industry in usp monograph modernization...5/11/2015 1 john s. punzi, ph.d. 1 role of industry in usp...
TRANSCRIPT
5/11/2015
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John S. Punzi, Ph.D.
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Role of Industry in USP Monograph ModernizationExcipientFest Americas 2015 APRIL 29, 2015
Agenda
• Impact of OTC’s + Complexity
• Monograph Modernization
• Industry Approaches– Acetaminophen Drug Substance
– Acetaminophen Drug Products
– Cough and Cold products
– Future
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Committed to promoting the role of OTC and Dietary Supplement
products through Science, Education and Advocacy
serving the self-medication industry since 1881
CHPA is committed to promoting the increasingly vital role of OTCs and dietary supplements in America's healthcare system through science, education, and advocacy.
OUR COMMITMENT
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CHPA’S MEMBERS
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IMPACT OF OUR MEDICINES
How Many OTC’s are Marketed?
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Active Ingredients
• OTC precondition for active ingredient monograph
[21 CFR 330.10(a)(2) VII] An official United States Pharmacopeia (USP)-National Formulary (NF) drug monograph for the active ingredient(s) or botanical drug substance(s), or a proposed standard for inclusion in an article to be recognized in an official USP-NF drug monograph for the active ingredient(s) or botanical drug substance(s).
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• Mid-2010 USP 2010-2015 Resolutions 2 (Strengthen Focus on Core Compendial Activities) and 3 (Strengthen Relationship with FDA).
• Oct 2010 Correspondence from Dr. Woodcock to USP on the importance of monograph modernization.
• Nov 2010 FDA task group formed. First priority list (APAP, diphenhydramine, etc).
• Aug 2011, Second FDA list. Additional priority monographs.
• And…by the way… include “products including the ai’s”
USP OTC Monograph Modernization History
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Modernization of Monographs Achieved by:
• Replacing outdated procedures (e.g., packed column GC, TLC, wet chemistry tests, etc)
• Adding critical tests to the monograph (e.g., impurities/degradants)
• Deleting non-value added tests, as needed (e.g., odor test, melting point)
• Modernization proposals published in PF for a 90-day comment period
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Wants and Needs for USP Monograph Modernization
• Public Safety• Unambiguous enforceable specifications• Referee method(s) / surveillance • U.S. scope, participate globally
• Public Standard• Align w/ FDA as much as possible• Broad brush approach• Worldly impact
• High Quality Products • Practical, meaningful, balanced• Requirement clarity, but flexibility • U.S. focused, but worldly scope
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FDA on USP’s Monograph Modernization Program:
• The direct participation of the pharmaceutical industry…. is encouraged to assist in providing updated public standards….. the submission of updated analytical methodology… as well as materials which could be used for independent validation….
• FDA encourages all stakeholders to fully support this effort.
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USP on USP’s Monograph Modernization Program
• USP’s greatest challenge is obtaining updated procedures and acceptance criteria—manufacturers are encouraged to submit proposals to USP
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USP OTC Monograph Modernization
• Substance monographs are relatively easy– 140 are in need of modernization
– Separate task force for priority substance updates
– Ex-US USP laboratories HPLC / UPLC methods
USP OTC Monograph Modernization
• Much of the industry sentiment from 2010 persists today
• The FDA OTC monograph system accommodates a large variety of products
• USP activities need to keep-up with OTC industry (flexible and fast to keep pace with seasonal and market driven needs)
• Alternatives needed for publishing methods, updating monographs
• Establish primary USP method and publish additional methods from industry
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USP OTC Monograph Modernization
• It’s still big (2600+ monographs to address to begin)
• It’s still complex (grouping like APIs/DPs and using general chapters is part of the solution … but is that enough?)
• It’s still wanted by all, but especially the FDA
• Keep pushing, do it within <the next> 5-year cycle
• Benefits accrue with stakeholder input (3-legged stool, et.al.)
USP OTC Monograph Modernization
• Industry Approaches– Acetaminophen
– Acetaminophen combination products
– Cough and Cold products
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Industry Approach Acetaminophen
CHPA Impurities Breakout Group (2010)Sub team for APAP
Evaluated methods for the API monographAgreed on 4-aminophenol limits with supporting tox and product data
•Members Invited to Acetaminophen Expert Panel (EP)•USP General Chapter <227>•Capable of assaying for 4AP in a variety of complex products
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Repeated Industry Approach
CHPA Monograph Modernization (2013)Sub team for Diphenhydramine
Evaluated methods for the API monographProposed Impurity Limits
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USP OTC Monograph Modernization Cycle Time
USP process – 2 years
OTC DPFormula 1
OTC DPFormula 2
OTC DPFormula 3
OTC DPFormula 4
USP monograph is potentially obsolete before it’s official.
Industry Approach Acetaminophen Existing Monographs
4050 products containing Acetaminophen
• 47% (1899) fall under 18 USP monographs
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USP OTC Monograph Modernization
• APAP Capsules• APAP Solution• APAP Effervescent for Solution• APAP Suppositories• APAP Suspension• APAP Tablets• APAP, ASP Tablets• APAP, ASP, CAF Tablets• APAP, PSE Tablets• APAP, CAF Tablets• Capsules with APAP and at least 3 CPM, DEX, PSE• Powders with APAP and at least 3 CPM, DEX, PSE• Solutions with APAP and at least 3 CPM, DEX, PSE• Tablets with APAP and at least 3 CPM, DEX, PSE• APAP, CPM, DEX Tablets• APAP, DOX, DEX, PSE Solution• APAP, DPH (citrate) Tablets• APAP, DPH, PSE Tablets
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USP OTC Monograph Modernization
• Industry Role is staffing USP expert panels and using committees to test products.
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USP OTC Monograph Modernization
• Industry Approaches– Cough and Cold products
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Total 2013 OTC Pharmaceutical Sales(Billions)
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$7.2 Cough and Cold Products
$33
$321
OTC
Rx
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How Many Cough & Cold Products?
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RegularOriginalCitrus
BubblegumGrapeCherryHoneyLemonPleasant
Mixed Berry Licorice
Fruit PunchWatermelon
Mint
How Many Cough & Cold Products?
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SolidsBalmsCapsule
Chewable pill
Caplets Dissolvable
pellets/powders
Effervescent Express gel
GelGelatin caplet
GelcapGummiLotionTablet
Liquids
DropsExlixerLiquicapLiquigel
Liquid ShotsLiquid SpraysSuspensions
Syrups
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How Many Cough & Cold Products?
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Other Dosage Forms??
GlobuleMedicated SwabMedicated VialMelt Away
OilPacketPastillePatchPowder
Quick MeltShotSquareStick
How Many Cough & Cold Products?
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~7200 OTC Products
Product sales >10,000 units in past 5 years containing
one or more:Acetaminophen, Chlorpheniramine, DEX,
Diphenhydramine, Doxylamine, Guaifenesin, Phenylephrine, Pseudoephedrine
~250 Unique Single Actives and Combinations of Actives
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CHPA Collaboration Cough/Cold Sub-TeamGoal: Develop Industry Consensus for Degradants
P&G PfizerNovartisBayerPerrigo McNeil/J&J
Legal Agreements by several companies with CHPA put in place (Oct 2014)
Data Sharing Sessions Started December 4, 2014
Actives•APAP, GG, PE, DOX, DEX, CPM, DPH•PSE‐Free (want to be on shelves and not behind the counter)Buffer•Na Citrate/citric acid pH 4.6Solvents•Ethanol•Propylene glycol•Glycerin•WaterPreservatives•Na BenzoateSweeteners•HFCS, Sorbitol, Sucralose•Na Saccharin, Acesulfame KDyes•Green #3 + Blue #1 + Yellow #6 + Yellow #10 + Red#40
The Formula of Everything for Cough/Cold Syrups
Confidential30
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DEX & DPHDOXAPAP
PE&
AceK
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Cough and Cold Products are Complex Mixtures
USP OTC Monograph Modernization
• Industry Approaches– Cough and Cold products
Agree on degradation products
Share the assay and impurities methods and limits
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Medicines Marketed Under FDA OTC Regulations: Strategy for Developing USP
Standards
• PF41(1), Jan 2015, Stimuli Article– Strategy – Individual Drug Product (DP) monographs that
reference General Chapters– ID + Assay by gradient UPLC-PDA– Only certain specified organic impurities – deg. product(s) / toxic
adducts by gradient UPLC-PDA• No “unspecified impurities” or “total impurities”• Coverage of “unspecified”, “others”, the “unexpected” via proposed
<427> and revised <1086> that make clear manufacturer responsibility re ICH Q3B approach to impurities
– EI, residual solvents, anti-microbial, antioxidants, etc.
Stimuli Article DP Monograph OutlineDefinition IDENTIFICATION
A. ID AB. ID B
ASSAYDrug Product Assays <321>
IMPURITIESDrug Product Impurities <327>Elemental Impurities <232>Residual Solvents <467>
SPECIFIC TESTSC. pH <791>D. Alcohol Determination <611>E. Anti‐microbial agents <341>F. Antioxidants <342>G. Preservatives <343>
PERFORMANCE TESTSH Dissolution <711>I. Uniformity of Dosage Units <905>J. Deliverable Volume <698>
ADDITIONAL REQUIREMENTSPackaging and StorageLabelingUSP Reference Standards <11>
<321> Drug Product AssaysAcetaminophen
Test 01 – from USP labTest 02 – from manufacturer xyzTest 03 – from manufacturer abc
AspirinTest 01 – from USP labTest 02 – from manufacturer abcTest 03 – from manufacturer tty
CaffeineTest 01 – from manufacturer xyzetc…
<
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OTC Drug Product Monographs
• Improve the environment for participation– Use of technology for publication
– OTC company direct input according to USP template
• Compromise– Allow multiple ID tests for Products but only require two
– Let industry be the one to propose UPLC
• Work toward incremental change
Benefits and Advantages
• Transparency – Manufacturer selected compliance route which is easily enforced by FDA, etc.
• Broad application• Flexibility for Manufacturers• Assay and Impurities – fast adoption, known path,
low threshold donor model• Easily extended as new actives and products come
into the market
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OTC Project Team
• Charge
The purpose is to enhance interaction between stakeholders and USP regarding the process and framework for modernization
• Consider and provide feedback on the proposed USP OTC monograph and General Chapter approach, and suggest other new or novel approaches (i.e. FDA guidance).
• Advise USP on strategy for development and prioritization of monograph revisions.
• Consider communication of OTC-related initiatives to industry, regulatory, and other stakeholders.
• Work with FDA and counsel to develop a better understanding of the legal requirements, goals and flexibility that the agency is willing to consider while modernizing the USP OTC drug substance and drug product monographs
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Role of Industry In USP OTC Monograph Modernization
• Concluding Remarks– Acetaminophen
– Acetaminophen products
– Cough and Cold products
– Future
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Contact
• Industry Liaison
John S Punzi, Ph.D.
Director Quality Assurance and Technical Affairs
Consumer Healthcare Products Association
1625 Eye Street NW Washington DC
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QUESTIONS?
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