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