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------------------------------------------------------------------------------------------------------------------------------------------- SCIENTIFIC SOLUTIONS: An Independent Consultant Serving the Needs of the Trace Element Community
What Does USP Chapter 2232 on Elemental Contaminants in Dietary Supplements Mean for
You?
June 25, 2015
Robert Thomas, Scientific Solutions Gaithersburg, MD
1
Outline of Today’s Presentation
Role and Mission of the United States Pharmacopeial Convention (USP) USP Compendial Methods My Involvement with USP Through the ACS Reagent Chemicals Committee Overview of Current USP Methods for Elemental Impurities in Pharmaceutical Materials and Dietary Supplements Detailed Look at USP Chapter 2232 for Heavy Metal Contaminants in Dietary Supplements Use of USP Chapter 233 for Analytical Procedures to Measure Contaminants in Dietary Supplements Implementation Timelines and Alignment with ICH Guidelines -------------------------------------------------------------------------------------------------------------------------------------------
SCIENTIFIC SOLUTIONS: An Independent Consultant Serving the Needs of the Trace Element Community 2
Role and Mission of USP
Mission - To improve the health of people around the world through public standards and related programs that help ensure the quality, safety, and benefit of medicines and foods USP sets standards for the quality, purity, strength, and consistency for drug products – critical to the public health and are recognized and used in more than 130 countries around the globe These standards, which are published in the United States Pharmacopoeia National Formulary (USP-NF), have helped to ensure public health throughout the world for close to 200 years
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USP Compendial Methods
The United States Pharmacopeia and The National Formulary (USP–NF) is a book of public pharmacopeial standards, containing standards for drug substances, dosage forms, compounded preparations, excipients, medical devices, and dietary supplements
It is a combination of two compendia, the United States Pharmacopeia (USP) and the National Formulary (NF)
The U.S. FDA designates the USP–NF as the official compendia for drugs marketed in the United States, which must conform to the standards in USP–NF to avoid possible charges of adulteration and misbranding
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USP Dietary Supplements Compendium
In 2009, USP introduced the Dietary Supplements Compendium (DSC)—a resource containing regulatory guidance documents, supplemental information, and reference tools for the industry
It includes nearly 800 monographs—documentary specifications of identity, strength, quality, and purity etc for dietary supplements, and dietary ingredients, from the USP–NF and FCC (Food Chemicals Codex)
It also includes information from the USP–NF General Chapters, which are relevant to the individual monographs
The compendium is published every three years….one is being published this year (2015)
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USP-NF Revision/Update Process
USP creates and continuously revises USP–NF standards through a unique public–private collaborative process, which involves scientists in industry, academia, and government as well as other interested parties from around the world
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ACS is an “Interested Party” Through its Handbook of Specifications, Standards and Procedures for Reagent Chemicals
ACS publish a handbook every 5 years of Specifications and Procedures for ACS-grade reagent chemicals
Contains purity specifications and analytical methods for over 1000 reagent chemicals and reference materials
I’ve been a committee member for the past 15 years on the ACS Reagent Chemicals Committee
Our committee, consisting of approx 25 people (users, manufacturers, academics, consultants), meets twice a year to work on new/updated methodology for the book
We are currently working on the 11th edition which will be published in October, 2015
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A Typical ACS-Grade Reagent Chemical Specification
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ACS-Grade Reagent Chemicals Specifications and Procedures
Because the pharmaceutical and dietary supplement industries use many ACS-grade reagent chemicals, we share many methods and specifications with the USP
Many reagent specifications in the USP-NF refer to the ACS-grade chemicals
USP scientists make presentations at our committee meetings to update us on the status of its methodology
Our members attend USP stakeholder meetings, and panel discussions groups
I have made a number of presentations at the USP, regarding the use of plasma-based methods for determining trace elements in various pharmaceutical and nutraceutical products
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ACS-Grade Reagent Chemicals Specifications and Procedures
One of our main objectives for the 11th edition is to replace the ACS heavy metals test with plasma-based methods
I lead the trace element impurities Task Force on the ACS Reagent Chemicals Committee
For the past three years we have been working on a spike recovery study to validate this new method
I was given the task of writing the method for the 11th edition of Specifications and Procedures
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Replacement of ACS Heavy Metals Test with A Plasma-based Method
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ACS Heavy Metals Test
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So Why a New USP Heavy Metals Test?
The test methodology for heavy metals currently in the USP–NF, was first introduced more than 100 years ago
The test described relies on precipitation of the metal sulfide in a sample, and comparing the color intensity to a lead standard
USP scientific experts felt that the elemental impurity standards should be updated to incorporate modern methods and health information
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Current USP Heavy Metals Test Chapter <231> Chapter 231is based on a sulfide precipitation of the
analyte elements with a thioacetamide solution, and assumes that all analytes behave in a similar manner to a lead standard (10 ppm) with which samples are compared
It was initially intended to detect a larger group of elements like Pb, Hg, Bi, As, Sb, Sn, Cd, Ag, Cu, Mo, and Se, but there was no clear definition of which individual elements the method was expected to detect
Many limitations including low recoveries, inconsistent results and interpretation of color varied with experience of the analyst
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Chapters <232>, <2232> and <233>
Chapter <231> is now in the process of being eliminated and replaced by: • Chapter <232>: Elemental Impurities in
Pharmaceutical Products — Limits • Chapter <2232>: Elemental Contaminants in
Dietary Supplements • Chapter <233>: Elemental Impurities
Pharmaceutical Products — Analytical Procedures
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Overview of New Chapters <232>, <2232> and <233>
Chapter <232>: Elemental Impurities Pharmaceutical Products and Materials - Limits
Specifies the list of 15 elemental impurities (Cd, Pb, As, Hg, In, Os, Pd, Pt, Rh, Ru, Cr, Mo, Ni, V, Cu) and their toxicity limits in pharmaceutical products and raw materials, defined as permitted daily exposure (PDE) levels of the four different drug administration categories - oral, parenteral (intravenous injection), inhalation and large volume parenteral
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Chapter <2232>: Elemental Contaminants in Dietary Supplements Specifies the list of 4 elements (Pb, As, Cd, Hg) and their toxicity limits, defined as permitted daily exposure (PDE) levels. This chapter refers to Chapter <233> for the analytical procedure to determine the elemental contaminants
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Overview of New Chapters <232>, <2232> and <233>
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Chapter <233>: Elemental Impurities - Procedures Covers the sample preparation, analytical procedure and QC validation protocols for measuring the elements, using ICP-AES or ICP-MS or any alternative technique that meets the validation requirements
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Overview of New Chapters <232>, <2232> and <233>
18
The objective of this general chapter is to set limits for the amount of elemental contaminants in finished dietary supplement labeled as conforming to USP-NF standards
The focus of this chapter is on the four major elements of toxicological concern – As, Cd, Pb and Hg
This chapter is not intended to set limits for the actual dietary ingredients – those limits are set in the individual monographs
General Chapter <2232> Elemental Contaminants in Dietary Supplements
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Chapter <2232> Permitted Daily Exposure (PDE)Levels The levels of elemental contaminants should be less than the Permitted Daily
Exposure (PDE) levels shown in the table below:
PDE levels derived from data supplied by the Food Agriculture Organization of the
United Nations (FAOUN) and World Health Organization (WHO), based on a body weight of 50 kg and other safety factors
Manufacturers are responsible for compliance with other applicable local requirements (e.g. Proposition 65 in California) differing from these PDE values
Elemental Contaminant USP Chapter <2232> PDE Limits (µg/day)
Arsenic (Inorganic) 15
Cadmium 5
Lead 5
Mercury 15 (total)
Methyl Mercury (CH3Hg) 2
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Element Oral Daily Dose PDE (µg/day)
Parenteral Daily Dose PDE (µg/
day)
Inhala9on Daily Dose PDE (µg/
day)
LVP Component Limit (µg/g)
Cadmium 5.0 2.5 3.4 0.25 Lead 5.0 5.0 5.0 0.5 Arsenic (Inorganic) 15 15 1.9 1.5 Mercury (Inorganic) 15 1.5 1.2 0.15 Iridium 100 10 1.5 1.0 Osmium 100 10 1.5 1.0 Palladium 100 10 1.0 1.0 PlaAnum 100 10 1.5 1.0 Rhodium 100 10 1.5 1.0 Ruthenium 100 10 1.5 1.0 Chromium * * 2.9 * Molybdenum 180 90 7.6 9.0 Nickel 600 60 6.0 6.0 Vanadium 120 12 1.2 1.2 Copper 1300 130 13 13
USP Chapter <232> Permitted Daily Exposure (PDE)Levels
PDEs based on an arbitrary adult human body weight of 50 kg (110 lb) (* = Not considered a safety concern) ------------------------------------------------------------------------------------------------------------------------------------------- SCIENTIFIC SOLUTIONS: An Independent Consultant Serving the Needs of the Trace Element Community 21
Comparison Between <2232>, and <232> for the 4 Major Elements of Toxicological Concern
Element/Species <2232> PDE (µg/day)
<232> Oral Daily Dose PDE (µg/day)
Arsenic (Inorganic) 15 15
Cadmium 5 5
Lead 5 5
Mercury (Total) 15 -
Methyl Mercury (as Hg)
2 -
Inorganic Mercury - 15
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Determination of Inorganic Arsenic and Methyl Mercury by Chapter <2232>
Arsenic may be measured using a non-speciation procedure, under the assumption that all arsenic contained in the supplement is in the inorganic form
Where the arsenic limit is exceeded using a non-speciation procedure, compliance with the limit for inorganic arsenic shall be demonstrated on the basis of a procedure described in Chapter 211 (conversion of As to AsH3 the complexed and measured colorimetrically)
Methyl mercury determination is not necessary when the content for total mercury is less than the limit for methyl mercury. When the total mercury content is higher than the methyl mercury limit, a speciation method is recommended (2232 specifies separation by LC and detection by cold-vapor AA)
But any method is suitable, as long as it gives equivalent results ------------------------------------------------------------------------------------------------------------------------------------------- SCIENTIFIC SOLUTIONS: An Independent Consultant Serving the Needs of the Trace Element Community 23
Chapter <2232> Options for Compliance with the Necessary Limits of Elemental Contaminants
In order for a dietary supplement to comply with the limits for elemental contaminants as described in this chapter, the levels in the finished product should be no more than (NMT) the PDE
The following three options are available for determining compliance with the limits for elemental contamination in dietary supplements: 1. Dietary Supplement Analysis Option 2. Individual Component Option 3. Summation Option
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Dietary Supplement Option
In this option, the finished dietary supplement is analyzed according to the procedure in Chapter <233>.
The results obtained from the analysis of a typical serving size, based on the maximum daily dosage of the supplement recommended on the label (servings/day) should be no more than the PDE values
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Individual Component Option This option is applicable to a finished dietary supplement with a
daily intake of a maximum of 10 g or less Carry out the analysis of the individual ingredients of the dietary
supplement according to method described in Chapter <233> The product meets the requirements when each component used
in production of the finished product meets the limits given in the table below
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Elemental Contaminant USP Chapter <2232> Individual Component Limit (µg/g) Based
on a Dosage of 10g/day
Arsenic (Inorganic) 1.5
Cadmium 0.5
Lead 0.5
Mercury 1.5 (total)
Methyl Mercury (CH3Hg) 0.2
26
Summation Option:
This option is used for the finished dietary supplement dosage that is consumed in quantities greater than 10 g/day, or where the acceptance limit for any contaminant in any component of the dietary supplement exceeds the individual component limit
Carry out the analysis of the individual ingredient and calculate the amount of each elemental contaminant (in µg/daily dosage) present in the dietary supplement
The amount of each elemental contaminant in the daily dosage should be no more than the PDE values
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Analytical Procedures for Total Elemental Contaminants in Dietary Supplements
Performance-based methodology for the analysis of elemental contaminants described in General Chapter <233>, is applicable for dietary supplements
With all 3 options described in this method, the use of validation protocols described in Chapter <233 are appropriate
Although the validation procedures described in Chapter <233> are strongly recommended for the analytical technique of choice, the level of validation is at the discretion of the supplement manufacturer and the regulatory authority
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This chapter describes the two analytical procedures for the evaluation of the levels of elemental impurities • Procedure 1: ICP-OES • Procedure 2: ICP-MS
Gives guidelines on sample preparation, calibration procedures, spike recoveries, precision and instrumental drift limit
The chapter also describes criteria for alternative procedures as long as they meet the validation requirements laid-out in this chapter
No speciation methods described in this chapter
General Chapter <233> Elemental Impurities: Procedures
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Chapter 233 Elemental Impurities –Procedures Sample Preparation
Neat: Used for liquid samples Direct Aqueous Solution: When a sample is soluble in an
aqueous/acid medium Direct Organic Solution: When a sample is only soluble
in an organic solvent Indirect Solution: When a sample is not directly soluble
in an aqueous or organic solvent • Closed vessel digestion procedures (e.g.. microwave) • Gives an example of a microwave digestion procedure
In certain cases, a leaching procedure can be used ------------------------------------------------------------------------------------------------------------------------------------------- SCIENTIFIC SOLUTIONS: An Independent Consultant Serving the Needs of the Trace Element Community 30
Chapter 233 Elemental Impurities –Procedures Calibration Procedure: Suitability of Technique
Target Limit/Concentration (J) is the concentration of the elements of interest, appropriately diluted to the working range of the instrument • E.g.: Limit for Pb = 5 µg/day. Based on a suggested dosage of 10 g of
supplement/day, that’s equivalent to 0.5 µg/g (ppm) Pb. If 0.2 g of sample is digested/dissolved and made up to 100 mL, that’s a 500-fold dilution, which is 1 µg/L (ppb). So J for Pb is 1 µg/L, based on this dilution factor
A Calibration is then made up of 2 standards • Standard 1= 2.0J, Standard 2= 0.5 J • For Pb that’s 2 µg/L (Std 1) and 0.5 µg/L (Std 2)
Calibration drift is measured by comparing results for Standard 1 before and after the analysis of all the sample solutions under test • Drift should be < 20% for each target element
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Chapter 233 Elemental Impurities –Procedures Validation Protocols
For elemental impurities limit procedures, validation tests should include: • Detectability (impact of matrix on target elements) • Precision (repeatability) • Specificity (impact of target elements on each other) • Accuracy (using reference materials) • Limit of Quantification (suitability of technique being used) • Linear Range (suitability of technique to measure “out of
spec” values using same calibration) • Ruggedness (robustness of method)
• Refer to USP-NF General Chapter <1225> Validation of Compendial Procedures for guidance
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Prepare a Standard Solution of target elements at J and a matrix matched blank
Prepare an unspiked sample Prepare a sample spiked at J – Spiked Sample
Solution 1 Prepare a sample spiked at 0.8J - Spiked Sample
Solution 2 • Note: The sample under test must be spiked
before any sample preparation/dilution steps are carried out
"
Chapter 233 Elemental Impurities –Procedures Validation Protocols - Detectability
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Chapter 233 Elemental Impurities –Procedures Validation Protocols - Detectability
Non-instrumental Acceptance Criteria (suitability of sample preparation procedure) • Spiked Sample Solution 1 must give a signal
intensity equal to or greater than the Standard Solution
• Spiked Sample Solution 2 must give a signal intensity less than the Spiked Sample Solution 1
• The signal for each spiked sample is not less than the unspiked sample
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Chapter 233 Elemental Impurities –Procedures Validation Protocols - Detectability
Instrumental (Assessment of Sample Matrix on Analyte Signal) • The average value of the three replicate
measurements of Spiked Sample Solution 1 is within ±15% of the average value obtained for the replicate measurements of the Standard Solution.
• The average value of the replicate measurements of Spiked Sample Solution 2 must provide a signal intensity less than that of the Standard Solution.
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Test samples: six independent test material solutions spiked at J Acceptance criterion: RSD < 20%
Chapter 233 Elemental Impurities –Procedures Validation Protocols – Precision/Repeatability
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The procedure must be able to unequivocally assess each Target Element in the presence of components that may be expected to be present, including other Target Elements, matrix components, and other potential interferences.
N+1 solution approach ( N= # of target elements) • Solution 1 – All Target elements • Solution 2 – All Target elements w/o Lead • Solution 3 – All Target elements w/o Cadmium • Solution 4 – All Target elements w/o Arsenic • Solution 5 – All Target elements w/o Mercury
Chapter 233 Elemental Impurities –Procedures Validation Protocols - Specificity
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Standard Solutions: • Prepare solutions containing target elements at concentrations ranging
from 50-150% of J using suitable calibration/reference materials
Test Samples: • Prepare samples under test by spiking at concentrations from 50-150%
of J using suitable calibration/reference materials
Acceptance Criteria: • Measure three replicates of the different concentration samples • Spike recovery of three reps should be 70%-150% at each concentration
Chapter 233 Elemental Impurities –Procedures Quantitative Procedure Validation: Accuracy, LOQ and Linear Range
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The effect of random events on the analytical precision of the method shall be established
Acceptable experiments for establishing intermediate precision include performing the ‘Repeatability’ analysis
• On 3 different days OR • With 3 different instruments OR • With 3 different analysts
Executing only one of these three experiments is required to demonstrate ruggedness
Acceptance criterion RSD <25% for each element
Chapter 233 Elemental Impurities –Procedures Quantitative Procedure Validation: Ruggedness
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Approval Status of USP Chapters on Elemental Impurities/Contaminants The pharmaceutical/nutraceutical industries were concerned about the
ambitious timing of these new chapters In addition, international regulatory agencies such as the ICH
(International Conference on Harmonization of Technical Requirements for Registration of Pharmaceuticals for Human Use), European Medicines Agency (EMA), and the European Pharmacopoeia (EP) and Japanese Pharmacopoeias (JP) disagreed about the list of elements and permitted daily exposure (PDE) limits defined in Chapter <232>
For this reason, there have been a number of revisions to both Chapter <232> and <233>, which resulted in implementation timelines being modified a number of times
However, a recent announcement by the USP Chemical Analysis Expert Committee stated that it is the intention to align Chapter <232> Elemental Impurities—Limits with the ICH Q3D Step 4 directives…. but no details yet!
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ICH Q3D Step 4 Guidelines: Official on 16 Dec, 2014
USP 232
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Comparison Between <2232>, <232> and ICH Guidelines for the 4 Major Elements of Toxicological Concern
Element/Species Chapter <2232> PDE (µg/day)
Chapter <232> Oral Daily Dose PDE
Limits (µg/day)
ICH Q3D Step 4 Guidelines for Oral
Daily Dose PDE Limits (µg/day)
Arsenic (Inorganic) 15 15 15
Cadmium 5 5 5
Lead 5 5 5
Mercury (Total) 15 - 30
Methyl Mercury (as Hg)
2 - -
Inorganic Mercury - 15 -
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Chapter published in the First Supplement to USP 36–NF 31 on February 1st, 2013
It became official on December 1st, 2014 with the publication of 2nd Supplement to USP 37–NF 32
However, full implementation will be dependent on implementation of Chapters <232> and <233> on Elemental Impurities – Limits and Procedures, which is still on target for January 1st, 2018 (assuming alignment with ICH guidelines is on schedule?)
ICH Guidelines will become official on Dec 16, 2017
So What is the Status of USP General Chapter <2232> at this Moment in Time?
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Further Reading on the Topic (USP) United States Pharmacopeia General Chapter <231> Heavy Metals Test in USP National
Formulary (NF); http://www.usp.org/usp-nf/notices/affected-omission-general-chapter-231-heavy-metals
United States Pharmacopeia General Chapter <232> Elemental Impurities in Pharmaceutical Materials – Limits: 1st Supplement of USP 37-NF 32; http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/2013-12-27_232_pf40-2.pdf
United States Pharmacopeia General Chapter <233> Elemental Impurities in Pharmaceutical Materials – Procedures: 1st Supplement of USP 37-NF 32; http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/key-issues/2013-12-27_233_pf40-2.pdf
General Chapter <2232> Elemental Contamination in Dietary Supplement: 1st supplement of USP 37 – NF-32; http://www.usp.org/usp-nf/notices/general-chapter-elemental-contaminants-dietary-supplements
USP's Proposed Standards for Elemental Impurities: Frequently Asked Questions; http://www.usp.org/support-home/frequently-asked-questions/frequently-asked-questions-usps-proposed-standards-elemental-impurities
USP 37 General Rules and Requirements: http://www.usp.org/sites/default/files/usp_pdf/EN/USPNF/revisions/2013-07-09_general_notices_usp37-nf32_final.pdf
United States Pharmacopeia Update Communications, Spring, 2015: http://www.usp.org/usp-nf/key-issues/elemental-impurities
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Further Reading on the Topic (Misc) ICH Quality Directives for Elemental Impurities, Q3D Step 4 Guidelines: http://
www.ich.org/fileadmin/Public_Web_Site/ICH_Products/Guidelines/Quality/Q3D/Q3D_Step2b.pdf
A Guide to California’s Proposition 65 for the Nutritional Supplement Industry: Alliance for Natural Health: http://www.anh-usa.org/wp-content/uploads/2013/04/Prop-65-manual.pdf
Heavy Metals: Analysis and Limits in Herbal Dietary Supplements, American Herbal Products Association: http://www.naturalhealthresearch.org/wp-content/uploads/2013/02/09_1214_AHPA_Heavy-Metals-White-Paper-Revised.pdf
US EPA Mercury Preservation Techniques: http://www.epa.gov/esd/factsheets/mpt.pdf Spectroscopy Online Webinar: Upcoming Changes and Implementation Timelines to USP–
NF General Chapters 231, 232, and 233 on Elemental Impurities: Dr. Kahkashan Zaidi, USP Liaison for Chapters 232/233 https://event.on24.com/eventRegistration/EventLobbyServlet?target=registration.jsp&eventid=778671&sessionid=1&key=FFBE22E284F2ED314FC85F320B0BB587&sourcepage=register
What's New in Testing Pharmaceuticals for Metals: Metals and Limits in Limbo; N. Lewen, Spectroscopy Magazine, Volume 29, Issue 5, pp. 42-50, May, 2014 http://www.spectroscopyonline.com/spectroscopy/Articles/Whats-New-in-Testing-Pharmaceuticals-for-Metals-Me/ArticleStandard/Article/detail/842937
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Further Reading on the Topic (RT)
Practical Guide to ICP-MS: A Tutorial for Beginners – 3rd edition: Robert Thomas, CRC Press, http://www.crcpress.com/product/isbn/9781466555433
Beginners Guide to ICP-MS: 15 part tutorial series: Robert Thomas, Spectroscopy Magazine, 2003: http://scientificsolutions1.com/icpmstutorial.html
PittCon Short Course: How to Select an ICP-Mass Spectrometer: The Most Important Analytical Consideration: Robert Thomas https://ca.pittcon.org/Technical+Program/tpabstra15.nsf/SCoursesByCat/15393F680829A5EB85257CF20071C32E?opendocument
PittCon Short Course: Implementation of New USP Chapters <232> <233> and <2232> on Elemental Impurities in Pharmaceutical Products and Dietary Supplements: Robert Thomas https://ca.pittcon.org/Technical+Program/tpabstra15.nsf/SCoursesByCat/024E2645EBA1F38A85257CF20072EEAD?opendocument
Determining Elemental Impurities in Pharmaceutical Materials: How to Choose the Right Technique, Spectroscopy, March 1, 2015; http://www.spectroscopyonline.com/determining-elemental-impurities-pharmaceutical-materials-how-choose-right-technique
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Assuming USP Doesn’t Move the Goalposts Again, Chapters <232> <2232> and <233> Should be Fully Implemented by January 1, 2018
Questions About USP Chapter 2232
Dr. Christopher Okunji USP Scientific Liaison for Elemental Contaminants in Dietary Supplements
Email: [email protected]
Questions About USP Chapters 232/233
Dr. Zaidi Kahkashan USP Scientific Liaison for Elemental Impurities in Pharmaceutical Materials
Email: [email protected]
Robert Thomas: [email protected]
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Thank You
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Thermo Scientific
Resources
50
Trace Elemental Product Information
• Links to Trace Elemental Products: Trace Elemental Analysis ICP-MS ICP-OES IC-ICP-MS LC-ICP-MS
51
Food/Beverage and Dietary Supplement Community: Resources • View application notes, on-demand webinars, product information, and
more resources on our Dietary Supplement and Food Communities pages: www.thermoscientific.com/dietarysupplements
www.thermoscientific.com/foodandbeverage
52
Thank You for Listening
Questions?
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