USP updates on Excipient Monograph Modernization and FDA Modernization Task Group list Catherine M. Sheehan, M.S., M.S. Sr. Director, Excipients US Pharmacopeia [email protected]ExcipientFest Baltimore, MD April 30-May1, 2013 USP Monograph Modernization Initiative – Background USP Monograph modernization strategy and approaches FDA Modernization Task Group (MMTG)/FDA ORA – Review the FDA Lists of priority excipients USP Monograph modernization – Progress on NF Excipients – Collaborative efforts with stakeholders – USP Lab method development in collaboration with stakeholders “Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances” Topics
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EF13 May 1, Hall B #3, Catherine Sheehan (USP)...Sr. Director, Excipients US Pharmacopeia [email protected] ExcipientFest Baltimore, MD April 30-May1, 2013 USP Monograph Modernization Initiative
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USP updates on Excipient Monograph Modernization and FDA Modernization Task Group list
Catherine M. Sheehan, M.S., M.S.Sr. Director, Excipients US [email protected]
ExcipientFest Baltimore, MD April 30-May1, 2013
USP Monograph Modernization Initiative
– Background
USP Monograph modernization strategy and approaches
FDA Modernization Task Group (MMTG)/FDA ORA – Review the FDA Lists of priority excipients
USP Monograph modernization – Progress on NF Excipients– Collaborative efforts with stakeholders– USP Lab method development in collaboration with stakeholders
“Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances”
Topics
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
– Content does not reflect current expectations for procedures and acceptance criteria
– Complaints from the public
– General lack of specificity
Modernization is a subset of USP’s ongoing revision work, started using the term “modernization” in 2009
FDA Modernization Task Group ( Nov. 2010)
List of priority excipients - most recent, July 2012 list of 13.
– Safety/environmental issues such as eliminating use of chlorinated solvents
– hard to find equipment
Increases consistency across monographs
USP Monograph Modernization
ExcipientFest 2011: Keynote Speaker - Dr. Steven Wolfgang, Ph.D. , “A Vision for Total Excipient Control”
Calcium Benzoate (FCC) was identified as a potential monograph for modernization due to a nonspecific assay based solely on the titration of the metallic ions.
The monograph did not contain a method confirming the organic portion of the molecule.
USP R&D lab developed a HPLC method for a quantitative assay based on the amount of benzoic acid in the benzoate salts.
Two NF monographs Sodium Benzoate (NF and FCC), Potassium Benzoate (NF and FCC) were modernized using the same HPLC method.
Most importantly:
The USP Lab developed HPLC method showed that the commercial samples of Calcium Benzoate failed the HPLC assay.
Calcium Benzoate FCC Modernization
Overlaid Chromatograms of Calcium Benzoate Samples
Talc Letter 1 Nov 2010 Replace Limit of Asbestos and update Definition and Labeling
Talc Expert Panel formedAim: publish Stim article in PF 39(6)
Butylated Hydroxyanisole
Lette
r 3
Jul 2
012
Lack
of s
peci
fic ID
tes
t
Butylated Hydroxytoluene USP labs – Add Chromatographic Assay – ID test add RT agreement
Dextrose Excipient
Silicon Dioxide (Colloidal)
Titanium Dioxide
Croscarmellose Sodium(Croslinked CMC sodium)
USP labs – IR test
CarboxymethylcelluloseSodium (CMC sodium)
Gelatin PDG Stage 6 published as RB
Guar Gum USP labs: ID: chem. comp. by TLC
Microcrystalline Cellulose USP labs – ID by IR test
Pregelatinized Starch
USP labs – ID:IR and TLC methodsShellac
Harmonization with PDG S6 Mg(St)2Published in PF 39(4)
Calcium Stearate
FDA High Priority Excipients - ORA list of deficiencies -
Monograph Deficiency Modernization progress
Aspartame “Replace non specific assay titration and add impurities test” HPLC Procedure For LIMIT OF
5-BENZYL-3,6-DIOXO-2-PIPERAZINEACETIC ACID . USP Labs: EVALUATE FOR USE INASSAY
Titanium Dioxide (also on MMTG list)
“Assay method is out of date, involves digestion with concentrated acids, etc.” FDA recommendation: Use advanced methods for quantitation of TiO2 (Ref: "A novel volumetric method for quantitationof titanium dioxide in cosmetics," Journal of Cosmetic Science, Volume 57, Issue 5, Pages377-383, 2006).
USP Labs: evaluate method
Glycerin “Current assay method for glycerin is out of date (periodate method)).” FDA recommendation. Replace periodate method with quantitative GC method (USP method for determination of quantities of DiethyleneGlycol and Ethylene Glycol is a GC method).
Glycerin Expert Panel formed in Dec. 2012PDG monographUSP labs: evaluate method
Crospovidone(also on MMTG list)
“Test method for Peroxides is outdated”
FDA recommendation: Quantitative determination of trace levels of hydrogen peroxide in crospovidone and a pharmaceutical product using HPLC with coulometric detection." International Journal of Pharmaceutics, Volume 375, Issues 1–2, 2009, Pages 33–40).
Povidones Expert Panel formed in Jan. 2011PDG monographUSP Labs: evaluate method
ShellacIntroduce FTIR and chemical composition TLC in ID test
Industry/USP Labs USP weblist/MMTG llist
Butylated HydroxytolueneIntroduce ID by RT . Add Assay -HPLC /GC methods under evaluation
USP Labs USP weblist/MMTG llist
Sucrose Introduce FTIR in ID testUSP Labs
USP weblist
Potassium SorbateIntroduce FTIR in ID test. Replace Assay by titration with GC
USP LabsUSP weblist
Glycerin Expert panel formed to develop S3 draft Industry FDA ORA list
Aspartame Replace Assay titration with HPLC USP labs FDA ORA list
Microcrystalline Cellulose Introduce FTIR in ID test USP labs FDA MMTG list
Croscarmellose Sodium(Croslinked CMC sodium)
Introduce FTIR in ID test USP labs FDA MMTG list
Carboxymethylcellulose Sodium (CMC sodium)
Introduce FTIR in ID test USP labs FDA MMTG list
Excipient modernizations in development
Chinese Pharmacopoeia Commission (ChP) - USP MOU Working group #1 – Documentary standards and Reference Materials – Excipients
– 13th meeting of MOU discussion. USP first visit to China in 1990. Initial MOU signed 2005
– Cooperate to develop quality standards for excipients in the global supply chain
– Establish the 22 nd Medicines Expert Committee East Asia Expert committee (EAEC) to work on development of excipient monographs to support the Medicines Compendium and for potential adoption by both ChP and NF.
– Dr Jiasheng Tu serves as Chair of the ChP Commission Expert Committee on Excipients and a member of the Expert committee of Center for Drug evaluation, SFDA. He is also Chair of the USP EAEC, China and a member of the USP Excipient EC, USA.
– Ms. Han Peng is the ChP liaison to the MCEA EC.
– Provincial lab support.
Chinese Pharmacopoeia Commission – USP MOU
ChP also modernizing several excipients in ChP 2010 that appear on the USP web list
ChP reviewed USP’s Excipient modernization web list
USP Excipient Expert Committee agree to start work on the following excipients
– Calcium Stearate (USP Lab work complete)– Calcium Sulfate– Carnauba Wax– Cholesterol (USP Lab work complete)– Diethyl Phthalate– Ethyl Acetate– Hydrogenated Castor Oil (USP Lab in dev.)– Maltodextrin (Working with Industry) – Monobasic Potassium Phosphate– Sulfuric Acid– White Wax– Xanthan Gum (USP Lab in dev.)
ChP-USP work on excipient modernization
USP Rockville reviewed the ChP list of 150 monographs targeted for development in ChP 2015 edition
USP and ChP selected 15 new excipient monographs for development
Last 3 by 22nd MC EAEC and CFDA -China provincial labs.
ChP-USP work on excipient monograph development
USP effortsUSP will continue to use its lab resources and engage stakholders
Sourcing procedures from other compendia, literature, other
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
ChP - USP list of 15 new monographs and12 modernizations
Engage with other stakeholders
Moving Forward
• Excipient monograph modernization is a major initiative in the 2010-2015 revision cycle
• USP is devoting resources to this effort – new laboratory capabilities
• 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– Prioritizing and requesting submissions - with FDA involvement ,
the hope is that industry is much more likely to come to the table
Conclusion
Upcoming USP – Excipient related meetings
• The USP ExcipientsStakeholder Forum
– Planned for June 7, 2013,USP Headquarters, Rockville, Maryland
– Objective: focus on science and compliance topics related to pharmaceutical excipients.
– Industry and stakeholder participation in USP's public standards-setting process is essential to the development of authoritative, relevant USP–NF monographs.
– Free registration -open to all users, makers and distributors.
– Web based allowing greater access and global participation.
Ethylene Glycol, Diethylene Glycol, and Triethylene Glycol in Ethoxylated Substances.
USP Lab. Method development in collaboration with stakeholders
K. Gilbert, C. Chisolm, K. Ramakrishna, H. Wang, E. Biba and S. WahabSeparation Sciences Laboratory, U.S. Pharmacopeia, Rockville, MD 20852
Background
Samples
Method
Results
Conclusion
Outline
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USP currently undergoing a resolve to modernize and strengthen the monographs
of ethoxylated substances by adding testing for ethylene glycol (EG), diethylene
glycol (DEG), and triethylene glycol (TEG). An analytical gas chromatographic
procedure was developed and validated by our laboratory.
Currently, a general chapter <469> will be proposed in PF 39(4)[June-July 2013] for
public comment to include testing for ethylene glycol, diethylene glycol and
triethylene glycol in ethoxylated substances.
USP took into consideration the EP chapter 2.4.30. ETHYLENE GLYCOL AND
DIETHYLENE GLYCOL IN ETHOXYLATED SUBSTANCES and industry methods
in the development of the USP chapter.
Following testing, this method was found to be applicable to 17 different excipient
monographs.
Background
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Ethoxylation is a manufacturing process in which ethylene oxide is combined with alcohols and phenols to produce surfactants. The most common surfactants are synthesized by the ethoxylation process, which include alcohol ethoxylates, alcohol propoxylates and alcohol ethoxysulfates.
Ethoxylation Definition
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Ethylene oxide
Ethoxylated Substances in the Pharmaceutical Industry
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Ethoxylated substances such as polyoxyl fatty acid esters, polyethylene glycols and polysorbates are commonly used as pharmaceutical excipients in different formulations.
Example: Tween 20 (Polysorbate 20)
x+y+w+z =20
Blank: acetone
IS (Internal standard solution): 40 μg/mL solution of 1,3-butanediol in acetone.
Standard Solution: 25 μg/mL of EG and 40 μg/mL each of DEG and TEG diluted in IS.
EG Sensitivity Solution: 1.2 μg/mL of EG, 2.0 μg/mL of DEG and TEG diluted in IS.
DEG and TEG Sensitivity Solution: 0.8 μg/mL of EG and 1.2 μg/mL of DEG, TEG diluted in IS.
Sample Solutions: 40 mg/mL of the ethoxylated substance sample diluted in IS.
Sample Preparations
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Instrument: Gas chromatograph with flame ionization detectionCarrier Gas: HeliumLiner: Straight liner with wool Injector port: 270°Injector mode: SplitSplit ratio:2:1 Septum Purge Rate: 5 mL/minInjection volume: 1.0 μL Column: Restek Rtx-50; 0.53-mm x 30-m fused-silica analytical column; 1.0-μm layer of phase G3Column Mode: Constant flow Column flow rate: 5.0 mL/minOven Program:
Initial Temp.(°C) Time Ramp (°C/min) Final Temp.(°C) Hold time at Final Temp.(min.) 40 10 60 560 10 170 0 170 15 280 0, 60
Detector Temperature: 290°
Method
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The following ethoxylated compounds were tested and validated in four groups as follows: