USP Monograph Modernization Initiative:
Excipient update
ExcipientFest 2012
Catherine Sheehan, M.S., Director, Excipients United States Pharmacopeial Convention
USP Commitment to Modernization USP Monograph modernization strategy and approaches USP Weblist of excipients for modernization
Recent Revisions and Modernizations FDA MMTG and High-Priority monographs for modernization ChP- USP Harmonization efforts Moving forward Conclusions
Overview
USP Monograph Modernization
Primary driver is maintaining up-to-date standards to support USP’s commitment to public health
Need for modernization Monographs have been official for several years, decades in some cases
Content does not reflect current expectations for procedures and acceptance criteria
Complaints from manufacturers
General lack of specificity
Modernization is a subset of USP’s ongoing revision work, started using the term “modernization” in 2009
USP Monograph Modernization
Benefits Strengthens the public standards Moves from non-specific to specific procedures Considers practical factors
– removes unnecessary tests
– Safety/environmental issues such as eliminating use of chlorinated solvents
– hard to find equipment
Increases consistency across monographs
USP Monograph Modernization
USP’s greatest challenge is obtaining updated procedures and acceptance criteria—manufacturers are encouraged to submit proposals to USP
Pace of monograph modernization is linked to availability of procedures
FDA’s involvement is likely to encourage manufacturers to participate in the modernization efforts.
Excipient monograph modernization is a major initiative in the 2010-2015 revision cycle.
USP is devoting resources to this effort.
Collaboration with FDA, industry and other stakeholders is key to advancing the work.
USP Monograph Modernization
Recent efforts to increase visibility of the modernization effort Convention resolution (April 2010)
Launched monograph modernization web page (May 2010)
Working with FDA Monograph Modernization Task Group (MMTG, Nov 2010-ongoing)
Launched modernization “hot topics” web page (Feb 2011)
USP webinar on modernization (Feb 2011)
Presentation at USP Prescription/Nonprescription Stakeholder Forum (May 2011)
Monograph Modernization Strategy and Approaches
Continued Collaboration with FDA and Industry Prioritization
Timing considerations
April 24, 2010 Resolutions Supporting Public Health Adopted
by Convention
Strengthen USP’s Relationship with the U.S. Food and Drug Administration. USP resolves to strengthen its relationship with the Food and Drug Administration (FDA), and work with FDA and other public and private stakeholders to explore mechanisms to enable USP to provide and maintain up-to-date national standards for legally marketed drugs and excipients in the United States.
2010-2015 revision cycle: USP Commitment
USP Monograph Modernization Process
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) Follows USP’s standards-setting process Modernization proposals published in PF for a 90-day comment
period; accelerated revision process may be used, as needed Typical timeline for a complete proposal to reach official status is
about two years, depends on many factors
USP Monograph Modernization Prioritization
In 2005, USP Scientific Liaisons and Expert Committee members reviewed monographs and noted where modernization was needed
Work proceeded as monograph revisions, not a formal initiative
In 2009-2010, information was compiled into a master list and prioritized
Prioritization determined based on factors such as missing identification test, nonspecific identification test , missing or nonspecific assay or missing specific tests.
250+ excipient monographs included in master list.
A portion of the master list – the “Top 96” list – was posted on USP web site in May 2010 as a call for procedures
– http://www.usp.org/USPNF/submitMonograph/improveMon.html
– List is updated monthly to show progress (e.g., proposals received, etc)
Monograph Modernization
STRATEGIES
By Monograph
• Individual • Families
By Test
• ID • Assay • Impurities • Specific Test(s) • Other
By Technology
Platform
• Gas chromatography • Titrations • Spectrophotometry • Wet chemistry • Other
TACTICS
Sources of Data
• Manufacturers • USP Labs • FDA CRADA • Other
Pharmacopeias
General Chapters
• Monograph-specific procedures
• Performance-based procedures
CRITERIA
Non-specific ID Tests (e.g., ID by GC/HPLC retention time agreement only)
Outdated Technology • Packed column GC • Titration • Wet chemistry • Spectrophotometry • TLC
Missing tests (e.g, organic impurities)
Non-value added
tests (e.g, melting point)
Safety/environmental
concerns (e.g., odor tests, chlorinated solvents, pyridine, mercuric salts, etc)
MONOGRAPH TESTS
Identification
Assay
Impurities
• Organic • Inorganic • Residual Solvents • Heavy Metals
Specific Tests/Other
Excipient Monograph Modernization: Major Categories
Excipient Monograph Modernization: Major Categories
Total
No Identification (ID) or non-specific ID procedures 98
No Assay 27
Non-specific assay (titration, etc) 52
Outdated technologies: Packed column GC/TLC/UV, or wet chemistry test for impurities
25
No impurity tests (organic and inorganic) 2
–List of 96 on the USP website
–Majority of the work (about 90%) is to be done
http://www.usp.org/USPNF/submitMonograph/improveMon.html
14
USP Excipient Monograph Modernization Progress
• Over the past five years (2006 – April 2012) Submitted 179 monograph excipient revision proposals in
PF Of these, 85 (47%) are monograph modernization
proposals.
• Work in Progress (not published in PF yet)
28 excipient monographs with active modernization work • 10 (36%) proposals from manufacturers • 18 (64%) proposals USP-initiated (USP lab)
Monograph Modernizations Progress – Recent Examples
Monograph PF Modernization
Butyl Alcohol 38(3) Add ID by IR, Assay and impurities by GC
Maltose 38(3) ID by IR
Cylcomethicone 38(3) GC packed column to capillary
Sodium Benzoate 38(3) ID by IR and RT, Assay HPLC
Potassium Benzoate 38(3) ID by IR and Update assay to HPLC
Povidone (H6) 38(3) Add ID IR test
Povidone (H6) Feb 2011 Harmonization stage 6 Add impurity tests
Crospovidone (H6) Feb 2011 Harmonization stage 6
Update impurities test to HPLC
Stearic Acid (H6) Apr 2011 Harmonization stage 6 GC packed column to capillary
Magnesium Stearate (H6) Apr 2011 Harmonization stage 6
Update to AA from wet chemistry
Modernized NF Olive Oil in USP 33-NF 28 Reissue (2010)
Monograph Section NF 23 Olive Oil NF 28 Olive Oil 2010
Definition Revised Olive Oil is the fixed oil obtained from the ripe fruit of Olea europaea Linné (Fam.
Oleaceae). It may contain suitable antioxidants.
Identification None
Fatty Acid Composition <401>: meets its Fatty Acid Composition profile
Assay None
Fatty acid composition profile serves as assay
Impurities Revised
Heavy metals, Method II <231>: not more than 0.001%
Alkaline impurities: not more than 0.1 mL of 0.01 N hydrochloric acid is required
Absence of sesame oil: absence
Specific Tests
Deleted non
value tests-
Foreign kern oil,
Cottonseed oil,
Mineral Oil and
Foreign Fatty
oils, Free fatty
acid, Iodine
value, and
Saponification
value
Acid value <401>: not more than 0.3.
Peroxide value <401>: not more than 10.0.
Unsaponifiable matter <401>: not more than 1.5%
Specific absorbance: Dissolve 1.0 g of Olive Oil in cyclohexane, and dilute with
cyclohexane to 100 mL. Determine the UV-Vis absorbance of 10 mg/mL in cyclohexane
at a wavelength of 270 nm: the absorbance is not more than 1.20
Water, Method Ic <921> : not more than 0.1%
Sterol Composition <401>: meet its sterol composition profile
Packaging and
Storage
None Preserve in tight containers, and prevent exposure to excess heat
Labeling None
Label to indicate the name and quantity of any suitable antioxidants.
Benefits to revisions of Fixed Oil Monographs
• Helps protect against economically motivated adulteration (EMA) • Assures the Identity, Quality and Purity of substance • Fixed oils are expensive and prone to substitution with cheaper oils
– e.g., a mixture of almond oil and persic oil (1:1) would pass the Almond oil NF 23 monograph
• “Value added specific tests” included: – Identification: Add a fatty acid composition test that assures adequate
purity – Impurities: controls residues due to its origin, refining steps or residual
catalysts – Peroxide value: indicates primary oxidation products and stability of oil – Acid Value: accesses free fatty acids, an indicator for hydrolytic status
of oil product – Labeling: indicates presence of additives and if suitable for eg.,
injectable dosage forms – Sterol Composition: reveals the identity of the components in a mixture – Fatty acid composition: composition profile of individual fatty acids
USP revised the Glycerin monograph’s IDENTIFICATION to include: – Addition of Identification test B. LIMIT OF DIETHYLENE GLYCOL AND
ETHYLENE GLYCOL – GC method with flame ionization detection (FID) – NMT 0.10% each for diethylene glycol and ethylene glycol is found. – Official date: May 1, 2009
No longer part of the impurity testing, “Limit of DEG and Related Compounds”
– If DEG/EG detection and quantification is part of the IDENTIFICATION, the CGMP regulations at 21 C.F.R. § 211.84(d)(l) would require that manufacturers of drug products detect and quantify any DEG/EG present
– Manufacturers of glycerin cannot deviate from the DEG/EG limit since this would be an aspect of identity
– Consistent with FDA Guidance, Testing of Glycerin for Diethylene Glycol
Jan. 2009: FDA letter requested modernization of both Sorbitol Solution and Propylene Glycol consistent with the update to the USP Glycerin Monograph
2007: FDA Request to Revise “High Priority” Monograph
History of Glycerin adulteration with Diethylene Glycol
Country Year Incident
USA 1937 “Elixir sulfanilamide” – 107 deaths Resulted in the implementation of the1938 Amendment to the FFD&C Act
South Africa 1969 Sedative formulated with DEG – 7 deaths
Italy 1985 DEG in wines from Austria – no known deaths
India 1986 Medicinal glycerin laced with DEG – 14 deaths
Nigeria 1990 Acetaminophen syrup containing DEG – 40 deaths (some sources say 200 deaths)
Bangladesh 1990-2 Acetaminophen syrup containing DEG – 339 deaths
Haiti 1995/6 Cough medicine containing DEG – 85 deaths
Panama 2006 Cough and anti-allergy syrup containing DEG – 46 deaths (116 or 365 according to other sources)
USA 2006/7 Toothpaste containing DEG – no deaths
Panama 2007 Toothpaste containing DEG – no deaths reported Nigeria 2008/9 Teething formula contaminated with DEG from propylene glycol
– 84 deaths
Bangladesh 2009 Paracetamol syrup to children adulterated with diethylene glycol. Twenty-four children reported dead
FDA Guidance 2007– • Perform a specific identity test
that includes a limit test for DEG per cGMPs (NMT 0.10%).
• Reliance on COA is not sufficient to ensure quality of glycerin
• Recommends intimate knowledge of the supply chain
• As a result of collaboration with FDA and stakeholders, USP Lab. developed capillary gas chromatographic methods with FID and validated for analyzing EG and DEG (NMT 0.10%).
FDA “High Priority” Monograph Revisions for Limit of DEG and EG
A total of seven excipient monographs were categorized by FDA as ‘high-priority’ for modernization of Identification test consistent with Glycerin due to risk of EMA:
– Glycerin • Official date May 1, 2009 (USP 31-NF 26-2S)
– Sorbitol Sorbitol Solution – Sorbitan solution – Noncrystallizing sorbitol solution – Propylene glycol
• Official date February 1, 2010 (USP33-NF28 Reissue-1S)
– Maltitol Solution • Official date August 1, 2010 (USP 34-NF 29)
– Hydrogenated Starch Hydrolysate • Official date May 1, 2012 (USP 35-NF 30)
USP Modernization of “High-Priority’ Excipient Monographs
USP Modernization of “High-Priority’ Excipient Monographs
Contaminated pharmaceutical ingredients issue not limited to glycerin • Any ingredient is at risk if there is a willing buyer
– More interested in lowest cost ingredients than quality ingredients and
– Not insuring ingredient integrity has been preserved throughout the supply chain
• Most pharmaceutical ingredient safety problems have been due to a
lack of good supply chain controls
International Excipient Workshop
Excipient Quality Control, Testing, and International Harmonization
USP Headquarters, Rockville, Maryland July 20-21, 2009
Summary: Excipient Supply Chain Integrity
Excipient Workshop Outcomes
• Workshop concluded that recent events have shown that excipients are vulnerable to adulteration
• No one solution will fix the problem • Approach through a series of measures:
– Collaborate with industry and FDA to modernize monographs with more specific methods
– World-wide, pharmacopeias are working; industry co-operation is necessary but not always forthcoming
– Better understanding of our supply chains – Vigilance:
• Audits • Continuing assessment
• Led to creation General Chapter <1197> • Publication of the proposed draft <1197> chapter in PF 37(6) [Nov. Dec. 2011]. Target USP 36 NF 31 publication.
FDA Monograph Modernization Task Group (MMTG) The FDA Monograph Modernization Task Group was established within
the FDA Pharmaceutical Quality Standards Working Group, whose purpose it is to:
Facilitate monograph modernization and monograph prioritization activities of FDA.
Develop a science-and risk-based approach for ongoing prioritization and oversight of USP monograph modernization efforts.
Work with USP to achieve improvements to compendial monographs in accordance with USP Resolutions adopted for the 2010-2015 cycle.
Focus ongoing efforts for USP monograph modernization on those monographs and general chapters whose improvement would most greatly benefit the public health by reducing potential risks.
Provide any evolved recommendations in writing to USP.
Current pharmaceutical industry practices
• 40 percent of all finished pharmaceuticals and
• 80 percent of the active ingredients and bulk chemicals in U.S. drugs, are now sourced by industry from foreign countries.
• Up to half are purchased from plants in India and China.
• The number of non-U.S. plants we depend on has doubled in just the past decade.
• FDA oversight of manufacturing is overwhelmingly domestically-focused.
• This puts consumers at risk and American manufacturers on an uneven playing field.
Challenges
FDA Detects High Levels of Peroxide in Crospovidone
Issuing a Drug Safety Advisory on 10/21/2010
http://www.fda.gov/drugs/drugsafety/ucm230492.htm
• Peroxide levels found (1700 ppm) were 30-40x typical levels in this excipient
• Peroxides can degrade APIs resulting in sub-potent drug • Impurity levels were not being monitored by the manufacturer of
Crospovidone • USP revised monograph to add limit of peroxide
Posted on USP harmonization website on Feb. 25, 2011, Official Dec. 1, 2011 (Second Supplement to USP 34–NF 29)
FDA/PDA Pharmaceutical Supply Chain Conference June 6, 2011 Steven Wolfgang, Ph.D. Associate Director (Acting) for Risk Science, Intelligence and Prioritization,FDA/CDER/Office of Compliance/ Office of Drug Security, Integrity and Recalls
Are We Only Seeing the Tip of the Iceberg?
FDA/PDA Pharmaceutical Supply Chain Conference June 6, 2011 Steven Wolfgang, Ph.D. Associate Director (Acting) for Risk Science, Intelligence and Prioritization FDA/CDER/Office of Compliance/ Office of Drug Security, Integrity and Recalls
FDA MMTG Nov.16, 2010 letter requested revisions to: • USP Povidone, NF Crospovidone, NF Copovidone:
a) 3 Povidones not consistent w.r.t. impurity specifications. Should be harmonized within USP and to the EP monographs (Limit of Hydrazine; Limit of aldehydes; Peroxides; Heavy metals.
b) Nitrogen assay test (<461> Nitrogen Determination (by Kjeldahl method)). is non specific. Prefer a more specific method due to concerns about economically motivated adulterants, eg., melamine.
• Expert Panel formed, January 2012. • USP Talc:
a. Labeling statement should be revised to match the statement from the FCC monograph’s description thereby assuring that Talc is not sourced from mines that are known to contain asbestos.
b. USP should consider revising the current test for Absence of asbestos to ensure adequate specificity.
• Talc Expert Panel formed, May, 2011.
• Povidone: PDG Stage 6 adoption includes the addition of tests for
• Limit of hydrazine, Limit of aldehydes, Peroxides
• Crospovidone: PDG Stage 6 adoption includes the addition of tests for
• Peroxides, Limit of monomers (vinylpyrrolidinone)
• Both Stage 6 posted on harmonization website on Feb. 25, 2011, Official Dec. 1, 2011 (Second Supplement to USP 34–NF 29)
• Copovidone: PDG Stage 4 Official Inquiry
• PF 37(4) [July – Aug. 2011] . Scheduled for USP 35-NF 30-2S publication • Addition of Test for Lead.
• Revision of Limit of Monomers (change from titration,(0.1%) to HPLC (0.001%)
• Povidone: PDG Stage 6 adoption
• PF 38(2) [Mar. – Apr. 2012]. Scheduled for USP 36-NF 31-1S publication • Revision of Identification test to include an FTIR spectroscopy test. EP monograph includes
this test.
FDA High-Priority Monographs: in progress
Povidone, Crospovidone, Copovidone:
Alternative methods discussed include a combination ID/Assay test: ID product and ID impurities (organic and inorganic).
– Issue: needs to be suitable as a compendial test. USP Monograph Feasiblity Study. Samples were spiked with nitrogen rich organic adulterants
(melamine and urea) and inorganic adulterants (talc, calcium carbonate) to mimic the expected nitrogen range. CHN elemental analysis combined with total ash content could control
adulteration down to 1% levels.
2 Expert Panel participating companies prepared a series of spiked samples at various levels (0.5% - 2.0%). Run the existing compendial tests in USP, EP and JP to determine which methods can be part of the ID toolbox for controlling EMA.
Results to be discussed at May EP meeting
FDA High-Priority Monographs: in progress
Panel Accomplishments: No one single method is sufficient to adequately control asbestos contamination. As a result, Monograph will be revised in a Two Phase revision process Phase I: Revise X-Ray Diffraction (XRD) methodology and eliminate IR
test. Phase II: Development of orthogonal microscopy methods (Polarized
Light Microscopy (PLM), Scanning Electron Microscopy (SEM), Transmission Electron Microscopy (TEM)). Choice of method to be determined based on a flowchart protocol to be developed by Expert Panel.
Work on-going in parallel with ASTM working group
Labeling statement language to be addressed following finalization of methodology flowchart.
USP Monograph Modernization: Talc
Challenges to the Expert Panel No universally accepted definition of Asbestos. All proposed methods have limitations
XRD can give false positives due to interference of chlorite with serpentines and zinc stearate with amphibole.
Morphology alone cannot distinguish other inorganic phases, particles viewed on edge, or organic fibers
Detection limits may be too low for XRD in some cases Microscopy methods have limits based on particle size; small particles are
not suitable for PLM, larger particles not for TEM.
Reference material development and characterization will have unique challenges. Can we develop a pure “asbestos” reference standard? Can we develop a 100% “asbestos-free” talc reference standard,
spiked at various levels with amphibole or serpentines?
Sampling process will need to be defined.
USP Monograph Modernization: Talc
Modernization of General Chapter <911>:USP 35-NF 30 2S
• General chapter (GC) <911> Viscosity revised • Compendial Notice Alert targeted for April –May 2012 • Replace current <911> with the following two test chapters:
– <911> Viscosity Capillary Viscometer Methods ( major revision to exiting chapter)
– <912> Rotational Rheometer Methods (addition of new chapter)
• References to current GC <911> Viscosity will be changed to reflect the corresponding new chapter title and number based on the viscosity procedure specified in the individual monograph
• Current GC <911> Viscosity is referenced in 70 USP-NF monographs – 1 in DS (Dietary Supplements) – 9 Small Molecules – 60 Excipients
In USP 35-NF 30 S2, Reference <911> in Monograph
• An additional new test chapter proposed in PF 37(5) to complement revision to <911> – <913> Rolling Ball Viscometer Method
• Overarching Information chapter, <1911> Rheometry under development by the Physical Analysis Expert Committee
Meeting with ChP: Mr. Wang Ping, Deputy Director General and staff.
ChP are working on harmonization of excipient monographs and related Reference materials.
ChP to introduce 150 new excipient monographs into 2015 ChP edition
ChP to modernize 12 excipient monographs
USP meeting with ChP
150 • USP reviewed the ChP list of 150 monographs (via Penny/MOU) targeted for development in ChP.
93 • 57 of the 150 already official in the USP-NF or USP Dietary Supplements (DS) compendium.
• Equates to 48 official USP –NF or DS monographs. • Remaining 93 reviewed by USP.
49 • 36 of the 93 identified by USP to be developed by MC . No sponsor/alternative source. • 13 of the 93 identified by USP for collaboration and publication in ChP and USP-NF . In development • 44 remaining monographs not listed in IID.
ChP-USP: 12 Modernizations in progress ( USP 96 Weblist)
USP weblist of High Priority Excipients for
modernization - 12 on ChP list
USP ChP
List of 12 on the USP weblist Modernization in progress On PDG list
Hydrogenated Castor Oil USP Research lab. No USP to share Lab. results with ChP
Cholesterol USP Research lab. No USP to share Lab. results with ChP
Carnauba Wax * FDA CRADA* No USP to share Lab. results with ChP
White wax * No USP to share Lab. results with ChP
Xanthan gum Sponsor submission - request for
revision
No USP to share Lab. results with ChP
Maltodextrin Sponsor submission - request for
revision
No USP to share Lab. results with ChP
Calcium Stearate Waiting for sponsor submission No
Calcium Sulfate Waiting for sponsor submission No
Diethyl Phthalate Waiting for sponsor submission No ChP to share data with USP
Ethyl Acetate Waiting for sponsor submission No ChP to share data with USP
Monobasic Potassium Phosphate Waiting for sponsor submission No
Sulfuric acid Waiting for sponsor submission No
* FDA CRADA developing a GC assay that will be used by USP labs to modernize the remaining 5 NF Wax monographs, White Wax, Candelilla Wax, Cetylesters wax, Emulsifying wax, Microcrystalline wax, White wax, and Yellow wax.
Moving Forward
USP efforts Reviewing options for optimizing prioritization and efficiency of work Sourcing procedures from other compendia, literature, other USP will continue to use its lab resources Form Expert Panels, as needed, to address specific topics
Collaboration Explore possible lab support from CRADA with the FDA Collaborate with FDA MMTG, refine priorities as needed Engage IPEC, ISEO, Industrial Minerals Association and other
interested parties
Moving Forward
Communication and outreach “Design phase” approach bringing together manufacturers,
regulators, and stakeholders – Web meetings
– Public forums
– Workshops
Update the USP Monograph Modernization web page monthly Maintain the Modernization Hot Topics page
– For updates to high profile issues (e.g, FDA priority monographs) – http://www.usp.org/hottopics/monographs.html
Update progress on Expert Committee Work Plans (posted on USP web site at specified intervals)
• Excipient monograph modernization is a major initiative in the 2010-2015 revision cycle
• USP is devoting resources to this effort • Collaboration 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
• USP’s Challenges – Obtaining procedures and acceptance criteria – With FDA involvement in prioritizing and requesting
submissions, industry is much more likely to come to the table – Manufacturers are encouraged to submit proposals to USP
Conclusion