7/16/2015. Introduction to USP. The Role of the U.S. Pharmacopeial Convention in Manufacturing OTC Medicines and Dietary Supplements.

Transcription

1 The Role of the U.S. Pharmacopeial Convention in Manufacturing OTC Medicines and Dietary Supplements John B. Atwater, Ph.D. Senior Director, Verification Programs, USP Jon Clark VP, Industry Standards Collaboration, USP Behnam Davani, Ph.D., M.B.A Principal Scientific Liaison General Chapter, Science Division, USP Robert Shimahara Director, Strategic Customer Development; North, South, and Central Americas; USP Moderated by: Barb Kochanowski, VP, Regulatory & Scientific Affairs, CHPA Introduction to USP Robert Shimahara Director, Strategic Customer Development; North, South, and Central Americas; USP 1

2 USP: The Organization Private Standards-setting Organization, est Non-Profit, Non-governmental Organization Recognized in ~39 countries Volunteer based (>1000) ~5900 monographs >3400 RS (Revenue source) USP s Global Locations USP--Switzerland Basel USP China Shanghai USP--US Rockville, Maryland USP India Hyderabad USP Brazil São Paulo USP Council of Experts 6 2

3 USP Compendia and Reference Standards 7 USP-NF Archive Nine years of USP-NF content on a single USB flash drive Includes Nine consecutive previously official editions of the USP-NF (USP 28 NF 23 through USP 36 NF 31) Convenient access to an expansive set of public standards that are easily browsed, searched, and printed Relevant supplements, accelerated revisions, and Errata Pages watermarked to clearly identify archived status USP Compendia and Reference Standards 9 3

4 USP Compendia and Reference Standards USP Reference Standards Over 3,400 Reference Standards now available Support FDA-enforceable standards and test in the USP-NF Highly pure, with purity values provided for quantitative standards 10 Strategy for OTC Drug Standard Development Jon Clark, VP Industry Standards Collaboration United States Pharmacopeial Convention / (240) (desk) Assure Quality of Medicines Available to Self-Care Patients through Public Standards Current Situation:: Collaborative Development: Most OTC Products have only USP Drug Substance Monograph: Missing Product Monographs create a gap in an otherwise well regulated market Outside US the same products have standards Changing Formulations are technical challenges for analysis of each product Collaboration is a strong point for USP and its stakeholders Public Standards Drive Quality and Reliability: Collaborate Directly and Develop long before proposal (Thank You CHPA) Understand our stakeholder needs and specifications Assure Quality and Availability of product is maintained; No unnecessary compliance issues Sustained Focused Effort: Commitment of Expert Committee to execute on its work plan for next 5 year cycle Flexible Approach to remain relevant and effective across multiple stakeholders Maximize coverage of OTC market with Public Standards that serve Self-Care Patients 12 4

5 FDA Letters Regarding USP Monographs Modernization Status of FDA Priority APIs Used in OTC Drug Products Official Letter Monograph Status PF FDA Request Comments Publication API monograph revised to include organic Add organic impurities 16 Nov 10 impurities. An EP developed an assay and PAP procedure and monitor PAP in all and ACETAMINOPHEN Complete 39(6) 38 <227> procedure for acetaminophen acetaminophen containing 20 Dec 10 monographs. Development of impurities for DPs is monographs planned. ID revised to include RT match from assay. Assay DIPHENHYDRAMINE Add organic impurities 16 Nov 10 Complete 38(2) 36 1 changed to HPLC from titration and LC organic HYDROCHLORIDE procedure to API and DPs. impurities added. Add organic impurities ID revised to include RT match from assay. Assay procedure to API and DPs. 20 Dec 10 DIPHENHYDRAMINE CITRATE Complete 38(4) 36 2 changed to HPLC from titration and LC organic Possibly adapt from HCl impurities added. procedure. 22 Aug 11 CHLORPHENIRAMINE MALEATE Complete 38(6) 37 1 Revise deficient and add missing procedures. 22 Aug 11 DEXTROMETHORPHAN HYDROBROMIDE (Part 1) Complete 40(3) IRA IRA Revise deficient and add missing Updated ID and Assay. Removed optical rotation. procedures. 22 Aug 11 DEXTROMETHORPHAN HYDROBROMIDE (Part 2) Undergoing Internal Development 41(6) Add organic impurities and a test for Limit of N,Ndimethylaniline 22 Aug 11 PHENYLEPHRINE HYDROCHLORIDE Published 40(2) 38 2 Revise deficient and add missing ID, assay and impurities procedures updated to procedures. modern LC procedures. 22 Aug Aug 11 PSEUDOEPHEDRINE HYDROCHLORIDE PSEUDOEPHEDRINE SULFATE Internal Development Complete Undergoing Internal Development 41(6) 41(6) Existing assay and impurities procedures but will Revise deficient and add missing be revised in order to adapt Pseudoephedrine procedures. Sulfate monograph. There was a submission from Merck that was Revise deficient and add missing published in PF 38(5) and later canceled. Plan to procedures. revise assay, ID and add organic impurities. 13 Project Team to Expert Panel Converting Project Teams to Expert Panels Both report to Expert Committee 6 Project Teams: Outside USP formal process Acetaminophen Project Teams facilitated by CHPA! Expert Panel: Formal part of USP process Multiple panels are likely for OTC <227> 4-AP in Acetaminophen-containing drug products Concluded Acetaminophen OTC Monographs (Panel #2) In Progress for January Expert Committee 6 - Portfolio Existing USP OTC monographs (~500 Official Articles) New Monograph Focus Acetaminophen, Chlorpheniramine, Dextromethorphan, Diphenhydramine, Phenylephrine, Pseudoephedrine Compendial approaches for multi-active ingredient drug products 15 5

6 Proposed Monograph Elements Elements to be considered/discussed with Expert Committee Two Identification Tests RT match UV spectrum match Assay LC procedure Externally sourced Internally developed/validated Expert Panel developed (when desired to build greater consistency or alleviate issues) Organic Impurities Short term strategy Specified Impurities with limits Long term strategy Full impurities protocols, if possible 16 Drug Product Updates/Challenges Organic Impurities Approaches for greater consistency of monitoring impurity profiles Remains the focus and priority Performance Dissolution test approaches to build greater consistency of quality standards for solid oral dosage drug products Initial discussions/stages more input required 17 Drug Products without USP monographs Estimates are that thousands of OTC C&C medicines are not yet covered by a USP monograph. Setting standards for these will take time. Monographs (New Articles) Large number of proposals review time needed (Re)Labeling - implementation time needed General Chapters Coverage of many drug products, increases the time to review Applicability and implementation strategy TBD, may not work in every case Individual issues handled case-by-case 18 6

7 New OTC Drug Product Titles Approved NOM-EC ( ) ACETAMINOPHEN AND CAFFEINE ORAL SOLUTION ACETAMINOPHEN AND CHLORPHENIRAMINE MALEATE TABLETS ACETAMINOPHEN AND DEXBROMPHENIRAMINE MALEATE TABLETS ACETAMINOPHEN AND DEXTROMETHORPHAN HYDROBROMIDE ORAL SOLUTION ACETAMINOPHEN AND DEXTROMETHORPHAN HYDROBROMIDE ORAL SUSPENSION ACETAMINOPHEN AND DIPHENHYDRAMINE HYDROCHLORIDE CAPSULES ACETAMINOPHEN AND DIPHENHYDRAMINE HYDROCHLORIDE TABLETS ACETAMINOPHEN AND PHENYLEPHRINE HYDROCHLORIDE CAPSULES ACETAMINOPHEN AND PHENYLEPHRINE HYDROCHLORIDE TABLETS ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, AND DEXTROMETHORPHAN HYDROBROMIDE ORAL SOLUTION ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, AND DEXTROMETHORPHAN HYDROBROMIDE ORAL SUSPENSION ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, AND PHENYLEPHRINE HYDROCHLORIDE CAPSULES ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, AND PHENYLEPHRINE HYDROCHLORIDE FOR ORAL SOLUTION ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, AND PHENYLEPHRINE HYDROCHLORIDE ORAL SUSPENSION ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, AND PHENYLEPHRINE HYDROCHLORIDE TABLETS ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, AND PSEUDOEPHEDRINE HYDROCHLORIDE TABLETS ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, DEXTROMETHORPHAN HYDROBROMIDE, AND PHENYLEPHRINE HYDROCHLORIDE CAPSULES ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, DEXTROMETHORPHAN HYDROBROMIDE, AND PHENYLEPHRINE HYDROCHLORIDE EFFERVESCENT TABLETS FOR ORAL SOLUTION ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, DEXTROMETHORPHAN HYDROBROMIDE, AND PHENYLEPHRINE HYDROCHLORIDE ORAL SUSPENSION ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, DEXTROMETHORPHAN HYDROBROMIDE, AND PSEUDOEPHEDRINE HYDROCHLORIDE CAPSULES ACETAMINOPHEN, CHLORPHENIRAMINE MALEATE, DEXTROMETHORPHAN HYDROBROMIDE, AND PSEUDOEPHEDRINE HYDROCHLORIDE TABLETS ACETAMINOPHEN, DEXTROMETHORPHAN HYDROBROMIDE, AND PHENYLEPHRINE HYDROCHLORIDE CAPSULES ACETAMINOPHEN, DEXTROMETHORPHAN HYDROBROMIDE, AND PHENYLEPHRINE HYDROCHLORIDE FOR ORAL SOLUTION ACETAMINOPHEN, DEXTROMETHORPHAN HYDROBROMIDE, AND PHENYLEPHRINE HYDROCHLORIDE TABLETS ACETAMINOPHEN, DEXTROMETHORPHAN HYDROBROMIDE, DOXYLAMINE SUCCINATE, AND PHENYLEPHRINE HYDROCHLORIDE CAPSULES ACETAMINOPHEN, DIPHENHYDRAMINE HYDROCHLORIDE AND DEXTROMETHORPHAN HYDROBROMIDE ORAL SOLUTION ACETAMINOPHEN, DIPHENHYDRAMINE HYDROCHLORIDE, AND PHENYLEPHRINE HYDROCHLORIDE CAPSULES ACETAMINOPHEN, DIPHENHYDRAMINE HYDROCHLORIDE, AND PHENYLEPHRINE HYDROCHLORIDE FOR ORAL SOLUTION ACETAMINOPHEN, DIPHENHYDRAMINE HYDROCHLORIDE, AND PHENYLEPHRINE HYDROCHLORIDE ORAL SOLUTION ACETAMINOPHEN, DIPHENHYDRAMINE HYDROCHLORIDE, AND PHENYLEPHRINE HYDROCHLORIDE TABLETS Many more C&C Articles to be considered by EC 19 USP Up-to-Date aka USP Modernization Initiative (OTC) Behnam Davani, Ph.D., MBA Principal Scientific Liaison- General Chapter Science Division US. Pharmacopeia History Initial evaluations of monograph status Many monographs identified as needing revision 2009: USP identifies ~700 outdated monographs 2010: FDA sends first of three letters requesting specific monograph modernizations 21 7

8 History Present: - USP broadens list of outdated monographs to ~ USP lab capacity expanding to accelerate internal development of modern monographs -FDA-USP collaboration broadens through CRADA; WG 22 Approaches Donor model Sponsored monographs Internal Development model Samples procured from market/sponsor More comprehensive procedure developed in USP labs 23 Internal Modernization Approach Procedure is suitable for multiple sources More comprehensive (multiple tests within monograph) Adding test for impurities Adding orthogonal tests for identification 24 8

9 Monograph Modernization: Examples Monograph PF Citation Modernization Acetaminophen PF 38 (3) [May June 2012] Replace the TLC with HPLC retention time Delete the Ultraviolet Absorption test under Identification because it is nonspecific, and the monograph currently has two orthogonal identification tests. Delete the test for Melting Range or Temperature. Replace the UV spectrometric procedure for Limit of Free p- Aminophenol with more specific HPLC test. Monograph Modernization: GC Approach Monograph PF Citation Modernization Acetaminophen Capsules Acetaminophen Oral Solution Acetaminophen for Effervescent Oral Solution Acetaminophen Suppositories Acetaminophen Oral Suspension Acetaminophen Tablets Acetaminophen Extended-Release Tablets PF 39 (3) [May June 2013] On the basis of the October 12, 2010 correspondence from the FDA to USP on the importance of monograph modernization and the USP monograph modernization initiative, a new HPLC procedure for monitoring 4- aminophenol, based on general test chapter <227>, is being proposed. Prioritization Strategies Regulatory status/availability of the products in the market FDA Priority monographs requested for modernization including CRADA High Impact General Chapter revisions/replacement (e.g. <231>, <466>, <227>) Economic Priority The active use of the drugs in the market Family of monographs (drug substance and associated drug products) Similar class (structure) of monographs 27 9

10 Scope USP Monographs Drugs OTC Rx FDA Monographs (GRASE) NDA/ANDA Switches NDA/ANDA FDA OTC Monograph System 21 CFR, Part 330 FDA Monograph (therapeutic class) Limited content ( recipe book ) Active ingredients generally regarded and safe and effective (GRASE) Dosing and labeling requirements Rules on allowable dosing and combinations Private specifications OTC Monograph Development Challenges Specifications are not available to USP Not much incentive for donation of OTC monographs for drug products New formulations and combination products change frequently with many Individual Products Multi-source products with different impurity profiles, excipients, flavors, preservatives, color additives, etc. Analytical challenges due to complex matrix Traditional monograph development/revision is slow 10

11 General Chapter Approach Goal: Develop GC procedures for Multiple Products ID and Assay Organic Impurities (Specified impurities) For Development of new monographs For Modernization of existing monographs Performance Test (Dissolution) Under evaluation by USP Dosage Forms Performance Lab 31 Summary More emphasis on monograph modernization Donor model Internal model (single monograph, general chapter approach) Project Team and Expert Panel support FDA CRADA More emphasis on comprehensive modernization of monograph 32 Third Party Verification of Dietary Supplement Quality John B. Atwater, Ph.D. Senior Director, USP Verification Programs

12 What is it? Dietary Supplement Verification Program Comprehensive evaluation and testing program Serves public health by verifying quality, purity and potency of supplements Developed at the request of dietary supplement manufacturers in 2001 USP public quality standards form the foundation of the program Participation is voluntary Serves as a safe harbor for manufacturers Multi-step process 34 USP Verified Mark and Statement Making Quality Visible! USP has tested and verified ingredients, potency, and manufacturing process. USP sets official standards for dietary supplements. See 35 How Does It Work? 1. Product appropriate for inclusion in program 2. Audit of manufacturing sites for GMP compliance 6. Continuous surveillance: GMP audits, annual product reports, and product testing 3. Review of quality control and manufacturing product documentation Phase II 5. Review of conformance with mark usage guidelines 4. Laboratory testing of product samples Phase I Mark Approval 36 12

13 PHASE I: Program with Complimentary Process Performing just an on-site audit does not sufficiently ensure product quality GMP Facility Audit CMC Product Documentation Review Product Testing Indivisible Process Modeled after the FDA ANDA review and pre-inspection approval process PHASE II: Surveillance Monitoring Annual GMP manufacturing site audit Annual product review reports include: Lot history List of deviations and/or customer complaints List of changes (major or minor) Follow-up action depends on the type of change Annual product testing for conformance to specifications 38 The Bottom Line Buy and Recommend USP verified supplements! You can be assured that: What s on the label is in the bottle. It does not contain unacceptable levels of specified contaminants. It will break down properly to allow for absorption by the body. It has been made under safe, sanitary, well-controlled, good manufacturing practices

14 Items on the USP website: Manual for Participants List of participating companies and manufacturing sites List of verified products USP Verified 41 Questions 14

15 Contact Information John Atwater: Jon Clark: Behnam Davani: Robert Shimahara: 15