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Catherine SheehanSr. Director, Excipients United States Pharmacopeial Convention

Excipient Fest Puerto RicoApril 28-29, 2015

Challenges And Opportunities In Developing And Modernizing Public Standards For NF Monographs

• Overview of the U.S. Pharmacopeial Convention (USP)

• How USP Standards are Established through a Public Process

• Call for Candidates: 2015-2020 Council of Experts

• USP-NF Up to Date : overview of the USP Modernization Initiative

• Excipient Modernization – progress

• Summary

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Presentation Outline

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USP – An Overview

US Pharmacopeial Convention (USP) founded in 1820. USP is a scientific, nonprofit, nongovernmental, private, independent, and self-funded organization

2015 USP is headquartered in Rockville, MD; 800+ employees; facilities in India, China, Switzerland, Brazil, Ghana and Ethiopia

USP is cited in United States Law…

1848: Drug Import Act

1906: Pure Food and Drug Act

1938: Federal Food, Drug and Cosmetic Act (FFD&C Act)

– Definition of a drug

– Adulteration

– Misbranding

– Drug product name

1994: Dietary Supplement Health and Education Act (DSHEA)

2003: Model Guidelines for Medicare Formularies

• In the FFD&C Act, both United States Pharmacopeia (USP) and the National Formulary (NF) are recognized as official compendia for drugs marketed in the United States. The USP-NF is two separate books published as one compendium.

USP – An Overview

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The United States Pharmacopeia and the National Formulary (USP–NF)

– Published annually with 2 supplements.

Food Chemicals Codex

USP Dietary Supplements Compendium

Reference Standards

Other Resources

– Pharmacopeial Forum

– FCC Forum

– USP Dictionary

Core Compendial Programs

Pharmacopeial Forum and FCC Forum

USP’s vehicles for public notice and comment

PF a free online-only service as of January 2011

Includes an archive back to PF 28 (2002)

FCC Forum online only

Contents– Interim Revision Announcements

(PF Only)

– In-process Revision

– Stimuli to the Revision Process

– Nomenclature

– Harmonization

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USP creates and continuously revises USP–NF standards through a unique public–private collaborative process

This involves scientists in industry, academia, and government as well as other interested parties from anywhere in the world.

Public input and interaction are vital to the development of USP standards.

The standards generally originate from sponsors who provide draft standards and supporting data to either create new or revise (modernization) existing monographs and general chapters.

Standards Established through a Public Process

USP's scientific staff and volunteer experts review sponsor’s input, conduct laboratory tests (if necessary), and publish the proposed new or revised monograph or general chapter inthe Pharmacopeial Forum (PF) for public review and comment.

The public comment process helps to refine USP standards for publication as official text in the USP–NF.

Prior to publication as official text, all USP-NF monographs and general chapter proposals must be approved by a USP Expert Committee (EC).

EC is comprised of volunteer scientists, academicians, practitioners, and other professionals elected on the basis of their knowledge and expertise.

http://www.usp.org/usp-nf/pharmacopeial-forum

Standards Established through a Public Process

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Expert Committee Role in Standards-setting Processes

• Work with Scientific Liaisons and Reference Standard Scientists

• Evaluate all input and comments (from the public, Expert Panel, staff, etc.)

• Decide whether to incorporate comments into the final text without republishing for public review or if additional public review is needed before revision is adopted

• Vote to adopt official/effective/authorized text

• Approve monograph and general chapter text and the use(s) of USP Reference Standards in the monograph or general chapter

• Maintain confidentiality of standards-setting documents, information and activities

• Declare conflicts of interest

Seeking experts in pharmaceutical, biological, and food sciences; pharmacy; medicine; and related disciplines to volunteer for USP’s Council of Experts and Expert Committees for the 2015-2020 cycle

Application deadlines: May 15, 2015: Expert Committee members

May 27-28, 2015: CoE Orientation and Election of Expert Committee members

July 2015: 2015-2020 Council of Experts and Expert Committees begin their work

Visit https://callforcandidates.usp.org/node and click the Call for Candidates banner to access information and to create an application account.

Call for Candidates: 2015-2020 Council of Experts

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USP Expert Committee Member Application Process

USP Expert Committee Member Application Process

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USP collaborated with FDA and excipient stakeholders (users, makers, and distributors) to modernize excipient monographs.

To date, 62 monograph identification, 30 assay, 11 impurity tests and a General Chapter <1197> Good Distribution Practices for excipients were developed.

The new compendial quality specifications and general chapters help improve testing controls and provide tools to qualify an excipient for intended use.

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2010-2015 Excipient Expert Committee achievements

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2015-2020 Excipient Expert Committees

Exc

ipie

nt M

onog

raph

s 1 EXC A Subcommittee (SC)

Small molecules

EXC B SC

(Polymers, Proteins, Clays)

EXC C SC

(Oils, Fats, Waxes, Plants)

EXC-B&B Cross Cutting Subcommittee (CCSC)

General Chapters CCSC Exc

ipie

nt M

onog

raph

s2 PDG Monographs

8 Subcommittees (SC)

(D-K)

PDG General ChaptersCross Cutting Subcommittee

(CCSC)

Bilateral Harmonization SC

Prospective Harmonization SC

Excipient Monograph Collaborative EC

Expert Panels on <1059> and <1197> Expert Panel on Talc, Glycerin and Povidones

New monograph development with associated RS

Monograph modernization with associated RS

New excipient related chapters development

Excipient General Chapters update

International harmonization

–PDG

–Bilateral harmonization

–Prospective harmonization of API, DP & Excipients

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Focus Areas for 2015-2020 revision cycle

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USP has resolved to bring its compendia, the United States Pharmacopeia—National Formulary (USP–NF), up to date by 2020.

The objective of this initiative is to develop standards that reflect “state-of-the-industry” techniques for sufficiently monitoring drug quality, purity, and strength.

This includes an effort to ensure that all monographs in the USP–NF —including those for chemical medicines, excipients, and biologics—are current, relevant, and suitable for their intended use.

USP–NF Up to Date by 2020

• USP has made tremendous progress in modernizing outdated methodologies in the USP–NF through collaborative efforts with FDA and its stakeholders.

• Modernization of Heparin, Glycerin and Acetaminophen are examples of USP, FDA, and industry working together to enhance global health through the improvement of public quality standards.

• USP’s intensified focus on updating USP–NF is expected to result in an increase in monograph proposals over the next five years.

• USP’s outreach to stakeholders will be proactive; encourage industry to contact USP in this effort.

• USP will dedicate additional resources and optimize its internal processes to successfully accomplish this goal by 2020.

What is meant by USP–NF “up to date”?

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Primary driver is maintaining up-to-date quality standards to support USP’s commitment to public health

Need for modernization Monographs have been official for several years, decades in some

cases and have not kept pace with scientific advancements

Content does not reflect current expectations for scientific procedures and acceptance criteria

Complaints from stakeholders

General lack of specificity

Unsafe or use of hazardous materials

Modernization is a subset of USP’s ongoing revision work, started using the term “modernization” in 2009

USP Monograph Modernization Initiative

Benefits Strengthens USP public standards to current pharmaceutical

practices

Moves from non-specific to specific procedures

Considers practical factors – removes unnecessary and outdated tests

– Safety/environmental issues considered such as eliminating use of chlorinated solvents

– hard to find equipment that is no longer available

Increases consistency across monographs

USP Monograph Modernization Initiative

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Approaches to monograph and reference material procurement and

development:

Traditional donor model (‘externally sourced’)

– Very difficult to engage sponsors

USP laboratories (‘internally sourced’)

– Extensive testing facilities for procedure development

– Collaborative testing sites in US, India, China and Brazil

FDA (CRADA: ORA Labs)

Expert panels to leverage industry expertise, gain early stakeholder input and buy-in

Adapt/Adopt (Other Pharmacopeias e.g. E.P., J.P., B.P., ChP, etc.)

– Identify alternate source procedures (i.e., procedures that can be used from other pharmacopeias)

– In some cases, the alternate source procedure for one test (e.g., Impurities) may be the starting point for an R&D lab project for modernization of another test (e.g., Assay)

Monograph Modernization Strategies

USPAnalytical

Laboratories

USP Global Laboratory Capabilities

43,000 sq.ft

65,000 sq.ft.6,400 sq.ft

53,000 sq.ft.

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Modernization of monographs achieved by

– Replacing outdated technology and methodology with more current procedures

– Adding critical tests to the monograph

– Deleting non-value added tests, as needed (e.g., odor test, melting point)

Follows the USP standards-setting process (i.e., with publication in PF for 90-day comment period)

FDA to provide input to USP on prioritization of excipients (FDA MMTG and ORA lists) in the U.S.

Other considerations

–Use procedures from other pharmacopeias–May need RS materials –Revising the monograph “family”, as needed

USP Monograph Modernization Process

No Identification or non-specific Identification procedures

No Assay or non-specific Assay procedures

– Stainless steel/packed column GC procedures

– Titration to GC/HPLC where appropriate

No impurity test, (e.g., Povidones and peroxides/aldehydes)

Safety-related concerns (e.g., chlorinated solvents).

Additional requirements

Monograph Labeling deficiencies , e.g., when used in parenteral/injectable applications (Fit for Purpose)

Missing specific tests to control quality (e.g., Microbial/BE)

Excipient Monograph Modernization: Prioritization of Categories

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FDA Modernization Task Group (MMTG) Nov. 2010

MMTG was established within the FDA Pharmaceutical Quality Standards Working Group

– Concern that USP-NF excipients at an elevated risk of adulteration because of a lack of specificity of the Identification test.

– Total of 19 high priority excipients including ORA list of 4

– List includes USP-NF excipient monographs in the Pharmacopeial Discussion Group (PDG) work program.

Modernization initiative is helping USP as the lead/coordinating pharmacopoeia in approaching steps 1-3 of the PDG process.

USP has began to convene global Expert Panels for PDG related excipient monographs to ensure that the standard is agreed upon by global experts prior to PDG discussion. (Talc, Povidones and Glycerin)

USP Monograph Modernization - Excipients

USP Monograph Modernization - Excipients

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FDA MMTG/ORA lists of Priority Excipient  NF Monographs in need of modernization 

http://www.usp.org/usp‐nf/key‐issues/monograph‐modernizationMonograph  List  FDA Recommend  PF for comment /Status 

Povidone (H)

Crospovidone (H)

Copovidone (H)

MMTG Replace non‐specific  N determination Assay  

<461> Kjeldahl method. Add Peroxide test

PDG S6 – Add ID by IR, 

add Impurities tests ‐

Peroxide, hydrazine

Talc (H) MMTG Revise Limit of Asbestos. Update Definition & 

Labeling

PF 40(4)‐Stim article 

Butylated Hydroxyanisole MMTG Lack of specific ID  PF40(6)

Butylated Hydroxytoluene MMTG Lack of specific ID  PF 40(2) 

Calcium Stearate  MMTG Lack of specific ID  PF 39(4)

Croscarmellose Sodium (H)  MMTG Lack of specific ID  in development

Carboxymethylcellulose Sodium (H) MMTG Lack of specific ID  in development

Dextrose (H) MMTG Lack of specific ID  in development

Gelatin  (H) MMTG Lack of specific ID  PDG Stage 6 official 

Guar Gum  MMTG Lack of specific ID  PF 39(5)

Microcrystalline Cellulose (MCC) (H) MMTG Lack of specific ID  Target PF 41 (5)

Pregelatinized Starch  MMTG Lack of specific ID  in development

Shellac  MMTG Lack of specific ID  PF40(4)

Silicon Dioxide (Colloidal) (H) MMTG Lack of specific ID  in development

Titanium Dioxide (H) MMTG Lack of specific ID  in development

Gelatin (H) MMTG Lack of specific ID in development

Aspartame ORA Replace nonspecific assay titration ; add impurities test PF40(4)

Glycerin (H) ORA Assay method for glycerin is out of date (periodate

method)in development

Titanium Dioxide (H) ORA Assay method is out of date, involves digestion with 

concentrated acids.in development

Crospovidone (H) ORA  Test method for Peroxides is outdated in development

The USP Excipient (Exc) Expert Committee has created 3 Expert Panels

to address FDA’s request to modernize 3 excipient monographs for

Glycerin (S3), Talc (S6) and Povidones (Povidone (S6), Crospovidone

(S6) and Copovidone (S4) ).

These monographs are also part of the Pharmacopeial Discussion Group’s

workplan.

Expert Panels allow for global participation of excipient users, makers,

distributors, governmental and academics in method development and

testing that provide recommendations to the Exc Expert Committee.

Aim is to submit EP’s/Exc EC proposed methods to PDG for

consideration in the development of a harmonized PDG monograph.

Talc EP published a stimulus article in PF 40 (4) on the revision of the

Test for “Absence of asbestos”. USP still accepting comments on the

article. ( email Kevin Moore at ktm@usp.org )

USP Expert Panels (EP) supporting Modernization

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Case StudyModernization and Harmonization of Cellulose-based Excipient MonographsMicrocrystalline Cellulose (MCC), Carboxymethylcellulose Sodium (CMC Na) and Croscarmellose Sodium (CROS Na)

The FDA MMTG identified several cellulose-based excipient monographs as high priority for modernization that may be at an elevated risk of adulteration due to a lack of specificity of the Identification (ID) test.

Microcrystalline Cellulose (MCC), Carboxymethylcellulose Sodium (CMC Na) and Croscarmellose Sodium (CROS Na)

Develop a compendial ID to establish identity; also be specific and discriminate compounds of closely related structure, such as

MCC, CMC Na and CROS Na, hydroxypropyl cellulose (HPC) and low-substituted hydroxypropyl cellulose (LS-HPC), hypromellose (HMPC), etc.

Under CGMP regulations, pharmaceutical drug manufacturers must perform at least one test to verify the identity of all component ingredients used to make the finished drug product and, where available, the compendial identity test is often used.

Modernization of Identification for Cellulose-based Excipient Monographs

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For some excipients, one ID test may not suffice

May be necessary to include orthogonal test(s) under the Identification.

Challenges exist in developing compendial specifications for cellulose-based excipients

known variability based on grade (i.e. degree of polymerization, particle size, solubility, etc.), manufacturer’s processing parameters (site, processing, potential mixtures/additives) and raw material origin.

The EXC EC began by implementing a comprehensive approach to develop specific ID tests for these chemically-similar cellulose-based excipients based on infrared (IR) spectroscopy in combination with simple orthogonal methods.

Modernization of Identification for Cellulose-based Excipient Monographs

Eight monographs have ID by IR either official in the USP-NF monographs or proposed in Pharmacopeial Forum (PF), as shown in our USP Poster presentation, Table 1.

The EXC EC concluded that for chemically and structurally similar compounds, such as the Carmellose family (Carmellose, CMC Ca, CMC Na, and CROS Na), orthogonal tests, such as ion identification and/or solubility, may be necessary to distinguish the individual materials.

The USP staff and the EXC EC are currently reviewing the Identification section for the remaining seven cellulosic-based excipient monographs.

Stakeholders are encouraged to sponsor and submit methods/validation data to USP.

Modernization of Identification for Cellulose-based Excipient Monographs

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USP’s Opportunities/Challenges to Modernization

• Challenges:• Obtaining procedures and acceptance criteria from sponsors

• With FDA involvement, prioritizing and requesting submissions -the hope is that industry is much more likely to submit a proposal.

• Opportunities:

• New approaches to modernization, especially use of USP China laboratory facilities to develop and validate procedures.

• Global expert panels and stakeholder collaborations can stimulate additional avenues for both modernization and harmonization.

• Sourcing procedures from other compendia, literature, etc.

► Excipient monograph modernization continues as a major initiative in the 2015-2020 CoE revision cycle. Monograph Modernization is critical given global supply chain threats

► 2 newly elected Excipient Monograph Expert Committees will continue the modernization initiative beginning in July 1, 2015

► Modernized excipient test methods helps to eliminate the opportunity to substitute or falsify excipient ingredients

► Obtaining samples, procedures and acceptance criteria from Sponsors is challenging

► Opportunities to collaborate with FDA, industry and other stakeholders is key to advancing the work

► Long-term goal is to implement a regular monograph review process to monitor the needs for further modernization

Summary

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Upcoming Events for Excipients

http://www.usp.org/sites/default/files/usp_pdf/EN/excipients/newsletter/201502-newsletter.pdf?utm_source=iContact&utm_medium=email&utm_campaign=Excipients&utm_content=Excipients+e-news+template+201502

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