeias 10th edition, which is planned for 2015. Among the activities during the trip, USP staff received a tour of Guangzhou BaiYunShan Pharmaceutical Company, Ltd. (half government, half publicly owned company) to learn how Chinese manufacturers control the quality of excipients and the key attributes used in quality control. They also met with officials from the China National Center for Food Safety Risk Assessment to learn about their responsibilities for food safety risk assessment and surveillance, and also their safety alerts and emergency responses.

USP Hosts Indian Delegation under New Training Program

As part of a new international training program being offered by USP, three scientists from the Indian Pharmacopoeia Commission (IPC) spent a week at USPs headquarters, April 30May 4, 2012. The goal of the USP International Training Program is to promote the exchange of scientific expertise between global organizations committed to the quality of medicines and foods. Participants in this inaugural program were Dr. Raman Mohan Singh, principal scientist and head, Research & Development Division; Dr. Pawan K. Saini, scientist; and Mr. Anuj Prakash, senior scientific officer. biologics and biotechnology, general chapters, excipients, food ingredients and dietary supplements, publications and reference standard development; verification programs; and the USP Medicines Compendium. Participants toured USPs Biologics and Biotechnology, Spectrometry, Dosage Form Performance, Reference Standard Production and Separations Laboratories, as well as USPs warehouse and distribution area and packaging unit. The participants stated that the training clarified many questions they had about USP, and that it provided them with a vision of how they could improve current work under way at IPC.

Mutual Dedication to Quality Medicines in South Korea, U.S. Strengthened through MOU
Recognizing the critical importance that access to good-quality medicines has in South Korea, Asia and the United States, Dr. Hee-Sung Lee, commissioner of the South Korea Food and Drug Administration (KFDA), and Dr. Roger L. Williams, chief executive officer of USP, signed a Memorandum of Understanding (MOU) on behalf of their organizations in April 2012. The MOU will strengthen the burgeoning relationship between KFDA and USP. Prior to the MOU signing in December 2011, three scientists from KFDA worked at USP headquarters in order to gain firsthand knowledge of USPs organizational structure, quality management systems and reference standard development process. Additionally, on September 7, 2011, USP hosted five delegates from the National Institute of Food and Drug Safety Evaluation, a division of KFDA. The delegates sought to learn about USP operations and relationship with the U.S. Food and Drug Administration, and also to understand how USP develops standards for food ingredients. The global pharmaceutical community is inextricably connected, making arrangements like this important to both countries, the region and the world, said Dr. Williams. This agreement will allow for further collaborations that will benefit the people of both countries by advancing the mutual desire for universally trustworthy medicines. I believe that the MOU between KFDA and USP for cooperation in pharmaceutical standards and specifications will serve as an excellent opportunity to share our contributions in enhancing pharmaceutical quality and the important role we play to secure the safety and quality of medicines, said Dr. Lee. I hope to exchange our experience and establish mutual trust to further facilitate the pharmaceutical trade between the two countries. Potential areas of collaboration identified in the MOU include scientific meetings; collaborative studies on reference standards; and joint education and training programs.

IPC scientists with USP CEO Roger L. Williams.

The training program included multiple presentation sessions, various tours, two meetings with senior USP staff and a final presentation by the Indian delegation to USP employees. Specific topics included USP in the law; overviews of USPs work in the areas of small molecules,

Closing the week-long training, Dr. Roger L. Williams, USP chief executive officer, outlined a vision for the future collaboration between the two organizations, including joint reference materials, new meeting opportunities and other avenues.

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Ambassador of Kenya Visits USP

Recently, with input from citizens, the government of Kenya drafted a strategic plan titled Vision 2030, which provides an outline of future growth with the goal of making Kenya a middle-income country by the year 2030. Although no formal plans have been established, it is anticipated that USP can collaborate with Kenya to help combat counterfeit drugs and food adulteration. Through PQM, USP has a history of work with Kenya dating back to 2009. Since then, PQM has conducted an assessment of quality assurance capacities and established a drug His Excellency Odembo (center) and Counsellor Ole-Sein (second from left) with USP staff. quality monitoring program. Currently, there are five centers in Kenya employing a sustainable protocol for In a visit that was the first of its kind for the organization, USP monitoring the quality of antimalarials and there are plans to welcomed His Excellency Mr. Elkanah Odembo, the ambassador expand this to include other essential medicines. PQM has of the Republic of Kenya, to its headquarters in April 2012. trained 14 staff from the Pharmacy and Poisons Board of Kenya Joining the ambassador on his visit was Ms. Nairimas Ole-Sein, in Minilab basic tests, sampling strategies and reporting. PQM counsellor, diaspora, education and protocol at the embassy of also is working with the Kenyan National Quality Control the Republic of Kenya. While at USP, Ambassador Odembo Laboratory to assist them in obtaining ISO 17025 accreditation. learned more about the organization, the work it does through its Promoting the Quality of Medicines (PQM) program, which Independently, USP has established a Technical Assistance is funded by the U.S. Agency for International Development, Program (TAP), which provides documentary and reference and USPs new initiative, Global Health Impact Programs. standards to quality control laboratories in various countries, including Kenya. TAP has enabled local authorities to test drugs Kenya is home to more than 35 local pharmaceutical manufacto identify counterfeit and substandard medicines. Through turers. Kenya is also the regional hub for transportation and this program, two representatives from Kenya attended a communication and has a population of more than 40 million. regional training program in Ghana in 2011. Additionally, in Still, Kenya has fallen victim to a prevalence of substandard collaboration with the Management Sciences for Health/Health and counterfeit drugs. Ambassador Odembo stated that the Commodities and Services Management of Kenya, PQM plans problem of counterfeit drugs is likely much greater than is to test the quality of antimalarials at sites where adverse drug currently thought. Food adulteration is also a problem for reaction signals are monitored to assess the link between drug the country, and the government has begun to take action to quality and adverse drug reactions. address this issue.

USPs Visiting ScientistsWhere Are They Now?

International collaborations play an important part of USPs global initiatives. In recent years, USP has continued to expand its partnerships with other international bodies through agreements and coordinated projects. Central to many of these efforts has been the exchange of information and scientific knowledge regarding the development of quality standards. Through USPs Visiting Scientist Program, approximately 40 scientists from pharmacopeial, regulatory and related organizations around the world have been hosted by USP at its headquarters in Rockville, Md. Program participants have had an opportunity to work one-on-one with USP scientists and management to learn about the organizations standardssetting process. These opportunities have also enabled USP and visiting scientists to work together on projects that have helped to advance the organizations goals of further improving and harmonizing drug quality standards. In this new column, The Standard provides readers with a glimpse into the work accomplished by scientists through this program. The Standard has also reached out to former visiting scientists to find out how their experiences at USP have helped them in their professional growth and to ask, Where are they now? In the spring of 2010, Dr. Felipe Loureno of the University of So Paulos Laboratory for the Control of Medicines, Cosmetics, Household Cleaning Products, Similar Products and the Respective Raw Materials (CONFAR), Brazil, and Mr. Minghao Zhou of the Zhejiang Provincial Institute for Food and Drug Control, China, worked collaboratively for three months under the technical guidance of Dr. Michael Ambrose, director of USPs Biologics and Biotechnology Laboratory. After being trained on USPs standards-setting process, the two visiting scientists set out to work jointly on a project on the potency measurement of the antibiotic, neomycin. The classic method for testing for the potency of an antibiotic is a test that measures the ability of a drug to inhibit microbial growth and takes about three to four days to complete, according to Dr. Ambrose. Through the work done by Felipe and Minghao, we tried to determine if we could use a technique like high-performance liquid chromatography (HPLC)which is a faster methodto replace the traditional test. The output generated from an HPLC test is a set of peaks representing individual components of the material being tested. The scientists worked together to determine that results using the traditional method and the HPLC approach were comparable, and that peak height was a viable determinant for potency.

Mr. Zhou (top center) and Dr. Loureno (bottom center) pose with other USP visiting scientists in 2010.

Combining Mr. Zhous expertise in HPLC testing and Dr. Lourenos knowledge of classic Zone of Inhibition Assay, the two scientists were successful in demonstrating that the HPLC method could, in fact, serve as an alternative to the classic approach. Further work is still required to validate their findings. However, the combined effort between Mr. Zhou and Dr. Loureno was an important first step in identifying a potential alternative method for measuring antibiotic activity. Formerly the vice director of his institutions chemical drugs laboratory, Mr. Zhou is now the director of the health food and cosmetics laboratory. He has been able to apply some of the experiences he gained at USP to his current laboratory management responsibilities. In addition, Mr. Zhou now holds the title of Masters tutor of Zhejiang University of Technology in analytical chemistry. Since his time at USP, he has also been invited to serve as a volunteer expert reviewer for a U.S.-based peer-reviewed journal on analytical chemistry. Dr. Loureno is now a professor at the Pharmaceutical Sciences School of the University of So Paulo. One of the greatest benefits of my experience at USP was to have contact with the scientists from USP and other institutions, said Dr. Loureno. He is currently working on the development and validation of alternative methods related to antibiotics, in addition to teaching undergraduate students. Dr. Ambrose hopes to work with more visiting scientists in the future. Regardless of what cultural differences we may have, he says, we all speak the same language in terms of science.

Worlds Pharmacopoeias Come Together to Discuss Global Harmonization

The history of convening pharmacopoeias and pharmacopoeial harmonization is a rich one. Representatives of pharmacopoeias of the world began meeting in the late 1860s with the desire to create uniform standards through development of an international pharmacopoeia. During the late 19th and early 20th centuries, several attempts were made to create such a publication. The dream was finally realized following the end of World War II, under the aegis of the newly established World Health Organization (WHO), with the first edition of The International Pharmacopoeia published in 1951. The desire for harmonized pharmacopoeias continues today. From February 29 to March 2, 2012, in Geneva,
Continued on page 18. See WHO Meeting

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USP Joins the Clinton Global Initiative

As it expands its work in the area of global public health with a focus on substandard, falsified and counterfeit medicines, USP was invited to create a Commitment to Action as a member of the Clinton Global Initiative (CGI) in March 2012. Established in 2005 by President Bill Clinton, CGI convenes global leaders to create and implement innovative solutions to the worlds most pressing challenges. Among the critical and complex problems facing the international community and developing countries in particular is the proliferation of poor-quality medicines. Such medicines can have devastating consequences. These may include exacerbating the course of a patients disease and even leading to death; contributing to the growth of drug-resistant disease parasites, undermining the efficacy of these medicines for all patients; and hampering the economic growth of nations, whose foundation rests on a population of healthy citizens. USP envisions a world in which all people have access to high quality, safe and beneficial medicines, said Mr. Brian Hendrix, executive vice president and chief operating officer of USP. This should not be a privilege limited to those who live in developed countries, but a fundamental right that we all enjoy. USP is in a unique position to leverage our nearly two centuries of work in improving the quality of medicines to help achieve such a reality. Joining the CGI community is a critical step in furthering our efforts, particularly as we seek partners to help us maximize the benefit our experience can provide to underserved nations and populations. Each CGI member creates a Commitment to Actiona concrete plan to address a major global challenge. Examples of these commitments, which can be found at www.clintonglobalinitiative. org, include Fighting HIV through the Workforce, Helping Haiti Build Back and Empowering Girls and Women. Through its Global Health Impact Programs (GHIP), USP strives to transform the global health landscape by addressing the systemic problems that hamper access to good-quality medicines for patients in need. USP has engaged in such work for decades through its flagship initiativethe Promoting the Quality of Medicines (PQM) programand its predecessor programs, funded by the U.S. Agency for International Development.

PQM Introduces Medicines Quality Monitoring Program to Burma

After careful preparation and due regard for emerging diplomatic and legal considerations, the Promoting the Quality of Medicines (PQM) program held its first training workshops in the recently opened country of Burma in May 2012. Supported by the Presidents Malaria Initiative through U.S. Agency for International Development (USAID) Regional Development MissionAsia, PQM representatives taught trainees the processes and techniques of compendial analysis and how to establish a medicines quality monitoring program as well as how to conduct a medicines quality survey. These efforts are designed to help strengthen the capacity of the Ministry of Health in its efforts to contain the dangerous increase of Artemisinin-resistant malaria in the country. The World Health Organization (WHO) recommends the use of Artemisinin Combination Therapy for the treatment of uncomplicated malaria in malaria-endemic countries. PQM and its collaboratorsWHO, Burma Food and Drug Administration, Department of Medical ResearchLower Burma (DMR) and Vector Borne Disease Control conducted a workshop for 25 trainees on establishing a medicines quality monitoring (MQM) program and testing antimalarial medicines using the Global Pharma Health Fund (GPHF) Minilab. The six sites where monitoring will occur lie primarily along the border areas where the resistant malaria is most prevalent. Dr. Richard Jhnke, GPHF project manager and developer of the Minilab, was also among the instructors along with PQM experts providing the hands-on training in its use. PQM staff also trained 11 analysts from the Nay Pyi Taw Quality Control Laboratory, Mandalay Quality Control Laboratory, and the DMR in compendial analysis of antimalarials, using the USP reference standards PQM provided, as the analysts will be performing MQM confirmatory testing.

PQM South Korea Workshop Seeks to Make Affordable, Good-quality Tuberculosis Medicine a Reality
In an effort to increase the availability of affordable, quality protected second-line anti-tuberculosis medicines, the U.S. Agency for International Development (USAID) and its Promoting the Quality of Medicines (PQM) program (implemented by USP) partnered with the World Health Organization (WHO) and the Global Drug Facility to host a workshop in Seoul, South Korea. The workshop was designed to help South Korean manufacturers improve their adherence to Good Manufacturing Practices (GMPs) and educate them about how PQM can assist with obtaining WHOs prequalification for tuberculosis medicines. The workshop took place February 2829, 2012, and was attended by 47 manufacturers. Tuberculosis (TB) kills approximately 1.7 million people around the world every year, claiming most of its victims from developing countries. Tuberculosis is an airborne disease that primarily attacks the lungs and in recent years has mutated into forms that are multidrug-resistant (MDR-TB) or extensively drug-resistant (XDR-TB). While these forms of tuberculosis can be treated, they require more expensive and less available second-line medicines. Second-line medicines are reserved for use in the treatment and management of strains of MDR-TB that are resistant to the tuberculosis medicines isoniazid and rifampicin. Currently, there are not enough WHO-prequalified second-line tuberculosis medicine manufacturers nor a sufficient supply of quality products to treat patients with MDR-TB. To help ensure good-quality products, only medicines prequalified by WHO, or approved by stringent regulatory agencies, are suitable for procurement. During the workshop, PQM staff provided information about how the program can help South Korean manufacturers by providing technical assistance, at no cost, in preparing medicines dossiers, evaluating manufacturing practices, providing gap analysis and guiding them through the facility inspection process. Although tuberculosis most often afflicts patients in developing countries, it is the responsibility of the global health community to ensure that no one is forced to go without the treatment they need, said Dr. Patrick Lukulay, vice president of global health impact programs and director of the PQM program at USP. It is our hope that this workshop provided manufacturers in South Korea with the resources and information needed to adhere to standards of Good Manufacturing Practices and thus help them access global markets. Manufacturers who opt to work with PQM are not guaranteed WHO prequalification status for any medicine; they are, however, given the opportunity to initially present a stronger, higher-quality dossier. To date, PQM is working with 25 manufacturers in 12 countries around the world to obtain WHO prequalification for their medicines.

These efforts are designed to help contain the dangerous increase of Artemisinin-resistant malaria in the country.

To gain a broad idea of the quality of medicines in target areas of the country, PQM and WHO also will conduct a baseline survey of selected medicines in some states. All the trainees, plus some others, learned about sampling and testing protocols, data recording and management, and reporting of a baseline data survey for antimalarials and certain antibiotics. The partners involved developed an action plan and discussed the importance of correct and effective sampling procedures.

These initial training workshops brought the key partners together for the first time to exchange ideas and learn techniques to address the quality of antimalarials and contribute to the countrys goal of malaria resistance containment. With continued collaboration between the U.S. and Burma governments, PQM expects to continue its crucial work in ensuring the quality, safety and efficacy of medicines to benefit the public health.

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Inside USP

Inaugural Listening Tour Dinner Held in New Orleans

As a way of further strengthening the relationship between USP and its Convention members, the USP Council of the Convention (CoC) hosted its first Listening Tour event in New Orleans on March 10, 2012. Over dinner, more than 40 delegates and executive officers from member organizations offered responses and discussed three questions posed by the CoC: What do you see as USPs greatest strength or capability? What are the primary issues facing your organization that USP might be able to help resolve, given its mission and capability? What challenges do you see on the healthcare horizon that USP could help to address? Of the event, USP CEO Dr. Roger L. Williams said: I was pleased to be present to hear first hand from our members about what they expect and need from USP. The input will help to guide resolution development, for which the CoC has responsibility. The feedback was candid and invaluable, and I look forward to hearing from other delegates throughout the year. Feedback from the event has been posted on the Member webpage at www.usp.org/members-overview/2012-usplistening-tour. The following is a sample of what USP heard from Convention members: USPs international reputation and recognition are great strengths, adding to USPs credibility. USP speaks with authority and influence and can improve the opportunity for good medicine use. USP is the only organization that brings together pharmacy and medicine, combining the science and practice of two disciplines. On drug shortages: The problem is complex; however, using its strength as a neutral convener, USP could gather stakeholders and work toward finding solutions to this critical and likely ongoing challenge in healthcare. USPs guidance would be beneficial to assure continued quality of medicines. USP can continue to provide leadership with regard to compounding for pediatric and geriatric patients as a means of mitigating the shortage problem. On personalized medicines: Biologics and diagnostics will work together to create miracles in personalized medicine; however, pharmacy will need guidance about what are good diagnostics and biologics. USP could focus on diagnostics that provide true measurement to improve confidence that the right medicine is being developed for each patient. Dates for other Listening Tour events are: June 14 in Chicago, July 15 in Kissimmee and September 18 in Boston. Delegates and executive officers of Convention member organizations are encouraged to take advantage of this opportunity to let their voices be heard. For additional information, please email membership@usp.org.

Convention News Continued from page 3.

Council of the Convention Expands USP Convention Members (June 2012)

The Council of the Convention (CoC) is one of only four committees of the USP Convention. The CoC has responsibility for identifying and vetting organizations for potential membership as well as recommending the removal of member organizations for cause. The CoC also has sole responsibility for inviting observers to the Convention, which is often a status that leads to full membership. Further, the CoC has been charged with developing new approaches to engage members between five-year meetings, and developing resolutions for consideration and adoption at the 2015 Membership Meeting. Recently, USP Convention President and CoC Chair Dr. Timothy Franson expanded this body by appointing six additional organizations. With the members noted below, the CoC now comprises 21 of its 25-member total. For the first time, the CoC has members from outside the United States and from a new constituency of members: non-governmental standards-setting and conformity assessment bodies. American Society for Nutrition John E. Courtney, Ph.D., executive director

WHO Meeting Continued from page 14.

Switzerland, WHO gathered representatives from 23 pharmacopoeias to discuss global harmonization and strengthening WHOs role when developing global standards for the production and testing of medicines. Over the course of the meeting, a number of challenges were discussed, including infrastructure and resources, harmonization efforts, adulteration, and the role and future of pharmacopoeias. In terms of infrastructure and resources, most pharmacopoeias, even well-resourced ones, face challenges to fulfill the increasing workload related to their mandates. One way to cope with this widespread burden could be effective harmonization. Overall, it was agreed that prospective actions for harmonization would be easier than retrospective ones. Experience from various pharmacopoeial harmonization efforts were shared, including those carried out under the Pharmacopoeial Discussion Group (PDG), in which USP participates, and the Mercado Comn del Sur (MERCOSUR). New platforms for the pharmacopoeial harmonization process should be identified and open to all pharmacopoeias wishing to participate. To help combat adulteration, it was agreed that the creation of a common general chapter to act as a toolbox with rapid screening methods using various modern technologies could be implemented to complement pharmacopoeial tests. While new ideas and strategies for the future were reviewed, the main emerging suggestion was for the development of Good Pharmacopoeial Practices to favor prospective harmonization. An initial drafting group was formed during the meeting and is composed of representatives from Argentina, Brazil, Europe, India, Japan, Mexico, Russian Federation, Ukraine and the United States (USP), with editorial assistance being provided by the United Kingdom. However, the process of drafting the guidance will be open to all pharmacopoeias. To ensure progress continues to be made, it was proposed that meetings of the worlds pharmacopoeias be held on a regular basis. Opportunities for further collaboration this year through this WHO effort include the International Pharmaceutical Federation Centennial Congress in Amsterdam and the International Conference of Drug Regulatory Authorities conference in Tallinn, Estonia, both in October.

Association of American Veterinary Medical Colleges Ronette Gehring, BVSc, M.Med.Vet. (Pharm), MRCVS, DACVCP, associate professor of clinical pharmacology, College of Veterinary Medicine at Kansas State University Clinical and Laboratory Standards Institute Glen Fine, CAE, executive vice president Health Canada Natural Health Products Directorate Scott Sawler, L.L.M., M.B.A., director general Jordan Association of Manufacturers of Pharmaceuticals and Medical Appliances Hanan J. Sboul, M.B.A., CAE, secretary general Pharmacy Council Accreditation Board Joe Cabaleiro, R.Ph., executive director

representation within the membership and then established a framework for an expansion that would address those gaps. USPs activities and relationships within various regions were part of the CoCs assessment and the resulting new member recommendations are beginning to move the Convention to a truly international body. When the CoC started in late 2010, less than five percent of Convention members were located outside the United States. Today, that number has increased to 12 percent. Under the guidance of President Franson, the CoC is also expanding the number of observers to the Convention. Earlier this year, the CoC applied a new bylaws provision and recommended that the Board of Trustees remove 61 organizations from the Convention for cause. (These organizations had failed to name a delegate for over a year 28 U.S. medical schools, 24 state medical societies, two state pharmacy associations, one manufacturing organization and three health practitioner organizations.) The Board acted on that recommendation. The removal of inactive members frees slots for new organizations that wish to engage with USP. Of the current 446 Voting Organizational Members, 95 percent have a delegate!

20102015 Resolutions Status Report

The updated status of the resolutions adopted at the 2010 Membership Meeting is available on the resolutions web page at www.usp.org/about-usp/our-vision/2010-2015resolutions.

Globalization of Membership
The CoC has been strategic in its approach to globalizing the USP Convention membership. It analyzed gaps in

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Student Pharmacists Compete in National Compounding Event

Demonstrating the talent and ingenuity of the pharmacists of tomorrow, students from 14 schools of pharmacy from around the United States came together to compete in the Student Pharmacist Compounding Competition (SPCC). The annual SPCC is organized and sponsored by the MEDISCA Group of Companies in collaboration with the University of Florida College of Pharmacy. The competition took place March 1718, 2012, in Gainesville, Fla. USP participated in the event with staff giving Compounding pharmacists of tomorrow participate in the SPCC. keynote presentations and judging parts of the competition. The team from University of Oklahoma College of Pharmacy at Tulsa was awarded first place. The competition took place in three phases: a compounding classic, a regulatory challenge and a poster session. Each school sent three students and one faculty member to compete. For the compounding classic, teams were given a set of chemicals to make three preparations, with each chemical required to be used in most preparations only once. Participants were able to bring in any material of their choice to assist them, including USPNF, which contains compoundingrelated general chapters such as <795> Pharmaceutical CompoundingNonsterile Preparations, <797> Pharmaceutical CompoundingSterile Preparations and <1160> Pharmaceutical Calculations in Prescription Compounding. The teams were judged based on their performance, written documentation and final preparations. They also participated in a regulatory challenge in which they were given a series of controversial issues based on regulatory standards of practice. Each team drafted a written response detailing a reasonable approach to dealing with the issue. The poster session was a visual representation of the students response to the regulatory challenge, affording them the opportunity to also defend their position publicly. The students participating in the competition were some of the best and brightest in the country. Given the high-pressure environment they were competing in, the preparations and responses they achieved were more like those of a practicing pharmacist, rather than of a student, said Dr. Rick Schnatz, senior scientific liaison at USP and keynote speaker at SPCC. Based on what I saw this weekend, I am confident that these students will become successful compounding pharmacists, making valuable contributions to public health. Keynote presentations spoke to a number of relevant compounding topics such as the importance of compounding in todays healthcare environment, how to start a compounding pharmacy, improving the perception of compounding and the role of USP standards in safe preparations of medicines. Presenters came from numerous organizations related to compounding including: Family Care Pharmacy, International Academy of Compounding Pharmacists (IACP), International Journal of Pharmaceutical Compounding (IJPC), Pharmacy Compounding Accreditation Board (PCAB) and USP. Schools of pharmacy participating in the contest were Albany College of Pharmacy, Albany College of Pharmacy at Vermont, Mercer University, St. Louis College of Pharmacy, Texas Tech, University of Appalachia College of Pharmacy, University of Connecticut, University of Findlay, University of Florida College of Pharmacy, University of Missouri at Kansas, University of New Mexico, University of New York at Buffalo, University of Oklahoma College of Pharmacy at Oklahoma and Oklahoma College of Pharmacy at Tulsa.

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