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

Transcription

1 Excipient Fest Puerto Rico April 28-29, 2015 Challenges And Opportunities In Developing And Modernizing Public Standards For NF Monographs Catherine Sheehan Sr. Director, Excipients United States Pharmacopeial Convention Presentation Outline Overview of the U.S. Pharmacopeial Convention (USP) How USP Standards are Established through a Public Process Call for Candidates: Council of Experts USP-NF Up to Date : overview of the USP Modernization Initiative Excipient Modernization progress Summary 2 1

2 USP An Overview US Pharmacopeial Convention (USP) founded in 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 An Overview 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. 2

3 Core Compendial Programs 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 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 3

4 Standards Established through a Public Process 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 in the 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. 4

5 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 Call for Candidates: Council of Experts 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 cycle Application deadlines: May 15, 2015: Expert Committee members May 27-28, 2015: CoE Orientation and Election of Expert Committee members July 2015: Council of Experts and Expert Committees begin their work Visit and click the Call for Candidates banner to access information and to create an application account. 5

6 USP Expert Committee Member Application Process USP Expert Committee Member Application Process 6

7 Excipient Expert Committee achievements 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. 13 7

8 Excipient Expert Committees Excipient Monograph Collaborative EC Excipient Monographs 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 Excipient Monographs 2 PDG Monographs 8 Subcommittees (SC) (D-K) PDG General Chapters Cross Cutting Subcommittee (CCSC) Bilateral Harmonization SC Prospective Harmonization SC Expert Panels on <1059> and <1197> Expert Panel on Talc, Glycerin and Povidones Focus Areas for revision cycle 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 16 8

9 USP NF Up to Date by 2020 USP has resolved to bring its compendia, the United States Pharmacopeia National Formulary (USP NF), up to date by 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. What is meant by USP NF up to date? 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

10 USP Monograph Modernization Initiative 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 10

11 Monograph Modernization Strategies 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) USP Global Laboratory Capabilities 43,000 sq.ft 53,000 sq.ft. 6,400 sq.ft USP Analytical Laboratories 65,000 sq.ft. 11

12 USP Monograph Modernization Process 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 Excipient Monograph Modernization: Prioritization of Categories 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) 12

13 USP Monograph Modernization - Excipients FDA Modernization Task Group (MMTG) Nov 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 13

14 FDA MMTG/ORA lists of Priority Excipient NF Monographs in need of modernization nf/key issues/monograph modernization Monograph List FDA Recommend PF for comment /Status Povidone (H) Crospovidone (H) Copovidone (H) Talc (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 PF 40(4) Stim article MMTG Revise Limit of Asbestos. Update Definition & Labeling 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 in development method) Titanium Dioxide (H) ORA Assay method is out of date, involves digestion with in development concentrated acids. Crospovidone (H) ORA Test method for Peroxides is outdated in development USP Expert Panels (EP) supporting Modernization 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. ( Kevin Moore at ktm@usp.org ) 28 14

15 Case Study Modernization and Harmonization of Cellulose-based Excipient Monographs Microcrystalline Cellulose (MCC), Carboxymethylcellulose Sodium (CMC Na) and Croscarmellose Sodium (CROS Na) Modernization of Identification for Cellulosebased Excipient Monographs 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 lowsubstituted 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. 15

16 Modernization of Identification for Cellulosebased Excipient Monographs 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 Cellulosebased 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. 16

17 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. Summary Excipient monograph modernization continues as a major initiative in the 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 17

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