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Report from Washington D.C. Metro Area No.5 December 2010

Nobuo UEMURA        12/27/2010


 In mid-February I moved to the United States Pharmacopeia (USP) secretariat office as a visiting scientist of USP General Chapter team from Japan and a liaison official of MHLW/PMDA ("Ministry of Health, Labour and Welfare" and "Pharmaceuticals and Medical Devices Agency").

 This is the fifth report on the USP and FDA issues. However this report is my personal views and opinions, and it does not necessarily represent the formal position of MHLW, PMDA, FDA and USP.


1. USP's Rockville Facility

 USP headquarters are located in the Rockville city after moving from New York City in 1968.
 In 2008 USP celebrated the new USP Headquarters building. The new 156,000 square feet headquarter building, which was built around an existing 69,000 square feet building on the corner of Fisher Lane and Twinbrook Parkway, has analytical and bio-analytical testing and research laboratory space and conference center. (It is near to the "Twinbrook" metro station and the former FDA Headquarter Parklawn Building.)
 The laboratory space is equipped with both existing and cutting-edge technology that supports the scientific work of developing and comparing the new standards.
 The conference center has an auditorium and several meeting rooms. A large world map etched on the round shape glass exterior of the auditorium represents USP's global presence in the world and its dedication to such international cooperation.
 The new headquarter building of a nearly 200-year old organization (founded in 1820) was developed under the 21st century concept of technology, environmental friendliness and design.
 These buildings include a green-roof, energy efficient lighting and HVAC (heating, ventilation and air-conditioning).
 The special attention to the landscaping and streetscaping was paid so that USP would present a pleasant appealing appearance for visitors and residents of the surrounding area.
 USP has been awarded the 2010 Preservation Award for New Construction and Design by the community-based organization in Rockville city.

2. Contents of USP-NF

 The United States Pharmacopeia-National Formulary (USP-NF) is a combined book of two official compendia. Monographs for drug substances and preparations are featured in the USP. Monographs for dietary supplements and ingredients appear in a separate section of the USP. Excipient monographs are in the NF.

Contents of USP 33-NF 28 publication


-Mission Statement and Preface


-Articles of Incorporation

-USP Governance



-General Chapters

-Reagents, Indicators, and Solutions

-Reference Tables

-Dietary Supplements








3. Process of Monograph setting

 USP creates and continuously revises USP-NF standards, and publishes a book of public standards (Compendium) every year.
 USP revises Monograph through the following public-private collaborative process.

  1. Submission is received, and development is initiated.
  2. Scientific Liaison performs technical review, and drafts the monograph.
  3. Proposal is submitted to Expert Committee, and published in Pharmacopeia Forum (PF) for 90-day public review and comment period.
  4. Scientific Liaison reviews and submits comments to Expert Committee.
  5. Expert Committee discusses and ballots
  6. When Expert Committee approves, the monograph is published in Compendium.

 The Monograph Expert Committees approve not only the definitions, packaging, storage and labeling requirements, specifications, but also the dissolution tests and microbiological tests (e.g. sterility, microbial limits, bacterial endotoxins). The Committees also approve the uses of USP Reference Standards in monographs. A separate Nomenclature Expert Committee approves the title of the monograph (the official name of the ingredients or preparations).
  USP recently started a prospective pilot study with EDQM, and co-developed several drug substance monographs and their associated Reference Standards aiming toward harmonization with EP.


 USP's Pharmacopeial Forum (PF) becomes a free online-only publication on January 3, 2011.

4. USP's relationship with FDA (Part 2)

 USP has a history of shared initiatives with FDA. Followings are some examples.

1)Vitamin Advisory Board and Reference Standards Program

 In 1924, USP developed standards for vitamin A and D content in cod liver oil, leading to the inclusion of a bioassay reference standard for vitamin A in USP X. In order to facilitate the adoption of this biological assay, the Bureau of Chemistry, original of the present FDA, worked with USP to supply reference standards meeting USP requirements. In 1930, the Bureau discontinued this service and transferred full responsibility for the reference standards program to USP. In 1932, the Board of Trustees of USP announced the establishment of the Vitamin Advisory Board to provide expert advice on the development of vitamin standards. Afterwards, USP formed Advisory Boards for sterile products, hormone products, and anti-anemia preparations pursuant to FDA's request.

2)Creation of Insulin Advisory Committee

 To respond to the emergency need for insulin standards before the University of Toronto's patent expiration (Christmas Eve 1941), USP formed an Insulin Advisory Committee chaired by FDA's Herbert O. Calvery. This committee announced the development of a USP Reference Standard for insulin on December 1, 1941. USP and the American Medical Association appealed to Congress to give FDA authority over insulin certification, and the FDCA had been amended to require FDA certification of each batch of insulin prior to distribution, and an official insulin standard was issued in USP's Interim Revision Announcement.

3)Penicillin Standard and Antibiotic Certification

 USP, FDA NIH and the War Production Board held a series of conferences in 1943 and 1944 to develop penicillin standards. By March 1944, the Subcommittee on Scope approved penicillin standard for admission to the USP, and in 1945 the FDCA was amended to require FDA certification of penicillin. Subsequent amendments extended this certification to encompass all antibiotics. Antibiotics had to pass FDA's batch certification program, to be approved batch by batch, and to adhere to drug monographs published by FDA. This process was costly and time consuming for FDA and manufacturers.
 By 1978, USP had taken over responsibility for creating antibiotic reference standards, previously prepared by FDA. In 1982, FDA eliminated its batch certification program in favor of relying on compendia specifications and FDA GMP Regulations and Policies. In 1997, FDA Modernization Act merged the regulatory scheme for antibiotics into the other drugs'.

4)Drug nomenclature

 In 1961, the American Medical Association-United States Pharmacopeia Nomenclature Committee was formed, and it evolved into the United States Adopted Names (USAN) Council in 1964 through the sponsorship of the USP, AMA and APhA. In 1967, FDA joined the USAN Council as a means of consolidating the work of selecting suitable nonproprietary names for drugs on behalf of the federal government with the work of the council.
 The USP Nomenclature Expert Committee was established in 1985 to work closely with the USAN Council to determine the title of monograph. The present Nomenclature, Safety and Labeling Expert Committee is expected to address mutual topics of interest to both USP and FDA.

5)Drug Product Problems Reporting Program (DPPR) and Medication Errors

 FDA initiated a program in 1970 to help identify drug defects in the marketplace. The program expanded the following year to include USP and the American Society of Hospital Pharmacists (ASHP). In 1972, FDA contracted for USP's enhanced involvement with DPPR, and USP processed reports of drug defects, adverse reactions, and other drug problems. USP established the Medication Errors Reporting (MER) Program in 1991. Since FDA created the MedWatch program in 1993, USP cancelled the DPPR and concentrated its efforts and resources on medication error reporting and prevention. However, in 2008, USP transferred these reporting programs to other organizations.

6)Strengthening of Compendial Standards

 The 1974 Congressional Office of Technology Assessment (OTA) report on drug bioequivalence called for the creation of one compendia organization. FDA responded to this report and the Bureau of Drugs formed the Compendial Liaison Staff Office as one vehicle for this effort. The liaison staff served as the chief communication conduit between the FDA bureaus and USP. In addition, in 1979, FDA formed the Compendial Operations Policy Committee to help improve compendia tests, and the Compendial Monograph Evaluation Development Program to evaluate existing USP monographs, and assist in the development of new monographs.

7)Ferrules and Cap Over-seals

 Deaths involving the misadministration of Potassium Chloride injection prompted USP in 1991 to revise monograph labeling specifications for the drug, requiring a black cap and over-seal with a cautionary statement: "Must Be Diluted." The new standard was published, and a joint "FDA-USP Advisory Panel on Simplification and Improvement of Injection Labeling" was formed to reduce medical errors by simplifying labels.

8)Cooperative Research and Development Agreement (CRADA)

 Between 1985 and 2000, FDA collaborated with USP to evaluate some 1,500 reference standard candidates. In 2000, USP and FDA formalized this joint effort with a Cooperative Research and Development Agreement (CRADA), aiming for ensuring high quality reference standards be available in the U.S.
 In 2006, USP and FDA developed another CRADA, titled Substance Registration System. This is a project between FDA's Office of Critical Path Programs and USP to support health information technology initiatives by providing a Unique Ingredient identifier (UNII), a unique non-proprietary identifier for substances in drugs, biologics, botanicals, food, and devices based on molecular structure and/or identifying descriptive information. The UNII has been incorporated into FDA's Product Labeling information, and the USP Dictionary.

9)Dissolution and bioequivalence

 While the importance of the consistent dissolution of solid dosage form medicines is recognized, in 1970, USP published an official dissolution test in 12 monographs. During the 1970s, scientists found great variation between dissolution results from one apparatus to another, leading USP and FDA to work on standardization of dissolution testing. In 1975, USP began developing calibrators for dissolution testing, and the FDA developed detailed bioequivalence and bioavailability regulations that were finalized in 1977, followed by its guidance: Guidelines for Dissolution Testing.
 In 1999, the dissolution and disintegration tests were made a priority for harmonization by the International Conference on harmonization (ICH). The harmonized USP General Chapters <701> Disintegration and <711> Dissolution became official in 2006. The next year, a new FDA Draft Guidance for Industry was published, which replaced the use of "calibration tablets" with "mechanical calibration", when calibrating apparatuses used to comply with GMP requirements for dissolution testing. The FDA's final guidance recommends that an enhanced mechanical calibration procedure may be used as an alternative to the current Apparatus Suitability procedure for Dissolution apparatus 1 and 2 described in USP General Chapter <711> Dissolution, for GMP purposes.

10)International harmonization PDG-ICH

 The Pharmacopoeial Discussion Group (PDG) formed in 1989 to work on phamacopeial harmonization topics, with representatives from the European Pharmacopoeia (EP by EDQM), Japanese Pharmacopoeia (JP by MHLW/PMDA), and USP.
 This was followed by the formation of the International Conference on harmonization (ICH), which includes members from European, Japanese, and U.S. regulatory bodies and pharmaceutical industry organizations. In 2003, ICH created Q4B; Evaluation and Recommendation of Pharmacopoeial Texts for Use in the ICH Regions, which comprises regulatory and pharmaceutical organization representatives from the three regions and focuses on regulatory interchangeability of harmonized standards. While not a part of ICH, PDG meets in conjunction with ICH and provides the ICH Steering Committee with progress reports. To synchronize the United States' position in this effort, USP and FDA began closely coordinating on their Q4B PDG/ICH activities.

11)Glycerin Monograph

 Beginning in 2006, several worldwide health incidences occurred due to products containing glycerin intentionally contaminated (so-called economic adulteration) with DEG (Diethylene Glycol), resulting in hundreds of deaths. In response, USP received a letter from FDA in April 2007, requesting revision of the glycerin monograph to incorporate a DEG limit test. The FDA then published "Guidance for Industry: Testing of Glycerin for Diethylene Glycol", which referenced USP's new glycerin monograph identification test. The new glycerin standard became official May 1, 2009.

12)Heparin Contamination

 In February 2008, reports of hundreds of adverse reactions and nearly 150 deaths were reported among patients given heparin, a commonly used blood-thinner. In response, some lots of heparin products were recalled and FDA issued a Public Health Advisory and other update information to the public.
 FDA contacted USP to validate and optimize detection methods for contaminants, and to update the monograph and Reference Standards for heparin. USP completed the stage 1 and 2 revision updating the heparin monograph through collaboration with FDA. Stage 3 revisions are currently under way.

5. Extension of Continuing Resolution, FY 2011 Year Long Funding Act, and FY 2011 Consolidated Appropriations Act

 After the result of 2010 Midterm election, the Congress started the budget process, and passed 2nd Continuing Resolution by December 2, which extended the 1st Continuing Resolution through December 3 up to December 18, 2010. (The resolution was approved through voting by House and Senate on the report of the Conference Committee of both Houses)
 On December 8 the House passed (212-206) the FY 2011 Year Long Funding Act, which will freeze discretionary appropriations at the FY 2010 level.
 This funding law would provide increase of several program budgets and adjust other funding at the same time, totally providing $45.9 billion less than the President requested. It would provide extra funding for Medicare, correction to the food safety modernization bill recently passed by the Senate on November 30 and by the House on December 21, additional resources for FDA to increase safety inspections of food, drug and medical devices, etc. On the other hand it would adjust funding for the request of Department of Defense and other agencies, including the high-speed rail funding.
 On the other hand, on December 14, the Senate released details of the FY 2011 Consolidated Appropriations Act, a substitute amendment to the House passed Continuing Resolution. The legislation was $29billion below the President request.
 The Consolidated Appropriations Bill for FY 2011 Agriculture, FDA, and Rural Development Appropriations would reduce about a billion dollars of total discretionary appropriations to the FY 2010 enacted level, but the FDA was funded $2.541 billion, $37million above the President's request and $195 million above fiscal year 2010 enacted level.
 However, these omnibus bills were withdrawn, and the Senate made the 4th Continuing Resolution that would allow continued government operations through March 4, 2011, while amending the funding Act which the House approved on December 8.
 The Continuing Resolution has been approved by the Senate and the House on December 21, 2010.

6. Regulatory science at FDA

 FDA is acting on a vision for collaborative "regulatory sciences" to promote and protect public health and safety.
 FDA define their regulatory science as the science of developing new tools, standards and approaches to assess the safety, efficacy, quality and performance of FDA-regulated products.
 The field and the outcome of regulatory science include both the tools themselves and the knowledge generated in developing new tools.
 Regulatory sciences develop, assess and provide tools, methods, models, standards, guidance, and pathways for evaluation.
 Regulatory sciences help bridge the gap between basic science (proof of principle) and actual products for patients and public health.

 FDA is currently (FY2011) focusing priorities of regulatory science on the following 7 agendas ;

1)Accelerating Delivery of New Medical Treatments to Patients

2)Improving Pediatric and Child Health

3)Protecting Against emerging Infectious Diseases and Terrorism

4)Enhancing Safety and Health Through Informatics

5)Protecting the Food Supply

6)Modernizing Safety Testing

7)Meeting the Challenges for Regulating Tobacco

 Examples of scientific emphasis areas;

-Personalized medicine, diagnostics, biomarkers, imaging, innovative clinical trial designs, combination and/or multiple interventions

-Products for global diseases, emerging threats, pandemics and national security

-Platform technologies for vaccines, drugs and diagnostics for rapid mobilization for new threats and for dual uses.

-Regenerative medicine as new treatments for diabetes, cardiac and neurodegenerative diseases.

-Modernizing toxicology, product characterization, and rapid accurate detection of pathogen and contaminant, environmental or chemical hazard assessment.

-Monitoring of safety using health care and public health data.

-Leadership to strengthen and support science and to promote innovation, by cross-center working groups, coordination, scientific guidance, shared resources and infrastructure, scientific computing.

-Scientific excellence and professional development, through scientific exchanges, agreements and access to universities, NIH etc.

 Major ways in implementation are;

-Recruitment of outstanding scientists by fellowship programs

-Program specific activities and Chief Scientist's challenge grants

-FDA/NIH research partnerships

-Collaboration and partnerships such as Centers of Excellence in Regulatory Science(CERS), joint appointments with academia, partnerships with NIH, CDC, NIST, NTP etc

-Transparent input of internal and external advisors and public.

 FDA has outlined a four-part strategic framework and activities to advance regulatory science.

1)Leadership, coordination, strategic planning, and transparency to support science and innovation

-The Science and Innovation Strategic Advisory Council within the agency

-The FDA Science Board

2)Support for mission-critical applied research, both at FDA and collaboratively

-Joint Leadership Council created by FDA and NIH

-Academic Centers of Excellence in Regulatory Science

-Strategic collaboration and coordination with other governmental agencies

-Support and focus for the Critical Path Initiative

-Reagan-Udall Foundation

3)Scientific excellence, professional development, and a learning organization

-Access to cutting-edge, continuing education and professional development for FDA staff

-Scientific exchange programs with academic and governmental institutions and with international regulatory counterparts

4)Recruitment and retention of outstanding scientists

-Recruit and support promising newly independent scientists expert in emerging technologies to be research-reviewers

-Merit awards for accomplished and productive FDA scientists

-FDA Expert Physician program to support joint part-time, academic faculty / FDA positions

 The examples of activities either FDA has done or can do are as follows;

1)Accelerating the Delivery of New Medical Treatments to Patients

-Method for stem cell characterization (tests and standards for different types of stem cells)

-Personalized treatment for cancer (I-SPY2 TRIAL)

-Safer pain medications (less potential for abuse and misuse)

-Vaccines, drugs and diagnostics for tuberculosis (drug resistant tuberculosis)

-Greater availability of generic drugs (developing validated methods for determining bioequivalence for inhalers, topical products etc.)

-Modernized manufacturing and product quality ("Quality by Design (QbD)")

2)Improving Pediatric and Child Health

-Addressing adolescent suicide resulting from antidepressant use

-Ensuring the safety of sedatives and anesthetics on children and infants

-Rapid and practical methods for detecting microbial pathogens in food

-Preventing tobacco use in children and youth

-Combating obesity

-Reducing the risk of toxins in the foods

3)Protecting against Emerging Infectious Diseases and Terrorism

-Prevented contamination of the blood supply (West Nile Virus)

-Developing and validating improved predictive models and new biomarkers

-Platform technologies to product development and manufacturing (DNA vaccine, recombinant protein expression system etc.)

-Rapid, sensitive, high through-put sterility assay

-Methods to improve stability of drugs and vaccines

-Statistical approaches to assessing efficacy where data is limited

-Cell culture and in silico modeling of safety and efficacy

-New point-of-care diagnostics during an emergency

-New dosing forms and delivery methods (ex. needle-free systems)

-Database for emerging infectious diseases (Real-time assessment)

-Enhanced risk assessment and communication

4)Enhancing Safety and Health through Informatics

-Clinical Data Interchange Standards Consortium (CDISC)

-Real time monitoring of safety data using healthcare data

-Data mining and scientific computing

5)Protecting the Food Safety

-Development of new chemical tests to assess food safety (in the Gulf of Mexico after the Deepwater Horizon Oil Spill)

-Developing effective tools and strategies for sampling, testing and analysis for pathogens such as E.coli O157, salmonella, and Listeria

-Tracking Salmonella in the food supply

-Preventing microbiological hazards

-Responding to food-borne illness

-Controlling toxins

-Monitoring antibiotic resistance in food-borne pathogens

6)Modernizing Safety Testing

-Novel kidney biomarkers for preclinical toxicity studies (FDA, EMA, academic and industrial groups in consortia)

-Cell culture methods, genomics microarrays, proteomics, metabolomics

-In vitro and computer-based modeling systems for toxicology

7)Meeting the Challenges for Regulating Tobacco

-Biomarkers for tobacco-associated pathogenesis and disease

-Tobacco product standards

-Tobacco product advertising and marketing

  FDA requested the following FY 2011 science budget:

-Science and innovation leadership and support

-Nanotechnology review and safety

-Stem cell initiative

-Critical path

-Drug review standards for new technologies for complex products and biosimilars

-Scientific capacity for animal biotechnology (for safe use)

-Nutrition for public health

-National medical device registry

 These activities are reported to the meeting of the Science Board to the FDA, and described in the report "Advancing Regulatory Science for Public Health" issued in October 2010.

- To be Continued -

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Report from Washington D.C. Metro Area No.5 December 2010